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Isolated systolic hypertensionHeesen, Willem Frederik

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ISOLATED SYSTOLICHYPERTENSION

PATHOPHYSIOLOGY AND EFFECTS OF TREATMENT

Design and layout:

- omslag: �ISH: an old problem revised�

idee WFH (met dank aan Leonardo)

Realisatie: Caro Kropveld - studio BROCAAT

- inhoud: WFH (WPWin 6.1)

Drukkerij: Het Grafisch Huis B.V.

Groningen

Copyright © W.F. Heesen, 1998

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or

transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise,

without the prior written permission of the author.

Alle rechten voorbehouden. Niets uit deze uitgaven mag worden verveelvoudigd, opgeslagen in een

geautomatiseerd gegevensbestand of openbaar gemaakt worden in enige vorm of op enige wijze, hetzij

electronisch, mechanisch, door fotokopieën, opnamen of op enig andere manier, zonder voorafgaande

schriftelijke toestemming van de auteur.

ISBN-nummer: 90-367-0932-6

NUGI: 742

Key words: hypertension, systolic, elderly, hypertrophy, cardiac, vascular,

pathophysiology, antihypertensive treatment, cardiovascular risk

RIJKSUNIVERSITEITGRONINGEN

ISOLATED SYSTOLICHYPERTENSION

PATHOPHYSIOLOGY AND EFFECTS OF TREATMENT

PROEFSCHRIFT

ter verkrijging van het doctoraat in de

Medische Wetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de Rector Magnificus,

Dr. F. van der Woude, te verdedigen op

woensdag 24 juni 1998

des namiddags te 1.15 uur

door

Willem Frederik Heesen

geboren op 9 januari 1966

te Borculo

SOLATED SYSTOLIC HYPERTENSION

Promotores: Prof. Dr. K.I. Lie

Prof. Dr. B. Meyboom-de Jong

Prof. Dr. P.A. de Graeff

Co-promotores: Dr. J.F. May

Dr. A.J. Smit

ATHOPHYSIOLOGY AND EFFECTS OF TREATMENT

Promotiecommissie: Prof. Dr. P.E. de Jong

Prof. Dr. Th. Thien

Prof. Dr. P.A. van Zwieten


Financial support by the Praeventiefonds and the Netherlands Heart Foundation for the

publication of this thesis is gratefully acknowledged

Studies in this thesis have been made possible by Parke-Davis B.V., Zeneca B.V., and the

Eelke Ytsma Foundation (Achtkarspelen)

Additional sponsoring for publication of this thesis is gratefully acknowledged from ASTA

Medica, Astra, Bayer, Bristol-Myers Squibb, Byk, Knoll, Leo, Lorex Synthélabo, Menarini,

Merck Sharp & Dohme, Novartis Pharma, Pfizer, Rhône-Poulenc Rorer, Roche, Servier, and

SmithKline Beecham.


Voor Lisette

en voor mijn ouders


- 9 -

CONTENTS

INTRODUCTION

1. Introduction: the problem of ISH ......... 11

2. Methods ........ 33

3. Aim of this thesis ........ 57

ARTICLES

4. Prevalence of ISH ........ 87

�Prevalence of new cases and regression to the mean of systolic hypertension

in follow-up of an elderly population�

5. Vascular compliance in ISH ........ 107

�Distensibility of large and smaller arteries in isolated systolic hypertension�

6. Detection of LVH in hypertension-I: the ECG ........ 123

�Prediction of the left ventricular mass from the electrocardiogram in

systemic hypertension�Am J Cardiol 1996;77:974-978

7. Detection of LVH in hypertension-II: Echocardiography ........ 139

�A simple nomogram to determine left ventricular geometry�Am J Cardiol 1998(in press)

8. Consequences of ISH ........ 155

�High prevalence of concentric remodeling in ISH�Hypertension 1997;29:539-543


- 10 -

9. Treatment of ISH - I ........ 175

�Effect of quinapril and triamterene/hydrochlorothiazide on cardiac and

vascular end-organ damage in isolated systolic hypertensionJ Cardiovasc Pharmac 1998;31:187-194

10. Treatment of ISH - II ........ 199

�Long-term effects of Lisinopril treatment on cardiac and vascular end-organ

damage in isolated systolic hypertension�

DISCUSSION

11. Summary, discussion and future implications ........ 225

12. Nederlandse samenvatting en discussie ........ 237

13. Dankwoord ........ 253

II NTRODUCTION

- 11 -

CCCCHAPTERHAPTERHAPTERHAPTER 1111

IIIINTRODUCTIONNTRODUCTIONNTRODUCTIONNTRODUCTION

CONTENTS

1.1 Introduction: the problem of ISH in the elderly

1.2 Prevalence and risk of ISH

1.3 Vascular pathophysiology of ISH

1.4 Cardiac end-organ damage in ISH

1.5 Effects of treatment of ISH: SHEP and SYST-EUR

CHAPTER 11

- 12 -

II NTRODUCTION

References Chapters 1-3: see Chapter 31

- 13 -

1.1 INTRODUCTION: THE PROBLEM OF ISH

This thesis focuses on isolated systolic hypertension (ISH), a cardiovascular

disorder frequently occurring in the elderly. ISH is defined as elevated

systolic blood pressure (BP) with normal diastolic blood pressure (> 160 mm

Hg, and < 95 mm Hg, resp.). ISH occurs especially after the age of 60 years,

because of the tendency of systolic BP to rise with age while the rise of

diastolic BP levels off. In younger subjects, the predominant pattern ofKannel’81 1

hypertension is elevated diastolic blood pressure. Because of this age-pattern,

diastolic hypertension has received most attention in the past decades; most

knowledge about the beneficial effects of treatment has been derived from

younger patients with diastolic hypertension.Collins’90

Not long ago, ISH was considered a �normal� consequence of ageing, not

necessary to be treated. Lowering of this blood pressure was even thought to

be harmful. This was despite the fact that a high systolic blood pressure has

been known for long to be a cardiovascular risk factor, even stronger than

diastolic hypertension in most studies. Recently, studies becameKannel’71

available on the benefits of treatment of ISH in terms of reduction of

cardiovascular risk, and since then, systolic hypertension has gained renewed

interest. However, studies on cardiovascular pathophysiologic changesSmulyan’97

in ISH, and effects of treatment on these changes are still markedly less in

number than studies in diastolic hypertension. Increase of our knowledge on

these changes will make us to understand ISH better, and may alter our

approach to ISH. This is important, since the problem of ISH can be expected

to increase further in the near future, viewing the strong increase of the

proportion of elderly in our Western population.

CHAPTER 11

- 14 -

Figure 1.1 . First measurement of(systolic) blood pressure by theclergyman Stephen Hales; England,1733

1.2 PREVALENCE AND RISK OF ISH

Historic overview and risk of ISH

The current status of systolic hypertension may be elucidated by a brief

historic overview. The first blood pressure measurement was done by an

English clergyman in 1733, who measured the rise of a column of blood in a

glass tube inserted in the neck artery of a horse (see figure 1). To his

astonishment, this column of blood rose as high as nine feet up. This first

measurement of blood pressure was a measurement of the peak or systolic

blood pressure. Also, the first measurements performed with the mercury

sphygmomanometer, developed a hundred years ago by Riva-Rocci,

determined the systolic level of blood pressure. It was only a few years later,

with the introduction of the auscultatory method of Korotkoff, that the lower

point of blood pressure could also be determined: the diastolic blood

pressure. Still, systolic blood pressure was considered the most important,

and physicians became aware that a high systolic blood pressure could be

harmful to the patient.

In the fifties and sixties, the role of cardiovascular risk factors became much

more established, exemplified among many other studies by the Framingham

Heart Study. In this large cohort study, from which so much of our current

* systolic BP (in mmHg), with diastolic BP < 90 mmHg

35-64 65-94

age (years)

0

10

20

30

40age-adjusted biennal rate/1000

<140 *140-159

>160

II NTRODUCTION

- 15 -

Figure 1.2. Relation between isolated systolic hypertension andFigure 1.2. Relation between isolated systolic hypertension and

occurrence of congestive heart failure.occurrence of congestive heart failure. (From: Kannel �91)

knowledge on cardiovascular risk factors has been derived, all adult

inhabitants of the town of Framingham, USA, were carefully followed from

1948 on with bi-annual examinations. Cardiovascular risk factors were

registrated, and their relation with development of cardiovascular disorders

was investigated. From this and many other studies, systolic hypertension

was known to be strongly associated with occurrence of stroke, myocardial

infarction, and other cardiovascular disorders. In fact, theKannel’81,Staessen[review]’90

contribution of systolic hypertension as a cardiovascular risk factor exceeds

that of diastolic hypertension in the majority of these studies. Also with

congestive heart failure, another disorder frequently occurring in the elderly,

a strong increased risk with ISH can be observed (figure 1.2).

Treatment studies: the (temporary) shift towards diastolic hypertension

Knowledge on a relation between a risk factor and subsequent disease is

important, but knowledge whether treatment of this risk factor can prevent

disease is even more important. Thus, large intervention trials have been

conducted to evaluate whether treatment of hypertension did improve

prognosis. These trials, conducted in the seventies and eighties, were based

on databases of large institutional corporations mainly in the USA, involving

working, middle-aged men. Here the focus in hypertension research shifted

towards diastolic instead of systolic hypertension, since elevated diastolic

CHAPTER 11

- 16 -

blood pressure is the main pattern of hypertension in these middle-aged men.

This has led to diastolic blood pressure being considered the type of

hypertension to be treated, as was recommended so in national andBinsbergen’91

international guidelines. It was only in the past decade that systolicJNC-IV�88

hypertension has received renewed attention again, and treatment of systolic

hypertension was recommended in guidelines, both internationally (JNC-

V) , and nationally (NHG-standard, first revision). This revival ofJNC-V�93 Walma�97

isolated systolic hypertension was based on the positive results of the

intervention trials in ISH who are now available also: the SHEP-study SHEP�91

and the SYST-EUR study (both discussed later).Staessen�97

Prevalence of ISH

The prevalence of ISH will be discussed in Chapter 4, with the results as

observed in the Achtkarspelen survey. In the literature, the prevalence of ISH

has been reported with rather considerable differences, ranging from 1 to

41%. This prevalence depends, among other factors, on the number ofAmery�91

measurements and occasions, showing in one study a drop from 13.9% at first

visit to 2.7% at the third visit. That is why three separateColandrea�70

measurements are demanded for definition of ISH, showing a systolic blood

pressure of 160 mmHg or more. A difference still exists on the level of

diastolic blood pressure in the definition of ISH: the US definition is below 90

mmHg of diastolic pressure, while the European and WHO-guidelines

require a diastolic pressure below 95 mmHg. The latter definition appears to

be the most logic one, and is used in this thesis also. This logic is based on

using the same cutoff value as with the definition of diastolic hypertension, as

illustrated in figure 1.2. As with all cut-off values, these values are of course

arbitrarily chosen points on a continuous rising line of risk. A borderline

elevated systolic blood pressure (between 140 and 160 mm Hg) was also

shown to bear increased cardiovascular risk compared with lower blood

pressures.Sagie�93

Figure 1.3 also shows the difference between isolated elevated diastolic

hypertension, and diastolic combined or systolo-diastolic hypertension

(SDH). This discrimination is not often made in literature: in most studies

both are gathered under �diastolic hypertension� (DH). For instance, in most

studies on �diastolic hypertension� in the elderly, the majority of subjects

included has SDH or combined hypertension. It appears to be likely that

II NTRODUCTION

- 17 -

SYSTOLIC BP (MMHG):

DIASTOLIC BP: < 160 > 160

< 95 NORMOTENSIVE ISH

> 95 (I)DH SDH

Figure 1.3. Division of categories of hypertension according toFigure 1.3. Division of categories of hypertension according to

cutoff levels of blood pressure.cutoff levels of blood pressure.

Legend: BP = blood pressure, (I)DH = (isolated) diastolic hypertension, ISH=

isolated systolic hypertension, SDH= (combined or) systolo-diastolic hypertension

between two patients with the same level of diastolic hypertension (for

instance: one 154/104, the second 178/104 mmHg), the difference in systolic

blood pressure does make a difference in terms of cardiovascular risk, based

at least on a higher mean arterial pressure. Also, the underlying

pathophysiologic vascular features determining these blood pressures are

likely to differ between these subjects. It remains to be proven whether

treatment should differ according to the classification or subtype of

hypertension.

CHAPTER 11

for discussion about “distensibility” and other features of vascular functions: see Chapter 2.2

Methods

- 18 -

1.3 THE PATHOPHYSIOLOGY OF ISH

Arterial distensibility in ISH

The main pathophysiologic feature of ISH is a decreased distensibility, or

loss of �Windkessel function� of the aorta and large arteries. Such a decreased

distensibility causes an increase in peak systolic pressure, which may be

accompanied by a decrease in diastolic BP when the blood runs off, thus

explaining the high systolic and low diastolic pressure in

ISH. This decreased distensibility is not just a �natural�Mann’92,Nichols’92,Safar[Book}’96 2

consequence of aging, as can be seen when comparing normotensive and

hypertensive elderly (see Chapter 7). This is an argumentMuntinga’97, Meaney’95

against the earlier belief that elevation of systolic blood pressure itself is also

merely a consequence of ageing.

In calling a decreased aortic distensibility a pathophysiologic feature of ISH,

a causal relation is suggested. However, it is not known whether an abnormal

distensibility comes first, causing elevation of systolic blood pressure, or the

other way around. As a high systolic pressure itself also increases wall

tension, the relation may also be the other way around, and systolic

hypertension may equally well be responsible for an abnormal arterial

distensibility. Even further, systolic hypertension and decreased distensibility

may be interacting processes, causing a disproportionate rise in systolic blood

pressure what may lead to ISH. Determination of the actual sequenceO’Rourke’90

of this relation between blood pressure and arterial distensibility is difficult.

Optimally, such data should come from longitudinal studies in humans

investigating arterial distensibility and blood pressure, but these are difficult

to conduct, and such studies are not known. Most information available is

gained from cross-sectional studies, comparing vascular properties among

different ages. These cross-sectional data may present a relation, butMeaney’95

less likely a causal explanation of the interaction between blood pressure and

vascular changes. Other information may come from studies investigating

risk factors such as salt intake, or genetic factors as possible explanations for

II NTRODUCTION

- 19 -

occurrence of abnormal arterial distensibility. Additional information about

the important difference between such a pressure-dependent and a �true�

structural effect on the vascular wall may also be derived from treatment

studies, comparing the effects of antihypertensive drugs known to have the

ability to influence arterial wall properties (such as ACE-inhibitors), and

drugs of which the main effect is to lower blood pressure (such as diuretics).

Arterial changes in ISH compared to diastolic hypertension

The observed vascular alterations in ISH may be compared with those in

diastolic hypertension (DH). In DH, the problem has been reported to be a

decreased distensibility of the smaller arteries and resistance vessels.Safar’96

An increased �peripheral� resistance explains the elevated diastolic pressure

as seen in DH. As the blood flow at the end of the arteries is more difficult,

the pressure will have dropped less at the end of the diastole, which causes

the elevated diastolic blood pressure. These vascular changes differ from the

changes in aortic distensibility in ISH as described above. This difference, and

also the differences in occurrence between DH and ISH (DH mainly in

middle-aged subjects and ISH mainly in the aged), supports the view that

ISH and DH are distinctive pathophysiologic feature. Hence, information

gained from studies in DH may not be translated to ISH without further

proof.

Another point of discussion could be whether it is correct to define �DH� as

one subtype of hypertension. Many elderly in fact have combined or systolo-

diastolic hypertension (SDH). In terms of vascular pathophysiology, these

subjects may suffer both from vascular alterations underlying �true� DH, and

of decreased distensibility of the large arteries explaining the high systolic

blood pressure. Surprisingly few studies have made a differentiation between

true IDH and SDH.

CHAPTER 11

- 20 -

1.4 CARDIAC END-ORGAN DAMAGE IN ISH

Development and risk of left ventricular hypertrophy

Probably the most studied and best known measurements of end-organ

damage in hypertension are those concerning the heart. Especially left

ventricular hypertrophy (LVH) is a well known independent risk factor for

cardiovascular events. Presence of LVH increases theAronow’91,Casale’86,Levy’89&’90

cardiovascular risk for hypertensive subjects 2 to 7-fold. The first studies on

LVH were performed using electrocardiography, but thisSokolow’49,Romhilt’68

method is known to be rather insensitive. Furthermore, the electrocardiogram

(ECG) can only measure the presence or absence of LVH rather than estimate

the LV mass itself, although efforts have been made to develop such

continuous models. Most studies are therefore done withWolf’91

echocardiographic measurement of LV mass, known to be more sensitive

than the ECG for the detection of LVH, while still carrying the sameReichek’81

prognostic value. When for instance in an uncomplicated hypertensive

population the prevalence of LVH detected with the ECG is approximately 2-

4%, the echocardiogram shows LVH in about 20% of cases. Even while the

echocardiogram is more expensive, this better detection appears to pay off in

terms of better cost-effectiveness than the ECG.Devereux’87

The use of terminology of �end-organ damage� instead of pathophysiology

(as in vascular measurements) appears confusing, but it may better reflect the

causal relation with hypertension. Development of LVH is more likely to be a

consequence rather than cause of hypertension. The term end-organ damage

also better reflects the increased severity of the problem: the occurrence of

LVH strongly increases the cardiovascular risk of the hypertensive subject.

Although true scientific proof from studies is not available yet, it appears that

reduction of LV mass indicates a reduction of cardiovascular risk. Muiesan’95,

This position of LVH between risk factor (hypertension) and endpointDevereux’96

(myocardial infarction, heart failure, death) is very useful to illustrate the

possible course of a risk factor to its final consequence, as illustrated by the

diagram in figure 1.5.

II NTRODUCTION

- 21 -

RISKRISK

FACTORSFACTORS

<transition to

disease>PRECLINICALPRECLINICAL

DISEASEDISEASE

<triggers of

morbidity>MORBIDMORBID

EVENTSEVENTS

hypertensionö

hypertrophy

(cardiac/ vascular)ö

myocardial infarction

cholesterol

diabetesö

atherosclerosis

(coronary/carotid)ö

stroke

cigarettesö

renal dysfunctionö

arrhythmic sudden

death

Figure 1.4. Interposition of hypertrophy and other end-organ damage disorders between riskFigure 1.4. Interposition of hypertrophy and other end-organ damage disorders between risk

factors and morbid events according to Devereux and Aldermanfactors and morbid events according to Devereux and Alderman ..�93�93

This illustrates that some subjects with risk factors will progress to preclinical disorders (or indicators of end-organ

damage), and subsequently to morbid events. Thus, these signs of end-organ damage are markers for those at higher risk,

which may lead to different (e.g. more aggressive) treatment.

[Note: for simplification only straight arrows are presented, but factors are also cross-related, such as cholesterolö

hypertrophy and hypertension ö renal dysfunction; and furthermore, some relations may be direct from risk factor to

morbid events, as with hypertensionö stroke).]

However, little is still known on why some subjects develop LVH and why

some others do not, even with comparable level and duration of

hypertension. Genetic predisposition may be one of the factors explaining

such differences. For one of these alterations in genetic expressions, in the

angiotensin-converting enzyme gene, it was indeed suggested to be related to

increased prevalence of LVH. However, these observations couldSchunkert’94,Iwai’94

not be confirmed in other studies.Lindpaintner’96

Results of treatment of LVH

Numerous studies have been published evaluating the effect of various

antihypertensive drugs on regression of LVH, as indicated by meta-analysis

including over 100 studies. The first meta-analysis by Dahlof, including 109

studies, appeared to indicate a favourable effect of angiotensin-converting

enzyme inhibitors above other classes of antihypertensive drugs, in reduction

of LVH (figure 1.5). However, some remarks must be made to thisDahlof’92

analysis, particularly with respect to the possibility of selection bias. All 109

studies included were analysed equally, without taking into account the size

CHAPTER 11

- 22 -

Figure 1.5. Reduction of left ventricular hypertrophy - meta-analysis Dahlof ’ ‘92

Abbreviations: DIU= diuretics, BBL = beta-blockers, CAA =calcium antagonists, ACE= angiotensin-converting enzymeinhibitors

of the study (eg. sample size was taken arbitrarily as N=1 for all studies).

Also, the selection criteria and methods differed considerably: some studies

evaluated regression of left ventricular mass in unselected populations, while

others investigated only effects of treatment in selected subjects with LVH,

eg. selection of severe cases. Furthermore, many (positive) studies on ACE-

inhibitors were published at that time and included in the analysis, possibly

overestimating the effect of these drugs (publication bias). In another meta-

analysis of 104 studies, ACE-inhibitors were less evident superior in

reversibility of LVH, although still more effective than other drugs such as

calcium-antagonists (dihydropiridines).Cruickshank’92

In contrast, no difference between a number of antihypertensive drugs (and

dietary treatment) was observed in a large study on mild-moderate

hypertension: the TOMHS-study. It may be hypothesized that perhapsNeaton’93

lowering blood pressure is one of the main factors in reducing LV mass, at

least in uncomplicated mild-moderate cases of hypertension. Future studies

should elucidate whether some of the antihypertensive drugs have

favourable effects, either in certain groups of patients, or in the strength of

reduction or in time needed for reduction.

Left ventricular diastolic function

II NTRODUCTION

- 23 -

Another cardiac consequence in hypertension is disturbance of diastolic

function or filling of the heart. The LV diastolic function isTaylor[review]’92, Hoit’94

known to be impaired in hypertension, possibly early in the course of

hypertension, and apparently accompanying LV hypertrophy. As a

consequence, the filling of the heart becomes more difficult, which could

finally result in (diastolic) heart failure when filling is inadequate to maintain

adequate systolic output. In this way, diastolic dysfunction could be a

possible linking mechanism between hypertension and occurrence of heart

failure. The underlying pathophysiologic alteration may be increased collagen

deposition in the heart, or the increased size of myocardial cells that are also

known to be disarrayed (eg. the normal order is disturbed). However, no

studies are available which clearly confirm such a connection between

diastolic dysfunction and HF.

One of the problems in evaluating diastolic function is the variation in

measurements. Technical measurement errors and biological variations such

as respiration and heart rate all contribute to a stronger variation in

measurements as compared with LV mass measurements, up to approximate

10% variation for intra-observer variation, while inter-observer variations

probably are even larger. Also, age is a strong determinant of LVGalderisi’92

filling measurement. For instance, an early (E) to atrial (A) filling ratioTakasaki’96

(E/A-ratio) of �1" is clearly abnormal for younger subjects, but may be normal

for elderly free of any heart disease. While several attempts have been made

to correct for these variations, such as models correcting for heart rate and

age, these influences do impair interpretation of measurements in theStewart’92

individual patient. A specific problem in LV diastolic function measurement

is the appearance of a normal E/A-ratio, while diastolic function actually is

disturbed (�pseudo-normalization� - see Chapter 2: Methods).Hoit’94

With regard to the effects of antihypertensive treatment on LV diastolic

function, different results have been published. While in some studies

diastolic function did appear to improve with treatment, mostly along with

reduction in LV mass, in several other studies no effectSchneeweiss’90,Petersen’96

could be observed. Probably the main limitation of diastolicShahi’90,Chang’96

function measurements is the lack of proof of a relation to cardiovascular risk,

either specifically to heart failure, or in general.

Cardiac end-organ damage studies in ISH

CHAPTER 11

- 24 -

Most of the studies presented on cardiac consequences of hypertension

were based on subjects with diastolic hypertension; far less studies have been

directed to subjects with ISH. The latter studies have shown that LVMI is

elevated in ISH, but information on the effects ofKrumholz’93,Pearson’91,Psaty’92

antihypertensive treatment on LV mass is scarce. One of the few reports

available, from a subset of the SHEP-study, showed regression of LVMI with

diuretic therapy. Disturbance of LV diastolic function was shown to beOfili’91

impaired also in ISH-subjects, but effects from intervention trials are notDart’93

known. Hence, there is a clear lack of studies of pathophysiologic alterations

in ISH and the effects of treatment om these alterations.

II NTRODUCTION

- 25 -

1.5 TREATMENT OF ISH

Antihypertensive drugs and blood pressure in ISH

Several studies have revealed that reduction of blood pressure can be

achieved in ISH, with different kinds of antihypertensive drugs. Table 1.7

summarizes a number of comparative studies available on antihypertensive

effects in ISH.

Although most of these trials are rather small in size and short of duration,

the general conclusion can be that representatives of the different classes of

antihypertensive drugs are capable of lowering blood pressure in ISH. A

striking phenomenon in these studies is that the reduction of systolic blood

pressure clearly exceeds that of diastolic BP reduction. This may be indicative

of a change in distensibility of the large arteries, either structural or

bloodpressure dependent. The small reduction of diastolic BP may be an

argument against the initial fear: that too much lowering of blood pressure in

these elderly patients may be hazardous, because of the risk of inadequate

perfusion of the cerebrum and other organs. However, the perfusion pressure

does drop with treatment.

CHAPTER11

-26-

1 author th patients design follow-up treatment n= initial BP BP reduction

Duchier1984

age 80 + 4 yrs,27% male

R, D, P 12 weeks ISDN(placebo)

40 192 / 95 - 27 */ -4 (-13 / -?)

De Quattro1988

age 61 + 2 yrs singledrug

8 wks(4 wks plac)

labetalol 16 154 / 83 &-12 / -3

Silagy 1990

age 50-85 yrs,58% male

R,D,P,C

4 wks dilevalol (placebo)

19 175 / 8 5 -12 */ -5 * (-1 / -1)

Silagy 1992

age > 60 yrs,38% male

R, D, C 8 wks HCTZenalapril atenolol isradipine

24 175 / 79175 / 79172 / 77 179 / 81

-18 */-7 *-14 */-7 *-11 */-5 *-20 */-7 *

Webster1993


R,D, PAR

8 wks enalapril amlodipine

1615

183 / 88185 / 86

-23 */ -8 -21 */ -7

Wing1994


R, C 4x 6 wks felodipine metoprolol felod+ metopr

21 177 / 78 -17 *†/-5- 6 / -5-19 *†/ -9 *

Avanzini 1994

age > 65 yrs;34%male

O, R 6 mths HCTZ +amiloride nifedipine SR atenolol atenolol + chlorthalidone (50%; control )

52482627155

177 / 85177 / 84177 / 86178 / 82178 / 84

- 22 */ -3- 23 */ -5- 15 / -4- 26 */ -5- 8 / -1

Tomlinson 1994

age > 60 yrs,30% male

R,D,P 8 wks isradipine spirapril

1816

179 / 82185 / 82

-20 * / -10 *-24 * / -6 *

Table 1.1. Results of blood pressure reduction of various intervention trials in ISHDesign: R= Randomized, D= double-blind; PAR= parallel-group, C= cross-over design, P= placebo-controlled., O= open*: indicates significant reduction to baseline/placebo; †: indicates significant difference in reduction between medication groups. :&

results of 24 hour ambulatory BPAbbreviations: BP = blood pressure, chlorth = chlorthalidone; HCTZ = hydrochlorothiazide; ISDN = isosorbide dinitrate, SR = slow release

II NTRODUCTION

- 27 -

Reduction of risk in ISH: the SHEP and SYST-EUR study

More important than the mere fact that a decrease of blood pressure can be

achieved in ISH, is the finding that such a reduction is associated with a

reduced cardiovascular risk for subjects with ISH. The first study providing

information on risk reduction in ISH was the Systolic Hypertension in the

Elderly Program (SHEP) study. This study, published in 1991, comparedSHEP’91

the effects of diuretic treatment on cerebrovascular accidents and

cardiovascular morbidity and mortality in general in subjects with ISH. The

number of subjects treated and the results on blood pressure are depicted in

table 1.8. Occurrence of strokes, the primary endpoint, was significantly

reduced with treatment in the SHEP. These results were found both in

younger elderly and in the very old, and both in subjects who were treated

before the study and who were not previously treated for hypertension. Also,

cardiac endpoints were significantly reduced, with a strong decrease of

occurrence of heart failure (-56%). Mortality did not change significantly,

neither from strokes nor from cardiovascular causes. The achieved reduction

in cardiovascular risk is even more remarkable when considering that in the

SHEP-study, about 35% of all subjects randomized to placebo had actually

received active treatment at end of the study for various reasons. Thus, the

observed benefits of treatment may even be stronger than the figures in the

table. One limitation of the SHEP-study may be that the subjects included

were selected from a very large sample of possible eligible subjects: only 1%

of all persons screened were finally included in the trial.

CHAPTER 11

- 28 -

Results: published:

SHEPNEJM 1991

SYST-EURLancet 1997

N =mean age (yr), % malesduration of follow-upinclusion BP

473672 (43%)4.5 years

160-219 /<90 mmHg

469570 (33%)2 years #

160-219/<95 mmHg

first drug (dosage in mg/d) + additional drugs

chlorthalidone (12.5-25) + atenolol

nitrendipine (10-40) + enalapril/HCTZ

initial BP (mmHg) - reduction active treatment: - placebo group:

170 / 77 -27 / -9 * -15 / -5

174 / 86 -23 / -7 * -13 / -2

Endpoints: (in N per 1000 pat.yrs; active tr./placebo (% reduction))

- strokes (total) - cardiac endpoints (AMI, HF) - all cardiovascular endpoints - cardiovascular mortality - overall mortality

9.0 / 14.0 * (-36 %)9.2 / 16.5 * (-44 %)27.2 / 38.8 * (-32 %)8.5 / 10.5 (-20 %)20.0 / 22.7 (-13 %)

7.9 / 13.7 * (-42 %)15.1 / 20.5 * (-26 %)23.3 / 33.9 * (-31 %)9.8 / 13.5 (-27 %)(0.07)

20.5 / 24.0 (-14 %)

Table 1.2. Design and main outcomes of the large intervention trials in ISH.Both trials were double-blind, placebo-controlled, and included subjects aged 60 years and over. *: indicates significant difference active treatment vs. placebo. : median duration: stopped previously#

because of reaching endpoint. Abbrev.: AMI = acute myocardial infarction, BP = blood pressure, HCTZ = hydrochlorothiazide, HF = heart failure

Most of the beneficial results from the SHEP were confirmed by the SYST-

EUR study, which was published six years later. Also in this study,Staessen’97

occurrence of stroke, and of cardiac endpoints was significantly reduced with

active treatment. Active treatment in this study was the long-acting calcium-

channel entry blocker nitrendipine, with addition of the angiotensin-

converting enzyme inhibitor enalapril (or the diuretic hydrochlorothiazide).

Thus this study was one of the first studies evaluating these representatives

of the �newer� classes of antihypertensive drugs; most previous large scale

studies have been done with the �classic� diuretics or beta-blockers.

Some other interesting observations can be derived from the results of these

trials. For instance, office blood pressure is lowered not only with active

treatment, but also in the placebo group. Several explanations are possible,

such as presence of the regression to the mean-phenomenon (=subjects

selected on high values are always likely to show lower values in time, by

II NTRODUCTION

- 29 -

chance and/or natural variation). Another explanation may be that

behavioural changes (diet, exercise) occur in these subjects who are made

aware of having high blood pressure, or by the placebo-effect itself. In the

SHEP-publication it is not clear whether the results of blood pressure

reduction in the placebo group are from those truly untreated, or all subjects

including those who did receive antihypertensive drugs. Regardless of this

placebo-effect, it can again be seen that systolic blood pressure in ISH-subjects

is lowered to a clearly greater extent than diastolic BP. This lowering is also

larger in magnitude than the known effects of the trials on diastolic

hypertension, showing in a meta-analysis about 5-6 mmHg lowering of

diastolic BP, and about twice as much (10-12) of systolic hypertension.Collins’90

Comparison of results with other studies

Adequate comparison of the results of different studies is sometimes not

that easy, because results of intervention trials are often presented in �%

reduction� and do not take into consideration the baseline risk in the study

population. A disadvantage of this is that no information is given about the

absolute decrease: a reduction from 3 to 2 events and from 300 to 200 events

both is a 33% reduction, but the second is of greater clinical interest. More

information is provided by presenting the number of events prevented for

1000 persons treated for one year (�patient-years�). Even of greater practical

interest is the number of subjects that needs to be treated (NNT) to prevent

one event. It is with these numbers that the results from the ISH-intervention

trials will be compared with the other trials (diastolic/mixed hypertension) in

elderly, and also those of younger hypertensive subjects, to evaluate the

effects of intervention in ISH with those �established� benefits of

antihypertensive treatment (table 1.3). Presented are those endpoints

CHAPTER 11

- 30 -

Studies

strokes (fatal and nonfatal)

cardiovascular deaths(combined)

% RR. NNT % RR. NNT

SHEP 36 * 33 20 100

SYST-EUR 42 * 34 27 54

Australian 34 NR 61 -

Coope/Warrander 42 * 22 22 38

EWPHE 36 * NR 27 * 15

MRC-II 25 * 74 9 154

STOP 47 * 14 40 NR

MRC-I 45 * 167 4 1000

Table 1.3. Comparison of effects of large intervention trials in ISH (SHEP, SYST-EUR), with trials in elderly with DH/mixed hypertension (Australian to STOP), andwith younger hypertensives with DH (MRC-I). Comparison of % risk reduction (RR),and numbers to treat to prevent one event (NNT), for five years of treatment. NR : results not reportedSummary of trials (SHEP AND SYST-EUR: see previously):

N= age: 1 drug: entry BP:th

- Australian : 582 60-69 thiazide 95-109Manag.Comm.’80

- Coope/Warrander : 884 60-79 ß-blocker 105-120‘86

- EWPHE : 840 60-96 thiazide 90-119 / 160-239Amery’85

- MRC-II : 4396 65-74 thiazide/ß-blocker <115 / 160-209MRC‘92

- STOP : 1627 70-84 thiazide/ß-blocker [mixed]Dahlof’91 1

- MRC-I : 17354 35-64 thiazide/ß-blocker 90-109MRC‘85

1: 90-120 or 105-120/180-230 or <180

Abbreviations: BP = blood pressure, EWPHE = European Working Party on Hypertension inthe Elderly, MRC = Medical Research Council, STOP = Swedish Trial in Older Patients

Based in part on Lever ‘95

considered most important in hypertension studies: strokes (either fatal or

non-fatal: strong impairment of quality of life!), and combined cardiovascular

mortality. Starting with percentage of reductions for strokes, a fairly similar

result is seen among all trials. However, the rates for numbers needed to treat

are much more different, varying from 167 subjects to be treated for five years

to prevent one stroke according to the MRC-I (younger patients, diastolic

hypertension), to only 14 subjects according to the STOP-trial (older subjects,

mixed hypertension (most SDH, also ISH)). Thus, antihypertensive treatment

appears to be more effective in the elderly than in the �younger� subjects. The

II NTRODUCTION

- 31 -

favourable results of both ISH-trials appear to be comparable with the

diastolic hypertension trials in the elderly.

One of the main explanations for the observed differences in prevented

cardiovascular complications among the various studies is the basic risk in the

population. When occurrence of any complicating event is very rare, it will

take many patients to prevent one, and the reverse is true in case of a high

incidence of complications. Indeed, the prevalence of stroke in the STOP-trial

(rate in placebo-group) was over 30/1000 pat.years, compared to only 2/1000

pat.years in the MRC-I. Thus, treatment in the elderly appears to be more

favourable in the old than in the younger. However, an important remark to

this conclusion is that the effects in the younger subjects may be

underestimated, due to relative short observation periods in most

studies. Still, a long-term treatment does have its price in costsMancia’96,Sytkowski’96

of medications and in possible side-effects. In elderly hypertensives,

treatment of hypertension has been shown to be actually cost-saving.Jönsson’96

Based on the comparable effects in elderly with combined hypertension and

ISH, the same is probably true for ISH. In all, the conclusion may be that

prevention of cardiovascular complications in hypertension is more effective

in elderly than in younger patients, at least in the short-term, necessitating

less patients to be treated to prevent one event. Treatment of isolated systolic

hypertension appears to be as effective and favourable as treatment of

diastolic or combined (systolo-diastolic) hypertension in the elderly.

In summary...

Isolated systolic hypertension (ISH) is an old problem, long known to be a

strong cardiovascular risk factor, but until recently receiving less attention

than diastolic hypertension. This may have been due to the fact that ISH

occurs especially in the elderly. Recently, large scale studies have become

available, showing beneficial effects of treatment on stroke and

cardiovascular disorders. The vascular pathophysiology of ISH is a decreased

distensibility of the aorta and large arteries and left ventricular mass and

diastolic function are known to be disturbed, but few studies are available on

effects of treatment on these cardiovascular changes in ISH.

CHAPTER 11

- 32 -

LAW NUMBER I:

GOMERS (�GET OUT OF MY EMERGENCY ROOM�) DON�T DIE.

SAMUEL SHEM, THEHOUSE OFGOD

ETHODS

- 33 -

CCCCHAPTER HAPTER HAPTER HAPTER 2222

MMMMETHODS ETHODS ETHODS ETHODS

CONTENTS

2.1 The Groningen Hypertension Service

2.2 Measurements of vascular pathophysiology

2.3 Measurements of cardiac end-organ damage

CHAPTER

- 34 -

results diastolic hypertension - age 25-60 years

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1980-1993 n = 31509

1980 Vries n = 2850 1981 Marne n = 3128 1981 Baflo n = 754 1983 Eelde n = 1770

1983 Delfzijl n = 4298 1985 Veendam n = 4945

1987 Bedum n = 2047 1988 Appingedam n = 3548 1990 Loppersum n = 1933

1993 Achtkarspelen n = 6236 .

0 2 4 6 8 10 12 14

untreated DBP > 95 mmHg; treated DBP > 95 mmHg; treated DBP < 95 mmHgAAAA

AAAA

av. untreated: 4.6%

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- 35 -

Figure 2.1. Results of the Groningen Hypertension Service 1980 - 1993.The different studies and sample sizes are given at the left side; results presented are the prevalences of diastolichypertension according to treatment status, in persons aged 25-60 years.

2.1 THE GRONINGEN HYPERTENSION SERVICE

The studies in this thesis are based on investigations initialized by the

Groningen Hypertension Service (GHS). This service, founded in 1980, is a

cooperation of general practitioners and medical doctors from the

Departments of Cardiology, Internal Medicine and Clinical Pharmacology,

Academic Hospital Groningen and Groningen University, and from the

General practitioners� laboratory in Groningen. Since 1992, the Department of

General Practice of the Groningen University is involved also. The aim of the

GHS is �to improve detection and treatment of hypertension in the general

population�. For this purpose, large population-based screening programs are

CHAPTER

- 36 -

conducted, in which all inhabitants of a municipality are invited to have their

blood pressures measured. Results of these screening programs are reported

to the treating general practitioners, either directly or after installation of

treatment. This treatment is sometimes done by means of clinical research

trials. Results of these screening programs and trials have led to several

publications and theses. The advantageBerge’90 Havinga’91,Leeuwen’93,Schuurman’85,van der Veur’85

of such a population screening model for scientific research is, that it enables

selection of relatively large groups of previously untreated hypertensives.

This avoids bias of previous treatment, and also bias due to selection of worse

or therapy-resistant cases, as in trials on referred or hospitalized patients.

The present investigation, in the municipality of Achtkarspelen, was the

tenth investigation, resulting in over 30.000 persons of 25-60 years of age

screened in 14 years (see figure 2.1). This number is in fact even larger,

because in the last screening programs elderly aged 60 years and over were

included also. In the Achtkarspelen study, 4100 elderly aged 60 and over

were invited, of which over 2700 did respond (65%). These elderly are the

principal subjects of study in this thesis.

ETHODS

References Chapters 1-3: see Chapter 3. [Note: only major references are quoted; for full list1

of references used see Chapter 3]

- 37 -

2.2 MEASUREMENTS OF VASCULAR PATHOPHYSIOLOGY

Before discussing the different measurement techniques of vascular

pathophysiology as used in this thesis, a short introduction is given on the

normal functions of the arterial system, and the various definitions and

terminology used, to facilitate the interpretation of the results of these

measurements.

FUNCTIONS OF THE ARTERIAL SYSTEM

The conduit and cushion function of arteries

The arterial system has two functions, which are interrelated but still

distinguishable: the conduit function and the cushion function. Safar’96 1

The conduit function is the function of the arteries to deliver an adequate

supply of blood to the tissues of the body, required to fulfil their metabolic

needs. An adequate pressure must be maintained throughout the arterial

system for perfusion of the various tissue compartments in the body. This is

determined by the pressure delivered to the arterial system by the heart and

the vascular resistance of the system. This vascular resistance is determined

by the size and shape of the blood vessels, and the viscosity of the blood.

In younger, non-hypertensive subjects, systolic blood pressure increases and

diastolic pressure decreases slightly from aorta to peripheral arteries.Safar [Book]’95

Thus, measurement of systolic blood pressure at the arm will slightly

overestimate �true� blood pressure in the aorta in a young person (in rest).

This pattern disappears in the elderly, in whom blood pressure in central

arteries is equal or even slightly higher than in peripheral arteries. This may

be particularly so in elderly with systolic hypertension. Hence, central aortic

systolic pressure and left ventricular load may be underestimated in the

elderly with ISH by blood pressure measurements at the arm.

CHAPTER

- 38 -

The cushion function of the arterial system can be understood by the

difference in flow pattern entering the system, which is the pulsatile flow

from the heart, and the constant flow required by the tissues at the end of the

vascular system. Therefore, the arteries must be capable to dampen the

pressure pulses ejected with each contraction of the heart: the �Windkessel-

effect�. This effect can be best imagined by a balloon-like distension ofO’Rourke’92

the aorta when the blood is pumped in during systole, to store the extra

amount of blood. This distension will decrease again in diastole, by run-off of

the blood peripherally. This simplified model is helpful in understanding

abnormalities in the large arteries. Loss of the Windkessel-effect is one of the

main determinants of ISH. Dart’93,Nichols’92,Smulyan’97

The arterial pulse wave

The distension of the large arteries as described above appears not to be a

slow, local distension in the beginning of the aorta, but more a rapidly

travelling wave-like distension over the arterial system. The pressureSafar’89

pulse wave travels with a speed of several metres/seconds (to be

distinguished from the actual speed of blood flow: cm/s) from the aorta over

the arterial branches. This velocity can be measured, by registration of the

pressure pulse waves at two places with Doppler echo-probes. AnLehman’96

interesting phenomenon is that the pressure pulse wave is reflected

somewhere peripherally. The point of reflection is variable, but theO’Rourke’93

reflected pulse wave can be identified. This is illustrated in figure 2.2 . In this

figure, a schematic representation of an artery (left) is given, with the

(perpendicular) distension caused by the pressure pulse, and the pulse wave

travelling along the vessel. On the right, the aortic pressure curve is given,

showing the reflected pulse wave seen normally in diastole.

The figure also illustrates the changes when arterial distensibility is altered,

as with aging and hypertension (top of figure). In both conditions, a

decreased arterial distensibility causes a decreased distension of the arterial

systole

ETHODS

- 39 -

Figure 2.2. Schematic illustration of effect of decreased distensibility on pulsewave propagation.- Left: aorta with extending ejection pulse wave; Right: aortic pressure curve. - Bottom: normal distensibility (closed arrow), with normal pulse wave velocity (openarrow). Returning of pulse wave occurs in diastole (cross arrow/surge in pressure curve.- Top: decreased distensibility: reduced distensibility, with increased pulse wave velocity.Returning of pulse wave occurs in systole.

wall, and as a consequence an increased pulse wave velocity. When aortic

distensibility is strongly impaired and pulse wave velocity is high enough, the

returned pulse wave may reach the heart in systole, causing an extra load on

the heart with values as high as 50 mmHg. The measurement of pulseO’Rourke’93

wave velocity can be used to evaluate aortic distensibility, and this is done so

also in this thesis.

CHAPTER

- 40 -

TERMINOLOGY OF ARTERIAL FUNCTION

In studies on arterial function, several terms are used. They are not always

that clearly defined, what can be confusing for interpretation of the results.

Therefore, a short definition of the most widely used terms is given, together

with their formulas: O’Rourke’92, Safar [Book]’96

Compliance: this is the change (delta or )) in dimension or volume (V)

following a change in stress or pressure (P):

C = ))V / )) P

Distensibility: this is the compliance relative to the initial volume:

D = ))V / )) P * V

The advantage of distensibility measurements over compliance is that the

initial volume of the arterial system is taken into account. However, it is not

always possible to measure volumes, and therewith distensibility.

Furthermore, neither distensibility nor compliance are pressure-independent,

thus changes in pressure can cause changes in compliance and distensibility

measurements without actual structural or functional changes in the vascular

wall.

In many methods, change in arterial diameter or length is used instead of

change in volumes. This is possible, because the relative change in volume

can be replaced by relative change in cross-sectional area and diameter. This

is the method to calculate distensibility with visualising techniques, such as

carotid echography. Other techniques of measuring volumes depend onRoman’92

changes in electrical impedance. When an inflated cuff is released from

suprasystolic to below diastolic blood pressure, changes in impedance reflect

changes in arterial volume. This enables calculation of compliance and

distensibility. This is the method used in the upper-arm bio-impedance

measurement. Muntinga’95

ETHODS

- 41 -

The possible adaptation mechanisms of the vascular wall to respond to such

an increased pressure can be derived from Laplace� law:

Wall stress = P * D / 2* wall thickness

Thus, to protect itself from an increased wall stress in situations of high

pressures (hypertension), the artery can respond either by decreasing its

diameter, or increasing the wall thickness. This mechanism does occur in

hypertension: many studies have shown an increase of wall thickness

especially for the carotid artery, including in ISH. TheSutton’87,Roman’92,Benetos’93,Bots’93

pathophysiologic mechanism probably is an increased growth of smooth

muscle cells, mediated by modulated genetic expression and growth factors

(among which local components of the renin-angiotensin system).

Elastic versus muscular arteries

An important discrimination in terminology is the difference in structural

composition of the arterial wall: elastic vs. muscular arteries. This different

composition apparently is related to the function of the specific artery. The

main function of the aorta and proximal large arteries is the storage of blood

or the cushion function, as described previously. For this, the large arteries do

have a relative large amount of elastin deposited in the wall, making the

artery smooth and easily distensible. The function of the smaller, more

peripheral arteries is regulation of blood flow, or the conduit function. These

arteries, such as the brachial artery, are more muscular arteries which fits

better with this regulatory function. Thus, composition of arteries is

heterogenic, changing from elastic to muscular, and from smooth to more

rigid descending from the aorta to smaller arteries. This heterogeneity may

also be present among different types of hypertension including

ISH, and different arteries may also differ in their response toBenetos’93,Smulyan’97

treatment. However, most studies on changes in vascular pathophysiology in

ISH only included one single derivate parameter of arterial properties,Meaney’95,

few techniques are available allowing analysis of different partsDahan’90,Vardan’83

of the arterial tree at one time.

Atherosclerosis and intimal-medial thickening

CHAPTER

- 42 -

Finally, a difference must be made between atherosclerosis and

arteriosclerosis or intimal-medial thickening. The difference between these

terms is not always clear. Atherosclerosis is the process of deposition of lipids

in the arterial wall, initially forming fatty streaks who may be already present

in childhood. Increased uptake of cholesterol and collagen depositionMaseri’‘95

and invasion of macrophages and smooth muscle cells increase the size of the

defect, finally resulting in the �calcified� atherosclerotic plaques (the

�response to injury-theory�). These plaques may be responsible forRoss’86

impairment of blood flow or even arterial occlusion, as in myocardial

ischemia and infarction. This process occurs preferably in the aorta and large

and medium-sized arteries, including the coronary arteries, and although

damage may be very extensively, it is by definition a focal process. Although

hypertension is a risk factor for ischemic heart disease, the relation withNeaton’92

atherosclerosis appears to be not that direct, as correlation between systolic

blood pressure and extent of atherosclerotic lesions (post-mortal) was only

weak.Sorlie’81

Arteriosclerosis suggests a process comparable to atherosclerosis in more

smaller arteries and arterioles. However, the underlying abnormality is better

described by thickening of the intima-medial wall of the arteries. This

thickening may be due to an increased amount of smooth muscle cells in the

arterial wall, and/or increased deposition of collagen and fibrinogen. This

growth may be a response to increased wall stress, as with high blood

pressure, and mediated by growth factors. In contrast to the focal

atherosclerotic plaque, intimal-medial thickening is a more diffusely located

abnormality. It occurs in the smaller muscular arteries, but also in the large

arteries such as the carotid and femoral artery, with perhaps preference for

the first. Sutton’87,Roman’92,Benetos’93,Bots’93

A remark must be that these descriptions of changes in the arterial wall are

simplified, and clearly underestimates the heterogeneity and complexity of

actual changes. It remains helpful to distinguish the atherosclerotic plaque

formation from increased intimal-medial thickening of the arterial wall, with

hypertension perhaps more associated with the latter.

ETHODS

- 43 -

METHODS USED FOR MEASUREMENT OF ARTERIAL FUNCTION

The aortic pulse wave velocity measurement

Aortic pulse wave velocity measurement can be understood rather easily,

when recalling the rapid travelling wave-like distension over the arterial

system (see section 2.2.1). In the method, the pulse wave is detected at the

approximate beginning of the aorta (subclavian artery) and the ending

(femoral artery). Then, the time interval between both signals can be

measured, and with a known length of the aorta (estimated from suprasternal

notch to inguinal fold), the speed of propagation of the aortic pressure pulse

wave or aortic pulse wave velocity (PWV) can be measured. TheSafar’89,Lehman’96

time interval between both waves is measured automatically, with a

computer program, developed in our own institute. From the pulseLubbers’93

wave velocity measurements, distensibility can be calculated by the formula:

D= 1/(DD * v ) 2

in which D represents the density of the blood and v the pulse wave velocity

(unit D: 1/MPa). The interpretation of results can be understood by knowing

that in a stiffer aorta, the pulse wave velocity is increased, as expressed in the

formula: higher values of v result in lower values for the distensibility D.

The bio-impedance measurement

With the bio-impedance method, vascular compliance and distensibility

from various parts of the arterial vasculature (and also veins) can be studied

in one measurement. This method, developed at the Department ofMuntinga’95 &'97

Medical Physiology of the Groningen University, provides this rather unique

opportunity by measuring over a range of controlled changes of pressure

continuously volume changes. The pressure is controlled using a cuff

wrapped around the upper arm. The transmural pressures is measured by

distracting the cuff pressure from the actual blood pressure in the patient.

This is illustrated in figure 2.4: the cuff pressure is quickly inflated to

suprasystolic (systolic BP in this example approx. 180 mmHg), and then

gradually deflated. Directly after cuff pressure equals the systolic BP of the

01s. 1 2 3 4 5 6

time (min)

0

50

100

150

200

250inflation pressure (mmHg)

AA

DD

BB

CC

CHAPTER

- 44 -

Figure 2.3. Schematic representation of cuff pressure during bio-impedancemeasurement, and relation with parts of the arterial vasculature studied. Line in graph represents cuff pressure, which is inflated quickly to suprasystolic (inseconds). After two minutes, the cuff is gradually deflated. When cuff pressure equalssystolic BP of the patient (line B), the large arteries start to fill (point A). With a furtherdecrease of cuff pressure, subsequent filling of smaller arteries (C) and arterioles (D)will occur.

patient (= transmural pressure or P =0), the arteries start to fill again, totm

begin with the large arteries which is in this case the brachial artery. With a

further decrease of the cuff pressure, smaller arteries start to fill also. Finally,

the veins are filled. The volume changes are measured by impedance

measurement, using electrodes positioned on the same arm segment (under

the cuff). From this, volume changes can be related to changes in filling of the

different components of the arterial system: the volume at P =0 representstm

the volume of the large arteries, and so on. From the rate of changing of

filling, the compliance of the corresponding part of the curve can be

calculated (according to the formula C = ))V / )) P; see earlier).

Thus, the bio-impedance method offers the advantage of estimations of

changes in compliance and distensibility along different parts of the vascular

system in the arm segment. Changes in arterial distensibility do not need to

be the same in all vessels, as was previously discussed. For instance,Smulyan’97

while diastolic hypertension has been related to decreased distensibility of

the smaller arteries and arterioles, systolic hypertension has been related to

ETHODS

- 45 -

decreased distensibility of the large arteries.

The strain gauge plethysmography

The strain gauge plethysmography-method allows limb flow measurement

under different conditions. This method uses strain gauges around a limb

segment (in this case the calves), to assess changes in volumes. TheSumner’93

volume changes during periodic venous occlusions represent arterial inflow.

The initial increase in volume or slope of arterial inflow is measured after

inflating a cuff to supra-venous pressures (approx. 50 mmHg). Flow

measurements are performed at rest, during postocclusive hyperaemia and

after exercise. The purpose of hyperaemia and exercise is to achieve

(maximal) vasodilation, and thereby determine the minimal vascular

resistance. This minimal resistance represents the condition of the arteries,

being decreased in diseased conditions.

During the measurement, subjects are lying down on a bench in a room

with a constant temperature, with feet and calves elevated slightly above

heart level. A mercury-filled rubber strain gauge is placed around the widest

part of each calf, and occlusion cuffs are placed above the knees. Resting

measurements during venous occlusion (cuff inflation 50 mmHg) are done

with alternating inflation and deflation of the cuffs during five minutes.

Hyperaemic measurements are taken immediately after five minutes of

arterial occlusion (cuff inflation 200 mmHg), and post-exercise measurements

after a heel kicking exercise (cumulative performance of 1000 Joule). Calf

blood flow (CBF) is calculated from the rate of the initial increase in calf

circumference during venous occlusion, and is expressed as millilitres per 100

ml of calf tissue per minute. A simultaneous blood pressure measurement

allows the calculation of calf vascular resistance: CVR= MAP / CBF (MAP =

mean arterial pressure).

CHAPTER

- 46 -

2.3 CARDIAC END-ORGAN DAMAGE MEASUREMENTS

ECHOCARDIOGRAPHIC LV MASS MEASUREMENT

The most widely used method for measuring left ventricular (LV) mass with

echocardiography is the cubic equation method. In this method, based on the

�old� one-dimensional motion (M)-mode measurement, the thickness of the

posterior wall of the left ventricle and the interventricular septal thickness are

measured, together with the end-diastolic diameter of the LV. TheDevereux’77

cubic equation is based on calculation of the volume of the total �cube� with

distraction of the internal cube, leaving the volume of the cardiac muscle.

This model has been shown to correlate well with actual (post-mortem) LV

mass, when corrected adequately. Thus, even while moreReichek’81&’83, Devereux’86(2x)

sophisticated methods such as 2- or even 3-dimensional measurements

became available, this technique is still the basic echocardiographic LV mass

measurement in hypertension, based on its established correlations and

relations with subsequent cardiovascular risk, as proven in many

studies. The same holds true for the comparison with otherCasale’86,Levy’90,Aronow’91

measurements such as magnetic resonance imaging (MRI): they may be more

accurate, but need to be confirmed.

Although widely used for a rather long time, echocardiographic LV mass

measurements still do present some problems, which are important for

performing the measurements and comparing the results. First, there are

different methods of measurement of wall thickness and end-diastolic

diameters (necessary for calculation of LV mass according to the cubic

model). These different methods, depicted in conventions, are the Penn-

convention and the American Society of Echocardiography (ASE)-

convention. The difference between these two methods is that in theDevereux’87

ASE-convention measurements are made from leading edge to leading edge,

thus including endocardial thickness, while in the Penn-convention the

endocardium is not included in the measurement of wall thickness (see figure

2.4). This difference is not arbitrary: it may cause a difference of

approximately 1 mm in wall thickness, on thickness values ranging from 8 to

14 mm. This is also expressed in the different formulas for calculations of LV

mass, as corrected by Devereux. Which convention is used is notDevereux’86

ETHODS

- 47 -

Figure 2.4. Illustration of difference between Penn- and ASE-convention. Note that endocardial echoes are excluded from wall thickness measurements in thePenn-convention, while these are included in the ASE-convention. EDD = end-diastolicdiameter, IVS= interventricular septum, PW =posterior wall. Devereux’87

always mentioned in publications. Initially, the Penn-convention

measurements appeared to be slightly favourable, although the ASE-

convention measurements may be more easily applicable, because errors in

the size of the endocardial thickness (to be excluded with the Penn) are

avoided. The division appears to be about fifty-fifty, with perhaps a slight

preference for the ASE-convention in North-American studies, and for Penn-

convention in the other studies.

Another problem in LV mass studies is the variation in literature in

indexation methods and cut-off values for LV mass. Indexations used vary

from corrected for body surface area to body mass index, and several indices

of height. Of these, body surface area is probably the most widely used,

adequately correcting for differences in LV mass due to body size, although

underestimation of LV mass may occur in obese persons (due to

overcorrection). With regard to the variety in LV hypertrophy cut-off values,

these may vary as much as 108 g/m in one study to 160 g/m in2 DevereuxAJH’93 2

the CASTEL-study, for the definition of LVH. Obviously, such huge

differences strongly limit comparison of the various study results.

Comparison of �% LVH� must also be viewed with caution, depending on

CHAPTER

- 48 -

which cut-off values used. The answer to this problem should be an uniform

agreement on indexation methods and cut-off values used. In the mean time,

cut-off values should be chosen known to be related to subsequent

cardiovascular risk. Examples are criteria of Devereux (% 134 g/m , & 1102

g/m ) , Koren (125 g/m ), and the Framingham report (125 g/m,2 Devereux’86 2 Koren’91

indexed for height). Krumholz’95

The recording of echocardiograms requires experience and skill in order to

obtain accurate LV mass measurements. Correct visualisation of the largest

dimension of the left ventricle, errors in perpendicularity of measurements or

angling errors, and specific problems such as the inclusion of papillary muscle

and the moderator band in measurements of wall thickness, must be avoided

because all of these may strongly influence LV mass measurements. When

these problems can be avoided, the variability of measurements of LV mass

should be possible to remain within 10% (inter-observer variability). This

appears to be acceptable for clinical study purposes.

Another problem is that adequate recordings can not be obtained in all

subjects. Even with improved transducer techniques, approximately 10 to

20% of subjects will not allow adequate echocardiographic recordings, due to

interference by air, bone or fat. Other techniques such as magnetic resonance

imaging (MRI) may avoid this. However, echocardiography remains far more

easily applicable and better validated, and therewith remains the method of

choice to determine LV mass in hypertension.

ETHODS

- 49 -

Normal RWT RWT increased

No LVH normal concentric remodeling

LVH eccentric LVH concentric LVH

Figure 2.5. Classification of LV geometryBased on absence or presence of left ventricular hypertrophy (LVH: > 125g/m ), and of normal or increased relative wall thickness (RWT: > 0.45)2

Presentation of results of left ventricular mass: index, hypertrophy, or geometry

There are various methods to present results of measurements of LV mass:

as continuous variable (LVM or LVMI: I= indexed, for body surface area of

height), or as presence or absence of hypertrophy (LVH). For study purposes,

the continuous measurement of LV mass is to be preferred, as comparisons

between groups and effects of treatment can be better assessed. Clinicians

however may prefer to use the dichotomous variable LVH, for easy

discrimination of those with high cardiovascular risk. However, in this way

only the top of abnormality will be discovered.

Another approach to discrimination of abnormal LV mass is the

classification of LV geometry as proposed by Koren. In this classification,NEJM’91

the relative wall thickness (RWT) is taken into account, next to LVH. RWT is

defined as the ratio between wall thickness of septum (IVS) and posterior

wall (PW), and enddiastolic diameter (EDD):

RWT = (IVS + PW) / EDD

Hence, an increased RWT indicates an inappropriate increased thickness of

the LV wall when compared to the internal diameter. In the study of Koren, a

cut-off value of 0.45 was used. When combining abnormality of RWT and of

LVH, four mutually exclusive classes can be discriminated: see figure 2.5.

With this classification, a discrimination is possible between different patterns

of increased LV mass: of LVH due to increased wall thickness (concentric

LVH), and LVH due to enlargement of the LV without clear increased wall

thickness: eccentric LVH). Furthermore, a new intermediate class is

cardiovascular events cardiovascular mortality total mortality0

5

10

15

20

25

30

35

(% p

atie

nts)

normal concentric remodelingeccentric LVH

concentric LVH

CHAPTER

- 50 -

Figure 2.6. Patterns of LV geometry and associated risk on cardiovascular events and cardiovascular andtotal mortality (% patients, 10.2 years follow-up). Difference in risk between the four classes was statisticallysignificant for all three endpoints. Adapted from Koren NEJM ‘91

discriminated, of subjects with increased wall thickness without yet reaching

criteria of LVH: concentric remodeling.

Importantly, these four classes were shown to be associated with

cardiovascular risk. Figure 2.6 shows the increased risk for cardiovascular

mortality from normal to concentric remodeling to both types of LVH. This

pattern was also present for cardiovascular morbidity or events, and for total

mortality. In later studies, the increased risk of subjects with concentric

remodeling was confirmed, having an Odds ratio of 2.56 versus normal

geometry. The same group could not confirm a significant differenceVerdecchia’95

in cardiovascular risk between both types of LVH. Verdecchia’96

Thus, while the continuous variable of LV mass (index) is to be preferred in

research, the classification of LV geometry can be useful in clinical practice,

not only discriminating those with clearly abnormal patterns and associated

high cardiovascular risk (LVH), but also those with intermediate abnormal

pattern of concentric remodeling, who are also at increased risk for

cardiovascular complications. A disadvantage of the LV geometric

classification is that the underlying calculations are rather complex, making

determination of LV geometry rather difficult in daily practice without

computer calculations.

ELECTROCARDIOGRAPHIC ASSESSMENT OF LV HYPERTROPHY

ETHODS

- 51 -

Most measurement methods of LV hypertrophy based on the

electrocardiogram (ECG) are based on voltage measurements of separate lead

recordings of the 12-lead standard ECG. The diagnosis of LVH isSokolow’49,Casale’85

then based on voltages exceeding threshold levels, either from indivivual

leads, from sum of certain leads, or the sum of all 12 leads voltages.Okin’95

Other criteria used are repolarization abnormalities (�strain� pattern), or time

measurements of ventricular depolarization, such as the ventricular activation

time (VAT= the initial upstroke measured at V4-V6).

From these definitions of voltage measurements, one problem of ECG

measurements of LVH can already easily be understood. When factors other

than the myocardial thickness influence ECG voltages, the criteria will be less

reliable. For instance, obese subjects have by definition lower voltages, and

will thus less easily reach criteria of LVH (while occurrence of LVH is in fact

increased in obesitas). Also, conduction disturbances will disturb reliability of

these measurements. These limitations contribute to the general problem of

ECG LVH-measurements, i.e. a low sensitivity. While ECG-LVH is known to

have a high specificity (=if measurements are abnormal, LVH is very likely to

be present), many cases are missed (=low sensitivity). Furthermore, aCrow’95

problem is the dichotomy of the evaluation �yes-no LVH�: this limits analysis

of changes of the continuous variable LV mass. Several attemps have been

made to create ECG-models to predict LV mass, but most show rather

moderate correlations with actual LV mass. Wolf’91

CHAPTER

- 52 -

ECHOCARDIOGRAPHIC LV DIASTOLIC FUNCTION MEASUREMENT

Another cardiac consequence of hypertension is disturbance of diastolic

function or filling of the heart. The method of echocardiographic diastolic

function assessment is based on measurement of the inflow pattern across the

mitral valve, as recorded with pulsed Doppler signal recording. TheTaylor’92,Hoit’94

sample volume is positioned between the tips of the mitral leaflets from the

apical 4-chamber view. In this flow pattern, an early (E) and an atrial (A) peak

filling velocity can be distinguished (see figure 2.7). The ratio between these

two measurements (E/A-ratio) is the most widely used echocardiographic

measurement for LV diastolic function. Another measurement of diastolic

function is the duration of the isovolumetric relaxation time (IVRT)of the left

ventricle. The IVRT can be measured also with echocardiography, with

placing the pulsed Doppler sampling area between the mitral inflow pattern

of the LV and the outflow pattern to the aortic valve. In this pattern, which

can be best recorded just above the tip of the anterior mitral valve leaflet in

the apical 5-chamber position, the time difference between both signals can

be measured.

With more sophisticated equipment, allowing on-screen tracking

measurements, more details from the E and A wave can be detected. These

additional measurements include the time velocity integrals (=area under the

curve) of E and A-wave, and acceleration and deceleration time of the E-

wave. These measurements may provide more information than the �crude�

peak velocity, but since they have not been used on large scale, knowledge on

normal values and interpretation of changes is less well known.

One of the problems of echocardiographic diastolic function measurements

is the reproducibility of measurements. Errors such as angling errors of the

Early Atrial

E A A

B

E A

C

E A

D

ETHODS

- 53 -

Figure 2.7. Patterns of LV diastolic fil l ing. Figure 2.7. Patterns of LV diastolic fil l ing.

Normal pattern is AA: E/A-ratio > 1. In disease, this may progress to BB: impaired filling:

E/A-ratio < 1. When end-diastolic pressure is increased, early filling may be increased

again: CC: �pseudo-normal patternpseudo-normal pattern�� (note the shorter deceleration time as compared

with A). DD: restricted filling pattern

recorded signal, variation in sample positioning or in positioning of the probe,

easily result in differences in flow patterns recorded. Furthermore, biologic

variation is more a problem as compared with LV mass measurements;

variations in expiration, heart rate, and LV filling status all influence filling

velocities and therewith interpretations of LV diastolic function

measurements, without actual changes in LV diastolic function being

present. Perhaps of even stronger influence is the age of subjects, asGalderisi’93

can be derived from normal values: while normal value of young subjects for

EA-ratio is about 2.0, this may decrease to normal values of 1.0 for elderly

aged + 60-70 years. Thus, age always has to be taken into considerationStewart’92

in interpretation of (ab)normality of measurements.

Furthermore, it must be remembered that velocities of flow are measured,

not volumes or pressures. Thus, abnormalities in flow measurements can not

always be translated into abnormalities of pressure or volume changes. An

illustration of this problem is the situation of �pseudonormalization�. This

quasi-normal pattern of flow velocities can be obtained when in a situation of

initially disturbed diastolic filling (=low EA-ratio), LV end-diastolic pressure

is increased. This may increase the peak early filling again: hence, EA-ratio

may appear normal again (see figure 2.9). Since pressure measurements are

not possible with echocardiography, this pattern is difficult to differentiate

CHAPTER

- 54 -

from truly normal LV diastolic filling. A possible difference with the normal

filling pattern can be a shorter deceleration time or pressure half time

(=steeper downslope E-wave).

A final problem of diastolic function measurements has already been

discussed in Chapter 1: the lack of correlation of values with cardiovascular

risk, and the lack of clear effects of treatment.

ETHODS

- 55 -

CHAPTER

- 56 -

LAW NR. II

GOMERS GO TO GROUND

IMS AND REFERENCES

- 57 -


AAAAIMS OF THIS THESISIMS OF THIS THESISIMS OF THIS THESISIMS OF THIS THESIS

This thesis is directed to isolated systolic hypertension (ISH) in the elderly.

In the previous introduction, several questions have already been raised. The

principal aim of this study is to increase the understanding of the

pathophysiology of ISH, and possible changes with treatment. To achieve

this, the following aims are investigated:

� determination of the prevalence and the incidence of ISH, and of

factors predicting this development of ISH

� assessment of cardiac and vascular pathophysiologic changes in

untreated ISH-subjects

� improvement of detection methods for pathophysiologic changes in

ISH

� investigation of the effect of antihypertensive treatment on

pathophysiological changes in ISH

To answer these questions, several studies have been conducted. First, the

prevalence and incidence of ISH was determined in a large population

screening program (Chapter 4). The alterations of arterial distensibility

(Chapter 5) and of left ventricular hypertrophy (Chapter 8) in ISH were

compared with those in normotensive controls and in subjects with diastolic

hypertension. Improved methods for detection of LV hypertrophy were

investigated, for electrocardiography (Chapter 6) and for echocardiography

(Chapter 7). The effect of treatment of ISH was investigated in two studies,

assessing pathophysiologic changes during treatment with angiotensin-

converting enzyme inhibitors compared with placebo and with diuretic

CHAPTER

- 58 -

treatment (Chapters 9 and 10). The results from these investigations will be

summarized in Chapter 11 (in Dutch: Chapter 12), including discussion and

implications for future detection and treatment of ISH.

All these questions are investigated in an unselected (e.g. non-clinical)

elderly population, mainly based on a population survey under the aegis of

the Groningen Hypertension Service. This survey in the municipality of

Achtkarspelen (the Netherlands), was conducted in 1993, and repeated in

1995. The only exception is chapter 9, but ISH-subjects in this treatment study

were also derived from general practitioners� offices, and the inclusion

criteria of this study were similar to the second treatment in Chapter 10.

IMS AND REFERENCES

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LAWNR. III

AT ACARDIACARREST, THE FIRST PROCEDURE

IS TO TAKE YOUROWN PULSE

REVALENCE OF ISH

- 87 -


HHHHIGH PREVALENCE AND INCIDENCE OFIGH PREVALENCE AND INCIDENCE OFIGH PREVALENCE AND INCIDENCE OFIGH PREVALENCE AND INCIDENCE OF

ISOLATED SYSTOLIC HYPERTENSIONISOLATED SYSTOLIC HYPERTENSIONISOLATED SYSTOLIC HYPERTENSIONISOLATED SYSTOLIC HYPERTENSION

Wilfred F Heesen MD ; Frank W Beltman MD,PhD ; Johan F May MD,PhD ;a b a c

Andries J Smit MD,PhD ; Pieter A de Graeff MD,PhD ; Tjeerd K Havingac d c d e

MD,PhD ; Enno van der Veur PhD ; Frits H Schuurman PhD ; Pieter J de Kam,c c c

MSc ; Betty Meyboom-de Jong MD,PhD ; Kong I Lie MD,PhDa b a

Submitted

Departments of Cardiology, General Practice, Internal Medicine and Clinicala b d e

Pharmacology, University of Groningen and Groningen Hypertension Servicec

Groningen, The Netherlands

This investigation was supported by the "Praeventiefonds", grant number 28-2219

CHAPTER

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ABSTRACT

Introduction

In the past, most attention in treatment studies in hypertension has focused

on diastolic hypertension, despite the known higher prognostic risk of systolic

hypertension. The beneficial results of the SHEP- and SYST-EUR trials have

brought about a revival of interest in isolated systolic hypertension (ISH).

Reports on prevalence of ISH show a wide variety in rates, while studies on

incidence of ISH and controbuting factors are scarce.

Methods

An unselected population of elderly was screened, and this was repeated

after two years. Prevalence and incidence of different subtypes of

hypertension were determined. The influence of initial blood pressure on

changes in blood pressure during follow-up was analysed using Oldham�s

plotting method, taking into account the regression to the mean-

phenomenon.Results

Among 2356 attendants (rate 55%) at the first screening, ISH was the most

prevalent subtype of hypertension. Among definite cases (> 3 measurements)

of untreated subjects, rate of ISH was 10%. This prevalence increased strongly

with age. In two years follow-up, overall systolic BP increased with 4 mm Hg,

while diastolic BP did not change significantly. The increase in systolic BP

was highest among those with consistently high systolic blood pressures

(r=0.20; P< 0.05). This correlation was much less for diastolic hypertension,

while results for pulse pressure were intermediate. After two year follow-up,

20% of initially normotensives had become hypertensive, among which the

majority (13% of total) had ISH. Multiple regression analysis showed that

initial systolic BP itself was the strongest predictor for an increase of systolic

BP in follow-up.

Conclusion.

This study shows that among elderly isolated systolic hypertension is the

most prevalent hypertensive subtype, both at initial screening and the

incidence in follow-up. The high rate of development of new cases warrants

regular control of BP in the elderly. Among factors related to this incidence,

systolic hypertension itself appears to be a main contributing factor.

REVALENCE OF ISH

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INTRODUCTION

While in the past decades (seventies and eighties) most attention in the

treatment of hypertension focused on elevated diastolic blood pressure,

systolic hypertension has regained new interest. Elevated systolic blood

pressure is known for long to be an important cardiovascular risk factor, being

a stronger predictor of cardiovascular morbidity and mortality than diastolic

hypertension. Less evidence was available on the benefits of treatment1 2 3 4 5

of systolic hypertension, especially isolated systolic hypertension (ISH). With

the recent published beneficial results of the SYST-EUR trial , confirming6

those of the SHEP-trial , this evidence now appears to be solid. Revision of7

the importance of ISH is therefore necessary.8

Several reports are available on the prevalence of ISH, showing a wide

variety ranging from 1 to 41 %, differing between males and females. 9 10 11 12 13

Less is known about the incidence of ISH, as few of these studies14 15 16 17

included follow-up analysis. This would be important for daily practice, as

the occurrence of ISH is known to increase with age, as a consequence of

several factors. First, systolic blood pressure increases after the age of 60,

while diastolic blood pressure remains unchanged or even decreases. 18 19

Reasons for this increase in systolic blood pressure with age might be related

to the �normal� determinants of high blood pressure, such as sodium intake,

serum cholesterol, cigarette smoking, glucose intolerance, body weight,

physical exercise and alcohol consumption. A more specific contributing20 21

factor is less distensibility of the large arteries. A decreased distensibility of

the aorta and other large arteries, or the loss of the �Windkessel-function�, is

known to be the main pathophysiologic feature of ISH. Interestingly,22 23 24

systolic blood pressure itself is one of the determinants of aortic distensibility.

This may lead to the hypothesis of a vicious circle of high systolic blood

pressure decreasing aortic distensibility which in itself increases systolic

blood pressure: systolic hypertension begets systolic hypertension.

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Aim of this study was to investigate the hypertensive pattern in an elderly

population, in particular the contribution of (isolated) systolic hypertension.

Prevalence at first screening of ISH, and incidence at two year follow-up were

determined in a large population screening program of elderly aged 60 and

over. The influence of the initial blood pressure level on increase of blood

pressure during follow-up was analyzed along with other factors such as age,

to investigate the hypothesis whether an increased systolic blood pressure

itself contributes to a further increase of blood pressure in follow-up.

REVALENCE OF ISH

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METHODS

Study population and blood pressure measurements

A population screening program was conducted in a rural municipality

(Achtkarspelen) in The Netherlands in 1993. All inhabitants aged 60 years of

age and over were invited to participate by mailed personal invitation cards,

preceded by general mailing and advertising announcements. Blood pressure

was measured in schools and community centers as close to the homes as

possible. Elderly homes were also visited to measure those not able to attend

the screening centers. After five minutes rest, the sitting blood pressure (BP)

was measured by trained volunteers using a sphygmomanometer. When BP

was elevated (systolic BP: > 160 mm Hg, diastolic > BP 95 mm Hg) its

measurement was repeated by a physician. When BP remained elevated, the

patient was invited for a third and fourth measurement on two separate

occasions. A fourth measurement was not done in those receiving

antihypertensive treatment, and in elderly aged 75 years and over. All

subjects were asked whether they were currently treated for hypertension.

Subjects were defined to have isolated systolic hypertension (ISH) if

untreated systolic BP was > 160 mmHg at each measurement, with diastolic

BP <95 mmHg on at least the last two occasions, and average diastolic BP less

than 95 mmHg. The definition of isolated diastolic hypertension (IDH) was

DBP of 95 mmHg or more, with normal systolic BP (< 160 mm Hg). In case of

both elevated diastolic and systolic BP (> 160 mm Hg and > 95 mm Hg, resp.),

subjects were defined as systolo-diastolic hypertension (SDH). All categories

were considered to be �definite� when at least three BP measurements were

available. When less measurements were available the classification was

based on those results of available measurements (�average� ISH, IDH or

SDH). For analysis of changes in blood pressures in follow-up, all

measurements were used. All participants were asked whether they were

currently treated for hypertension, had a history of hypertension, or a family

history of hypertension. Furthermore, all participants received an extensive

questionnaire with questions on presence of other cardiovascular risk factors

such as high cholesterol, diabetes, smoking, and exercise capacity as assessed

with the Duke Activity Status Index questionnaire. 25

The screening program was repeated in 1995, two years after the initial

screening, in the same population and in the same season. The procedure of

BP measurement and of definition of hypertensive categories were the same

as in the original investigation. All results of BP measurements had been sent

CHAPTER

- 92 -

to the treating general practitioners, who were free in their decision to install

treatment. Also, a number of untreated hypertensive subjects was

investigated in a drug intervention trial between both screenings.

Statistical analysis

The influence of regression to the mean is assessed by Oldham�s plotting

method. In this method, the relation between the average of two26

measurements, and the difference between both measurements is plotted. If

the slope of the correlation line in the plot of this relation differs from

horizontal, a relation between initial measurement and the change in time is

present. The statistical significance of this slope between initial measurement

and change in time is calculated with univariate analysis. Also, Pearsons

coefficient of correlation is calculated. Furthermore, multiple logistic

regression analysis is performed to analyse which (other) factors are related to

changes in systolic blood pressure at follow-up. The procedure used is

backward removal of insignificant factors. Factors analysed are age and sex,

results of the initial blood pressure and heart rate measurements, and

cardiovascular risk factors as obtained from the questionnaire. The

(uncorrected) regression to the mean-phenomenon itself was analyzed also,

by division of the initial measurements into quartiles, and assessment of the

change in time per quartile.

Continuous data are reported as mean + S.D. . Logistic or categorical

variables are reported as frequencies (%). Difference between categories, as

between males and females, are analyzed with Student� t-test for continuous

variables, and with Chi-square testing for logistic or categorical variables. All

analyses are done with SAS statistical software analysis (SAS statistical

software V 6.12, Cary, N.C.). All differences are considered statistically

significant when the two-sided P-value < 0.05.

REVALENCE OF ISH

- 93 -

males females

N=attendance (%)age (years)systolic BP (mm Hg)diastolic BP (mm Hg)heart rate (bpm)treated for hypertension (%)previous hypertension (%)familial hypertension (%)weight (kg)smoking (%)diabetes (%)high cholesterol (%)exercise capacity (DASI-score)

103955

67 + 7.2162 + 24.487 + 12.079 + 13.5

142518

79 + 9.93964

40.3 + 14.5

131754

68 + 7.9 *164 + 24.4 *

86 + 12.080 + 23.7

24 *38 *32 *

72 + 11.2 *13 *9 *7 *

32.1 + 16.4 *

Table 1. Baseline characteristics according to gender (firstscreening, N= 2356)Abbreviations: BP = blood pressure; bpm = beats per minute.*: significantly different between males and females (P< 0.05)

RESULTS

Initial screening

Of the 4251 inhabitants aged 60 years and over 2356 (55%) attended the first

screening, with equal attendance among males and females (table 1). As

shown in table, 1, attending females had slightly higher age and systolic BP,

were more often treated for hypertension, and had more frequently diabetes

or high cholesterol, whereas males were more often smokers. The blood

pressure values presented (first measurement) cover all subjects including

those receiving antihypertensive treatment.

In table 2 the hypertensive categories are given, according to 5-years age

group, for untreated and treated subjects. Among the untreated subjects, the

percentage normotensive subjects is almost 70% in the youngest age-group,

declining with higher age to values under 50% after the age of 75 years. ISH is

the most prevalent subtype of hypertension among all age groups except for

the youngest, where it equals prevalence of combined or systolo-diastolic

60

-64

65

-69

70

-74

75

-79

80

-84

85

-89

>9

06

0-6

46

5-6

97

0-7

47

5-7

98

0-8

48

5-8

9>

90

age category (years)

40

60

80

10

0

12

0

14

0

16

0

18

0

20

0p

ulse

pre

ssure

(mm

Hg

)

males

females

CHAPTER

-94-

Age: 60-64 65-69 70-74 75-79 80-84 85-89 > 90 Total

untreated subjects (%):

N = 614 493 342 230 130 52 17 1878

- normotensive (%)- ISH (%)- SDH (%)- IDH (%)

68.214.315.12.3

57.624.117.01.2

52.328.717.31.8

43.940.915.2-

44.640.813.80.8

42.342.313.51.9

35.364.7--

56.925.815.81.5

treated subjects :

N= 148 136 86 61 29 14 4 478

- normotensive (%)- ISH (%)- SDH (%)- IDH (%)

35.125.037.22.7

22.845.627.93.7

18.644.236.01.2

16.447.532.83.3

27.655.217.2 -

50.035.714.3-

- 50.050.0-

25.939.532.02.5

Table 2. Prevalences (%) of hypertensive categories at first screening according to age (5-years categories) inuntreated and treated subjectsAbbreviations: ISH = isolated systolic hypertension; IDH = isolated diastolic hypertension ; SDH = systolo-diastolic hypertension

Figure 1. R

elation between blood pressure (B

P) and age

First B

P m

easurement of first screening, untreated subjects only (N

=1878). B

arsrepresent pulse pressures (top: systolic B

P, bottom

: diastolic BP

).

ISH9,6%

SDH11,5%

DH0,7%

normot78,1%

REVALENCE OF ISH

- 95 -

Figure 2. Hypertensive patterns (%) at first screening of untreated subjects (Definite cases only, N=1158) Abbreviations: normot= normotensives, IDH = isolated diastolic hypertension, ISH =isolated systolic hypertension, SDH = systolo-diastolic hypertension (definitions: seetext).

CHAPTER

- 96 -

hypertension (SDH). Isolated diastolic hypertension (IDH) is very rare in this

population. A similar predominance of ISH can be seen among the subjects

who were on antihypertensive treatment, reaching an overall percentage of

40%. The percentage of normotensives among these treated subjects is just

over 25%, the remaining 75% still being hypertensive. The changes of blood

pressure with age are depicted in figure 1 (first measurements, only untreated

subjects). In males, systolic blood pressure increases with age, while diastolic

blood pressure decreases slightly. The same pattern is observed, although

increase of systolic blood pressure may level off at higher age. No significant

differences were found between males and females for these changes. The

pulse pressure of males in the age category 85-89 years appears to be higher,

but this was based on a relatively low number of measurements (52).

The hypertensive categories in table 2 are based on �definite� and �average�

results: 720 subjects had less than 3 measurements and were classified

according to average results. As this may influence the analysis of

hypertensive categories, the results of �definite� cases only (and untreated,

N=1158) are presented separately, in figure 2. When these cases are analyzed,

prevalence of ISH was again high, comparable to SDH, while prevalence of

IDH was less than 1%.

Follow-up screening

Attendance at the second screening after two years was 2212 persons

(50.5%). Of these, 1632 subjects were untreated, of whom 66.1% was

normotensive, 22.8% had ISH, 9.1% SDH, and 2.0% IDH. The remaining 580

were treated for hypertension, of which 27.1 % was normotensive, 46.9% had

ISH, 24.5 % SDH and 1.6% IDH.

Combined results from first and second screening were available from 1403

subjects, enabling evaluation of blood pressure changes. Figure 3 shows what

happened with those subjects who were normotensive and untreated at the

initial screening (N=873). Less than 80% of these initially normotensive

subjects were still normotensive after two years. Among those who had

become hypertensive, ISH was the most frequently classified hypertensive

category, accounting for over 60% of the cases. IDH was again a rare

classification, occurring in less than one percent. A comparable predominance

of ISH and SDH could be seen among those who were meanwhile treated for

hypertension (Figure 3: smaller circle).

SDH3,2%

ISH13,2%

IDH0,9%

normot78,7%

treated4,0%

ISH25,7%

SDH8,6%

normot 65,7%

REVALENCE OF ISH

- 97 -

Figure 3: Incidence of hypertension (%) at two year follow-up among subjects normotensive and

untreated at first screening (N= 873) . Abbreviation: see previous figure

Changes in blood pressure and estimation of regression to the mean-effect

The main results of analysis of changes in blood pressure patterns are given

in figure 4, as Oldham�s plots correcting for regression to the mean by plotting

the average of both values against the differences between both values. In

these figures, the results are plotted of first measurements of initial and

follow-up screening, of untreated subjects only.

As figure 4.A shows, there is a relation between the height of the systolic

blood pressure and change over time: the higher the blood pressure, the

higher the increase in time from first to second screening period. This relation

is significant, with a Pearson coefficient of correlation 0.20 (P< 0.01). The

slope of the line is 0.18, significanty different from zero, thus systolic BP

increases 1.8 mm Hg for each 10 mm Hg of average systolic BP. The absolute

increase (horizontal line) is 3.9 (+ 17.5) mm Hg at two year follow-up.

For diastolic blood pressure, no such relation is observed (figure 4.B): the

slope of the regression line is nearly horizontal, not significantly different

from zero. In absolute change, virtually no change over time is seen (+0.1

mmHg). The results of pulse pressure (figure not shown) were intermediate

CHAPTER

- 98 -

Figure 4. Oldham’s plots for change in systolic (SBP - top) and diastolic bloodpressure (DBP) Results plotted are first measurements of untreated subjects both at first and secondscreening (N= 1153). The sloped (solid) line shows the correlation line between averagemeasurements and change during follow-up, the horizontal line (dotted) shows the absolutechange in follow-up (for statistics, see text).

REVALENCE OF ISH

- 99 -

between those of systolic and diastolic BP.

The regression to the mean-phenomenon itself was analyzed by division of

the initial measurements into quartiles, and assessment of the change in time

per quartile. For systolic blood pressure the following results were observed:

in the lowest quartile there was an increase of 9.3 mmHg, changing from + 3.6

mmHg in the second and + 2.8 mmHg in the third quartile to a decrease in

the fourth quartile of highest initial systolic blood pressures: - 5.9 mmHg.

In multiple regression analysis, all factors as depicted in table 1 were

investigated, to examine predictive factors for the increase of systolic BP

during follow-up. Factors not significantly related were removed, starting

with the least significant (backward procedure). In the final model, Initial

systolic blood pressure was the strongest predictor (P= 0.0001). Other factors

included in the model were initial diastolic BP (P= 0.01), familial history of

hypertension (0.03), and weight ( 0.03). Age was also kept in the model,

because of marginal signficance (0.06).

CHAPTER

- 100 -

DISCUSSION

This study shows that almost all cases of elevated blood pressure in the

elderly are due to systolic hypertension, either alone (ISH) or in combination

with diastolic hypertension while isolated diastolic hypertension occurs only

infrequently. Prevalence of ISH is about 10% in males and females over the

age of 60, increasing up to the highest ages. Perhaps of even greater clinical

importance are the results on new cases or incidence of hypertension in the

elderly. Two years after the initial screening almost 20% of initially

normotensive subjects became hypertensive, of whom the majority showed

ISH. Even while actual changes in blood pressure in time were not always

that pronounced, this high incidence of new cases of ISH is of considerable

clinical interest. One implication could be that blood pressure screening in the

elderly should be performed regularly, even in those with normal blood

pressure values.

This high incidence of ISH in the elderly could be related to its

pathophysiology. The mechanism of elevation of systolic blood pressure is a

decrease of distensibility of the large arteries. Since systolic hypertension27 28

itself also negatively influences aortic distensibility, a vicious circle may

develop: of systolic hypertension itself contributing to a further increase in

systolic blood pressure (�systolic hypertension begets systolic hypertension�).

Support for this hypothesis can be drawn from the observation that the

change of systolic blood pressure depends on the height of the initial value. A

problem of such analysis may be the regression to the mean-effect.

Measurements selected on high initial values are likely to show a decrease

while low values tend to increase. As shown in our study, the regression to

the mean-phenomenon is present: the group with the highest initial systolic

blood pressure showed a decrease during follow-up, and the group with the

lowest initial results an increase. However, both intermediate groups also

showed an increase of SBP in follow-up, suggesting an overall increase of

SBP. A method to correct for the regression to the mean is Oldham�s plotting

method, which compares the average of the results of both screenings with

the change during follow-up. Those subjects who have consistent high (or

low) values are taken together, thus avoiding some of the variation due to the

regression to the mean-phenomenon. As the plots show, a high SBP is related

to a higher increase of SBP during follow-up, confirming the earlier

hypothesis of systolic blood pressure itself contributing to (further) increase of

systolic blood pressure. It is also shown that such a relation is not present for

REVALENCE OF ISH

- 101 -

diastolic BP. Finally, multiple regression analysis also showed that initial

systolic BP was by far the strongest predictor of change of SBP during follow-

up.

Comparing these results with other reports, a comparable predominance of

ISH in a community-dwelling elderly population has been observed by Ekpo

et al.. One of the differences between these results and ours is that a decline29

of prevalence in ISH and of systolic blood pressure was observed after the age

of 80 years. As shown, the prevalence in ISH in our study increases up until

the highest age groups, a pattern observed also in other studies. Another30

main difference is that the report of Elko et al. lacked a follow-up, therefore

our results of newly developed cases of hypertension can not be compared.

Another study which does present comparable information on the

development of (systolic) hypertension is a report from the Framingham

study. It was observed that the majority (80%) of subjects with borderline31

systolic hypertension (SBP 140-159, with diastolic < 90 mmHg) progressed to

definite hypertension, as opposed to 47% of those with lower blood pressures.

However, this progression was seen after 20 years follow-up. As the present

study shows, the rate of development of new cases in the elderly may be

much faster, although the observations in the present study would be

strengthened if more than one follow-up screening would have been

performed. Another potential problem of our study is the problem of selection

or voluntary bias, i.e. the phenomenon that more healthy and health-minded

subjects are likely to attend such screening projects. We did try to estimate

the magnitude of this problem, by conducting an investigation among non-

responders as part of an investigation for prevalence of chronic disorders in

the same population. In approximately 200 non-attenders, blood pressure was

somewhat lower: 153/80 versus 163/87 mm Hg in responders (P< 0.05 for

systolic BP). However, some of this difference might be due to the fact that

blood pressure measurements were doone at home, instead of at sreening

sessions.

In conclusion, this study shows that in an unselected population of elderly

systolic hypertension is the predominant pattern of hypertension, either

isolated or combined with diastolic hypertension. After two years follow-up,

ISH is also the predominant subtype of hypertension. The highest risk for

development of ISH is among those with higher initial values of systolic

blood pressure, which may raise the hypothesis that (isolated) systolic

hypertension begets systolic hypertension. This high rate of development of

new cases of hypertension may warrant a regular blood pressure control in

the elderly. In general, knowing the favourable effects of treatment, ISH

CHAPTER

- 102 -

probably should derive more attention than is given so far in daily practice.

Taking into consideration the increased proportion of elderly in our Western

population, management of ISH will present a major challenge both in terms

of medical and socio-economical burden.

REVALENCE OF ISH

- 103 -

1. Kannel WB. Hypertension and other risk factors in coronary heart disease. Am Heart J

1987;114:918-925

2. Shekelle RB, Ostfeld AM, Klawans HL. Hypertension and risks of stroke in an elderly

population. Stroke 1974;5:71-75

3. Mann SJ. Systolic hypertension in the elderly. Pathophysiology and management (Review). Arch

Intern Med 1992;152:1977-1984

4. Staessen J, Amery A, Fagard R. Editorial review: Isolated systolic hypertension in the elderly. J

Hypertens 1990;8:393-405

5. Applegate WB. Hypertension in elderly patients (review). Ann Intern Med 1989;110:901-915

6. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, Bulpitt CJ, de Leeuw

PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O�Brien ET, Rosenfeld J, Rodicio

JL, Tuomilehto J, Zanchetti A, for the Systolic Hypertension in Europe (SYST-EUR) trial

investigators. Randomised double-blind comparison of placebo and active treatment for older

patients with isolated systolic hypertension. Lancet 1997;350:757-764

7. The SHEP cooperative research group. Prevention of stroke by antihypertensive drug treatment

in older persons with isolated systolic hypertension. JAMA 1991;265:3255-3264

8. Smulyan H, Safar ME. Systolic blood pressure revisited. J Am Coll Cardiol 1997;29:1407-1413

9. Silagy C, McNeil JJ. Epidemiologic aspects of isolated systolic hypertension and implications for

future research. Am J Cardiol 1992;69:213-218

10. Amery A, Fagard R, Guo C, Staessen J, Lutgarde T. Isolated systolic hypertension in the elderly:

an epidemiologic review. Am J Med 1991;90 (Suppl. 3A):64S-74S

11. Kannel WB, Dawber TR, McDee DL. Perspectives on systolic hypertension. The Framingham

Study. Circulation 1980;61:1179-1182

12. National center for health statistics. Blood pressure levels of persons 6-74 years. United States,

1971-1974. Rockville, MD: National center for health statistics, 1977. (Vital and health statistics,

series 11: Data from the National Health Survey no. 203)

13. Garland C, Barrett-Connor E, Suarez L, Criqui MH. Isolated systolic hypertension and mortality

after age 60 years. Am J Epidemiol 1983;118:365-376

14. Cubb JD, Borhani NO, Entwisle G, Tung B, Kass E, Schnaper H, Williams W, Berman R. Isolated

systolic hypertension in 14 communities. Am J Epidemiol 1985;121:362-370

15. Staessen RB, Ostfeld AM, Klawans HL Jr. Hypertension and risk of stroke in an elderly

population. Stroke 1974;5:71-75

References

CHAPTER

- 104 -

16. Psaty BK, Furberg CD, Kuller LH et al. Isolated systolic hypertension and subclinical

cardiovascular disease in the elderly: initial findings from the Cardiovascular Health Study.

JAMA 1992;268:1287-1291

17. Rutan GH, Kuller LH, Neaton JD, Wentworth DN, McDonald RH, Smith WM. Mortality

associated with diastolic hypertension and isolated systolic hypertension among men screened

for the Multiple Risk Factor Intervention Trial. Circulation 1988;77:504-514

18. Amery A, Fagard R, Guo C, Staessen J, Lutgarde T. Isolated systolic hypertension in the elderly:

an epidemiologic review. Am J Med 1991;90 (Suppl. 3A):64S-74S

19. Wilking SV, Belanger A, Kannel WB, D�Agostino RB, Steel K. Determinants of isolated systolic

hypertension. JAMA 1988;260:3451-3455

20. Fletcher A, Bulpitt C. Epidemiology of hypertension in the elderly. J of Hypertens 1994;12 (Suppl.

6):S3-S5

21. Van Wilking SB, Belanger A, Kannel WB, D�Agostino RB, Steel K. Determinants of isolated

systolic hypertension. JAMA 1988;260:3451-3455


23. Meaney E, Soltero E, Samaniego V, Alva F, Moguel R, Vela A, Gonzales V. Vascular dynamics in

isolated systolic arterial hypertension. Clin Cardiol 1995;18:721-725

24. Muntinga JHJ, Schut JK, Visser KR. Age-related differences in elastic properties of the upper arm

vascular bed in healthy adults. J Vasc Res 1997;34(2):137-148

25. Hlatky MA, Boineau RE, Higginbotham MB, Lee KL, Mark DB, Califf RM, Cobb FR, Pryor DB,

A brief self-administered questionnaire to determine functional capacity (The Duke Activity

Status Index). Am J Cardiol; 1989; 64: 651-65

26. Hayes RJ. Methods for assessing whether change depends on initial value. Statistics in Medicine

1988;7:915-927



28. Muntinga JHJ, Schut JK, Visser KR. Age-related differences in elastic properties of the upper arm

vascular bed in healthy adults. J Vasc Res 1997;34(2):137-148

29. Ekpo EB, Ashworth IN, Frenando MU, White AD, Shah IU. Prevalence of mixed hypertension,

isolated systolic hypertension and isolated diastolic hypertension in the elderly population in the

community. J Hum Hypertens 1994;8:539-543

30. Kannel WB, Dawber TR, McGee DL. Perspectives on systolic hypertension. Circulation

1980;61:1179-1182

31. Sagie A, Larson MG, Levy D. The natural history of borderline isolated systolic hypertension. N

Engl J Med 1993;329:1912-1917

REVALENCE OF ISH

- 105 -

CHAPTER

- 106 -

LAW NR. IV:

THE PATIENT IS THEONE WITH THEDISEASE

RTERIAL DISTENSIBILITY IN ISH

- 107 -


CCCCHANGES IN DISTENSIBILITY IN LARGE AND SMALLERHANGES IN DISTENSIBILITY IN LARGE AND SMALLERHANGES IN DISTENSIBILITY IN LARGE AND SMALLERHANGES IN DISTENSIBILITY IN LARGE AND SMALLER

ARTERIES IN ISOLATED SYSTOLIC HYPERTENSIONARTERIES IN ISOLATED SYSTOLIC HYPERTENSIONARTERIES IN ISOLATED SYSTOLIC HYPERTENSIONARTERIES IN ISOLATED SYSTOLIC HYPERTENSION

Wilfred F Heesen MD*; Frank W Beltman MD, PhD ; Jaap HJ Muntinga, MD, PhD ;� #

Johan F May MD,PhD* ; Andries J Smit MD,PhD ; Pieter A de Graeff MD,PhD ;¶ �¶ �¶§

Pieter J. De Kam, MSc*; Betty Meyboom-de Jong MD,PhD ; Kong I Lie MD,PhD*�

Submitted

Departments of *Cardiology, General Practice, Physiology; Internal Medicine and� # �

Clinical Pharmacology, University of Groningen and Groningen Hypertension§ ¶

Service. Groningen, The Netherlands

CHAPTER

- 108 -

ABSTRACT

Background

Isolated systolic hypertension has regained new interest recently, after the

evidence that treatment can favourably influence the cardiovascular risk of

ISH. However, studies on pathophysiologic changes in ISH are relatively

scarce. While aortic distensibility is known to be decreased in ISH, changes in

smaller arteries are less well known.

Methods

Eligible subjects with previously untreated ISH (N=47) were selected from a

population screening program, together with normotensive controls. Aortic

distensibility was measured with pulse wave velocity measurement, and

distensibility of different sized arteries arteries was measured with bio-

impedance measurement at the upper arm.

Results

Distensibility of the aorta and large arteries was decreased in ISH-subjects

compared to normotensive controls. In contrast, distensibility of smaller

arteries was increased in ISH. In subjects with ISH, these opposite patterns in

changes in distansibility of large and smaller arteries were related to pulse

pressure: the higher the pulse pressure, the lower the distensibility of large

arteries and the higher the distensibility of smaller arteries.

Conclusion

We observed an increased distensibility of smaller arteries in subjects with

ISH, as opposed to the known decrease in large arteries. This observation

shows that changes in arterial distensibility in ISH are heterogeneic. An

explanation for the increased distensibility in smaller arteries may well be a

compensatory mechanism for the decreased distensibility of the large arteries,

and the resulting high pulse pressures from this decrease.


- 109 -

INTRODUCTION

Isolated systolic hypertension (ISH) has regained new interest recently.

ISH was already known to be an important cardiovascular risk factor

frequently occurring in the elderly, but now evidence is available that1 2 3 4 5

treatment can favorably influence its related morbidity and mortality. In6 7

comparison with diastolic hypertension, studies on pathophysiologic

alterations in ISH are relatively scarce. The main important pathophysiologic

change in ISH is a decreased distensibility of the aorta and large arteries,

with loss of the �Windkessel function�. This decreased distensibility8 9 10 11 12

will cause systolic blood pressure (BP) to be higher, while diastolic BP may be

lower, resulting in high pulse pressures as known in ISH. Changes in

distensibility of smaller arteries are less well known. We observed an

increased distensibility in smaller arteries in ISH-subjects with bio-impedance

measurement, perhaps as a compensatory mechanism for the reduced

distensibility of the large arteries.13

The aim of this study was to compare the arterial distensibitily of large and

smaller arteries in newly-found, previously untreated elderly with isolated

systolic hypertension with that in normotensive controls. Arterial

distensibility was measured with pulse wave velocity measurement, and with

bio-impedance measurement providing parameters of various parts of the

arterial bed, from larger to smaller arteries.

CHAPTER

- 110 -

METHODS

Study population

A population screening program was done in a rural municipality

(Achtkarspelen) in The Netherlands. All inhabitants aged 60 years and over

were invited to participate. After five minutes rest, the sitting blood pressure

(BP) was measured by trained volunteers using a sphygmomanometer. If BP

was elevated (for systolic BP: >160 mmHg, for diastolic BP > 95 mm Hg), the

BP measurement was repeated by a physician. If BP remained elevated, the


occasions.

Subjects were defined to have isolated systolic hypertension (ISH) if

untreated systolic BP was >160 mmHg at each measurement, with diastolic


than 95 mmHg. Furthermore, a group of normotensive controls was selected

from the same program (BP <160/95 mmHg, and unknown with

hypertension).

All subjects fulfilling these criteria were eligible for investigation of vascular

end-organ damage. Exclusion criteria for this study were: recent myocardial

infarction (<three months), cerebrovascular accident (<one year),

symptomatic congestive heart failure, hemodynamically significant valvular

heart disease or cardiac arrhythmia (other than atrial fibrillation), or any other

disabling medical condition hampering patient participation. Diabetes was

added as exclusion criterium for subjects with diastolic hypertension, due to a

planned intervention trial. The general physician was consulted about patient

eligibility for further investigation. The study was approved by the Medical

Ethical Committee of the Groningen University Hospital, and written

informed consent was obtained from all participants.

Blood pressure measurements and cardiovascular risk factors

Office blood pressure and heart rate were obtained as average of two

measurements, after five minutes rest. Also, subjects underwent a 24-hour

ambulatory blood pressure measurement (ABP) (SpaceLabs 90207; SpaceLabs

Inc. Washington, USA). Ambulatory measurements were done every 30

minutes during the day (07.00-23.00 hours) and every 60 minutes during the

night (23.00-07.00 hours); data were analyzed without data-editing using

time-weighted means. The history of smoking, diabetes, and myocardial


- 111 -

infarction was obtained. Height and weight were measured, and body mass

index was calculated. The fasting serum lipid profile, including high density

lipoprotein-cholesterol and triglycerides, was measured with conventional

assay methods. Fasting serum glucose was also determined; patients with

plasma glucose >7.8 mmol/l (WHO-criterium) were considered to be

diabetic, in addition to those already known with, or on treatment for

diabetes mellitus.

Vascular end-organ damage measurements

Vascular compliance was assessed by two different methods: the dynamic

compliance of the aorta using pulse wave velocity (PWV) measurement, and

the static peripheral vascular compliance of the upper arm vasculature using

impedance measurement.

Pulse wave velocity measurement. The aortic pulse wave was detected

using two Doppler probes, one at the approximate origin of the aorta (right

subclavian artery), and the other at the approximate end of the aorta (right

femoral artery). The time between the foot parts of the two recorded pulse

waves was measured using computer analyzing programs, developed in our

laboratory. The pulse wave velocity was calculated as the quotient of the14

aortic length (estimated by measurement of the distance from upper sternal

manubrium to the inguinal ligament) and the time delay between both pulse

waves. From the pulse wave velocity, the aortic distensibility (AoD) is

calculated using the formula D= 1/(D * v ) , in which D represents the density2

of the blood (taken 1050 kg/m ) and v the pulse wave velocity (unit D:3

1/MPa). For the analysis, three adequate consecutive recordings of 1515 16

seconds were obtained for each patient, of which a minimum of 30 adequate

wave recordings had to be analyzable. The pulse wave velocity was

calculated as an average of all measurements available.

Bio-impedance measurement. The blood volume of the upper

arm-vasculature was assessed with bio-impedance measurement as

developed in our laboratory. In this method, the impedance of a segment of17

the upper arm is measured during controlled cuff deflation from suprasystolic

to zero. From the volumes (V), derived from the impedance values at

CHAPTER

- 112 -

Figure 1. Example of pressure-compliance curves of bio-impedancemeasurement Examples chosen are of two subjects (one ISH: dotted line, one control: straightline) with approximate average values for both groups. For explanation ofcurves: see text.

different (transmural) pressure (P) levels, the compliance (C) was calculated

as C= )V/)P. Transmural pressure was defined as the difference between cuff

pressure and mean arterial blood pressure, the latter being measured with

Finapres BP measurement at the opposite arm (with correction for any

differences in BP between both arms as assessed by previous Finapress

measurements at the measurement arm). The results are represented by the

relation between compliance and transmural pressure (see figure 1 for

illustration). At a P of �0" the cuff pressure equals systolic pressure,tm

indicating start of refill of large arteries. Higher transmural pressures (right

side of X-axis) correspond with the refill of smaller arteries and arterioles.

Important characteristics of these curves are: C = the maximal compliancemax

(top of curve, unit µl.mmHg .cm ), P = the transmural pressure at C-1 -1

0 max

(mmHg), P = the half-width pressure (related to the width of the curve,1

mmHg), C = the compliance at the prevailing arterial pressure, i.e. thea

average of the mean arterial pressure during the measurement

(µl.mmHg .cm ). From the compliance and volume, the distensibility can be-1 -1

calculated using the general formula D= )V/() P*V) ()=delta, P= pressure,

V= volume), which was done for P = 0 (D ) and P = 80 mmHg (D ).tm 0 tm 80

Furthermore, the volume of the arterial (Va) bed at the prevailing blood

pressure was obtained.


- 113 -


Primary analysis of this study was the comparison of differences between

arterial distensibility in ISH and normotensive controls. For the various

measurements of arterial distensibility, normality was investigated, and

logarhitmic transformations were used in further analysis if parameters were

not normally distributed. The comparison of baseline characteristics and

blood pressure measurement results was done with the unpaired Student� t-

test for continuous variables, or Chi-square test in case of nominal variables.

Comparison of the different parameters of arterial distensibility and

compliance between ISH and controls was done with multiple regression

analysis, in which next to the group variable for hypertension (ISH versus

controls), age, gender and body mass index were included as independent

predictors, based on the known influence of these factors on arterial

distensibility measurements. The vascular distensibility parameters18

analyzed were aortic distensibility (AoD) as derived from pulse wave

velocity measurement, and several other parameters characterizing the

pressure-compliance and pressure-volume curves and derived using the bio-

impedance measurement, of which the distensibility at transmural pressure

P = 0 mmHg (D ) and at P = 80 mmHg (D ) was considered of mosttm 0 tm 80

interest.

All differences were considered statistically significant if the two-sided p-

values were <0.05. All analyses were done with SAS statistical software (V.

6.01, Cary, N.C.).

CHAPTER

- 114 -

Measurement and unit ISH controls

N = 47 51

gender (% males) 49 41

age (years) 67 + 4 67 + 4

body mass index (kg/m )2 26.5 + 3.5 26.1 + 3.2

total-HDL cholesterol ratio 5.3 + 1.4 5.9 + 1.7

diabetes (%) 2 4

smokers (%) 30 * 10

previous MI (%) 0 6

systolic OBP (mmHg) 185 + 12.9 * 141 + 10.4

diastolic OBP (mmHg) 88 + 5.1 * 80 + 6.5

24 h-avg. systolic ABP (mmHg) 137 + 14.5 * 118 + 8.8

24 h-avg. diastolic ABP (mmHg) 77 + 7.6 * 71 + 5.3

heart rate (bpm) 80 + 13 80 + 10

Table 1. Baseline differences, risk factors and results of blood pressure measurements ifsubjects with isolated systolic hypertension (ISH and normotensive controlsAbbreviations: HDL = high-density lipoprotein cholesterol, MI= myocardial infarction, OBP = officeblood pressure, ABP = ambulatory blood pressure. Statistics: *: difference P < 0.05

RESULTS

Baseline characteristics and blood pressure measurements

Table 1 shows the subject characteristics and results of blood pressure

measurements at baseline in the included subjects. The differences between

baseline characteristics and between cardiovascular risk factors in ISH and

controls are small, only the prevalence of smokers was higher in ISH-subjects.

The differences in systolic blood pressure values were as expected on the

basis of the inclusion criteria, while diastolic blood pressures were also higher

in ISH-subjects.


- 115 -

Measurement and unit ISH controls

aoD (aortic distensibility, 1/MPa) 5.1 + 2.1 ** 6.6 + 2.5

D0 (distensibility at P =0, 10 .mmHg ) tm-3 -1 23.8 + 7.0 * 26.7 + 6.0

Da (distensibility at PMAP, 10 .mmHg )-3 -1 1.8 + 0.8 2.0 + 0.8

D 80 (distensibility at P =80, 10 .mmHg )tm-3 -1 2.8 + 1.0 *** 2.3 + 0.7

C max (max. art. compliance, rl.mmHg .cm )-1 -1 16.6 + 7.2 * 22.9 + 7.7

P 0 (transmural pressure at C , mmHg)max 24.5 + 8.1 22.0 + 5.9

P 1 (halfwidth pressure, mmHg) 29.7 + 12.2 * 25.3 + 8.9

V a (arterial volume, ml.cm )-1 1.2 + 0.5 *** 1.5 + 0.5

Table 2. Results of measurements of arterial distensibility between ISH (N=47) and normotensivecontrols (N=51) Abbreviations: PMAP = prevailing mean arterial pressure. Statistics: *: P < 0.05; **: P< 0.01; ***: P< 0.001(multiple regression analysis, with covariables age, sex and body mass index)

Arterial distensibility measurements

Table 2 shows the results of the various measurements of arterial properties

as derived from aortic pulse wave velocity measurement (aoD), and bio-

impedance measurement at the upper arm (all other measurements). Aortic

distensibility was lower in ISH-subjects when compared to normotensive

controls (Table 2). A similar difference was seen in the medium-sized arteries,

i.e. the larger arteries of the upper arm (D ). In more smaller arteries, this0

pattern appeared to reverse: although the distensibility at the prevailing

mean blood pressure (D ) showed comparable values in both groups, thea

distensibility of the more smaller arteries (D ) showed higher values in ISH-80

subjects compared to normotensives. This reverse pattern has been visualized

by plotting the results of the distensibility measurements against the results

of the blood pressure measurements, in this case the pulse pressure (figure 2).

As depicted in the figure, the higher the pulse pressure, the lower the

distensibility of the large arteries (D ). The reverse can be seen for D80: the0

higher the pulse pressure, the higher the distensibility of the smaller arteries.

This relation was sigificant only in ISH-subjects: for D the R was 23% (P=0

2

0.001) versus 4 % (N.S.) for normotensive crontrols; and for D the R was80

2

19% (P=0.002) versus 2% (N.S.) for controls.

CHAPTER

- 116 -

Figure 3. Correlation plots for pulse pressure and arterial distensibility at larger

arteries (D ; figure 3.A), and at smaller arteries (D ; figure 3.B). 0 80

Abbreviations: ISH = isolated systolic hypertension


- 117 -

DISCUSSION

The methods used in this study allow analysis of properties of different

parts of the arterial vasculature: from the aorta (aoD), to medium-sized

arteries in the upper arm (D ), and towards more smaller arteries and0

arterioles (D , D ). The distensibility of the large body arteries is clearly lowera 80

in ISH compared to normotensive controls, which was already known: this

loss of the �Windkessel-function� is considered the main pathophysiologic

alteration in ISH. The difference appears to be also present in the larger sized

arteries of the arm as well, since similar results could be observed for D .0

However, in the smaller arteries, the differences change into the opposite

direction: while distensibility at prevailing (mean) arterial pressure (D )ashows comparable values between ISH and controls, the larger values for D80

indicate that the distensibility of the more smaller arteries is increased in ISH

compared with normotensive controls. The increased distensibility of smaller

arteries in ISH confirms our earlier hypothesis of a compensation for the

decreased distensibility of aorta and large arteries. Background for this

hypothesis is that with loss of the Windkessel-function of the large arteries,

blood flow will be less dampened, resulting in larger differences between

peak systolic and diastolic blood pressure, e.g. in higher pulse pressures. Since

blood flow at the end of the arterial system has to change from a pulsatile

flow to a more continuous flow, the higher pulse pressure will at least

partially be compensated for by an increased distensibility in the smaller

arteries. Such a relation between pulse pressure and distensibility of large and

smaller arteries was present in ISH: the higher the pulse pressure, the stronger

the opposite changes in distensibility of large and smaller arteries were.

While changes of aortic and large artery distensibility have been studied

earlier in ISH, few of these studies included the investigation of smaller

arteries. Often, results of one single derivate parameter is presented, such as

indices of aortic stiffness, Doppler studies, cardiac impedance19 20

measurements, and measurements of systemic vascular resistance, which21

has been reported to be increased in ISH-subjects. However, such single22

parameters can not discriminate between different changes in different parts

of the arterial tree, and therewith surpass the heterogeneity of vascular

changes in ISH as shown in the present and other reports. Other methods8

are available for studying changes in �smaller� arteries, such as the brachial

and radial artery in echographic studies. However, based on their actual size

CHAPTER

- 118 -

and on the comparable changes observed in these arteries and in the aorta as

reported in the present study, it is more appropriate to qualify these arteries

as (medium)-large sized arteries. The present study further corrobates our

previous finding that the changes associated with ISH are opposed to23

�normal� changes with ageing. With ageing, the distensibility of the large

arteries is known to diminish, but the distensibility of smaller arteries8 24

remains unchanged.25

The pathophysiologic changes underlying the observed increase in

distensibility of the smaller arteries in ISH are not known. Total arterial

volume is shown to be diminished in ISH-subjects, which suggests a

reduction of arterial diameter. However, as the bio-impedance method

measures a segment of the upper arm, not separate arteries, an alternative

explanation could be rarefaction of arteries. The intimal-medial thickness also

can not be assessed with this method, although the observed improved

distensibility of the smaller arteries suggests beneficial functional changes in

the wall of these arteries in ISH. With regard to the more medium-sized

arteries such as the brachial artery, some studies are available showing an

increase in intima-medial wall thickness in ISH, without clear changes in

internal diameter of these arteries. However, as stated before, the changes26

we observed in these arteries more resemble those in large arteries than those

in truely small arteries.


- 119 -

1. Cubb JD, Borhani NO, Entwisle G, Tung B, Kass E, Schnaper H, Williams W, Berman R. Isolated

systolic hypertension in 14 communities. Am J Epidemiol 1985;121:362-370




Hypertens 1990;8:393-405




6. The SHEP cooperative research group. Prevention of stroke by antihypertensive drug treatment


7. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, et al, for the Systolic

Hypertension in Europe (SYST-EUR) trial investigators. Randomised double-blind comparison of

placebo and active treatment for older patients with isolated systolic hypertension. Lancet

1997;350:757-764


9. Shimada K, Miyashita H, Kawamoto A, Matsubayashi K, Nishinaga M, Kimura S, Ozawa T.

Pathophysiology and end-organ damage in elderly hypertensives. J Hypertens 1994;12(Suppl

6):S7-S12

10. Nichols WW, Nicolini FA, Pepine CJ. Determinants of isolated systolic hypertension in the

elderly. J Hypertens 1992;10(Suppl. 6):S73-S77

11. Pannier BM, London GM, Cuche J-L, Girerd X, Safar ME. Physical properties of the aorta and

cardiac hypertrophy in essential hypertension. Eur Heart J 1990;11 (Suppl. G):17-23

12. Chapter 3. Pulsatile pressure and hypertension in large arteries. In: Safar M. Arteries in clinical

hypertension. pp. 21-30, Lippincott-Raven, Philadelphia, 1996

13. Van Leeuwen S, Heesen WF, Muntinga JHJ, Smit AJ, May JF, Lie KI. Static vascular compliance

in patients with isolated systolic hypertension and normotensive controls. Eur J Clin Invest 1994;

24(Suppl. 2): A22

14. Lubbers J, Someren van R, Journee HL. An instrument for the measurement of pulse wave

velocity in man (Abs). Eur J of Ultrasound 1993; 1 (Suppl. 1): S33

15. Lehmann ED, Hopkins KD, Gosling RG. Aortic compliance measurements using Doppler

ultrasound: in vivo biochemical correlates. Ultrasound in Med & Biol 1993;19(9):683-710

References

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16. Asmar RG, Topouchian JA, Benetos A, Sayegh FA, Mourad JJ, Safar ME. Non-invasive

evaluation of arterial abnormalities in hypertensive patients. J Hypertens 1997;15 (Suppl. 2):S99

17. Muntinga JHJ, Visser KR. Estimation of pressure-related parameters by electrical impendance

measurement. J Appl Physiol 1992;73(5):1946-1957

18. Muntinga JHJ, Gels ME, Terpstra WF, Visser KR. Age-related differences in elastic properties of

te upper arm vascular bed in healthy adults. J Vasc Res 1997;34(2):137-147



20. Dahan M, Paillole C, Ferreira B, Gourgon R. Doppler echocardiographic study of the

consequences of aging and hypertension on the left ventricle and aorta. Eur Heart J 1990;11

(Suppl. G): 39-45

21. Galarza CR, Alfie J, Waisman GD, Mayorga LM, Cámera LA, del Río M, Vasvari F, Limansky R,

Farías J, Tessler J, Cámera MI. Diastolic pressure underestimates age-related hemodynamic

impairment. Hypertension 1997;30:809-816

22. Vardan S, Mookherjee S, Warner R, Smulyan H. Systolic hypertension in the elderly.

Hemodynamic responce to long-term thiazide diuretic therapy and its side-effects. JAMA

1983;250:2807-2813

23. Muntinga JHJ, Leeuwen JTM van, Gels ME, Terpstra WF, Smit AJ, Visser KR. Arteriolar

constriction in mild-to-moderate essential hypertension: an old concept requiring

reconsideration? J Hypertens 1997;15(4):411-420



25. Smulyan H, Csermely TJ, Mookherjee S, Warner RA. Effect of age on arterial distensibility in

asymptomatic humans. Arteriosclerosis 1983;3:199-205

26. Girerd X, Moulin C, Safar M, Laurent S. Normalization of the elastic modulus of large artery

wall by long-term treatment in elderly essential hypertensives [Abs]. Hypertension 1995;26:560


- 121 -

CHAPTER

- 122 -

LAW NR. V:

PLACEMENT COMES FIRST

REDICTION OF LV MASS WITH THE ECG

- 123 -

CCHAPTER HAPTER 66

PPREDICTION REDICTION OOF F TTHE HE LLEFT EFT VVENTRICULAR ENTRICULAR MMASS ASS FFROM ROM TTHEHE

EELECTROCARDIOGRAM LECTROCARDIOGRAM IIN N SSYSTEMIC YSTEMIC HHYPERTENSIONYPERTENSION

Sybolt O. de Vries, MD*, Wilfred F. Heesen, MD , Frank W. Beltman, MD , Albert� � § �

H. Kroese, PhD , Johan F. May, MD, PhD , Andries J. Smit, MD, PhD , Kong I.|| � � ¶ �

Lie, MD, PhD .�

Am J Cardiol 1996;11:974-978

* Department of Health Sciences, Medical Decision Making, Faculty of Medicine, University of

Groningen; Department of Cardiology, University Hospital Groningen; Groningen Hypertension� �

Service; Department of General Practice, Faculty of Medicine, University of Groningen; Department of§ ||

Mathematical Statistics, Faculty of Mathematics and Physics, University of Groningen; ¶ Department of

Internal Medicine, University Hospital Groningen; The Netherlands

This investigation was in part supported by a PIONIER award from the Dutch Organization for Scientific

Research

CHAPTER

- 124 -

ABSTRACT

Although echocardiography provides a reliable method to determine left

ventricular (LV) mass, it may not be available in all settings. Numerous

electrocardiographic (ECG) criteria for the detection of LV hypertrophy have

been developed, but few attempts have been made to predict the LV mass itself

from the ECG. In a community-based survey program in the general population

277 subjects with untreated diastolic (diastolic blood pressure 95-115 mmHg, 3

occasions) or isolated systolic hypertension (diastolic blood pressure < 95 mmHg

and systolic blood pressure 160-220 mmHg, 3 occasions) were identified. All

subjects underwent ECG and echocardiography on the same day. A multiple

linear regression analysis was performed, using a random training sample of the

data-set (n=185). The independent variables included both ECG- and non-ECG

variables. The resulting model was used to predict the LV mass in the remainder

of the data-set, the validation sample (n=92). Using sex, age, body surface area,

the S-voltage in V1 and V4, and the duration of the terminal P in V1 as

independent variables, the model explained 45% of the variance (r=0.67) in the

training sample and 42% (r=0.65) in the validation sample. This result exceeded

that of 2 existing ECG-models for LV mass (r=0.40 and 0.41). The correlation

between LV mass and combinations of ECG variables used for the detection of

LV hypertrophy, such as the Sokolow Lyon Voltage (r=0.03) and the Cornell

Voltage (r=0.31), were comparatively low. In settings where echocardiography is

not available, or too expensive and time-consuming, prediction of the LV mass

from the ECG may offer a valuable alternative.


- 125 -

INTRODUCTION

A large number of studies concerning the relation between

electrocardiography (ECG) and left ventricular (LV) mass has been published in

the medical literature. In these studies the attention is almost exclusively

focused on the development or evaluation of ECG-criteria that are designed to

discriminate between LV hypertrophy and normal LV mass. Numerous ECG-

criteria have been proposed, the Sokolow Lyon criterion probably being the one

most widely known and used. In general, the diagnostic performance, and1

especially the sensitivity of these ECG-criteria, is poor to moderate. Most ECG-

criteria for LV hypertrophy are largely based on voltages of the QRS-complex.

These voltages do not depend solely on the LV mass, but also on body build,

race, sex, and age, for example. Heterogeneity within the study populations2-7

with respect to these determinants may partly explain the poor diagnostic

performance that is reported. In contrast to the multitude of ECG-criteria for the

presence or absence of LV hypertrophy that exists, few attempts have been

made to predict the LV mass itself from the ECG. Wolf et al. published 2 models

in 1991, which were based on data of patients who had been admitted to the

cardiology ward for investigation of chronic cardiac problems. Their study did8

not include a prospective evaluation of the models that were developed,

however, and their study-population included very few hypertensive patients.

In a recent study of hypertensive patients relatively poor correlation is reported

between echocardiographic LV mass and various combinations of ECG-

variables, including one of the above models (correlation range: -0.12 to 0.43). It9

is suggested that the diagnostic performance of ECG may be improved by taking

more non-ECG characteristics into account. In the present study a multiple

linear regression model is developed and prospectively validated that predicts

LV mass in patients with hypertension, using both ECG- and non-ECG variables.

This new model is compared to existing ECG-models for LV mass and various

combinations of ECG-variables used for detection of LV hypertrophy.

CHAPTER

- 126 -

METHODS

Study subjects

In a community-based survey program in the general population subjects with

untreated diastolic or isolated systolic hypertension were identified. Subjects

were included in our study if they met 1 of the 2 following criteria: 1) age 25-75

years and mean diastolic blood pressure 95-115 mmHg on $ 3 occasions, or 2)

age 60-75 years, mean systolic blood pressure 160-220 mmHg and mean diastolic

blood pressure < 95 mmHg on $ 3 occasions (isolated systolic hypertension).

Excluded were subjects with a QRS-duration > 120 milliseconds, digitalis

treatment, or recent myocardial infarction.

The clinical characteristics that are generally considered to be predictors of LV

mass include sex, age, body surface area, height, and body mass index. A

recently proposed power-transform of height (height for adults) is alsox 2.13

included in this list of candidate-independent variables. Blood pressure was10

excluded from the above set of variables, since the regression weight for blood

pressure from our untreated population may not be appropriate in a population

of patients that are being treated for hypertension. Race is not included, since

virtually all the subjects in our population were Caucasians.

We identified 277 subjects who met the criteria for this study, 186 with

diastolic hypertension and 91 with isolated systolic hypertension. All subjects

underwent ECG and echocardiography on the same day.

Electrocardiography

Standard 12-lead ECG�s were obtained for all study subjects. All ECG�s were

evaluated by the same examiner (SOV), independently of the echocardiographic

data. Per subject the value of each of the ECG-variables was averaged, where

possible, over 3 consecutive heart-cycles. Voltage is expressed in milliVolts and

time is expressed in milliseconds. The following ECG-variables were included

in the list of candidate-independent variables: voltage and duration of the

terminal P in V1, voltage of R in I, aVL, V5, V6, voltage of S in III, V1-V4, voltage

of T in aVR, V1, V5, V6, QRS-axis and -duration, and the ventricular activation

time (V4-V6). Most of these variables are elements of the various ECG-criteria

for LV hypertrophy that have been proposed.


- 127 -

Echocardiography

Echocardiography (Acuson XP 128, 2.0 or 2.5 MHz transducer) was performed

by the same examiner in all patients (WFH), and measurements were obtained

according to the Penn-convention. The estimation of the LV mass that is used as

the reference standard in this study is based on the approximation proposed by

Devereux and Reichek :11

LV mass (g) = 1.04*((LVPW+IVS+LVEDD) -(LVEDD) )-13.6,3 3

where LVPW is the LV posterior wall thickness (mm), IVS the thickness of the

interventricular septum (mm), and LVEDD the internal end-diastolic diameter

(mm), averaging over 3 consecutive measurements.

Statistical methods

A random 2/3 training sample (n=185) was drawn from the original data-set.

The number of patients with diastolic hypertension (n=124) in this subset was

proportional to the number of diastolic hypertensives in the original set of

patients. The remainder of the data was kept apart for evaluation purposes (the

validation sample). A multiple linear regression analysis was performed on the

training sample data, using the LV mass as the dependent variable. A backward

elimination procedure was used to select variables from the set of candidates12

listed above. In the first step all characteristics were entered as independent

variables, and in subsequent steps variables were removed from the model one

by one, in order of increasing significance, until the F-statistic dropped by more

than a predetermined critical value, which is analogous to using a

predetermined level of statistical significance. Since our objective was to

construct a predictive rather than a descriptive model, the critical value was set

to 4 in order to obtain a parsimonious model. Finally, the model was used to

predict LV mass in the validation sample, as a prospective evaluation. All

analyses were performed using STATA statistical software version 3.0

(Computing Resource Center, 1640 Fifth Street, Santa Monica, California 90401).

CHAPTER

- 128 -

DH (n=186)

ISH (n=91)

Sex (number of women (%)) 88 (47%) 48 (53%)

Age (years) 53±10 68±4

Systolic blood pressure (mmHg) 155±16 176±15

Diastolic blood pressure (mmHg) 98±7 88±8

Heart rate (bpm) 79±12 76±12

Height (cm) 172±9 168±9

Weight (kg) 79±11 77±11

Body mass index (kg/m )2 27±3 27±4

Body surface area (m )2 1.92±0.17 1.87±0.17

LV mass (g) 166±40 181±42

TABLE I. Baseline characteristics (mean±standard deviation) of subjects with diastolic(DH) and isolated systolic hypertension (ISH).

RESULTS

Table I lists the baseline characteristics for patients with diastolic and isolated

systolic hypertension. The average LV mass is higher in the group of patients

with isolated systolic hypertension (p=0.003).

A multiple linear regression analysis was performed, using the training sample

data. The model that was obtained is described in more detail in the Appendix.

The following 3 clinical characteristics were selected as independent variables:

sex, age, and the body surface area. In addition, 3 ECG variables were selected:

the S-voltage in V1, the S-voltage in V4, and the duration of the terminal P in V1.

All variables, and male gender were positively associated with increased LV

mass. The model explained 45% of the variance of the LV mass in the training

sample.

In the next step, interaction terms between sex and the other independent

variables were entered into the model. This is similar to constructing separate

models for males and females, and was used to detect differences across

categories of gender in weights assigned to the independent variables. None of

the interaction terms reached the conventional levels of statistical significance.

Separate models were constructed for subjects with diastolic hypertension and


- 129 -

Figure 1. Predicted value of left ventricular (LV) mass,using the new regression model described in the appendix,versus the observed values for echocardiographic LVmass in the validation sample (N=92). A solid line indicatesoptimal prediction.

subjects with isolated systolic hypertension. It appeared that the contribution of

age in the model for subjects with diastolic hypertension was no longer

statistically significant. Also with univariate analysis the correlation between

age and LV mass in this group of patients was very weak (r=0.10).

To assess its validity, the former combined model was used to predict the LV

mass in the validation sample (n=92), using the estimates of the b-coefficients

that were based on the training sample (see Appendix). We found a relatively

high correlation between the predicted and the observed LV mass, r=0.65,

corresponding to 42% of explained variance. Figure 1 illustrates that our model

may be somewhat conservative with respect to the higher values for LV mass.

To put these results into perspective, table II shows the correlation coefficients

between the LV mass and combinations of ECG variables that have been

proposed for the detection of LV hypertrophy. Recent studies have shown1,13-19

that additional consideration of QRS duration improves ECG recognition of LV

hypertrophy, therefore we also included 2 of the proposed QRS voltage-duration

products in this list. To enable comparison we restricted the analysis to the18,19

CHAPTER

- 130 -

Model Definition r P value

Present model see appendix 0.65 0.000

Lineair regression model Wolf-II 8 see appendix 0.41 0.000

Lineair regression model Wolf-I 8 see appendix 0.40 0.000

Logistic regression model for LVH 15 see Casale et al 15 0.36 0.001

Cornell voltage 14,15 RaVL + SV3 0.31 0.004

12-lead QRS voltage-duration product 18,19 QRSsum x QRSduration 0.27 0.014

12-lead QRSvoltage 17 12-lead QRS-sum 0.16 0.136

RV6/RV5 16 RV6/RV5 0.15 0.161

Cornell voltage/duration product 18,19 Cornell volt.x QRS duration 0.14 0.219

Sokolow-Lyon voltage 1 SV1 + RV5 or RV6 0.03 0.804

Gubner and Ungerleider 13 R I + S III -0.01 0.921

Table II. Correlation between the echocardiographically determined LV mass and the value predicted bythe regression model developed in this study (present model), compared with other models. Analysis isbased on the validation sample data (n=92, see text).Abbrev.: r = Correlation coefficient. *: Sex-specific Cornell voltage adjusted by increasing 0.8 mV for women

data of the validation sample. In addition, we used the 2 regression models

proposed by Wolf et al. to predict the LV mass (Model I and II, see Appendix).8

The original models were designed to predict the LV mass index, which is the

ratio of the LV mass and the body surface area, rather than the LV mass.

Therefore, we multiplied the LV mass index predicted by the 2 models by the

body surface area. The correlations between the values predicted by the models

of Wolf et al. and the values observed (Model I: r=0.40 and Model II: r=0.41)

were smaller than the correlation obtained for our model (r=0.65).


- 131 -

DISCUSSION

In the present study a regression model was developed for the prediction of

LV mass in subjects with hypertension, based on both ECG- and non-ECG

variables. Prospective evaluation of the model in a random validation sample

showed a relatively strong association between the predicted and the observed

values for the LV mass, over 40 % of the variance being explained by the model.

A possible limitation of our study relates to the set of inclusion criteria used.

Subjects with diastolic hypertension were eligible if their age was 25-75, whereas

inclusion of subjects with isolated systolic hypertension was limited to ages 60-

75. However, in the general population the prevalence of isolated systolic

hypertension in age-groups < 60 yrs is very low, indicating that relaxing the age-

criteria for the latter group to 25-75 would not have influenced the results.

Our model contains 6 explanatory variables: sex, age, body surface area, the

duration of the terminal P in V1, and the S-voltage in V1 and V4. All variables

and male gender were positively associated with a larger LV mass, confirming

existing knowledge. The weights assigned to each individual variable were

found to be similar in patients with diastolic hypertension and patients with

isolated systolic hypertension, except for age. In the former group of patients the

association between age and LV mass appeared to be much weaker than in the

latter. A possible explanation is that age per se is a weak stimulus to LV

hypertrophy, but that it is strongly correlated with systolic blood pressure in

isolated systolic hypertension but not in diastolic hypertension . In contrast to20,21

our approach, others have developed separate models for males and females.

For comparability, we reported the predictive value of the combination rather

than that of the separate parts of the sex-specific models used for comparison in

our study. For our new model, we found that constructing separate models by

entering interaction terms did not improve the predictive value. In our view,

part of the strength of our model is the small number of parameters, which may

account for the stability of R in the test sample, and constructing separate2

models would dramatically increase the number of parameters to be estimated.

Blood pressure was not included as an independent variables, because the

regression weight for blood pressure from our untreated population may not be

appropriate in a population of patients treated for hypertension. Still the validity

of our model in such a population needs to be determined.

CHAPTER

- 132 -

It can be argued that a correlation coefficient of 0.65 (R = 0.42) leaves much of2

the variance to be explained. At this point it should be remembered, however,

that the echocardiographic measurement of the LV mass itself is subject to error.

A comparison to post-mortem measurements showed that echocardiography

explains 85% of the variance. This suggests that, even in the presence of a22

perfect relation between the "real" LV mass, which was unavailable for

observation in our study, and the one predicted by ECG, some unexplained

variance is to be expected if echocardiography is used as the reference standard.

Furthermore, the correlation coefficient that we found for our regression model

compares favorably with those that are obtained for other combinations of ECG

variables, such as the Sokolow-Lyon Voltage and the Cornell Voltage: in this

study we found correlation coefficients ranging from -0.01 to 0.41 for the

alternatives examined. In a recent study of hypertensive patients, Crow et al.

reported similar ranges of correlation coefficients between LV mass and various

combinations of ECG variables (range: -0.12 to 0.43).9

Our study has much in common with a study published by Wolf et al. in 1991 ,8

although several differences exist. The dependent variable in their study was

the LV mass index, which is the LV mass divided by the body surface area. This

widely used indexation suggests a linear relationship between the body surface

area and the LV mass with a regression line that has an intercept of zero. We

could not confirm the zero intercept in our population. Recent publications

reflect the ongoing debate on the most appropriate indexation of LV mass.

Evidence is provided that a power transform of height may capture more of the

relation between LV mass and body size than height itself or body surface

area. The choice of an appropriate indexation is of critical importance when10,23

the focus is on the detection of LV hypertrophy. In our study, however, the focus

is on the prediction of LV mass, and it seems that the choice of the indexation is

not the key issue here. We chose to let the LV mass be the dependent variable,

with body surface area, height, and the suggested power transform of height as

candidate explanatory variables. To enable comparison, the values of LV mass

index predicted by the models of Wolf et al. were multiplied by the body surface

area before the correlation with the observed LV mass was determined. In

comparison to the study by Wolf et al., definite advantage of our study is the

inclusion of a prospective validation of the model. The validity of our model in

comparable hypertensive populations is suggested by the small drop in R that2

was observed when it was used to predict LV mass in a validation sample. The

model that was developed in the present study contains fewer ECG-variables

than the 2 models of Wolf et al., and fewer parameters are estimated (7 for the

new model vs. 10 and 14 for model I and II of Wolf et al. respectively). As a

comparison, we evaluated the 2 models proposed in their paper. It showed that


- 133 -

a large part of the variance remained unexplained (R =0.16 and 0.17 for model I2

and II respectively). Model II strongly resembles a model published by the same

group in 1988. Results for the 1988-model (R =0.16, not shown) were24 2

comparable to the results obtained for model II. In comparison to these existing

models, the results for our regression model may reflect a considerable

improvement.

Despite these promising results, echocardiographic determination of LV mass

remains the method of choice in most clinical settings. Where echocardiography

is not available, or too expensive and time-consuming, for example in large

epidemiological studies, prediction of LV mass from the ECG may offer a

valuable alternative.

Acknowledgments

The authors thank Mereke Gorsira for helpful comments on an earlier version

of this paper.

CHAPTER

- 134 -

REFERENCES

1. Sokolow M, Lyon TA. The ventricular complex in left ventricular hypertrophy as obtained by

unipolar precordial and limb leads. Am Heart J 1949;37:161-186.

2. Antman EM, Green LH, Grossman W. Physiologic determinants of the electrocardiographic

diagnosis of left ventricular hypertrophy. Circulation 1979;60:386-396.

3. Devereux RB, Phillips MC, Casale PN, Eisenberg RR, Kligfield P. Geometric determinants of

electrocardiographic left ventricular hypertrophy. Circulation 1983;67:907-911.

4. McLechanan JM, Henderson E, Morris KI, Dargie HJ. Electrocardiographic diagnosis of left

ventricular hypertrophy: influence of body build. Clinical Science 1988;75:589-592.

5. Levy D, Labib SB, Anderson KM, Christiansen JC, Kannel WB, Castelli WP. Determinants of

sensitivity and specificity of electrocardiographic criteria for left ventricular hypertrophy. Circulation

1990;81:815-820.

6. Levy D, Bailey JJ, Garrison RJ, Horton MR, Bak SM, Lyons D, Castelli WP. Electrocardiographic

changes with advancing age. A cross-sectional study of the association of age with QRS axis,

duration and voltage. J Electrocardiol 1987;20(suppl):44-47.

7. Lee DK, Marantz PR, Devereux RB, Kligfield P, Alderman MH. Left Ventricular Hypertrophy in

black and white hypertensives. Standard electrocardiographic criteria overestimate racial

differences in prevalence. JAMA 1992;267:3294-299.

8. Wolf HK, Burggraf GW, Cuddy E, Milliken JA, Rautaharju PM, Smith ER, Warren JW. Prediction of

left ventricular mass from the electrocardiogram. J Electrocardiol 1991;24:121-127.

9. Crow RS, Prineas RJ, Rautaharju P, Hannan P, Liebson PR. Relation between electrocardiography

and echocardiography for left ventricular mass in mild systemic hypertension (results from

treatment of mild hypertension study). Am J Cardiol 1995;75:1233-1238.

10. de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on

variability of left ventricular mass: assessment of allometric signals in adults and children and their

capacity to predict cardiovascular risk. J Am Coll Cardiol 1995;25:1056-1062.

11. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in men.

Anatomic validation of the method. Circulation 1977;55:613-618.

12. Kleinbaum DG, LL Kupper, KE Muller. Applied Regression Analysis and Other Multivariable

Methods. Belmont, California: Duxbury Press, 1988: 324-325.


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13. Gubner R, Ungerleider HE. Electrocardiographic criteria for left ventricular hypertrophy. Factors

determining the evolution of the electrocardiographic patterns in hypertrophy and bundle branch

block. Arch Intern Med 1943;72:196-209.

14. Casale PN, Devereux RB, Kligfield P, Eisenberg RR, Miller DH, Chaudhary BS, Phillips MC.

Electrocardiographic detection of left ventricular hypertrophy: development and prospective

validation of improved criteria. J Am Coll Cardiol 1985;6:572-580.

15. Casale PN, Devereux RB, Alonso DR, Campo E, Kligfield P. Improved sex-specific criteria of left

ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation

with autopsy findings. Circulation 1987;75:565-572.

16. Koito H, Spodick DH. Accuracy of the RV6:RV5 voltage ratio for increased left ventricular mass. Am J

Cardiol 1988;62:985-987.

17. Dollar AL, Roberts WC. Usefulness of total 12-lead QRS-voltage compared with other criteria for

determining left ventricular hypertrophy in hypertrophic cardiomyopathy: analysis of 57 patients

studied at necropsy. Am J Med 1989;87:377-381.

18. Molloy TJ, Okin PM, Devereux RB, Kligfield P. Electrocardiographic detection of left ventricular

hypertrophy by the simple QRS voltage-duration product. J Am Coll Cardiol 1992;20:1180-1186.

19. Okin PM, Roman MJ, Devereux RB, Kligfield P. Electrocardiographic identification of increased left

ventricular mass by simple QRS voltage-duration products. J Am Coll Cardiol 1995;25:417-423.

20. Hammond IW, Devereux RB, Alderman MH, Laragh JH. Relation of blood pressure and body build to

left ventricular mass in normotensive and hypertensive employed adults. J Am Coll Cardiol 1988;12:996-

1004.

21. Dannenberg AL, Levy D, Garrison RJ. Impact of age on echocardiographic left ventricular mass in a

healthy population (the Framingham study). Am J Cardiol 1989;64:1066-1068.

22. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic

assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;

57:450-458.

23. de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH. Left

ventricular mass and body size in normotensive children and adults: assessment of allometric relations

and impact of overweight. J Am Coll Cardiol 1992;20:1251-1260.

24. Rautaharju PM, LaCroix AZ, Savage DD, Haynes SG, Madans JH, Wolf HK, Hadden W, Keller J,

Cornoni-Huntley J. Electrocardiographic estimate of left ventricular mass versus radiographic

cardiac size and the risk of cardiovascular mortality in the epidemiologic follow-up study of the first

national health and nutrition examination survey. Am J Cardiol 1988;62:59-66.

CHAPTER

- 136 -

APPENDIX

Multiple regression analysis, using a random 2/3 sample of the data-set and a backward

variable elimination procedure , yielded a model that is represented by the following12

equation:

LV mass (g) =

-137.5 - 13.1*SEX + 1.1*AGE + 101.4*BSA + 0.43*PV1 + 28.7*SV1 + 26.5*SV4dur

where SEX refers to gender (0=male, 1=female), AGE is age (years), BSA is body surface

area (m ), PV1 is the duration of the terminal part of the P-wave in V1 (msec), and SV12

dur

and SV4 refer to the S-voltages (mV) in the corresponding precordial leads V1 and V4

(R =0.45, Mean Squared Residual=1020). Statistical significance level of the b-coefficients:2

SEX (p=0.034), AGE (p=0.000), BSA (p=0.000), PV1 (p=0.009), SV1 (p=0.000), SV4dur

(p=0.000). Where the above model explains 45% of the variance, a model with only SEX,

AGE, and BSA as independent variables explains 31%, indicating that an additional 14% of

the variance is explained by the ECG-variables. We found no evidence for collinearity

problems in our model, with all Variance Inflation Factor values < 2.12

As a comparison to the above model, 2 models proposed by Wolf et al. were used to8

predict LV mass. Of the 2 the first model was expected to be the most stable in other

populations. They were designed to predict the LV mass index (LVMI), which is the ratio

of LV mass and body surface area (BSA), rather than the LV mass itself. Separate

regression equations are given for women and men.

Wolf - Model I:- LVMI = 20.60 +14.5*(RaVL+SV3) + 9.31*(SV1+RV5) + 72.0*T V1 + 0.675*AGE WOMEN POS

- LVMI = -36.53 +11.3*(RaVL+SV3) + 84*(SV1+RV5) + 90.2*T V1 + 1.003MEN POS

Model II:- LVMI = 84.282+14.55*RV5-90.17*SI+36.15*SV5+113.17*T V1-74.2*T V6+40.67*T aVFWOMEN POS POS NEG

- LVMI = -2.108+7.1*RV5+10.64*SV1+15.33*SIII+174.28*T V6-84.85*T aVR+0.8765*QRSMEN NEG POS DUR

where RaVL and RV5 are the R-voltages in aVL and V5 (mV), SI, SIII, SV1, SV3, and SV5

are the S-voltages I, III, V1, V3, and V5 (mV), T aVR, T V1, T V6, T aVF, and T V6pos pos pos neg neg

are the positive resp. negative voltages of the T in aVR, aVF, V1, and V6 (mV), Age is age

in years, and QRS is the duration of the QRS-complex (msec).dur


- 137 -

CHAPTER

- 138 -

LAWNR. VI:

THERE IS NO BODYCAVITY THAT CAN NOT BE

REACHED WITH A # 14 NEEDLE AND AGOOD STRONGARM

OMOGRAM FOR LV GEOMETRY

- 139 -

CCHAPTER HAPTER 77

AA SIMPLE NOMOGRAM FOR DETERMINATION OF SIMPLE NOMOGRAM FOR DETERMINATION OF

ECHOCARDIOGRAPHIC LEFT VENTRICULAR GEOMETRY ECHOCARDIOGRAPHIC LEFT VENTRICULAR GEOMETRY

Wilfred F. Heesen MD* ; Frank W. Beltman MD, PhD ; Andries J. Smit MD, PhD) &)

; Johan F. May MD, PhD *#, $) , $)

Accepted for publication Am J Cardiol 1998

Departments of * Cardiology, General Practice, and Internal Medicine,) &) #)

University of Groningen and Groningen Hypertension Service$)


CHAPTER

- 140 -

ABSTRACT

Background

Recent data have shown that left ventricular (LV) geometry provides

additional information to the simple dichotomy of presence or absence of

LVH, concerning the cardiovascular risk of hypertensive patients. A �new�

class of concentric remodeling was created, discriminating a rather large

group of hypertensive patients who do have increased risk despite no LV

hypertrophy. As determination of LV geometry is not easy, our objective

was to develop a nomogram enabling determination of LV geometry in a

simple way.

Methods and results

The geometric classification is based on the combination of increased

relative wall thickness and LV hypertrophy (LV mass index > 125 g/m ),2

which are both calculated from wall thickness and end-diastolic diameter.

In the nomogram the calculated cut-off lines for relative wall thickness and

left ventricular hypertrophy are plotted, forming four quadrants which

represent the geometric classes. Two nomograms are made: one based on

Penn-convention measurement calculations and one based on American

Society of Echocardiography-convention measurements.

Conclusion

Thus, this nomogram provides a simple way to determine LV geometry,

and therewith a quick assessment of the additional cardiovascular risk of

the hypertensive patient. This is especially important for those subjects

with concentric remodeling, who would otherwise not have been identified

as having increased risk for cardiovascular disease.


- 141 -

BACKGROUND

Investigation of left ventricular (LV) mass with echocardiography is one

of the most widely used methods of determination of end-organ damage in

hypertension. The occurrence of LV hypertrophy is associated with a

clearly increased risk of cardiovascular disease. While such a1-4

dichotomous classification is very useful in clinical practice, it does not

accurately predict the cardiovascular risk for the individual subject, neither

does it takes into account that increase of LV mass may follow different

patterns. A novel classification was proposed by Koren, which not only

takes into account the presence or absence of LV hypertrophy, but also of

normal or increased relative wall thickness. The 4 mutually exclusive5

classes thus created were shown to carry different cardiovascular risk,

including the novel category of concentric remodeling: increased wall

thickness without LV hypertrophy. The problem is how to detect these6

categories easily in daily clinical practice. Another general problem in

echocardiographic LV hypertrophy studies is the variety in indexation

methods and measurement conventions as used in various studies. Also in

both reports underlying the geometric classification different measurement

conventions were used. Our objective was to develop a simple nomogram7

for determination of LV geometry, based on mathematical calculation of the

underlying formula, which should be useful in daily clinical practice to

determine the LV geometric pattern and thereby enabling assessment of the

attributable cardiovascular risk of the individual hypertensive patient. Two

nomograms were developed, to be used with the Penn-convention

measurements and with the American Society for Echocardiography-

convention measurements.

CHAPTER

- 142 -

METHODS AND FINDINGS

The geometric classification is based on the combination of presence of LV

hypertrophy, and of increased relative wall thickness. Background to the

development of this nomogram is that both LV hypertrophy and relative

wall thickness are determined by the same echocardiographic

measurements, being left ventricular wall thickness and end-diastolic

dimension. In the nomogram lines are plotted representing the cutoff

values for LV hypertrophy and relative wall thickness, based on values as

derived from the original report of Koren . The lines representing these5

cut-off values are determined using by the following formulas, given

separately for the Penn-convention and American Society for

Echocardiography-convention measurements.

LV mass index - Penn-convention

The formula for calculation of LV mass for Penn-convention

measurements, with the correction of Devereux is:7

(1) LV mass = 1.04 [(IVS + PW + EDD) - EDD ] - 13.6;3 3

In which IVS = interventricular septal thickness, PW = posterior wall

thickness, and EDD is end-diastolic diameter. This equation has too many

variables to be solved analytically. As a first step, the average of the

thicknesses of interventricular septum and posterior wall is used: the wall

thickness. This can be done, as twice the wall thickness is by definition

equal to the sum of the separate wall thicknesses of septum and posterior

wall: IVS + PW = 2* WT. We now can represent end-diastolic diameter by xand wall thickness by y, to solve this mathematical relation:

(2) LV mass = 1.04 [(2y + x) - x ] - 13.63 3

This equation still can not be solved, but since cut-off values for LV

hypertrophy are known, the left side of this equation can be calculated. The

cut-off value for LV mass is defined as LV mass index = 125 g/m according2

to Koren , indexed for body surface area (BSA): LV mass index = LV mass5

/BSA. (The formula for BSA is: BSA = (height) * (weight) * 0.0071840.725 0.425


- 143 -

(weight: in kg; height: in cm) .) Implementing this in (2) gives:8

(3) LV mass index * BSA = 1.04((2y + x) - x ) - 13.63 3

The final solution for solving this equation is entering of 4 predetermined

values of body surface area: 1.6, 1.8, 2.0 and 2.2 m . Now, the formula can2

be solved mathematically step by step, for example for 2.0 m :2

125 * 2.0 = 1.04((2y + x) - x ) - 13.6; or3 3

(250 + 13.6)/1.04 = (2y + x) - x ; or3 3

(4) 253.5 = 8y + 12y x + 6yx3 2 2

This final equation has no analytical solution. However, by entering

values for y, the corresponding values for x can be calculated by rewriting

the formula to the general form of ax + bx + c =0:2

(5) (6y)x + (12y )x + (8y - 253.5) = 02 2 3

which gives, by the general solution x = (-b + /(b -4ac))/2a :1,22

x =( -12y + /(12y ) - 24y(8y - 253.5))/12y1,22 2 2 3

Taking for instance y= 1 (cm):

x = (-12 - /6036)/12 or x = (-12 + /6036)/12; thus1 2

x = -7.47 or x = 5.471 2

For the purpose of the nomogram, x may be neglected because of its1

negative value; thus for wall thickness 1 cm and body surface area = 2.0 m ,2

end-diastolic diameter is 5.47 cm. This calculation is repeated for all values

for y between 0.6 and 1.6 cm of wall thickness (increment: 0.1 cm). The

result is a number of values for wall thickness and end-diastolic dimensions

through which an equation line can be drawn, representing LV mass

index= 125 g/m for body surface area = 2.0 m . This procedure is repeated2 2

for body surface area = 1.6 m , 1.8 m and 2.2 m , from step (3) onwards.2 2 2

CHAPTER

-144-

Figure 1.A: Nomogram for Penn-convention measurementsCut-off lines for LVH (LVMI= 125 g/m ) and RWT form four quadrants of LV geometry2

Abbreviations: BSA= body surface area; LVH = left ventricular hypertrophy; LVMI = LV mass index


- 145 -

LV mass - ASE-convention measurements

The same mathematical procedure is repeated for the American Society for

Echocardiography (ASE)-convention measurements. The formula for

calculation of LVMI for the ASE-measurements according to Devereux is:7

LV mass = 0.80 * {1.04[*(IVS + PW + EDD) - EDD ]) + 0.63 3

The same calculation steps are used as for the Penn-convention:

replacement of EDD and WT with x and y:

(2) LV mass = 0.80 *(1.04*[(2y + x) - x ]) + 0.63 3

Followed by implementing LV mass = LVMI * BSA

(3) LV mass index * BSA =0.80 *(1.04*[(2y + x) - x ]) + 0.63 3

Entering the cutoff value for LVMI (125 g/m ) and BSA = 2.0 m gives:2 2

125 * 2.0 =0.80 *(1.04*[(2y + x) - x ]) + 0.6 ; or3 3

(250 - 0.6)/0.80 = 1.04*[(2y + x) - x ]; or3 3

(4) 311.75/1.04 = 8y + 12y x + 6yx ,3 2 2

which can be rewritten as

(5) (6y)x + (12y )x + (8y - 299.8) = 02 2 3

This formula can be used again to enter different values for y or wall

thickness and calculating the corresponding values for x or end-diastolicdimensions, and this is repeated for the same body surface areas as done

with the Penn-convention measurements (2.2, 2.0, 1.8 and 1.6 m ).2

CHAPTER

-146-

Figure 1.B: Nomogram for American Society of Echocardiography (ASE)-convention measurements .Explanation and abbreviations: see figure 1.A.


- 147 -

Relative wall thickness

The relative wall thickness (RWT) is calculated by:

(6) RWT = 2 * WT/ EDD;

where WT = wall thickness. The cut-off value for relative wall thickness,

based on American Society for Echocardiography-measurements, is 0.45 .5,6

Note that the variables are the same as those used for determining cut-off

lines for LV hypertrophy; thus, this formula can also be rewritten as a

mathematical equation using x and y, given RWT = 0.45:

0.45 = 2 * y / x ; or

y = 0.225 * x

The resulting line representing this cut-off value of 0.45 can be plotted in

the nomogram also. A problem is that for Penn-measurements no validated

cut-off value for relative wall thickness is available. Recalling the difference

between both measurement conventions as mentioned in the introduction,

Penn-convention wall thickness measurements will be lower than ASE-

measurements, and hence the cut-off value for relative wall thickness

probably has to be lower. Based on our experience this difference is

approximately 0.1 cm in wall thickness. With this, we can assess which

relative wall thickness for Penn-measurements would correspond with

RWT = 0.45. Two calculation examples: in case of American Society forASE

Echocardiography-measurements of wall thickness (y) is 0.9 cm, the

corresponding end-diastolic diameter (x) is 4.0 cm for RWT=0.45 . The same

subject measured with Penn-convention would result in wall thickness 0.8

and end-diastolic diameter 4.2 cm, resulting in a RWT of 2*0.8/4.2= 0.38Penn

. Another example: ASE: WT=1.6, and EDD = 71.1 for RWT =0.45 givesASE

RWT = 0.41. Thus, in absence of validated cut-off values for Penn-Penn

convention measurements, the approximate value for RWT would be

around 0.40. The resulting line:

y = 0.2 * x

is plotted in the nomogram (figure 1.B).

CHAPTER

- 148 -

Plotting of nomogram, and patient example

Both obtained cut-off lines for RWT and for LVH can be plotted in the

same nomogram, since the underlying x or EDD and y or WT are identical.

In the final nomogram, these two lines form four �quadrants� of geometry.

With this, the geometric classification of a hypertensive subject can be

derived by plotting the individual values for wall thickness and for

end-diastolic dimensions in the nomogram. Figure 1.A presents the

nomogram for measurements according to the Penn-convention, and 1.B

for ASE-convention measurements. In both nomograms three different

lines are given for LVH, representing three body surface areas. The cut-off

line for RWT in the Penn-convention nomogram is based only on the

assumptions as made above. A range of wall thickness from 6 to 16

millimetres was selected based on clinical judgement of observed �normal�

values in hypertensive patients; similarly, the range of end-diastolic values

was chosen from 36 to 66 millimetres. In the lay-out, we chose millimetres

instead of centimetres, as standardly provided by most echocardiographic

equipments.

From the nomogram, the LV geometric classification can now be

determined easily. This can be illustrated with two examples measured

according to the Penn-convention: For instance, one subject has an average

wall thickness of 10 mm, with end-diastolic diameter of 56 mm, and the

body surface area is about 1.6 m . Plotting of these values shows that the LV2

geometric pattern is eccentric hypertrophy. Note that with the same values,

a subject with a body surface area of 2.2 m would have a normal geometry.2

Another example: average wall thickness 11 mm and end-diastolic

diameter 50 mm, with body surface area about 1.8 m : LV geometric2

pattern is concentric hypertrophy. Again, for the same measurements but

for body surface area 2.2 m , the pattern would be concentric remodeling.2


- 149 -

DISCUSSION

This nomogram provides a simple way to determine LV geometry,

allowing quick assessment of the additional cardiovascular risk of

hypertensive patients in daily clinical practice. Often, only the separate

echocardiographic values of LV measurements are known. This does not

enable determination of the presence of abnormal geometric patterns,

except for obvious cases of LV hypertrophy. Perhaps even more important

is the detection of the �new� category of concentric remodeling (increased

relative wall thickness without LV hypertrophy), which is also not easy to

recognize without complex calculations for each individual patient. This

recognition is important, because the prevalence of this risk-bearing pattern

is rather high, from about 13% to up to 40% in hypertensive populations. 9 -

Using the nomogram, the presence of concentric remodeling can be12

determined easily, thereby discriminating a group of patients who would

not have been considered at increased cardiovascular risk due to the

absence of LV hypertrophy. The nomogram can also facilitate detection of

LV hypertrophy, and furthermore, different patterns of hypertrophy:

concentric versus eccentric, although it is not clear yet whether a difference

does exist between these two patterns in attributable cardiovascular risk.13

It should be noted that the nomogram can only be used in hypertensive

populations, as no information on cardiovascular risk and LV geometry is

available for patients with other underlying heart diseases such as aortic

stenosis, ischemic heart disease or cardiomyopathies.

The validity of the present nomogram with its associated criteria is based

on two independent studies, showing positive relations while using the

same cut-off values and indexation methods (LV hypertrophy > 125 g/m2

for males and females) . However, even these two studies do have some5,6

differences in methodology. In the original study of Koren the

Penn-convention was used for calculation of LV mass index while the

American Society of Echocardiography-convention was used for calculation

of relative wall thickness , while in contrast Verdecchia used the American5

Society for Echocardiography-convention for both measurements. The6

major problem is not LV mass index, since different and validated

correction formulas are available. However, no such correction is known7

for relative wall thickness: in fact as both Koren and Verdecchia used the

American Society for Echocardiography-convention, no validated cutoff

CHAPTER

- 150 -

values for relative wall thickness for the Penn-convention measurements

are available. As shown, an approximate corresponding value can be

calculated, but this cutoff value needs to be confirmed. A second difference

between both studies is which wall thickness of the left ventricle should be

chosen for calculation of LV geometry. While in the original study of Koren

thickness of the posterior wall was used, Verdecchia et al. could establish a

significant difference in cardiovascular risk only when analyzing the

average of posterior wall and interventricular septal, not by posterior wall

thickness alone. Considering these results, we propose to use the average6

of both, which appear to give more reliable data also than with use of one

single wall thickness.14

One drawback of the nomogram is one that arises in LV hypertrophy

studies in general: that of the variety in cut-off values and indexation

methods. Cut-off values for LVH may or may not be gender-specific, in

some studies LV mass is indexed for BSA whereas in other this is done for

height. In a report from the Framingham study, different LVH1-7, 15,16 15

values (gender-specific) and indexation methods (by height) were used

when compared with Koren and Verdecchia. In this study a different risk5,6

was observed also for the different geometric classes, although it was

discussed whether this may be due to differences in LVMI among the

classes. With regard to RWT, different cut-off values dependent upon age17

have been proposed. All these differences in indexation, cut-off values18

and adaptations are important and form a general problem in

echocardiographic studies in hypertension. However, they do not

necessarily affect the usefulness of this nomogram, as it can be easily

adapted to any desired method of indexation or LVH values if desired so -

only the cut-off lines in the nomogram need to be changed. Furthermore, a

recent report comparing different criteria for LVH did not show large

differences among seven different LVMI cutoff values, with the

gender-independent value of 125 g/m , as used in this geometric2

classification, being among the better predictors of cardiovascular risk.19


- 151 -

Acknowledgments

The authors wish to thank Ms. W.M. Tadema, M.Sc., for her assistance in

analysis of the mathematical calculations in this manuscript.

CHAPTER

- 152 -

References

1 Levy D, Garrison RJ, Savage DD, Kannell WB, Castelli WP. Prognostic implications of

echocardiographically determined left ventricular mass in the Framingham heart study. N

Engl J Med 1990;322:1561-1566

2 Casale PN, Devereux RB, Milner M, Zullo G, Harshfeld GA, Pickering TG, Laragh JH. Value

of echocardiographic measurement of left ventricular mass in predicting cardiovascular

morbid events in hypertensive men. Ann Intern Med 1986;105:173-178

3 Aronow WS, Ahn C, Kronzon I, Koenigsberg M. Congestive heart failure, coronary events and

atherotrombotic brain infarction in elderly blacks and whites with systemic hypertension and

with and without echocardiographic and electrocardiographic evidence of left ventricular


4 Levy D, Garrison RJ, Savage DD, Kannell WB, Castelli WP. Left ventricular mass and

incidence of coronary heart disease in an elderly cohort. Ann Intern Med 1989;110:101-107

5 Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass

and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern

Med 1991;114:345-352

6 Verdecchia P, Schillacci G, Borgioni C, Ciucci A, Battistelli M, Bartoccini C, Santucci A,

Santucci C, Reboldi G, Porcellati C. Adverse prognostic significance of concentric remodeling

of the left ventricle in hypertensive patients with normal left ventricular mass. J Am Coll Cardiol

1995;25:871-878

7 Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in men.

Anatomic validation of the method. Circulation 1977;55:613-618

8 Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and

weight be known. Arch Intern Med 1916:17:863-871

9 Heesen WF, Beltman FW, May JF, Smit AJ, de Graeff PA, Havinga TjK, Schuurman FH, van

der Veur E, Hamer JPM, Meyboom-de Jong B, Lie KI. Prevalence of concentric remodeling in

elderly individuals with isolated systolic hypertension from a population survey. Hypertension

1997;29:539-543

10 Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, Vargui P, Simongini

I, Laragh JH. Patterns of left ventricular hypertrophy and geometric remodeling in essential

hypertension. J Am Coll Cardiol 1992;19:1500-1508

11 Shigematsu Y, Hamada M, Mukai M, Matsuoka H, Sumimoto T, Hiwada K. Clinical evidence

for an association between left ventricular geometric adaptation and extracardiac target organ

damage in essential hypertension. J Hypertens 1995;13:155-160

12 Tomiyama H, Doba N, Kushiro T, Yamashita M, Kanmatsuse K, Kajiwara N, Yoshida H,

Hinohara S. Prospective studies on left ventricular geometric patterns and exercise tolerance in


- 153 -

unmedicated men with borderline and mild hypertension. J Hypertens 1996;14:1223-1228

13 Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R, Zampi I, Santucci A, Santucci C,

Reboldi G, Porcellati C. Prognostic value of left ventricular mass and geometry in systemic

hypertension with left ventricular hypertrophy. Am J Cardiol 1996;78:197-202

14 Devereux RB. Detection of left ventricular hypertrophy by M-mode echocardiography.

Anatomic validation, standardization, and comparison to other methods. Hypertension 1987;9

(Suppl II):II-19 - II-26

15 Krumholz HM, Larson M, Levy D. Prognosis of left ventricular geometric patterns in the

Framingham heart study. J Am Coll Cardiol 1995;25:879-884

16 Hammond IW, Devereux RB, Alderman MH, Lutas EM, Spitzer MC, Crowley JS, Laragh JH.

The prevalence and correlates of echocardiographic left ventricular hypertrophy among

employed patients with uncomplicated hypertension. J Am Coll Cardiol 1986;7:639-650

17 Devereux RB. Left ventricular geometry, pathophysiology and prognosis (Editorial). J Am Coll

Cardiol 1995;25:885-887

18 Ganau A, Saba PS, Roman MJ, deSimone G, Realdi G, Devereux RB. Ageing induces left

ventricular concentric remodelling in normotensive subjects. J Hypertens 1995;13:1818-1822

19 Liao Y, Cooper RS, Durazo-Arvizu R, Mensah GA, Ghali JK. Prediction of mortality risk by

different methods of indexation for left ventricular mass. J Am Coll Cardiol 1997;29:641-647

CHAPTER

- 154 -

LAW NR. VII:

AGE + BUN (�BLOOD UREA NITROGEN�) = LASIXDOSE

ONCENTRIC REMODELING IN ISH

- 155 -


HHHHIGH PREVALENCE OF CONCENTRIC REMODELING INIGH PREVALENCE OF CONCENTRIC REMODELING INIGH PREVALENCE OF CONCENTRIC REMODELING INIGH PREVALENCE OF CONCENTRIC REMODELING IN

ELDERLY PATIENTS WITH ISOLATED SYSTOLIC HYPERTENSIONELDERLY PATIENTS WITH ISOLATED SYSTOLIC HYPERTENSIONELDERLY PATIENTS WITH ISOLATED SYSTOLIC HYPERTENSIONELDERLY PATIENTS WITH ISOLATED SYSTOLIC HYPERTENSION

FROM A POPULATION SURVEYFROM A POPULATION SURVEYFROM A POPULATION SURVEYFROM A POPULATION SURVEY

Wilfred F Heesen MD*; Frank W Beltman MD ; Johan F May MD,PhD* ; Andries J� ¶

Smit MD,PhD ; Pieter A de Graeff MD,PhD ; Tjeerd K Havinga MD,PhD ; Frits�¶ �¶§ ¶

H Schuurman PhD ; Enno van der Veur PhD ; Johannes PM Hamer MD,PhD*;¶ ¶

Betty Meyboom-de Jong MD,PhD ; Kong I Lie MD,PhD*�

Hypertension 1997; 29: 539-543

Departments of *Cardiology, General Practice, Internal Medicine and Clinical� � §

Pharmacology, University of Groningen and Groningen Hypertension Service¶



CHAPTER

- 156 -

ABSTRACT

Background

Echocardiographic determination of left ventricular mass index (LVMI) is

shown to be valuable in the assessment of cardiovascular risk. Determination

of LV geometry, including concentric remodeling (CRM), provides additional

prognostic information. In isolated systolic hypertension (ISH), the few

echocardiographic studies available show an increased LVMI, but criteria and

patient populations differ. No comparison with DH has been made, nor has

LV geometry (with CRM) been evaluated. We compared both LVMI and LV

geometry of newly-diagnosed ISH-patients with normotensives and DH-

patients, all previously untreated and from the same population.

Methods and Results

The echocardiographic LVMI of 97 previously untreated ISH-patients (4x

systolic blood pressure > 160 mmHg / diastolic < 95 mmHg) was clearly

elevated compared to age and sex-matched normotensives: 98 g/m versus 712

g/m (p<0.001). The geometric pattern was abnormal in most ISH-patients,2

with a high prevalence of CRM: 43%. Both LVMI and geometry of ISH-

patients did not differ significantly from DH-patients (LVMI: 92 g/m , CRM:2

56%). Gender differences in LV geometry in ISH were only present using the

Framingham-criteria, not with the Koren-criteria.

Conclusions

This study shows a high prevalence of concentric remodeling in elderly

with previously untreated ISH. The increase of LVMI and abnormality in LV

geometry are comparable with DH-patients, which further defines the place

of ISH as a cardiovascular risk factor in the elderly. Whether there are gender

differences in cardiac adaptation in ISH, and whether the geometric

classification can be used to adjust treatment, remain to be investigated.


- 157 -

INTRODUCTION

Isolated systolic hypertension (ISH) has for long been known as an

important cardiovascular risk factor , and the results of the Systolic1-4

Hypertension in the Elderly Program have shown that its treatment may lead

to a favorable outcome . The high prevalence of ISH in the elderly represents5

a major public health issue . Decisions in its management and treatment may6

be supported by knowledge about the presence of cardiovascular end-organ

damage in these patients. An accepted method to assess this damage in

hypertensive patients is measurement of the echocardiographic left

ventricular mass index (LVMI). In diastolic hypertension, the occurrence of

increased LVMI, with or without meeting the criteria for left ventricular

hypertrophy (LVH), is a strong and independent risk factor for cardiovascular

events in different populations, including the elderly .7-10

Koren et al. showed that also the geometry of the left ventricle bears

prognostic significance . The relationship of cardiovascular risk to the pattern11

of geometry: normal < concentric remodeling < eccentric LVH < concentric

LVH, was recently confirmed in hypertensive patients in a study from

Verdecchia et al. . In contrast to the original article by Koren they also12

included the interventricular septal thickness in calculation of LV geometry,

instead of only the posterior wall. This may alter the results since, as they

have described, isolated septal thickening might occur in hypertension .13

Another point of discussion is whether gender-dependent or gender-

independent criteria for LVH should be used; this obviously influences any

analysis of differences between males and females in LV adaptation in

hypertension .14

So far, very few studies have addressed LVMI in the elderly with ISH.

Comparison of the results of these studies is hampered by differences in

methodology and patient recruitment: the largest study (Cardiovascular

Health study) is unclear in the indexation of left ventricular mass, while

others are done in selected groups of patients, or use different criteria . No14-16

comparisons are presented with elderly patients with diastolic hypertension,

and none of these studies has determined LV geometry.

CHAPTER

- 158 -

The objective of this study was to determine the impact of previously

untreated ISH on left ventricular mass and geometry in elderly selected from

a population survey. The results are compared with an age- and sex-matched

normotensive control-group, and with patients with diastolic hypertension

from the same population survey.


- 159 -

METHODS

Study population

A population screening program was done in a rural municipality

(Achtkarspelen) in The Netherlands. All inhabitants between 60 and 75 years

of age were invited to participate. After five minutes rest, the sitting blood

pressure (BP) was measured by trained volunteers using a

sphygmomanometer. If BP was elevated (for systolic BP: >160 mmHg) the BP

measurement was repeated by a physician. If BP remained elevated, the


occasions. Patients were defined to have isolated systolic hypertension (ISH)

if untreated systolic BP was >160 mmHg at each measurement, with diastolic


than 95 mmHg. All patients fulfilling these criteria were eligible for

investigation of echocardiographic end-organ damage. Exclusion criteria for

this study were: recent myocardial infarction (<three months),

cerebrovascular accident (<one year), symptomatic congestive heart failure,

hemodynamically significant valvular heart disease or cardiac arrhythmia

(other than atrial fibrillation), or any other disabling medical condition

hampering patient participation. Patients were also excluded if both apical

and parasternal echocardiographic views were inadequate for obtaining

measurements. The general physician was consulted about patient eligibility

for further investigation. The study was approved by the Medical Ethical

Committee of the Groningen University Hospital, and written informed

consent was obtained.

A group of normotensive controls was selected from the same program (BP

at first measurement <160/95 mmHg, and unknown with hypertension).

They were matched to the ISH-patients for age, sex and a functional

classification (Duke activity status index) .17

Results of the ISH-patients were also compared with those of patients with

diastolic hypertension (DH). This group consisted of all DH-patients found in

the same population survey, with DH defined as untreated average diastolic

BP > 95 mm Hg (and <115 mmHg), measured on three separate occasions.

Exclusion criteria were the same as for ISH-patients, with addition of diabetes

mellitus (due to a planned intervention trial).

All patients (ISH and DH) and normotensive controls underwent a 24-hour

ambulatory blood pressure measurement (ABP) (SpaceLabs 90207; SpaceLabs

Inc. Washington, USA). Measurements were done every 30 minutes during

CHAPTER

- 160 -

the day (07.00-23.00 hours) and every 60 minutes during the night (23.00-07.00

hours); data were analyzed without data-editing using time-weighed means.

The history of smoking, diabetes, and myocardial infarction was obtained.

Height and weight were measured, and body mass index was calculated. The

fasting serum lipid profile, including high density lipoprotein-cholesterol and

triglycerides, was measured with conventional assay methods. Fasting serum

glucose was also determined; patients with plasma glucose >7.8 mmol/l

(WHO-criterium) were considered to be diabetic, in addition to those already

known with, or on treatment for diabetes mellitus.

Echocardiographic examination and LV mass calculations

The echocardiographic dimensions were measured with an Acuson (128 XP-

5, Acuson Corp., USA; transducer 2-2.5 MHz) according to the Penn-

convention, in the left decubitus position. Measurements of the left

ventricular internal end-diastolic (EDD) and end-systolic diameters, and of

interventricular septal (IVS) and posterior wall thicknesses (PWT) were

obtained from a standard parasternal long axis view. Measurements were

made from 2-D images perpendicular to the long axis of the left ventricle. The

left atrial dimension was measured in both the parasternal and the apical

view. All dimensions are averages of three end-expiratory measurements in

sinus rhythm (five in case of atrial fibrillation). Measurements were

performed on-line, by the same echocardiographer and videotaped. Intra-

observer variability of the echocardiographer (WFH), measured before start of

study, was within a 5% error margin. Left ventricular mass was calculated

according to the formula as corrected by Devereux and Reicheck :18,19

LVMI = 1.04 * ((IVS + PWT + EDD) - EDD ) - 13.6 ;3 3

and indexed for body surface area.

In the geometric analysis of Koren et al. LV geometry is subdivided using

presence or absence of LVH (defined as LVMI >125 g/m ) and of increased2

relative wall thickness (RWT= 2 x PWT/EDD; cutoff value: >0.45) . A normal11

RWT and no LVH is defined as normal geometry; LVH is subdivided into

concentric LVH when RWT is increased, and eccentric LVH when RWT is

normal. The pattern of increased RWT without LVH is called concentric

remodeling. In ISH, the geometric classification is also analyzed per gender to

investigate possible differences in cardiac adaptation.

For discussion purposes, two extra calculations were performed: first, the

geometric classification was repeated using the Framingham-criteria, with


- 161 -

LVMI indexed for height and sex-different cutoff values for LVH: 143 g/m for

males, and 102 g/m for females . Also, the relative wall thickness was14

recalculated with the septal wall thickness, and with the sum of posterior and

septal wall in the calculation of LV geometry.


Data are presented as mean + standard deviation. Differences among the

three groups are analyzed with Pearson chi-square testing in the case of

nominal data (Fishers' exact test in case of low numbers), and with one-way

analysis of variance (ANOVA) in case of continuous variables, with posthoc

corrections for multiple comparisons (Tukey's honestly significant difference).

Differences between two groups, as in analysis of gender, are calculated using

Student's t-test. Odds� ratios are calculated for ISH-patients with the

normotensive patients as case-controls, and are presented with 95%

confidence intervals. Differences are considered statistically significant when

the two-sided p-values are <0.05.

CHAPTER

- 162 -

ISHn= 97

DHn= 50

controlsn=97

gender (% males) 49 59 49

age (years) 68 + 4^ 63 + 3* 67 + 4

body mass index (kg/m )2 27.2 + 3.5^ 28.9 + 3.3* 26.1 + 3.4

total-HDL cholesterol ratio 5.3 + 1.6* 5.5 + 1.5* 6.1 + 2.2

diabetes (%) 5 0‡ 4

smokers (%) 28* 42* 11

previous myocardial infarction (%) 2 0 5

Table 1. Baseline characteristics and risk factors of patients with isolated systolichypertension (ISH), diastolic hypertension (DH) and normotensive controls. Abbreviations: HDL= high density lipoprotein (-cholesterol). *= p<0.05 compared with

controls; ^: p<0.05 compared with DH. ‡: diabetes was excluded in DH.

RESULTS

Of the 2776 inhabitants aged 60-74 years 1812 (65.2%) attended the

screening. After four measurements 150 persons met the criteria for ISH

(prevalence 8.3%). Of these, 97 patients participated in further

echocardiographic examination. Reasons for ineligibility were mainly lack of

interest by the patients (n= 30) or if they were considered unsuitable for

investigation by the general practitioner consulted (n= 12); major exclusion

criteria were met by 11 patients. The results were compared with those of 50

patients with previously untreated diastolic hypertension (DH), and with 97

normotensive controls matched to ISH-patients for age and sex.

Baseline characteristics and blood pressure measurements

Table 1 presents the baseline characteristics of the three groups, including

the other cardiovascular risk factors. Age and gender of ISH-patients and

controls were equal due to matching. The DH-patients, although recruited

from the same age-category of 60-74 years, were slightly, but significantly,


- 163 -

ISH DH controls

systolic BP 186 + 12.7* 182 + 16.4* 141 + 10.7

diastolic BP 87 + 5.9*^ 104 + 5.2* 79 + 6.7

24 h-avg. systolic ABP 138 + 13.6* 137 + 16.8* 120 + 10.5

24 h-avg. diastolic ABP 78 + 8.3*^ 85 + 8.9* 73 + 6.3

daytime ABP 143* / 82*^ 140* / 88* 124 / 77

nighttime ABP 126* / 68*^ 128* / 76* 111 / 65

heart rate (bpm) 76 + 12 80 + 12 79 + 13

Table 2. Results of office and ambulatory blood pressure measurementsAbbreviations: ISH and DH: see previously; (A)BP = (ambulatory) bloodpressure. *= p<0.05 compared with controls (ISH and DH); ^: p<0.05

compared with DH (ISH).

younger compared with the ISH-patients (and controls). Gender distribution

of DH-patients did not differ from ISH-patients and controls. The body mass

index of patients with diastolic hypertension (DH) was significantly higher

compared with controls, but not with ISH-patients. There were no significant

differences among the three groups in body surface area or length, which is

used for indexation of left ventricular mass. Some significant differences

could be observed in the other cardiovascular risk factors between the two

hypertensive groups and the normotensive controls: both hypertensive

groups contained more smokers; and the ratio of total to high density

lipoprotein (HDL) cholesterol was higher in the control group (due to lower

HDL-C).

Table 2 shows the results of the office and ambulatory blood pressure

measurements (ABP). Most of the differences in office blood pressures can be

explained by the different entrance criteria of the three groups; these

differences were confirmed in patterns of 24-hour ambulatory measurements.

All values of ISH-patients were significantly higher compared with

normotensive controls, including diastolic blood pressure. Diastolic blood

pressure values of DH-patients were higher compared with ISH-patients and

controls. Systolic blood pressure of the ISH-patients did not differ from that of

DH-patients, with office as well as ambulatory measurements. The difference

between daytime and nighttime measurements (the "dipping" phenomenon)

was the same in all three groups.

CHAPTER

- 164 -

ISH DH controls

LVMI (g/m )2 97.8 + 19.9* 92.0 + 20.4* 70.3 + 16.5

LVH (%) 9 9 2

RWT 0.46 + .07* 0.46 + .06* 0.39 + .05

IVS (mm) 10.0 + 1.1* 10.3 + 1.2* 8.6 + 1.0

PWT (mm) 10.3 + 1.1* 10.1 + 1.2* 8.4 + 0.9

EDD (mm) 44.9 + 4.1* 44.1 + 3.6* 43.5 + 4.5

ESD (mm) 30.3 + 4.1 32.1 + 3.5 31.7 + 4.4

LA-ps (mm) 35.7 + 4.2* 35.7 + 4.5 34.0 + 4.4

Table 3. Echocardiographic resultsAbbreviations: LVMI = left ventricular mass index; LVH = LV hypertrophy; RWT =relative wall thickness; IVS= interventricular septal thickness; PWT = posterior wall

thickness; EDD/ESD= end-diastolic/end-systolic dimension; LA-ps= left atriumdimension - parasternal view.

*= p<0,05 compared with controls; ^: p<0.05 compared with DH

Echocardiographic results

The results of the echocardiographic measurements are presented in Table

3. One ISH-patient and three controls had inadequate parasternal views for

LV mass measurement; therefore, the results are shown of 96 ISH-patients

and 94 controls, and of 50 DH-patients.

When comparing ISH-patients with normotensive controls, the left

ventricular mass index is significantly increased in the ISH-patients, due to

thickening of both the interventricular septal and posterior wall and to an

increase of the end-diastolic dimension. The relative difference in wall

thickness appears to be larger than the increase of the end-diastolic

dimension, as is shown by the significantly increased relative wall thickness

(RWT) of ISH-patients. The percentage of LVH (defined as LVMI > 125 g/m )2

in ISH-patients is only slightly, not significantly, higher compared with the

normotensive controls. The left atrial dimension is significantly increased in

ISH-patients compared with controls in the parasternal view only.

When comparing results of ISH with DH-patients, all the results of LV mass

measurements are comparable. LVMI, RWT and both wall and end-diastolic

dimensions show no significant differences between ISH and DH-patients.

34

72

56

48

5 4

43

86

0 2

12

normalconcentric LVH

eccentric LVHconcentric remodeling

0

20

40

60

80

100 DH ISH

controls


- 165 -

Figure 1. Result of LV geometric classification in isolated systolic (ISH) and diastolichypertension (DH), and normotensive controls (Koren-criteria).

The result of the LV geometric classification according to Koren is depicted

in Figure 1. Overall, LV geometry of ISH-patients clearly differed from the

normotensive controls (p< 0.001). Most of the normotensive controls (86%)

had a normal geometry, versus 48% of ISH-patients. Total LVH-prevalence in

ISH-patients was 9% (controls: 2%), without an apparent difference between

concentric and eccentric LVH. Concentric remodeling was found in 43% of

ISH-patients versus 12% of controls; expressed in odds ratio ISH-patients

were 6.5 times more likely (95% CI: 3.0 - 13.8; p< 0.001) to have this pattern

compared with the controls. Almost half (47%) of ISH-patients who might

have been considered as �normal� because of absence of LVH, have this

abnormal pattern of increased wall thickness.

When comparing the LV geometric pattern of ISH with DH-patients, no

significant difference is found (Pearson chi-square: p= 0.423). The percentage

of LVH in both groups is 9%; concentric remodeling in DH is present in 56%.

Gender differences and the influence of different criteria and formulae

45

49

4337

29

1420

normalconcentric LVH

eccentric LVHconcentric remodeling

0

10

20

30

40

50

60

malesfemales

%

45

49

43

51

60

43

0

10

20

30

40

50

60%

CHAPTER

- 166 -

Figure 2. Results of LV geometry according to gender.- top panel: with use of Koren-criteria (LVH > 125 g/m2): difference N.S.- lower panel: with Framingham criteria (males > 143 g/m, and females > 102 g/m): P< 0.05

With the Koren-criteria, analysis by gender of LV geometry in ISH showed

no significant differences between males and females (figure 2: top panel).

Eccentric LVH appeared to be more frequent in males with ISH; when

patients with LVH were analyzed separately this difference was of borderline

significance (p= 0.058). When the gender-dependent criteria of the

Framingham Heart study were applied to this population, the results were

remarkably different and did reach overall statistical significance (p < 0.05;

lower panel figure 2). Female ISH-patients showed more often an abnormal

geometric pattern: overall percentage of LVH was 43% with the Framingham

criteria, versus 6% with the original Koren criteria. These different results

appeared to be due solely to a different classification of females; the results of

males were comparable to those of the Koren-classification.

Concerning asymmetry of LV hypertrophy, we did not often find isolated

septal wall thickening, neither in ISH-patients nor in DH-patients and in

normotensive controls. Only two ISH-patients had a ratio of > 1.3 of one wall

thickness to the opposite side ; however, in both cases this was increased13

thickness of the posterior wall instead of increased septal thickening. The


- 167 -

influence of which LV wall thickness was used in the calculation of RWT, and

the resulting LV geometric classification, was only minor. The percentage of

increased RWT varied little when applying the original formula with the

posterior wall thickness (rate: 34%), with the septal thickness (rate: 32% of all

patients), or with the sum of both walls in the formula (30%).

CHAPTER

- 168 -

DISCUSSION

This study shows that the echocardiographic LV mass and geometric

pattern in patients with previously untreated isolated systolic hypertension

(ISH) are clearly abnormal, comparable with results of patients with diastolic

hypertension (DH) and significantly different from normotensive controls.

The pattern of abnormality is mainly an increase of wall thickness, apart from

enlargement of the ventricles. Results of the geometric classification show

that the majority of ISH-patients have an abnormal LV geometry, with a

moderate prevalence of LVH but a high prevalence of concentric remodeling.

This abnormal pattern of increased wall thickness is found in almost half of

the ISH-patients who were otherwise perhaps considered normal because of

the absence of LVH. We therefore conclude that these patients with ISH from

a general population clearly show an increased prevalence of cardiac end-

organ damage, to a level comparable with patients with DH. The importance

of this observation is that all patients in this population-based study are

previously untreated, which avoids any interference of medication on results.

With the proven attributable cardiovascular risk of increased LVMI and

abnormal LV geometry, this further defines the cardiovascular risk of ISH in a

general population.

Interestingly, the results in ISH and DH are comparable, despite the fact

that the underlying pathophysiological vascular changes are almost opposed

between ISH and DH: in ISH distensibility of larger arteries is increased with

no or little change in peripheral resistance, while in DH peripheral resistance

is clearly increased . In absence of (invasive) hemodynamic measurements20

no clear explanation can be given except that hemodynamic load, as derived

from values of LV mass and geometry, apparently is equal in these patient

groups.

Studies on echocardiography in ISH are rather scarce, often including only

small numbers of ISH-patients with varying selection criteria . The size of20,21

this study is second only to the Cardiovascular Health study, and (slightly)

larger than the SHEP-study and the Framingham ISH- report . All of these14-16

studies have shown a higher LVMI in ISH-patients compared with

normotensive controls. However, patient selection and criteria used differ,

which hampers comparison of results, and none of these studies included a

comparable group of diastolic hypertensives. In the Cardiovascular Health

Study, only the results of unindexed LV mass are reported, without separate

results on wall thickness and internal dimensions, which disables analysis of


- 169 -

geometric changes . Comparison of the results with the ISH-patients from12

the Framingham Heart study is complicated by the different indexation of

LVMI used (for height instead of for body surface area) . Such a different14

indexation may lead to markedly different results, as is shown in our results

on gender differences in ISH. The results of LV mass measurements in a

subpopulation of the Systolic Hypertension in the Elderly Program (SHEP)-

study are to some extent comparable with the present study, although the

selection of patients differs . In the SHEPstudy only 1% of referred patients16

finally participated, including previously treated patients. In our study,

almost two-third (65%) of all detected ISH-patients were included, all of them

previously untreated.

In the present study, some possible sources of bias must be discussed. First,

although attendance rate was rather high (60%), this study might as any

screening study suffer from �voluntary bias�: healthy and health-conscious

persons are more likely to attend. To analyze the possibility of differences in

blood pressure and health status (number of chronic diseases registered by

questionnaire), a �non-responder� investigation was done. Those not

attending did suffer from slightly more chronic diseases compared with the

attendants, and a somewhat lower blood pressure, but differences were not

significant. Secondly, of the 150 ISH-patients found in the screening, 97

underwent echocardiographic examination. Although this is a much higher

percentage (65%) when compared with some other reports, this can also be a

possible source for bias. However, only a minor portion was excluded due to

concomitant diseases, among which several for non-cardiovascular reasons;

most patients refused further investigation. Finally, a remark could be made

that inclusion criteria for ISH-patients in this study was diastolic BP < 95

mmHg, as opposed to other (North American) criteria of < 90 mmHg. This

was of no influence to the present results: LVMI of those patients with

inclusion diastolic BP 90-94 mmHg was 94.7 g/m , and thus comparable with2

mean value of total group, and prevalence of concentric remodeling was 45%,

with no patients with LVH in this group.

Previous studies have suggested a possible difference in cardiac adaptation

in ISH with sex: more concentric hypertrophy in females, and more eccentric

ones in males . This pattern is also observed in elderly patients with LV14

pressure overload by aortic stenosis . In such analyses the influence of use of22

different criteria is very important. When using the original criteria of Koren,

we could not confirm such a difference, although there was a trend towards

more eccentric LVH in males. However, when applying the (gender-specific)

criteria of the Framingham Heart study to our patients, a markedly difference

in geometry in females is seen, resulting in a significant difference between

CHAPTER

- 170 -

geometry of ISH-males and females. This is probably due to the rather large

difference in criteria for LVH for males and females: 143 g/m versus 102 g/m;

especially prevalence of abnormal patterns in females increased considerably

with application of these criteria.

A further point of discussion is whether only the posterior wall should be

used in calculation of RWT and thus LV geometry (Koren), or the

interventricular septal thickness as well (Verdecchia) . Not only does it seem13

illogical to define a pattern as "concentric" if only one side of the LV wall is

included; more important, Verdecchia could not observe an significant

difference in cardiovascular risk for concentric remodeling when only the

posterior wall thickness was included . We found that results were13

comparable with inclusion of either one or both walls; we did not observe a

significant prevalence of isolated septal thickening. In our experience, a large

proportion of the elderly shows an angling of the left ventricle towards the

echocardiographic transducer, and this is known to be a possible source of

overestimation especially of the septal thickness with M-mode measurement

. It is for this reason that we use 2-D measurement of wall thickness and23,24

lumen diameters in our laboratory. This makes it possible to do measurements

perpendicular to the LV long axis and thus avoid a possible overestimation.

In conclusion, this study is one of the very first to show that

echocardiographic LV mass index and geometry in patients with ISH are

comparable with patients with diastolic hypertension. A large number of

those perhaps initially considered to be normal because of the absence of

LVH show concentric remodeling, which indicates an increased

cardiovascular risk for these patients. These results further define the place of

ISH as a cardiovascular risk factor; it indicates that the risk of ISH is no less

than that of diastolic hypertension in the elderly. It remains to be established

which criteria are most predictive, and whether results from geometric

classification may be used to adjust treatment.


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References

1 Cubb JD, Borhani NO, Entwisle G, Tung B, Kass E, Schnaper H, Williams W, Berman R.

Isolated systolic hypertension in 14 communities. Am J Epidemiol 1985;121:362-370

2 Garland C, Barrett-Connor E, Suarez L, Criqui MH. Isolated systolic hypertension and

mortality after age 60 years. Am J Epidemiol 1983;118:365-376

3 Staessen J, Amery A, Fagard R. Editorial review: Isolated systolic hypertension in the elderly. J

Hypertens 1990;8:393-405

4 Applegate WB. Hypertension in elderly patients [Review]. Ann Intern Med 1989;110:901-915

5 The SHEP cooperative research group. Prevention of stroke by antihypertensive drug treatment


6 Silagy C, McNeil JJ. Epidemiologic aspects of isolated systolic hypertension and implications

for future research. Am J Cardiol 1992;69:213-218


echocardiographically determined left ventricular mass in the Framingham heart study. N

Engl J Med 1990;322:1561-1566

8 Levy D, Garrison RJ, Savage DD, Kannell WB, Castelli WP. Left ventricular mass and

incidence of coronary heart disease in an elderly cohort. Ann Intern Med 1989;110:101-107

9 Casale PN, Devereux RB, Milner M, Zullo G, Harshfeld GA, Pickering TG, Laragh JH. Value of

echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid

events in hypertensive men. Ann Intern Med 1986;105:173-178





11 Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass

and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern

Med 1991;114:345-352

12 Verdecchia P, Schillacci G, Borgioni C, Ciucci A, Battistelli M, Bartoccini C, Santucci A, Santucci

C, Reboldi G, Porcellati C. Adverse prognostic significance of concentric remodeling of the left

ventricle in hypertensive patients with normal left ventricular mass. J Am Coll Cardiol

1995;25:871-878

13 Verdecchia P, Porcellati C, Zampi I, Schillaci G, Gatteschi C, Battistelli M, Bartoccini C,

Borgioni C, Ciucci A. Asymmetric left ventricular remodeling due to isolated septal thickening

in patients with systemic hypertension and normal left ventricular masses. Am J Cardiol

1994;73:247-252

14 Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated systolic

hypertension. Am J Cardiol 1993;72:310-313

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15 Psaty BM, Furberg CD, Kuller LH, Borhani NO, Rautaharju PM, O'Leary DH, Bild DE,

Robbins J, Fried LP, Reid C. Isolated systolic hypertension and subclinical cardiovascular

disease in the elderly: initial findings from the cardiovascular health study. JAMA

1992;268:1287-1291

16 Pearson AC, Udipati C, Nagelhout D, Sear J, Cohen JD, Labovitz AJ, (techn: Mrosek D, St.

Vrain J). Echocardiographic evaluation of cardiac structure and function in elderly subjects

with isolated systolic hypertension. J Am Coll Cardiol 1991;17:422-430

17 Hlatky MA, Boineau RE, Higginbotham MB, Lee KL, Mark DB, Califf RM, Cobb FR, Pryor DB.

A brief self-administered questionnaire to determine functional capacity (the Duke Activity

Status Index). Am J Cardiol 1989;64:651-654



19 Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N.

Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy

findings. Am J Cardiol 1986;57:450-458

20 Dart A, Silagy C, Dewar E, Jennings G, McNeil J. Aortic distensibility and left ventricular

structure and function in isolated systolic hypertension. Eur Heart J 1993;14:1465-1470

21 Nagano N, Iwatsubo H, Hata T, Mikami H, Ogihara T. Effects of antihypertensive treatment on

cardiac hypertrophy and cardiac function in elderly hypertensive patients. J Cardiovasc

Pharmac1991;17(Suppl.2):S163-S165

22 Carroll JD, Carroll EP, Feldman T, Ward DM, Lang RM, McGaughey D, Karp RB. Sex-

associated differences in left ventricular function in aortic stenosis of the elderly. Circulation

1992;86:1099-1107

23 Fowles RE, Martin RP, Popp RL. Apparent asymmetrical septal hypertrophy due to angled

interventricular septum. Am J Cardiol 1980;46:386-392

24 Safar M, Benessiano JR, Hornysk AL. Asymmetric septal hypertrophy and borderline

hypertension (Editorial note) Int J Cardiol 1982;2:103-108


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CHAPTER

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LAW NR. VIII:

THEY CANALWAYSHURT YOUMORE

REATMENT OF ISH - I

- 175 -

CCHAPTER HAPTER 99

EEFFECT OF QUINAPRIL AND TRIAMTERENEFFECT OF QUINAPRIL AND TRIAMTERENE//HYDROCHLOROTHIAZIDE ONHYDROCHLOROTHIAZIDE ON

CARDIAC AND VASCULAR ENDCARDIAC AND VASCULAR END --ORGAN DAMAGE IN ISOLATED SYSTOLICORGAN DAMAGE IN ISOLATED SYSTOLIC

HYPERTENSIONHYPERTENSION

Wilfred F Heesen MD*; Frank W Beltman MD ; Andries J Smit MD,PhD ; Johan F� �¶

May MD,PhD* ; Pieter A de Graeff MD,PhD ; Tjeerd K Havinga MD,PhD ; Frits¶ �¶§ ¶

H Schuurman PhD ; Enno van der Veur PhD ; Betty Meyboom-de Jong MD,PhD ;¶ ¶ �

Kong I Lie MD,PhD*

J Cardiovasc Pharmacol 1998; 31 (2): 187-194

Departments of *Cardiology, General Practice, Internal Medicine and Clinical� � §

Pharmacology, University of Groningen and Groningen Hypertension Service¶


CHAPTER

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ABSTRACT

Aims

To compare in a prospective double-blind randomized study the effect of

the angiotensin-converting enzyme inhibitor quinapril (QUI) with that of

triamterene/hydrochlorothiazide (THCT) treatment on cardiovascular end-

organ damage in subjects with untreated isolated systolic hypertension

(ISH).

Methods

End-organ damage measurements, performed initially and after 6 and 26

weeks of treatment, included echocardiographic determination of left

ventricular mass index (LVMI) and of diastolic function, and measurement

of aortic distensibility and peripheral vascular resistance.

Results

Blood pressure was significantly lowered in the 44 subjects (21 QUI, 23

THCT) completing the study. Both LVMI and aortic distensibility had

changed already at 6 weeks, with comparable improvements in both groups.

LV diastolic function showed overall no significant changes, although

patterns of early filling did differ between the two drug groups. Peripheral

vascular resistance appeared to increase between 6 and 26 weeks in THCT-

subjects only, along with a decreased aortic distensibility.

Conclusion

Blood pressure and LV mass were rapidly and markedly reduced in both

treatment groups of ISH-subjects, paralleled by an improvement of aortic

distensibility. In interpreting these results, the pathophysiological alterations

in ISH need to be taken into account, since these differ strongly from those

in diastolic hypertension. Results of LV diastolic function and peripheral

vascular resistance were less clear but appear to show less favorable changes

in the THCT-subjects treatment group.

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INTRODUCTION

Isolated systolic hypertension (ISH) is an important cardiovascular risk

factor, frequently occurring in the elderly . The Systolic Hypertension in1-5

the ElderlyProgram (SHEP)-study showed that treatment of ISH with

diuretics (and additional betablockers) reduced the cardiovascular morbidity

and mortality . In treatment of hypertension, measurements of6

cardiovascular end-organ damage are often used in order to assess the

associated cardiovascular risk, and the possible reversibility with different

antihypertensive drugs. To date, most end-organ damage studies have been

carried out with subjects with diastolic hypertension; only a few studies

have looked at subjects with isolated systolic hypertension.

One of the most widely used determinants of end-organ damage is

echocardiographic left ventricular mass index (LVMI). In diastolic

hypertension an increased LVMI, reaching criteria for LV hypertrophy or

not, is a strong and independent risk factor for cardiovascular events in

various populations, including the elderly . This increased LVMI is7-11

reversible, and can be reduced by lowering the blood pressure with various

antihypertensive drug treatments . In ISH, a few studies have shown that12

LVMI is elevated , but further information on the effect of13-17

antihypertensive treatment is scarce. One of the few reports available,

published in abstract only, looked at a subpopulation of the SHEP-study.

This report showed a significant regression of LVMI with diuretic therapy

when compared with placebo . Echocardiography also facilitates18

assessment of another cardiac end-organ damage measurement: left

ventricular diastolic function. Results of intervention studies on diastolic

hypertension are varied, some showing regression also with angiotensin

converting enzyme (ACE)-inhibitors, but others showing only effects with

longer duration or no effect at all (including diuretics) . In the few studies19-25

available on ISH, the early to atrial (EA) filling ratio was shown to be

impaired , but effects of intervention have yet to be measured.14,17

Investigation of vascular compliance or distensibility (stiffness) may be of

even greater interest in ISH, since changes in vascular compliance is thought

to be a key factor in the pathophysiology of ISH . In ISH, the principal13, 26

changes in compliance is due to a reduced distensibility of the aorta and

larger arteries. Diastolic hypertension, however, is associated with increased

resistance of the smaller resistance arteries and arterioles . A number of13, 26

CHAPTER

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studies have shown beneficial effects on vascular compliance with various

antihypertensive drugs, including ACE-inhibitors, but these results are

mainly concerned with subjects with diastolic hypertension . Few studies27-30

have been done in ISH-subjects only; one such study showed a beneficial

effect on calculated systemic vascular resistance and stroke volume by long-

term treatment with hydrochlorothiazide .31

The aim of this study was to compare, in a double-blind, randomized,

parallel group design, the effect of ACE-inhibitor treatment (quinapril) with

that of diuretic therapy (triamterene/-hydrochlorothiazide) on

cardiovascular end-organ damage, in subjects with previously untreated

ISH. Several cardiovascular end-organ damage measurements were carried

out: echocardiographic left ventricular mass and diastolic function, aortic

distensibility measured by pulse wave velocity, and peripheral vascular

resistance measurement with strain gauge plethysmography. Since the

reduction of end-organ damage may take longer than the reduction of blood

pressure, two evaluation times were chosen: at six weeks and at six months.

REATMENT OF ISH - I

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METHODS

Study population

Eligible persons were referred in from two sources - by general

practitioners and from the outpatient clinic of the University Hospital

Groningen. Subjects were eligible if they had a history of elevated systolic

blood pressure (> 180 mmHg, or repeatedly > 160 mmHg, with normal

diastolic blood pressure: < 95 mmHg). The inclusion criterium for the study

was an untreated systolic blood pressure > 160 mmHg on three separate

occasions, with a diastolic blood pressure < 95 mmHg. Sitting office blood

pressure was measured with a sphygmomanometer after five minutes rest.

The exclusion criteria included the presence of any hemodynamically

significant cardiovascular disorders, or other major diseases or conditions

thought to interfere with the study results, including diabetes. Subjects were

also excluded when hemodynamically important valve abnormalities, or

inadequate parasternal and apical echocardiographic windows were found

at the initial echocardiographic examination. All remaining eligible subjects

were randomized after the baseline investigations, and received double-

blind quinapril or triamterene/hydrochlorothiazide. The study was

approved by the Medical Ethical Committee of the University Hospital

Groningen, and written informed consent was obtained.

Medication and follow-up

Medication allocation was double-blind, each capsule containing either

12.5/25 mg triamterene/hydrochlorothiazide (THCT) or 10 mg quinapril

(QUI). Subjects were assigned to random treatment groups, with a

stratification for age: �younger� elderly: 60-64 yrs, and elderly: 65-74 yrs.

After the initial visit, all subjects started with one capsule a day (taken in the

early morning). After three weeks, the dosage was doubled to two capsules

once a day and continued until the end of the study (25/50 mg THCT or 20

mg quinapril), except where orthostatic problems or other complaints had

occurred. The definition of orthostatic complaints was a drop of systolic

blood pressure of more than 20 mmHg from supine to standing blood

pressure after one minute, or accompanying symptoms such as dizziness or

fainting. At each visit, subjects were specifically asked about the occurrence

of possible side-effects

CHAPTER

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Follow-up examinations were done after six and 26 weeks of treatment. At

each study visit, including the initial visit, all subjects underwent the same

measurements of blood pressure and those of end-organ damage

determination. Blood pressure measurements included standard supine

(office) and 24-hour ambulatory measurements. The end-organ damage

measurements included echocardiographic LV mass and diastolic function

determination, and aortic pulse wave measurement and measurement of

peripheral compliance with strain gauge plethysmography of the calves.

Details of the methods of these end-organ damage measurements will be

explained separately. Office blood pressure was determined by the average

of three consecutive blood pressure measurements, after five minutes rest.

The 24-hour ambulatory blood pressure was measured with the Spacelabs

90207 device, with separate analysis of daytime and night-time

measurements (daytime measurements (half-hourly) 07.00-23.00 h; night-

time (1-hourly) 23.00-07.00). . Further measurements included height (only at

the initial visit) and weight, from which the body mass index (BMI) was

calculated.

Echocardiographic examination

At each visit (0, 6, 26 weeks), the left ventricular mass (LVM) was

calculated from measurements of left ventricular internal end-diastolic

(EDD), interventricular septal (IVS) and posterior wall thicknesses (PWT),

according to the formula as proposed by Devereux and Reichek :32

LVM = 1.04 * ((IVS + PWT + EDD) - EDD ) - 13.6 (g).3 3

These measurements were made according to the Penn-convention from

the standard parasternal LV long axis view in 2-dimensional mode, in

accordance with routine procedures in our echocardiographic laboratory.

LVM was indexed to body surface area (BSA); unit of obtained LVM index

(LVMI) is g/m . LVH is defined as LVMI > 125 g/m . End-systolic2 2 11

dimension and left atrial dimensions were also measured. All

echocardiographic measurements were the average of three end-expiratory

measurements. Measurements were performed on-line and videotaped, and

carried out on commercially available devices (Toshiba 60/1060, or Acuson

XP-10).

LV diastolic function was assessed with pulsed-Doppler echocardiography.

The sampling volume was placed between tips of the mitral valve leaflets, in

REATMENT OF ISH - I

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the standard apical four-chamber view. Peak velocities of early (E-wave)

and atrial (A-wave) diastolic filling phases were measured, and the

deceleration slope of the early inflow signal was measured (EF-slope). End-

expiratory measurements were taken, and calculated on-line on screen, or

printed out (50 mm/s) for analysis afterwards.

Vascular compliance measurements

The vascular compliance was assessed by two different methods:

compliance of the large vessels was measured with aortic pulse wave

velocity (PWV) measurement, and peripheral vascular compliance with

ECG-triggered strain gauge plethysmography of the calves. In the first

method the aortic pulse wave is detected using two Doppler probes, one at

approximate commencement of the aorta (right subclavian artery), and the

other at the end of the aorta (right femoral artery). The time delay between

the two simultaneously recorded Doppler curves at the probes is measured.

The foot part of the initial Doppler signal is measured with computer

analyzing programs, developed in our laboratory . The PWV is then33

calculated as the quotient of the aortic length (estimated by measurement of

the distance from upper sternal manubrium to the inguinal ligament) and

the pulse transmission time. From the PWV the aortic distensibility (D) is

calculated, using the formula D= 1/(D * v ) , in which D represents the density2

of the blood and v the pulse wave velocity (unit D: 1/MPa) . For analysis,34

three adequate consecutive recordings of 15 seconds were obtained for each

subject.

The calf blood flow (CBF) was measured with ECG-triggered strain gauge

plethysmography . This is performed at rest, during postocclusive35

hyperaemia and after exercise. The purpose of hyperaemia and exercise is to

achieve (maximal) vasodilation, and thereby determine the minimal

vascular resistance. During the measurement, subjects were lying down on a

bench in a room with a constant temperature, with feet and calves elevated

slightly above heart level. A mercury-filled rubber strain gauge was placed

around the widest part of each calf, and occlusion cuffs were placed above

the knees. Resting measurements during venous occlusion (cuff inflation 50

mmHg) were done with alternating inflation and deflation of the cuffs

during five minutes. Hyperaemic measurements were taken immediately

after five minutes of arterial occlusion (cuff inflation 200 mmHg), and

postexercise measurements after a heel kicking exercise (cumulative

performance of 1000 Joule). CBF is calculated from the rate of the initial

increase in calf circumference during venous occlusion, and is expressed as

CHAPTER

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milliliters per 100 ml of calf tissue per minute. A simultaneous blood

pressure measurement allows the calculation of calf vascular resistance:

CVR= MAP / CBF (MAP = mean arterial pressure). Only measurements with

stable baseline recordings, and adequate hyperaemic and postexercise

curves were used in the analysis.

REATMENT OF ISH - I

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The primary endpoints of this study were threefold: the left ventricular

mass index, the early to atrial (E/A) ratio and the aortic distensibility. The

secondary endpoints were the effects of treatment on separate

measurements underlying these endpoints, such as, for instance, the

(separate) effects on LV wall thickness and end-diastolic dimensions, and

calve vascular resistance. The general assumption was that a comparable

degree of lowering of (office) blood pressures would be found in both

groups. Both office and ambulatory blood pressure measurements were also

analyzed as secondary endpoints. The power analysis is based on the

changes in LV mass, because most evidence is available for this

measurement. Based on previous studies with ACE-inhibitors in diastolic

hypertension a 20% reduction (av. range 10-30%) was expected with a

standard deviation of 6%. With this, a difference of 5.5% could be detected

with p< 0.05 and a power of 85% in a group of subjects consisting of 35

persons. This difference was considered clinically important.

The analysis was carried out with repeated measurements with random

intercept model (SAS statistical software, V. 6.12 Cary, N.C.). In this36

analysis no replacement of missing values is done. All data are used to

estimate the intra- and intersubject variation components and the effects of

parameters related to the endpoints (e.g. time and medication effects).

Initially, linear effects in time were analyzed in the evaluation of differences

between both medication groups. If the data strongly suggested non-linear

differences in time between the two drugs, quadratic polynominal

interactions derived from the same repeated measurements model, or

analysis of separate time intervals with Student� t-test were analyzed also.

The results of the analysis were based on per-protocol analysis. Afterwards,

these results were compared with the results of intention-to-treat analysis;

these results were presented separately only if they were different.

All differences were considered statistically significant if the two-sided p-

values was < 0.05.

CHAPTER

- 184 -

RESULTS

Inclusion and withdrawals

Between May 1992 and February 1994 a total of 51 subjects entered the

study. Among five other subjects considered eligible, four were excluded

because of inadequate echocardiographic windows to obtain measurements,

and one on account of hemodynamically significant aortic and mitral

regurgitation. Most of the subjects were referred by General Practitioners;

two came from the outpatient clinic. From these 51 subjects, 25 (7 males)

were allocated to quinapril treatment, and 26 (5 males) to

triamterene/hydrochlorothiazide treatment. Age (67 + 4.5, THCT: 68 + 5.7)

and body mass index (QUI; 25.7 + 2.2; THCT: 25.3 + 3.5 kg/m ) were2

comparable between both treatment groups. Body weight remained stable

during the study. No subject suffered from orthostatic complaints after three

weeks of medication. Thus, all subjects receive a double dosage until the end

of the study. A total of 44 subjects completed the study protocol; four

subjects in the quinapril-group (QUI) and three subjects using

triamterene/hydrochlorothiazide (THCT) ended the study prematurely,

with one serious adverse event in each group: (myocardial infarction (QUI),

and unstable angina pectoris requiring hospitalization (THCT)). The other

reasons of withdrawal were withdrawal of consent (1 in each group);

pneumonia (QUI), and adverse gastrointestinal (QUI) and dermatological

(THCT) reactions. One quinapril-subject suffering from coughing only

reported this afterwards, after completing the study.

Results of blood pressure measurements

Office blood pressure was significantly reduced in both groups after 26

weeks (table 1): from 179/90 mmHg (baseline) to 156/87 mmHg in the

quinapril-group, and from 178/90 mmHg to 153/86 mmHg in the

triamterene/hydrochlorothiazide-group (differences between groups: n.s.).

Also, a significant reduction of 24-hour ambulatory blood pressures was

observed in both groups, without a significant difference between the two

therapies. All these changes in blood pressure occurred in the first 6 weeks

of treatment; little change was observed in the second treatment period from

6

REATMENTOFIS

H-I

-185-

quinapril THCT change over time diff. between groups mean (sd) mean (sd) (p-value) (p-value)

OSBP-baseline 179 (5.4) 178 (5.0)OSBP-6 wks (mmHg) 155 (6.3) 154 (6.0) 0.0001 0.9171OSBP-26 wks 156 (6.5) 153 (6.1)

ODBP-baseline 90 (2.0) 90 (1.9)ODBP-6 wks (mmHg) 87 (3.0) 86 (2.8) 0.0016 0.9826ODBP-26 wks 87 (3.8) 86 (3.5)

ASBP24-baseline 137 (5.3) 140 (5.3)ASBP24-6 wks (mmHg) 131 (4.4) 130 (4.4) 0.0001 0.0929ASBP24-26 wks 132 (9.1) 126 (9.1)

ADBP24-baseline 78 (3.2) 80 (3.2)ADBP24-6 wks (mmHg) 75 (2.4) 75 (2.4) 0.0001 0.6487ADBP24-26 wks 74 (5.4) 74 (5.4)

HR-baseline 77 (5.1) 78 (4.9)HR-6 wks (bpm) 77 (4.2) 81 (4.1) 0.3041 0.6546HR-26 wks 75 (4.5) 78 (4.4)

Table 1. Results of blood pressure and heart rate measurementsAbbreviations: BP = blood pressure, S = systolic, D= diastolic, O= office, A= ambulatory, THCT =triamterene/hydrochlorothiazide

CHAPTER

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LVMI-baseline 88.1 (8.9) 93.5 (8.7)LVMI-6 wks (g/m ) 70.6 (11.0) 71.7 (10.8) 0.0001 0.64412

LVMI-26 wks 63.6 (12.9) 65.6 (12.6)

LVPW-baseline 9.9 (0.6) 9.6 (0.6)LVPW-6 wks (mm) 9.2 (0.5) 9.3 (0.5) 0.0054 0.7723LVPW-26 wks 9.0 (0.5) 8.8 (0.5)

IVS-baseline 9.8 (0.6) 9.5 (0.6)IVS-6 wks (mm) 8.8 (0.6) 8.6 (0.6) 0.0001 0.7348IVS-26 wks 9.0 (0.5) 8.4 (0.5)

LVEDD-baseline 42.6 (1.8) 44.8 (1.8)LVEDD-6 wks (mm) 42.4 (1.7) 43.1 (1.6) 0.1457 0.3868LVEDD-26 wks 42.3 (1.4) 43.8 (1.4)

LVESD-baseline 28.2 (2.0) 29.3 (1.9)LVESD-6 wks (mm) 27.7 (2.1) 28.8 (2.1) 0.2827 0.8207LVESD-26 wks 28.6 (1.9) 30.1 (1.9)

RWT-baseline 0.47 (.11) 0.43 (.07)RWT-6 wks 0.43 (.08) 0.42 (.08) 0.0240 0.4272RWT-26 wks 0.43 (.08) 0.40 (.07)

Table 2. Results of left ventricular mass measurements Abbreviations: LVMI = left ventricular mass index; LVPW = LV posterior wall ; IVS = interventricular septalthickness; LVEDD = LV end-diastolic dimension; ESD = end-systolic dimension; RWT = relative wall thickness

REATMENT OF ISH - I

- 187 -

to 26 weeks. The results of the ambulatory blood pressure measurements

during daytime and nighttime periods were comparable to those of the 24-

hour averages (results not shown).

Echocardiographic results

The echocardiographic left ventricular mass index was significantly

reduced in both treatment groups (table 2). This reduction was already

apparent after six weeks of treatment. Analysis of the separate components

of LVMI showed that this reduction was mainly due to a reduction of wall

thickness, with significant reduction of both posterior and interventricular

septal wall thickness. The reduction of the internal end-diastolic dimension

was relatively less. This pattern of change of mainly wall thickness is

confirmed by the significant decrease of relative wall thickness. In all these

results, no differences were observed between the antihypertensive

treatment groups. End-systolic internal dimensions did not change

significantly during the study. Also, no differences were observed in the left

atrial dimensions, neither during the treatment period nor between the drug

groups (results not shown).

Concerning LV diastolic function, there was no overall statistical change

in time in the ratio of early to atrial (EA) filling (table 3). However, the

pattern of changes appeared to differ in the two drug groups: little changes

in QUI-treated subjects, compared with an initial decrease in THCT-subjects

with returning of values to baseline after 26 weeks. This pattern was also

present in peak early (E) velocity and in slope of early filling (EF); in the

latter there was a gradual decrease in QUI-treated subjects. When analyzed

statistically, the difference between both groups in the EA-ratio and the EF-

slope was of borderline significance with the linear polynominal analysis.

When additional quadratic analysis was performed, taking non-linear

changes into account, this difference in medication effect remained

borderline for EA-ratio (0.071), while it reached significance for EF-slope (p=

0.028).

Results of vascular measurement

The aortic distensibility was significantly increased during the treatment

period in both treatment groups (p< 0.01; fig. 1). The largest effects were

seen after six weeks treatment; after 26 weeks there appeared to be a slight

CHAPTER

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EAratio -baseline 0.78 (.08) 0.77 (.07)EAratio -6 wks 0.77 (.07) 0.72 (.07) 0.1302 0.0521EAratio -26 wks 0.76 (.08) 0.81 (.08)

peak E -baseline 0.68 (.07) 0.68 (.07)peak E -6 wks (m/s) 0.65 (.06) 0.60 (.06) 0.0627 0.1902peak E-26 wks 0.63 (.06) 0.65 (.06)

peak A -baseline 0.90 (.09) 0.89 (.09)peak A -6 wks (m/s) 0.86 (.08) 0.85 (.08) 0.0408 0.7452peak A -26 wks 0.86 (.07) 0.83 (.07)

EFslope -baseline 3.07 (.52) 3.02 (.51)EFslope -6 wks (m/s ) 2.53 (.53) 1.88 (.52) 0.0012 0.06432

EFslope -26 wks 2.20 (.51) 2.64 (.50)

Table 3. Results of LV diastolic functionAbbreviations: EA = early to atrial filling ratio; peak E = peak early filling flow velocity; peak A = peak atrial filling flowvelocity; EF-slope = early filling (deceleration) slope

0 6 26 weeks 0 6 26 weeks0

2

4

6

8Aortic distensibility (1/MPa)

quinapril THCT

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- 189 -

Figure 1. Changes in aortic distensibility after 6 and 26 weeks of treatment. Overall changes in both groups significant (p< 0.01); no difference between bothgroups. Abbreviations: THCT = triamterene/hydrochlorothiazide

decrease again, especially in the diuretic group. While the overall analysis

showed no significant differences between the two treatment groups,

analysis of this second interval from 6-26 weeks was significant for THCT-

subjects (p< 0.05 (Student� t-test), but not for QUI-treated subjects.

The overall analysis of results of calf vascular resistance showed no

significant changes when analyzed over the complete study period.

However, as shown in figure 2 a trend of increase from 6 to 26 weeks

appears to be present, especially in the diuretic group. When analyzed

separately, this difference did reach statistical significance (increase 6-26

weeks: p< 0.05 for THCT-subjects, n.s. for QUI-subjects; Student� t-test). The

results presented in figure 2 are derived from postexercise measurements;

the results from posthyperaemia testing (not shown) were similar. Also,

resting measurements of CBF showed no significant changes during

treatment or between groups (results not shown).

0 6 26 weeks 0 6 26 weeks0

1

2

3

4

5

6

7CVR post-exercise (mmHg/min /100 ml tissue

quinapril THCT

CHAPTER

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Figure 2. Changes in calve vascular resistance measurement (CVR) after 6 and26 weeks of treatment .No overall significant changes; but from 6 to 26 weeks change in THCT-patients p<0.05, while n.s. in quinapril-patients. Abbreviations: THCT = triamterene/hydrocholorothiazide

REATMENT OF ISH - I

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DISCUSSION

This study shows that lowering of blood pressure by treatment with both

quinapril and triamterene/hydrochlorothiazide in subjects with previously

untreated isolated systolic hypertension (ISH) results in a highly significant

reduction of the left ventricular mass, paralleled by a significantly improved

aortic distensibility. The marked reduction of LVMI was already observed

after six weeks of treatment, without significant differences between the two

treatment groups. This is one of the first double-blind end-organ damage

studies in ISH, comparing the effect of an ACE-inhibitor therapy with

diuretic therapy. Although a subject of discussion, it has been hypothesized

that ACE-inhibitors are more effective in reducing LV mass when compared

with other classes of antihypertensive drugs such as diuretics . ACE-12

inhibitors are also thought to improve arterial compliance , probably by27

reversal of structural changes induced by the activated tissue renin-

angiotensin system, activated also in elderly hypertensives . However,37

most of the results of these effects are derived from studies of subjects with

diastolic hypertension; comparative studies in ISH are scarce. Results in ISH

need not to be similar, since the pathophysiology of ISH clearly differs from

diastolic hypertension and thus, the effects of drug treatment may differ as

well .14,26

The major pathophysiological change in ISH - an increased stiffness of the

large arteries with no change or even a decrease in peripheral resistance, is

virtually opposite to the changes occurring in diastolic hypertension in

which an increase of peripheral resistance is the major determinant . Our14, 26

observations confirm these pathophysiological changes in ISH, showing

clearly decreased values of aortic distensibility at baseline that can be

reversed to near-normal values after treatment, when compared with

normotensive values of similar age . This decrease of aortic distensibility38

may have two important consequences on LV systolic afterload and,

therefore, on LVMI . Firstly, it will lead to an increased impedance of39, 40

blood flow in systole, with enhanced LV workload giving an increase of LV

mass. Secondly, the decreased distensibility causes an enhanced pulse wave

velocity, which can lead to wave reflection in systole rather than in diastole

. If present, this further increases LV systolic afterload with values up to40, 41

50 mmHg . Viewing the very rapid and marked decrease of LVMI observed42

in this study, it could be postulated that both mechanisms, both the

increased impedance and early wave reflection, were favorably influenced

CHAPTER

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with treatment in these ISH-subjects. Future studies including invasive

hemodynamic measurements may perhaps confirm whether both

mechanisms are indeed present in ISH-subjects.

Another important point in interpretation of results are the change in

blood pressure (BP). Our results show that in both treatment groups systolic

BP in particularly is markedly lowered over 20 mmHg. This change in BP is

larger than observed in most earlier studies on DH; for instance in a meta-

analysis of diastolic hypertension-trials the observed changes are 5-6 mmHg

reduction of diastolic BP, with changes in systolic blood pressure about

twice as high . This large reduction of systolic BP may have masked a43

possible additional class-specific effect. This relatively large reduction of

systolic BP has also been observed in other studies available on treatment of

ISH, without any clear difference between the various classes of

antihypertensive drugs . The results of 24-hour ambulatory blood44-48

pressure measurements as included in this study show lower baseline values

and therefore, an apparently less pronounced lowering of systolic blood

pressure with treatment. However, it is known that systolic blood pressure

with ambulatory measurement gives clearly lower values when compared to

office blood pressure, especially when high pressures are present as is the

case in ISH .49

As for the changes in LV diastolic function, the overall E/A ratio tends to

show different changes between both treatment groups. Furthermore, the

pattern of changes appears to differ during treatment between the two drug

groups: for instance the slope of early filling (EF) gradually decreases in

QUI-treated subjects, while in THCT an initial decrease is seen followed by

an increase. This pattern is seen in all measurements of early filling. In two

other comparative studies of diastolic hypertension, ACE-inhibition

treatment improved diastolic function, while treatment with THCT did not

change diastolic function parameters or even resulted in an acute

impairment probably due to decreased preload . Remarkably, both peak E20,24

and EF-slope values decrease, which at first sight suggests a worsening of

LV diastolic filling. However, it is known that after an initial decrease of EA

ratio as a marker of abnormal LV diastolic function, this ratio may increase

again due to a compensatory increase of left atrial pressure: a pattern known

as �pseudo-normalization� . This abnormal pattern has normal values for50, 51

E/A-ratio, but it may be distinguished from truly normal patterns by an

increased or steeper EF-slope. This phenomenon may indeed be present in

these ISH-subjects, because the comparison of their values with those of

normotensive controls from similar age shows that both peak E and EF-slope

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are elevated at baseline, approaching normal values after treatment .38, 52

While the conclusion may be that LV diastolic filling appears to be improved

with quinapril treatment, with less clear results with THCT, this will need to

be confirmed in studies, with perhaps longer duration of follow-up and

probably necessitating invasive hemodynamic measurements.

A comparable problem of interpretation concerns the results of peripheral

calf vascular resistance. Again, no significant difference is observed in time

nor between the two drug groups with the linear polynominal analysis over

the total study period, as was the primary analysis in this study. However,

changes in values of CVR, as well as of aortic distensibility, may depend

partially on changes in blood pressure (see formula of CVR and reference

14). To avoid this possible bias, a separate analysis was done for the period

of treatment between 6 and 26 weeks, because in this period BP appears to

change little or not at all. In this time period a difference is noted between

the two drug treatments, with an increase of peripheral resistance and

decrease of aortic distensibility in the THCT-group, and little or no change in

the quinapril-group. Further studies with a longer duration of follow-up will

have to be done to investigate whether such a favorable influence with

ACE-inhibitor treatment is actually present.

In summary, this study shows that echocardiographic LV mass index and

aortic distensibility can be significantly improved in ISH by antihypertensive

treatment. The rapid and large decrease of LVMI may be explained by

alteration of both aortic distensibility and pulse wave reflection, and by the

relatively large decrease in systolic blood pressure. No significant

differences were observed in the primary endpoints between the ACE-

inhibitor quinapril and the diuretic combination

triamterene/hydrochlorothiazide, but different patterns in LV diastolic

function and vascular measurements in time may be present. Larger studies,

with longer follow-up and perhaps invasive measurements are necessary to

confirm these results.

CHAPTER

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spirapril improves diastolic function at rest independent of vasodilation during treatment with

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22 Mayet J, Shahi M, Poulter NR, Sever PS, Foale RA, Thom SA. Left ventricular diastolic function in

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23 Schartl M, Bocksch WG, Dreysse S, Beckmann S, Franke O, Hunten U. Remodeling of

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24 Lumme JA, Jounela AJ. Left ventricular mass, serum electrolyte levels and cardiac arrhythmias in


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29 Van Merode T, Van Bortel L, Smeets FAM, et al. The effect of verapamil on carotid artery

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30 Asmar RG, Pannier BM, London GM, Safar ME. Cardiac hypertrophy and arterial compliance

following drug treatment in hypertension. J Cardiovasc Pharmacol 1991;18 (Suppl. 7):S37-S39

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31 Vardan S, Mookherjee S, Warner R, Smulyan H. Systolic hypertension in the elderly. JAMA

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33 Lubbers J, Someren van R, Journee HL. An instrument for the measurement of pulse wave velocity

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hypertension: its modifications during changes in aortic pressure. Cardiovasc Res 1982;16:646-656

35 Sumner S. Mercury strain gauge plethysmography (Chapter 22). In: Bernstein EF (ed.) Vascular

diagnosis; pp. 205-215,. Mosby, St. Louis 1993

36 Laird NH, Ware JH. Random-effects models for longitudinal data. Biometrics 1982;38:963-974

37 Hall WD. Hypertension in the elderly with a special focus on treatment with angiotensin-

converting enzyme inhibitors and calcium antagonists. Am J Cardiol 1992;69 (Suppl. E):33E-42E

38 Heesen WF, Beltman FW, May JF, Smit AJ, Meyboom-de Jong B, Lie KI. Echocardiographic

findings and vascular compliance in isolated systolic hypertension in a population survey

(abstract). J Hypertension 1994;12 (suppl. 3): S 82

39 Pannier BM, London GM, Cuche J-L, Girerd X, Safar ME. Physical properties of the aorta and


40 O�Rourke M. Coupling between the left ventricle and arterial system in hypertension. Eur Heart J

1990;11(Suppl. G): 24-28

41 Shimada K, Miyashita H, Kawamoto A, et al. Pathophysiology and end-organ damage in elderly

hypertensives. J Hypertens 1994;12 (Suppl. 6):S7-S12

42 O�Rourke MF, Kelly RP. Wave reflection in the systemic circulation and its implications in

ventricular function. J Hypertens 1993;11:327-337.

43 Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke and coronary heart disease, Part

II:Effects of short-term reductions reductions in blood pressure - An overview of the unconfounded

randomised drug trials in an epidemiological context. Lancet 1990;335:827-838

44 Staessen J, Bert P, Bulpitt CJ, et al.,on behalf of the Syst-Eur investigators. Nitrendipine in older

patients with isolated systolic hypertension: second progress report of the Syst-Eur trial. J Hum

Hypertens 1993;7:265-271

45 Webster J, Fowler G, Jeffers A, et al. A comparison of amlodipine with enalapril in the treatment

of isolated systolic hypertension. Br J Clin Pharmac 1993;35:499-505

46 Avanzini F, Alli C, Bettelli G, et al., for the study group. Antihypertensive efficacy and tolerability

of different drug regimes in isolated systolic hypertension in the elderly. Eur Heart J 1994;14:206-

212

47 Silagy CA, McNeill JJ, Farish S. McGrath BP. A comparison of dilevalol and placebo in the

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management of isolated systolic hypertension using ambulatory monitoring. Br J Clin Pharmacol

1990;30:657-664

48 Tomlinson B, Woo J, Critchley JAJH, Or KKH, Chan TYK, Sanderson JE. Sustained-release

isradipine compared with spirapril in the treatment of elderly patients with isolated systolic

hypertension. Am J Hypertens 1991;7:35S-39S

49 Staessen JA, Thijs L, Bienaszewski L, et al. Ambulatory monitoring uncorrected for placebo

overestimates long-term antihypertensive action. Hypertension 1996;27:414-420

50 Phillips RA, Goldman ME, Ardeljan M, et al. Determinants of abnormal left ventricular diastolic

filling in early hypertension. J Am Coll Cardiol 1989;14:979-985

51 Thomas JD, Weyman AE: Echocardiographic doppler evaluation of left ventricular diastolic

function. Circulation 1991; 84:977-990.

52 Benjamin EJ, Levy D, Anderson KM, Wolf PA, Plehn JF, Evans JC, Comai K, Fuller DL, St. John

Sutton M. Determinants of Doppler indexes of left ventricular diastolic function in normal subjects

(The Framingham heart study). Am J Cardiol 1992;70:508-515

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LAW NR. IX:

THE ONLYGOODADMISSION IS ADEADADMISSION

REATMENT OF ISH -

- 199 -

CCHAPTER HAPTER 1010

RRRREVERSAL OF PATHOPHYSIOLOGIC CHANGES WITHEVERSAL OF PATHOPHYSIOLOGIC CHANGES WITHEVERSAL OF PATHOPHYSIOLOGIC CHANGES WITHEVERSAL OF PATHOPHYSIOLOGIC CHANGES WITH

LISINOPRIL TREATMENT IN ISOLATED SYSTOLICLISINOPRIL TREATMENT IN ISOLATED SYSTOLICLISINOPRIL TREATMENT IN ISOLATED SYSTOLICLISINOPRIL TREATMENT IN ISOLATED SYSTOLIC

HYPERTENSIONHYPERTENSIONHYPERTENSIONHYPERTENSION

Wilfred F. Heesen , Frank W. Beltman , Andries J. Smit , Johan F. May , Pieter Aa b c,f a,f

de Graeff , Jaap HJ. Muntinga , Tjeerd K. Havinga , Frits H. Schuurman , Ennod,f e f f

van der Veur , Betty Meyboom-de Jong , Kong I. Lief b a

Submitted

Departments of Cardiology, General Practice, Internal Medicine, Clinical Pharmacologya b c d

and Medical Physiology, University of Groningen and Groningen Hypertension Service;e f



CHAPTER

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ABSTRACT

Objective

To evaluate in a prospective double-blind placebo-controlled study the

effect of long-term lisinopril treatment on cardiovascular end-organ damage

in isolated systolic hypertension (ISH).

Design and methods

Double-blind comparison of lisinopril treatment with placebo for 2 years, in

subjects with previously untreated ISH, including comparison with age- and

sex-matched normotensives (NT), all derived from a population screening

program. End-organ damage measurements, done initially and after 6 and 24

months of treatment, included measurements of aortic distensibility, and of

echocardiographic left ventricular mass index (LVMI) and diastolic function.

Blood pressure was measured both by office and ambulatory measurements.

Results

Of the 97 ISH-subjects selected from the screening, 62 (30 lisinopril)

completed the study according to protocol. While office blood pressure

decreased in both groups, ambulatory results significantly decreased with

lisinopril-treatment only. Aortic distensibility increased significantly with

lisinopril to normotensive levels, as opposed to a decrease in placebo-treated

subjects. LVMI decreased in both treatment groups, with a significantly

higher reduction in lisinopril-treated subjects. LV diastolic function showed

no significant changes in either group.

Conclusion

The vascular pathophysiologic alterations of ISH - a decreased aortic

distensibility - can be reversed with long-term lisinopril treatment, while

values deteriorate further in placebo-treated subjects. LV mass index,

moderately elevated at baseline, decreased stronger with lisinopril-treatment.

These results, in one of the first studies including previously untreated

ISH-subjects only, indicate that lisinopril treatment might favorably influence

the cardiovascular risk of ISH.

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INTRODUCTION

Isolated systolic hypertension (ISH) is an important cardiovascular risk

factor frequently occurring in the elderly, and its treatment (with diuretics

and beta-blockers) has been shown to favorably influence morbidity and

mortality. So far, few studies have addressed the effects of treatment1 2 3 4 5 6

on the cardiovascular pathophysiologic changes occurring in ISH. Most

previous end-organ damage intervention studies dealt with subjects with

diastolic hypertension (DH). However, since the underlying pathophysiologic

features between ISH and DH differ strongly, these results need not to be

applicable to ISH-subjects.

The main important pathophysiologic change in ISH is a decreased

distensibility of the aorta and large arteries, with loss of the �Wind-kessel

function�. This decreased distensibility causes an increase of peak7 8 9 10 11

systolic pressure in ISH, while diastolic blood pressure is lower. Another

consequence of the decreased aortic distensibility is acceleration of pulse

wave velocity. When aortic distensibility is strongly impaired, as may happen

especially in elderly with ISH, the reflection of the pulse wave may occur

during cardiac systole, augmenting left ventricular (LV) systolic load with

values up to 50 mmHg. As a consequence of the decreased aortic12

distensibility and of early pulse wave reflection the systolic workload is

increased, which may lead to increased left ventricular mass index (LVMI).8 13

In some reports this relation between early pulse wave reflection and

increased LVMI was observed independent of blood pressure. Increased14 15

LVMI is a strong and independent risk factor for cardiovascular events in

various populations, including the elderly. While studies have16 17 18 19 20

shown that LVMI is elevated in ISH, information on the effects of21 22 23 24

antihypertensive treatment is scarce. One of the few reports available showed

regression of LVMI with diuretic therapy. Disturbance of LV diastolic25

function, which is another cardiac consequence of hypertension, was shown

to be impaired in ISH, but effects from intervention trials in ISH are not[22]

known yet.

The aim of this placebo-controlled study was to evaluate in a double-blind,

randomized, parallel group design, the effect of long-term antihypertensive

treatment on cardiovascular end-organ damage in patients with previously

untreated ISH. Since the renin-angiotensin system may play an important

part in both decrease of vascular distensibility and increase of LVMI also in

CHAPTER

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elderly hypertensives, the long-acting angiotensin-converting enzyme26 27

inhibitor lisinopril was chosen as antihypertensive drug, to evaluate the

hypothesis whether inhibition of the renin-angiotensin system can restore

abnormal vascular compliance and LVMI in ISH-subjects. Age- and

sex-matched normotensive controls were investigated also, to distinguish

age-related from blood pressure-related alterations. Several cardiovascular

end-organ damage measurements were carried out initially and after 6 and 24

months of treatment: aortic distensibility measured with pulse wave velocity,

and echocardiographic measurement of left ventricular mass and diastolic

function.

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METHODS

Study population

ISH-subjects and normotensive controls were derived from a population

screening program, inviting all inhabitants between 60 and 75 years of age

from a rural area in the Netherlands (municipality of Achtkarspelen), based

on municipal records. The inclusion criterium for ISH was an untreated

systolic blood pressure (BP) > 160 mmHg measured on three separate

occasions, with diastolic BP < 95 mmHg at least at the last two occasions, and

average diastolic BP < 95 mmHg. The inclusion criterium for normotensive

controls was BP < 160/95 mmHg, untreated and no history of previous

hypertension. These controls were matched with ISH-patients for age (5-years

interval) and gender. The BP was measured with a sphygmomanometer after

five minutes rest. The first measurement was done by trained volunteers, all

further measurements were done by physicians. All office BP recordings were

read as nearest even reading of mm Hg. Exclusion criteria were recent

myocardial infarction (< 3 months), cerebrovascular accident (< 1 year),

symptomatic congestive heart failure, cardiac arrhythmia other than atrial

fibrillation, or any other disabling medical condition hampering subject

participation. Presence of any of these exclusion criteria, or any other

condition hampering study participation were checked with the patient�s

general practitioner. Subjects were also excluded if both apical and

parasternal echocardiographic views were inadequate for obtaining

measurements. The study was approved by the Medical Ethical Committee of

the University Hospital Groningen, and written informed consent was

obtained.

At each visit during the treatment study, office BP was measured twice and

averaged, with a sphygmomanometer after five minutes rest. In the treatment

study, blood pressure was also measured ambulatory. This was done initially

and after 6 and 24 months of treatment with the Spacelabs 90207 device, with

time-weighed analysis and with separate analysis of daytime and night-time

measurements (daytime measurements (half-hourly) 07.00-23.00 h; night-time

(1-hourly) 23.00-07.00). Further measurements included height (only at initial

visit) and weight, from which the body mass index was calculated. History of

smoking, of diabetes and of familial hypertension or cardiovascular disorders

was obtained. Serum lipid profile, including high-density lipoprotein

cholesterol and triglycerides, and serum glucose was measured after

overnight fasting with conventional assay methods. Persons with plasma

CHAPTER

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glucose greater than 7.8 mmol/l (World Health Organization criterium) were

considered to be diabetic, in addition to those already known with or treated

for diabetes. All laboratory values were reported to the general practitioner,

who was allowed to install treatment (dietary or pharmacologically) if

deemed neccesary, eg. in case of diabetes of hypercholesterolemia.

Medication and follow-up

Medication allocation was double-blind, each capsule containing either 10

mg lisinopril or placebo. Active medication was derived from Zeneca Farma

(the Netherlands). Identical tablets were used, with the only difference of

obtaining active drug or not (placebo). The package of medication was done

by an independent organization (Tramarko bv., the Netherlands), and

numbered from 1 to 100 in a block scheme with in each four numbers two

active medications and two placebo. Patients were randomized according to

the sequence of entering in the study. The randomization list was kept closed

until end of study: if a medical emergency occurred necessitating knowledge

of medication, the code was broken by the study observer from Zeneca

Farma, thus avoiding code breaking by the principal investigators.

After the initial visit, all patients started with one capsule a day (10 mg,

once daily (od.), taken in the early morning). The dosage was increased to 20

mg (o.d.) after one month, and 40 mg (o.d.) after three months if goal of blood

pressure reduction (< 160 mmHg, or at least 20 mmHg reduction) was not

achieved. The dosage was reduced in case of orthostatic hypotension, defined

as more than 20 mmHg drop of BP from supine to standing, or suggestive

complaints such as dizziness with rising.

All end-organ damage measurements from the initial visit were repeated

after 6 months and after 24 months of treatment (final visit). ISH-patients also

underwent regular controls of BP and complaints after one month of

treatment and each third month thereafter.

Vascular end-organ damage measurements

Pulse wave velocity measurement. The aortic pulse wave is detected using

two Doppler probes, one at the approximate origin of the aorta (right

subclavian artery), and the other at the approximate end of the aorta (right

femoral artery). The time between the foot parts of the two recorded pulse

waves was measured using computer analyzing programs developed in our

laboratory. The PWV was calculated as the quotient of the aortic length28

REATMENT OF ISH -

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(estimated by measurement of the distance from upper sternal manubrium to

the inguinal ligament) and the time delay between both pulse waves. From

the PWV the aortic distensibility (D) is calculated using the formulaD= 1/(D *

v ) , in which D represents the density of the blood (taken 1050 kg/m ) and v2 3

the pulse wave velocity (unit D: 1/MPa). For analysis, three adequate29 30

consecutive recordings of 15 seconds were obtained for each patient, of which

a minimum of 30 adequate wave recordings had to be analyzable. The PWV

was calculated as average of all measurements available.

Cardiac end-organ damage measurements

Left ventricular mass. The echocardiographic left ventricular mass (LVM)

was calculated from measurements of left ventricular internal end-diastolic

diameter (EDD), interventricular septal (IVS) and posterior wall thicknesses

(PWT), according to the formula as proposed by Devereux and Reichek:31

LVM = 1.04 * ((IVS + PWT + EDD) - EDD ) - 13.6 (g).3 3

These measurements were made according to the Penn-convention from the

standard parasternal LV long axis view in 2-dimensional mode, in accordance

with routine procedures in our echocardiographic laboratory. LVM was

indexed to body surface area (BSA). LV geometry was calculated according to

Koren, with LVH defined as LVMI > 125 g/m , and a cutoff value for relative2

wall thickness (RWT = 2 * PWT / EDD) of 0.45, resulting in four geometric

classes: normal, concentric remodeling, and eccentric and concentric LVH.32

End-systolic dimension and left atrial dimensions were measured also.

Diastolic function. The LV diastolic filling was assessed with

pulsed-Doppler echocardiography. The sampling volume was placed

between the tips of the mitral valve leaflets in the standard apical

four-chamber view, and measurements were taken end-expiratory. Peak early

(E) and atrial (A) diastolic filling velocities and the deceleration slope of the

early inflow signal (EF-slope) were measured. Also, time velocity integrals of

early and atrial filling were measured, by tracking of the signals and

automatic calculation of integrals (Acuson Corp., Acuson, NY). The

isovolumetric relaxation time (IVRT) was measured in the standard apical

five chamber view. In this view the Doppler sampling volume was placed

above the anterior leaflet of the mitral valve near the LV outflow tract,

obtaining simultaneously signals of LV inflow and LV outflow. IVRT was

defined as the time interval between both flow signals.

CHAPTER

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All echocardiographic measurements were the average of three

end-expiratory measurements, and were performed on-line using a 2- to

2.5-MHz transducer (Acuson 128 XP-5, Acuson Corp.). All measurements

were performed on-line by one investigator (WFH), with video-backup of

registrations enabling control of measurements afterwards. During this

control, recorded measurements judged to be too poor of quality for accurate

mesurements of LV mass and diastolic filling were excluded from analysis.

REATMENT OF ISH -

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To compare the effects of lisinopril and placebo treatment in ISH-patients,

repeated measurements analysis with random intercept model was used for

all end-organ damage measurements (Proc. Mixed, SAS statistical software V

6.12, Cary, N.C.). In this analysis no replacement of missing values was33

done, all data are used to estimate the intra- and intersubject variation

components and the effects of parameters on the endpoints (time and

medication effects). Three differences were analyzed and accompanying

P-values were reported: evaluation of baseline differences between groups,

analysis of an overall trend in time, and most importantly analysis of

differences over time between both treatment groups. While the primary

analysis was evaluation of linear changes, possible other (quadratic) changes

were also analyzed in case of apparent non-lineair changes in the data. For

comparison of differences between baseline results of ISH and normotensive

control subjects, the unpaired Student� t-test was used.

The analysis as described above was done according to the per-protocol

principle, leaving out the results of protocol violators. Violation of protocol

could be due to occurrence of adverse events causing termination of study,

withdrawal of consent during study, or any other condition resulting in not

completing the study according to protocol. Patients were kept in analysis if

at least all blood pressure measurements were available for all three

measurement visits. After completion of the study, the baseline results of

those fulfilling per-protocol were compared with the results of the protocol

violators, to assess the influence of leaving out these missing cases.

Additional analyses in differences between groups were analysed with Chi-

square testing in case of percentages, and with Student� t-test for continuous

variables. All differences were considered statistically significant if the

two-sided P-value was < 0.05.

CHAPTER

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RESULTS

Inclusion and withdrawals

In the screening program, 150 persons (prevalence 8.3%) met the criteria for

ISH. Of these, 97 agreed to participate in the present investigation. Reasons

for ineligibility were mainly lack of interest or refusal to participate (n=30),

being considered unsuitable by the general practitioner (n=12), or presence of

major cardiovascular disorders (n=7), and an additional 4 subjects were

excluded because of inadequate recordings of both parasternal and apical

echocardiographic windows. From the same screening program 97

normotensive controls were investigated, matched to ISH-subjects for age

and gender. Of the 97 ISH-subjects, 62 (30 lisinopril, 32 placebo) could be

included in the per-protocol analysis. Most frequent reasons for exclusion of

per-protocol analysis was withdrawal of consent during study (8 lisinopril/ 9

placebo). Major complications occurred in 7 subjects, among which 3 deaths

(1 lisinopril: myocardial infarction, and 2 in placebo: small cell lung carcinoma

and a rare malignant cerebral disease), the other major events were acute

myocardial infarction and cerebrovascular accident (one of each in each

group). Seven subjects ended the study prematurely because of possible

drug-related complaints: orthostatic complaints (2 lisinopril/ 3 placebo), and

coughing (2 lisinopril). Other single occurring reasons for premature ending

were: withdrawal because of preoperative high blood pressure (placebo),

traffic accident and progressive pulmonary complaints (emphysema) with

orthopnoic complaints (both lisinopril), and moving out of the area

(lisinopril). No significant difference between both medication groups was

found for these reasons of withdrawal.

Baseline characteristics

Table 1 shows the age, gender and body mass index (BMI) at baseline of the

ISH and normotensive controls. No differences were observed between ISH

and control subjects. Neither weight nor cholesterol level changed

significantly during the treatment period. When comparing the results of

ISH-subjects fulfilling per-protocol conditions and those not (withdrawals),

no differences were observed in these results except for body mass index

which was higher in withdrawals (28.1 g/m vs. 26.7; p< 0.05).2

REATMENT OF ISH -

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variable lisinopril placebo controls

number of patients 48 49 97

gender (% males) 54 43 48

age (years) 68 (3.9) 68 (4.2) 67 (4.0)

body mass index (g/m ) 27 (3.2) 28 (3.8) 26 (3.5)2

diabetes (%) 8 2 4

smoker (%) 35 20 11

total cholesterol (mmol/l) 6.1 (0.9) 6.5 (1.1) 6.0 (1.1)

Table 1. Baseline characteristics of ISH-subjects and normotensive controlsValues (except numbers) are means (standard deviations). Differences between lisinopril andplacebo, and between ISH and controls: all N.S.

Blood pressure measurements

Office blood pressure decreased in the lisinopril-treated group, but also in

the placebo-group (Table 2). With ambulatory blood pressures a clear

decrease of both systolic and diastolic BP was seen after 24 months in the

lisinopril-treated group, while no significant change could be observed in the

placebo group. In all BP measurements, baseline values did not differ

statistically between both treatment groups.

Compared to normotensive controls, all blood pressure measurements at

baseline were higher in ISH-subjects except for ambulatory diastolic BP of the

placebo-group. In analysis of the influence of withdrawals, only 24-hour

systolic ambulatory BP differed significantly between per-protocol subjects

and withdrawals (135 vs. 142 mmHg, respectively).

CHAPTER

-210-

Measurement groupresults: mean (S.D.) differences lisinopril-placebo (P<):

baseline 6 months 24 months baseline time medication

office SBP (mm Hg)lisinoprilplacebocontrols

175 (15.0)*

174 (15.6)*

135 (15.2)

158 (16.7)163 (17.9)

161 (15.6)163 (17.2)

n.s. 0.001 n.s.

office DBP (mm Hg)lisinoprilplacebocontrols

87 (8.1)*

87 (9.2) *

81 (8.8)

82 (9.6)84 (9.1)

81 (6.6)80 (9.1)

n.s. 0.001 n.s.

amb. SBP (mm Hg)lisinoprilplacebocontrols

138 (12.5)*

133 (12.6)*

120 (11.1)

127 (12.5)129 (12.2)

125 (13.4) 134 (14.1)

n.s. 0.001 0.001

amb. DBP (mm Hg) lisinoprilplacebocontrols

78 (8.0)*

75 (6.6)73 (6.3)

71 (6.7)73 (7.7)

71 (7.3)74 (8.2)

n.s. 0.001 0.01

heart rate (bpm)lisinoprilplacebocontrols

76 (12.3) 77 (10.6)79 (13.3)

79 (15.1)82 (13.5)

73 (6.8)74 (8.8)

n.s. n.s. n.s.

Table 2. Results of blood pressure and heart rate measurements (per-protocol analysis; N=62).

Abbreviations: SBP = systolic blood pressure; DBP = diastolic blood pressure; amb = ambulatory BP (24-hour average).*; indicates significant difference (P< 0.05) between baseline results of ISH-subjects (lisinopril/placebo) and nomotensive controls)

REATMENT OF ISH -

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Figure 1. Results of aortic pulse wave velocity measurements. Legend: M: lisinopril G: placebo ": normotensive controls (baseline only)

Aortic distensibility

Aortic distensibility as determined by pulse wave velocity measurement

showed divergent results in the two treatment groups: in the lisinopril-group

distensibility increased with treatment while in the placebo group a decrease

was seen (figure 1, difference between both groups P< 0.05). The main

increase of distensibility with lisinopril appears to occur between 6 and 24

months of treatment. Aortic distensibility of lisinopril-treated patients at 24

months approached baseline values in normotensive controls, i.e. the

difference in distensibility between both groups was not significant (p= 0.12).

The changes during this second time interval in aortic distensibility were also

analysed separately, because in that period blood pressure, known to interfere

with results, shows little of no change. In this period from 6 to 24 months, the

increase in lisinopril-treated subjects was significant, (P< 0.05; student� t-test).

Total number of measurements available for analysis was 173 (93%). Aortic

distensibility was not different between those analyzed per-protocol and

those not (4.8 resp. 4.9 1/MPa).

Echocardiographic measurements

CHAPTER

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At baseline, LVMI was lower in the placebo-group compared to

lisinopril-treated subjects. (table 3). While a decrease was seen in both groups,

the change with lisinopril was significantly greater: 25 g/m versus 17 g/m in2 2

the placebo-group. Changes in unindexed LV mass were similar, with a

decrease of 48 gram (25% reduction) in lisinopril-treated subjects, versus 31

gram decrease (18%) in placebo-treated subjects (P< 0.05). At baseline,

presence of abnormal LV mass was rather modest: overall percentage of LV

hypertrophy was 10%, and 27% had concentric remodeling,

withoutsignificant differeces between both treatment groups. After 24 months

treatment 89% showed a normal geometry, and the remaining 11% showed

concentric remodeling (N=3 in lisinopril, 4 in placebo). Results of the separate

measurements of wall thickness and end-diastolic diameter at baseline

showed an tendency for higher values in subjects in the lisinopril

treatment-group compared to placebo, resulting in significantly higher LV

mass measurements. With treatment, a reduction of wall thickness was

observed in both groups, while the end-diastolic diameter was lowered in

lisinopril-treated subjects only. Values of interventricular septal thickness (not

shown) were comparable with results of posterior wall thickness. No

significant changes during treatment were observed in end-systolic

dimensions or atrial dimensions (results not shown). From the total number of

186 recordings (62 per-protocol subjects * 3 visits), 6 (3%) were considered

inadequate on video-analysis for accurate measurements, and these were left

out of analysis. When compared with normotensive controls, values of LVMI

and of PWT appeared to decrease to normotensive levels with treatment in

both groups.

REATMENTOFIS

H-

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measurement groupresults: mean (S.D.) differences lisinopril-placebo (P<):

baseline 6 months 24 months baseline time medication

LV mass (g)lisinoprilplacebocontrols

194 (36.5)*170 (39.1)*133 (39.3)

146 (31.9)138 (35.0)

146 (32.0)139 (28.9)

0.05 0.001 0.05

LVMI (g/m )2

lisinoprilplacebocontrols

104 (17.6)*92 (20.1)*71 (17.5)

79 (16.4)75 (17.6)

79 (15.6)75 (14.8)

0.05 0.001 0.05

PWT (mm)lisinoprilplacebocontrols

10.3 (1.1)*9.9 (0.9)*8.5 (1.0)

9.0 (1.0)8.7 (1.0)

8.7 (0.7)8.5 (0.8)

n.s.(0.08) 0.001 n.s.

EDD (mm)lisinoprilplacebocontrols

46.2 (3.5)*44.3 (3.3)43.3 (4.5)

43.9 (3.3)43.5 (3.1)

44.6 (3.9) 44.4 (3.3)

n.s. (0.058) 0.01 0.05

EA-ratio lisinoprilplacebocontrols

0.78 (0.14)*0.85 (0.17)0.88 (0.18)

0.81 (0.27)0.84 (0.25)

0.77 (0.18)0.83 (0.17)

n.s. (0.10) n.s. n.s.

Table 3. Echocardiographic results (per-protocol analysis; N=62).

Abbreviations: LV = left ventricular; LVMI = LV mass index; PWT = posterior wall thickness; EDD = enddiastolic diameter;EA-ratio = ratio of peak early and atrial filling velocity*; indicates significant difference (P< 0.05) between baseline results of ISH-subjects (lisinopril/placebo) and nomotensivecontrols)

CHAPTER

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The LV diastolic function as assessed by early to atrial (E/A) filling velocity

ratio did not show significant changes with treatment in both groups (table 3).

This was also true for other parameters of diastolic function such as pressure

half time of early filling, time velocity integrals of early and atrial filling, and

isovolumetric relaxation time. From the total number of 186 recordings, 4 (2%)

were considered inadequate on video-analysis for accurate measurements

and were left out of analysis. When compared with normotensive controls,

baseline values of the EA-ratio in control subjects were higher compared to

lisinopril-treated patients, not to placebo.

Both LVMI and EA-ratio did not differ between those analyzed per-protocol

and those not.

REATMENT OF ISH -

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DISCUSSION

This study shows that long-term lisinopril treatment results in an increase of

aortic distensibility and thus reversal of the main pathophysiologic feature of

ISH. While in placebo-treated subjects aortic distensibility decreases further,

in lisinopril-treated subjects the values improve after two years treatment to

levels comparable with age-matched normotensives. Such an improvement of

distensibility can be caused indirectly by lowering of blood pressure, or

directly by structural effects on the arterial wall. The time pattern as observed

in this study shows that the increase of distensibility with lisinopril appears to

take place mainly on longer term, between 6 and 24 months treatment. Since

during this period blood pressure does not show significant changes, neither

with office nor with ambulatory measurements, this suggests that lisinopril

does improve the arterial distensibility directly by (long-term) structural

effects on the vascular wall. The comparison with normotensive controls as

done in this study distinguishes these blood pressure-related changes in ISH

from effects of ageing, which is known to affect arterial compliance also.34

The conclusion may be that long-term treatment with the ACE-inhibitor

lisinopril can reverse the pattern of arterial pathophysiologic changes in ISH,

while these changes are directed oppositely in placebo-treated patients.

With regard to the choice for placebo treatment, it should be mentioned that

this study was designed in 1992, when only the results from the SHEP-study

were available indicating favourability of treatment of ISH. At that time,

treatment of ISH was not incorporated in the guidelines for hypertension,

neither nationally nor internationally (JNC-V: published later in 1993).35 36

After the publication of the results of the SYST-EUR study in 1997, which37

confirmed the beneficial effects of treatment of ISH on cardiovascular risk

from the SHEP-study, placebo treatment probably can not be accepted

anymore.

Along with the improved aortic distensibility the left ventricular mass

decreased in lisinopril-treated patients, with the majority of subjects

achieving normal LV geometry again. A decrease was also seen in

placebo-treated subjects, although the reduction was significantly less. Such a

decrease with placebo treatment has been observed in other studies also, such

as the TOHMS study, perhaps due to behavioural changes (diet, exercise) of38

subjects. In this study, participants did receive general information about the

beneficial effects of salt reduction and exercise; furthermore, general

practitioners were allowed to treat diabetes or hypercholesterolemia when

CHAPTER

- 216 -

deemed neccesary. Another problem can be measurement errors: in this study

a single observer (WFH) design was chosen as recommended, and39

measurements were blinded for medication, but not for time. When

re-analyzing a set of (blinded) echocardiographic recordings after the study,

there appeared to be a tendency for smaller WT measurements in time of

approximately 1 mm, which may have accounted for a difference in LVMI of -

10%: a variation which is within accepted limits. The significantly larger40

reduction in the lisinopril-group appears to support a favourable effect of

lisinopril on LV mass in ISH, although overall the differences may be

considered relatively modest in terms of clinical importance. These modest

changes may be explained by the moderate level of abnormalities in LV mass

in these ISH-patients: the percentage of LV hypertrophy was about 10% in

untreated subjects. This moderate level can be explained by the selection of

uncomplicated hypertensives from a population screening program and does

not neccesarily indicate end-organ damage in ISH to be low. As we reported

previously the level of end-organ damage in ISH was comparable to that of

diastolic hypertensives from the same population screening program.41

For LV diastolic function, no change at all for any parameter was observed

in any treatment group. This lack of effect was not caused by normalcy of

measurements in ISH, since they were different when compared with

normotensive controls. Comparable treatment studies in ISH are lacking,

while in diastolic hypertension various results have been reported: some

showing improvement of diastolic function parameters (often in populations

with LV hypertrophy), but some others not.42 43 44 45

A discrepancy was observed between the results of office and 24-hour

ambulatory measurements in this study. While office blood pressure was

lowered in both treatment groups, ambulatory BP changes only in

lisinopril-treated subjects. Part of this �spontaneous� change in office blood

pressure, which has been observed in other studies also, may be explained46 47

by the regression to the mean-phenomenon. The ambulatory measurements

do not have this problem, not only because the effect of regression to the

mean is less with this method, but also because subjects were not selected48

on ambulatory BP levels. Therefore, the significant differences as observed

with ambulatory blood pressures between lisinopril and placebo-treatment

probably better reflect true changes in BP than the results of office

measurements. The lower absolute value especially of systolic ambulatory

measurements is in accordance with previously published results in ISH.49

This is one of the first double-blind studies on effects of antihypertensive

treatment in ISH regarding end-organ damage, including previously

REATMENT OF ISH -

- 217 -

untreated ISH-subjects only. More intervention studies on arterial compliance

have been reported, including effects of angiotensin-converting

enzyme-inhibitors, but most of these studies concerned subjects50 51 52 53 54

with diastolic hypertension or mixed populations without separate

conclusions on ISH. Viewing the different pathophysiology of ISH and

diastolic hypertension, exact answers about effects of antihypertensive

treatment in ISH should be derived from studies involving ISH-subjects only.

Most previous ISH-studies so far only involved changes in blood pressure

with various antihypertensive drugs, while others only addressed55 56 57 58

effects on calculated peripheral vascular resistance or presented data in59

abstract only. This study now showed that the pathophysiological[25] 60

alterations of ISH: a decreased distensibility of the larger arteries, can be

reversed with long-term treatment with ACE-inhibition. This provides

additional insight in possible mechanisms of reducing the cardiovascular risk

of ISH, a risk that can be reduced succesfully as shown by the SHEP-study

and the SYST-EUR study.

Acknowledgements

The authors wish to thank Pieter J. de Kam, MSc, for his assistance in statistical

analyses and interpretations of these results.

CHAPTER

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REATMENT OF ISH -

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CHAPTER

- 224 -

LAW NR. X:

IF YOU DON�T TAKE A TEMPERATURE, YOU CAN�T FIND A FEVER

UMMARY AND DISCUSSION

- 225 -


SSSSUMMARY ANDUMMARY ANDUMMARY ANDUMMARY AND DDDDISCUSSIONISCUSSIONISCUSSIONISCUSSION

The subject of this thesis is isolated systolic hypertension, the least well

studied subtype of hypertension. In this thesis, the following questions have

been investigated:

� the prevalence and incidence of isolated systolic hypertension (ISH)

� vascular and cardiac pathophysiologic alterations in ISH

� development of improved methods for detection of end-organ damage

� the effect of various treatment on these pathophysiologic alterations in

ISH.

The answers to these various questions will be addressed hereafter, by

summarizing the observations as made in the different chapters.

Subsequently, the possible implications of these observations for our future

approach to ISH will be discussed.

CHAPTER

- 226 -

SUMMARY

In chapter 1 the problem of isolated systolic hypertension (ISH) is presented.

The reason why ISH has received less attention in the past is discussed, and it

is explained that this lack of attention is not correct given the cardiovascular

risk of ISH. Also, an overview of the knowledge on cardiac and vascular

pathophysiologic alterations in ISH is presented, discussing the paucity of

data on the effects on pathophysiologic alterations by treatment in ISH-

subjects. Available results in antihypertensive treatment of ISH on morbidity

and mortality are reviewed, with special attention on two large trials: the

SHEP- and the SYST-EUR study. These results are compared with results of

treatment in other (diastolic/younger) subtypes of hypertension.

In chapter 2, the methods used in this thesis are explained. The Groningen

Hypertension Service is introduced, under whose aegis the studies in this

thesis have been conducted. The terminology of vascular function

measurements, such as distensibility and compliance, is explained. The

cardiac end-organ damage measurements are explained also, together with

difficulties in interpretation of these measurements. The aims of this thesis

are presented in chapter 3. The general aim was to increase our

understanding of the pathophysiology of ISH, of its occurrence, of changes in

vascular and cardiac pathophysiology with various (new) methods, and of

effects of treatment on these pathophysiologic changes in ISH.

As shown in chapter 4, isolated systolic hypertension is the most frequent

occurring subtype of hypertension after the age of 65 years. �True� or isolated

diastolic hypertension is rare in the elderly, and most remaining hypertensive

elderly have combined (systolo-diastolic) hypertension. Another important

observation from this investigation was the high incidence of new

hypertensive cases: up to 20% in a two year follow-up, predominantly due to

new cases of ISH. One of the factors predicting this occurrence of ISH is the

height of the systolic blood pressure itself, which leads to the hypothesis of

�systolic hypertension begets systolic hypertension�.

In chapter 5, vascular pathophysiology of ISH is discussed, as compared

with normotensive controls from the same age. A clear decrease of

distensibility of large arteries could be observed in ISH, both for the aorta and

for the large arteries in the upper arm, which is considered to be the main


- 227 -

pathophysiologic abnormality in ISH. Furthermore, an increase in

distensibility of the smaller arteries in ISH was observed. This new

observation might represent a compensatory mechanism to maintain the

continuous flow mandatory for adequate blood supply to the tissues.

Differences with age-matched normotensives are contrary to the old opinion

of stiffening of arteries being an unavoidable occurrence associated with

ageing, as is still considered so in some opinions.

In chapter 6 and 7, two methods for improved detection of end-organ

damage in hypertension are presented. In chapter 6, an algorithm to

determine left ventricular mass on the basis of the electrocardiogram (ECG) is

presented. The reason for this is that detection of left ventricular hypertrophy

with the ECG is known to be quite insensitive. Many subjects with no criteria

for LVH on the ECG actually do have LVH when measured

echocardiographically. As shown, a fairly sensitive algorithm could be

developed, which showed a better prediction of the left ventricular mass than

existing models. Furthermore, the continuous variable of this model of left

ventricular mass appears to have advantages over the dichotomous �no/yes�

variable of left ventricular hypertrophy as used in most older

electrocardiographic methods.

Another attempt to improve detection of end-organ damage is the

nomogram for echocardiographic LV geometry as presented in chapter 7. This

allows an easy differentiation of patterns of abnormality of LV mass,

especially a new class of left ventricular geometry: concentric remodeling.

Subjects with this abnormality, defined as an increased left ventricular wall

thickness without reaching criteria for LV hypertrophy, have been shown to

carry an increased risk for cardiovascular morbidity and mortality. The

problem is that underlying calculations of concentric remodeling and left

ventricular hypertrophy are rather complex. The nomogram developed in this

chapter presents an easy way to determine the geometric class of

hypertensive subjects, by simple plotting of the echocardiographic values of

wall thickness and end-diastolic diameter.

Consequences of ISH in terms of abnormality of echocardiographic left

ventricular mass and geometry are presented in chapter 8. Prevalence of left

ventricular hypertrophy is not high in these subjects, but almost half of ISH-

subjects do show the abnormal pattern of concentric remodeling, and thus do

carry an increased cardiovascular risk (see chapter 7). Levels of abnormality

CHAPTER

- 228 -

of LV mass in newly-discovered ISH-subjects are shown to be comparable

with those of subjects with diastolic hypertension from the same population,

indicating that the cardiac consequences of this risk factor do not differ from

diastolic hypertension.

Chapter 9 and 10 present two studies on the effect of antihypertensive

treatment in ISH. In chapter 9, the effect of the angiotensin-converting

enzyme inhibitor quinapril is compared with that of diuretic treatment. In this

medium-long term study (6 months treatment), both drugs were successful in

lowering blood pressure, and in reducing cardiac and vascular end-organ

damage parameters as indicated by changes in echocardiographic left

ventricular mass and aortic distensibility. However, some small differences

between quinapril and the diuretic in LV diastolic function and peripheral

vascular function could be clinically relevant.

In chapter 10, long-term treatment (2 years) with another ACE-inhibitor,

lisinopril, was shown to be successful in reversing abnormalities of aortic

distensibility in ISH. Aortic distensibility increased to levels comparable with

age-matched normotensives, while in the placebo-treated group these values

deteriorated further. Echocardiographic left ventricular mass, moderately

elevated at baseline, reduced with lisinopril treatment, but this was also

observed in the placebo-group. These studies are among the very first in

studying pathophysiologic alterations with treatment, in previously untreated

ISH-subjects only.


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DISCUSSION AND IMPLICATIONS FOR THE FUTURE

Revival of ISH as a risk factor

The results of our observations, together with the positive results on

reduction of cardiovascular morbidity and mortality from the major studies in

ISH, imply that ISH is not a harmless disorder but a strong cardiovascular risk

factor, which should be recognized and treated accordingly. In fact, there is

no evidence that the cardiovascular risk of ISH, or the effect of therapeutic

intervention on this risk, is any less than that in diastolic hypertension, which

is generally accepted as a risk factor to be treated. Subjects with ISH do show

abnormal patterns of left ventricular mass and arterial distensibility when

compared to normotensive controls. As shown, these pathophysiologic

alterations appear to be almost completely reversible following long-term

treatment.

When this statement of increased attention deemed for ISH is accepted,

several problems arise, regarding management and screening of subjects with

ISH in daily practice, on guidelines and cost-effectiveness regarding this

treatment in the elderly, and on scientific approaches to identify subjects

perhaps more at risk than others which also is important in choice of

treatment.

Daily management of ISH in the elderly

The high prevalence, and especially, the high incidence of ISH present a

problem regarding the management of ISH in daily practice. Addition of ISH

as risk factor to be treated will approximately double the number of

hypertension patients in the general practice. This problem becomes even

larger when accepting that all elderly should be checked regularly, given the

high rate of development of systolic hypertension in the elderly as observed

in this thesis. Such an advice for regular blood pressure control, for instance

once yearly, is in line with the recent Dutch hypertension guidelines.Walma’97

CHAPTER

For references: see Chapter 3.1

- 230 -

One solution for this increased workload in daily practice could be the

assistant of the general practitioner, as already described in the thesis of

Smilde. Another solution could be a blood pressure control centre, organized

from general practitioners� laboratories. Population screening programs, are

another in which many previously unknown hypertensive subjects can be

detected who can be treated further by the general practitioner. Such a

screening program was also the basis of the present thesis.

ISH: whom to treat?

Another question is, whether all subjects with ISH should be treated

pharmacologically. The implications of this question are large. A positive

answer would mean that prescription of antihypertensive drugs in the elderly

would be doubled, up to a total of approximately 20% of the total population

above 60 years of age. However, as stated in the introduction of this thesis,

the benefits of treatment appear to be large, with an appreciable limited

number to treat to prevent one event. Specific cost-effectiveness analysis for

treatment of ISH is not available, but studies such as by Jönsson did show’96 1

that treatment of moderate severe hypertension in elderly aged over 70

actually can be cost-saving, given the high risk on (expensive) cardiovascular

disorders as a consequence of hypertension. Thus, even while discussion is

ongoing on possible underestimation of long-term effects of treatment which

may disfavour results in younger patients, antihypertensive treatment in the

elderly appears to be cost-effective. Given the comparability of results in ISH

with results in other subtypes of hypertension, the same is probably true for

ISH.

Guidelines for treatment of ISH

In recent years, several hypertension guidelines have been published

regarding the problem of ISH. The major guidelines, including those of the

European Task Force, the recent JNC-VI, and also nationalPyörälä’94 JNC’97

guidelines, now do include the advice to treat ISH. This treatment isWalma’97


- 231 -

meant to be pharmacologically, with an exception made for those with

average systolic blood pressures between 160 and 180 mm Hg, who initially

may be treated non-pharmacologically, eg. with dietary and life-style

modifications. These modifications should always accompany drug treatment

in ISH. However, when other cardiovascular risk factors are present, or when

this level of blood pressure persists for months despite these modifications,

antihypertensive drug treatment should be installed. Next to presence of

other risk factors, presence of end-organ damage can also be a reason to start

treatment more aggressively, e.g. pharmacologically. It should be noted

however, that the benefits and safety of such a differentiated approach

should be confirmed by prospective studies.

The goal of blood pressure reduction in treatment of ISH should ideally be

normalization of blood pressure, e.g. < 140 mm Hg. However, not only will

this be a goal probably difficult to achieve, but it will also mean a huge

reduction for those with high initial blood pressures such as 200 mm Hg, with

the accompanying risk of side effects (dizziness, fractures). A more practical

advice would be a reduction to below 160 mm Hg, with a minimum reduction

of 20 mm Hg, This amount of reduction appears to be in line with the results

achieved in the major ISH-studies (SHEP, SYST-EUR; see table 1.1 and 1.2).

Identification of subjects at risk

As stated above, it is important to take prevalence of the other

cardiovascular risk factors into consideration, when assessing the individual

risk of an ISH-subject. An ISH-subject who smokes, has diabetes and has a

positive family history for cardiovascular disorders clearly has a risk

exceeding that of a subject in whom ISH is the only risk factor. More accurate

prediction models for cardiovascular risk have been established, allowing

calculation of risk percentage, on which further treatment can be based. For

individual subjects, this composed coronary risk profile can be calculated

with risk charts, or computer models. On larger scale, cardiovascularAnderson’91

risk factor management services can be deployed to enable such a complete

approach to the cardiovascular risk of a patient. Such a service is currently

under development in Groningen.

There are some other specific approaches which may identify subjects at

higher risk than others. One approach is implementation of ambulatory blood

pressure measurements, as described in the recent thesis of F.W. Beltman,

CHAPTER

- 232 -

also under aegis of the Groningen Hypertension Service. Measurements done

with this technique appear to correlate better with end-organ damage than

the normal office measurement, and might also be less subjective to

spontaneous variations or regression to the mean. Also, subjects with �white-

coat hypertension� can be identified, as defined by normal measurements

with ambulatory BP despite elevated office BP measurements. However, the

discussion about the true �normalcy� of white-coat hypertension is

longstanding and not yet resolved, certainly not for elevated systolic blood

pressure values. The height of ambulatory systolic blood pressure readings

are much lower with ambulatory than with office measurements, possibly

reflecting problems in accuracy of measurements with the oscillatory method

as used with the ambulatory devices. Another variant of blood pressure

measurements, home BP measurement, is cheaper than ambulatory

measurements, but its value as predictor of cardiovascular risk is not well

established yet, while correlation with end-organ damage is less than that of

ambulatory measurements.

Alternative approaches to identify those at risk with ISH may be

biochemical assessments, such as microalbuminuria, atrial of brain natriuretic

factor, or genotype analysis such as the angiotensin-converting enzyme

insertion/deletion (I/D) genotype, but the value of these measurements need

to be studied further. Another selection method, to identify subjects at high

risk is based on severity of end-organ damage such as echocardiographic left

ventricular hypertrophy. This will be discussed in the next section.

Accessibility of echocardiography and other end-organ damage measurements

Echocardiography will remain the preferable method of end-organ damage

assessment in the near future. It is an easy, non-invasive method, and the

results are clearly associated with cardiovascular risk of the hypertensive

subject. Such a clearly increase cardiovascular risk is not only associated with

the top of abnormalities or left ventricular hypertrophy (LVH), but also the

large intermediate group of concentric remodeling is now known to predict a

moderate increased cardiovascular risk. These abnormal patterns of left

ventricular mass can be easily determined with the nomogram presented in

this thesis. Regarding the connection between reduction of an increased left

ventricular mass and the reduction of cardiovascular risk, it must be stated


- 233 -

that the absolute evidence still is lacking. However, most smaller studies

available do indicate such a favourable connection.Kannel’88,Muiesan’95

An implication of this proven importance of left ventricular mass

measurement with the echocardiogram is that every subject with ISH (and

the other subtypes of hypertension) should derive such an investigation,

preferably before treatment is installed. With this, information on the

individual cardiovascular risk can be improved, and treatment can be

adjusted accordingly. For such an application on large scale of the

echocardiogram, the general practitioner should have easier access to

echocardiography, for instance without the usual automatic referral to a

cardiologist. Supervision of the latter will be necessary for correct

interpretation of the outcome of echocardiographic measurements, and of

possible abnormal findings in ventricular function or valvular dysfunctions.

A disadvantage of the echocardiographic examination is that in 10-20% of

cases no reliable measurements can be obtained due to disturbances of fat or

air. Furthermore, the variance between different centres and investigators is

often considerable, probably due to lack of correct application of

measurement conventions. This has to be improved before echocardiography

can be applied on large scale in hypertension. When comparing the

echocardiogram with the other methods of assessment of LVH, earlier

investigations have already assessed that echocardiography is at least as cost-

effective as use of the electrocardiogram (ECG). The ECG is cheaperDevereux’87

than the echo, but cases of LVH are less well diagnosed. Another alternative

is magnetic resonance imaging, probably more accurate than the

echocardiogram in measuring LV mass, but also much more expensive, and

not feasible for use on large scale. The usefulness of echocardiography can be

improved by performing �limited� echo�s specified for hypertensive heart

disease.Sheps’97

Measurements of vascular end-organ damage probably will not easily gain

access to daily routine. Vascular distensibility measurements do increase our

understanding of the pathophysiologic alterations, and with that perhaps of

our understanding of the effects of different antihypertensive drugs, but

relation with cardiovascular risk is less well defined. Also, the techniques

available, such as the bio-impedance method, are more complicated.

Type of antihypertensive (drug) treatment of ISH

The discussion on the type of treatment in ISH, eg. which type or class of

CHAPTER

- 234 -

antihypertensive drug is the most appropriate to be used, is still open. In

favour of diuretics, the �simplest� and cheapest of the major classes of

antihypertensive treatment is the fact that the first large study on reduction of

cardiovascular risk in ISH, the SHEP-study, was carried out with theSHEP’91

diuretic chlortalidone as first-choice drug. However, little is known on their

effect on cardiac and vascular pathophysiology in ISH, although reduction of

blood pressure with diuretic treatment was shown to be accompanied by

reduction of LV mass (this thesis). For beta-blocking agents, little is known on

their efficacy in ISH. Atenolol was used as second-choice drug in the systolic

hypertension in the elderly program (SHEP)-study, but other studies,

including those on effects on pathophysiological alterations, are lacking. In

another trial on antihypertensive treatment in the elderly, the medical

research coucil (MRC)-II trial, which also included subjects with ISH,MRC’92

beta-blocking therapy failed to show a significant reduction of cardiovascular

endpoints, whereas diuretic treatment did so. With regard to calcium-channel

entry blockers, the long-acting dihydropyridine nitrendipine was used in the

second large European study in cardiovascular risk in ISH: the SYST-

EUR. Treatment did result in a favourable reduction of cardiovascularStaessen’97

endpoints. Calcium channels appear to be involved in smooth muscle tonus,

and thus - in theory - in regulation of arterial distensibility. However, studies

on cardiac and vascular pathophysiology of calcium-antagonists in ISH are

too few in number to confirm this hypothesis. For the final group of major

antihypertensive drugs, the angiotensin-converting enzyme inhibitors, treatment

appears to be favourable, based both on the theory of the renin-angiotensin

system being involved in the pathophysiologic alterations in (systolic)

hypertension, and on the apparent favourable effect of these antihypertensive

drugs on left ventricular hypertrophy. As shown in this thesis, effects on

vascular pathophysiologic changes in ISH appear to be beneficial, with long-

term treatment reversing aortic distensibility towards normotensive values.

However, results on cardiovascular morbidity and mortality of ACE-

inhibitors are yet lacking, although enalapril was used as second-line drug in

the SYST-EUR study. With regard to the newer classes of antihypertensive

drugs, such as the angiotensin II receptor blockers, too few results are yet

available to evaluate their efficacy in the treatment of ISH.

In view of this ongoing discussion of favourable effects of one type of

antihypertensive drug over another, it may well be hypothesized that, at least

for the majority of subjects, �adequate lowering of blood pressure is more important


- 235 -

irrespective of type of drug used to achieve this�. This hypothesis is supported by

observations such as from the Treatment of Mild Hypertension Study

(TOMHS), which showed comparable results in blood pressureNeaton’93

lowering and reduction of LV mass with representatives of the major

antihypertensive drug classes, but also with (strict) dietary measurements.

In summary, efforts should be directed towards adequate lowering of blood

pressure. Next to an antihypertensive effect the choice of type of

antihypertensive drug may depend on costs and tolerability. Specific choices

for some classes may of course still be necessary in case of concomitant

disorders, such as diabetes mellitus or left ventricular dysfunction.

In conclusion ...

ISH should now be recognized as a disorder which warrants treatment, as

depicted in recent international and national guidelines. It is the most

prevalent subtype of hypertension in the elderly, and subjects with ISH do

show abnormal LV masses and patterns of arterial distensibility. These

pathophysiologic changes appear to be reversible with long-term

antihypertensive treatment. The high prevalence and incidence of ISH poses

a major challenge in daily practice, especially viewing the increase of the

proportion of elderly in our population in the future. Stratification studies, in

which subjects are treated in accordance with their cardiovascular status, are

needed in order to assess whether this can be used as a parameter to choose

therapy. Reversal of the influence of this major cardiovascular risk factor will

succeed in reduction of disorders such as strokes, myocardial infarction and

heart failure, all disorders with a major impact not only on survival but also

on quality of life of the elderly.

CHAPTER

- 236 -

LAW NR. XI:

SHOW ME A BMS (BEST MEDICAL STUDENT)WHO

ONLY TRIPLES MYWORK AND IWILLKISS HIS FEET

AMENVATTING EN DISCUSSIE

- 237 -


SSSSAMENVATTING ENAMENVATTING ENAMENVATTING ENAMENVATTING EN DDDDISCUSSIEISCUSSIEISCUSSIEISCUSSIE

Dit proefschrift gaat over het probleem van geïsoleerd systolische

hypertensie (afgekort ISH) ofwel te hoge bovenbloeddruk. Over deze vorm

van hoge bloeddruk is veel minder bekend dan over de �normale� hoge

bloeddruk, waarbij de diastolische of onderbloeddruk verhoogd is. In dit

proefschrift zijn de volgende aspecten van ISH onderzocht:

� het vóórkomen en optreden van geïsoleerd systolische hypertensie

(ISH)

� het optreden van veranderingen in de bloedvaten en het hart bij ISH

� ontwikkeling van verbeterde methoden om deze veranderingen in het

hart aan te tonen

� het effect van medicamenteuze behandeling op de veranderingen in

het hart en de bloedvaten in ISH

De antwoorden op deze vragen, zoals weergegeven in de verschillende

hoofdstukken van dit proefschrift, zullen eerst worden samengevat. Hierna

zal besproken worden of deze bevindingen, gecombineerd met wat reeds

bekend is over ISH, aanleiding geven om onze benadering van patiënten

met ISH te veranderen. In deze discussie zal ook worden ingegaan op de

gevolgen voor de dagelijkse praktijk.

CHAPTER

- 238 -

SAMENVATTING

In hoofdstuk 1wordt het probleem van te hoge bovenbloeddruk of

geïsoleerd systolische hypertensie (ISH) geintroduceerd. Via een kort

historisch overzicht wordt getoond dat systolische hypertensie eigenlijk al

heel lang bekend staat als een belangrijke risicofactor voor hart en

vaatziekten, maar dat in de jaren �60 de aandacht verschoven is naar

diastolische hypertensie. Reden hiervoor is, dat in die jaren de eerste grote

behandelingsstudies gedaan zijn naar het effect van

bloeddrukverlangende medicijnen op ziekte en sterfte bij werkende

mannen < 60 jaar. In deze groep is het belangrijkste probleem diastolische

hypertensie, ISH komt daar weinig voor. Vrij recent, in de jaren �90, zijn

alsnog soortgelijke studies verricht naar het effect van behandeling van

ISH. Deze studies laten zien dat het effectief is om mensen met ISH te

behandelen: dat voorkomt zo�n 40% aan beroertes en zo�n 20% aan

hartaandoeningen. Deze resultaten zijn minstens net zo goed als de

resultaten van diastolische hypertensie-studies. In dit hoofdstuk wordt ook

weergegeven wat er tot nu toe bekend is over veranderingen in het hart en

de bloedvaten bij ISH, waarbij blijkt dat er nog maar heel weinig studies

zijn verricht naar het effect van behandeling op deze veranderingen.

In hoofdstuk 2worden de methoden uitgelegd, zoals die in dit

proefschrift gebruikt zijn. De werkwijze van de Stichting

Hypertensiedienst Groningen wordt geintroduceerd, waarmee ook het

huidige onderzoek is uitgevoerd. Verder wordt de terminologie van

metingen en bepalingen van de bloedvaten besproken, en de verschillende

methoden voor metingen van de rekbaarheid van de bloedvaten uitgelegd.

Ook de metingen van de veranderingen in het hart, in het bijzonder van de

dikte van de hartspier worden in dit hoofdstuk uitgelegd, samen met de

mogelijke problemen die bij deze metingen spelen.

De doelstellingen van dit proefschrift worden gepresenteerd in hoofdstuk

3. Naast het vaststellen van de omvang van het probleem, was een

belangrijke doelstelling meer inzicht te krijgen in de veranderingen in hart

en bloedvaten bij patiënten met ISH. Dit is gedaan door metingen van ISH-

patiënten te vergelijken met ouderen met een normale bloeddruk, en ook

door het effect van medicamenteuze behandeling op deze veranderingen

in ISH te bestuderen. In dit hoofdstuk is tevens een lijst opgenomen met

gebruikte literatuurreferenties.

In hoofdstuk 4wordt het vóórkomen van hoge bloeddruk beschreven,


- 239 -

zoals gevonden in het bevolkingsonderzoek in de gemeente Achtkarspelen

(NL). Geïsoleerd systolische hypertensie blijkt de meest voorkomende

vorm van hoge bloeddruk na het 65 levensjaar te zijn. Alléén verhoogdee

onderbloeddruk komt op deze leeftijd maar zelden voor; de andere

personen met hoge bloeddruk tonen een verhoging van zowel de onder-

als de bovenbloeddruk. Een andere belangrijke bevinding komt voort uit

de herhaling van dit onderzoek na 2 jaar. Na deze periode blijkt van de

personen die oorspronkelijk een normale bloeddruk hadden circa 20% een

te hoge bloeddruk te hebben gekregen. Ook bij deze nieuwe gevallen is

ISH weer de meest voorkomende vorm van hoge bloeddruk. Het blijkt dat

de stijging van de systolische bloeddruk in deze twee jaar met name

optreedt bij de hogere systolische bloeddrukken, wat leidt tot de hypothese

dat hoge bovenbloeddruk zelf bijdraagt tot het ontstaan van hoge bovenbloeddruk.

In hoofdstuk 5worden de veranderingen in de bloedvaten beschreven

bij patiënten met ISH. Het blijkt dat de rekbaarheid van de grote

lichaamsslagaders duidelijk is afgenomen. Deze afgenomen rekbaarheid

wordt beschouwd als het belangrijkste kenmerk van ISH. Een nieuwe

bevinding is dat de rekbaarheid van de kleine slagaderen juist lijkt te zijn

toegenomen. Een verklaring hiervoor zou kunnen zijn dat deze

toegenomen rekbaarheid van de kleine bloedvaten een compensatie is

voor de afgenomen rekbaarheid van de grote bloedvaten, teneinde de

bloedvoorziening naar de weefsels te handhaven. De duidelijke

verschillen die gevonden worden tussen patiënten met ISH en personen

van dezelfde leeftijd met een normale bloeddruk, benadrukken nogmaals

dat het stugger worden van de bloedvaten (en daardoor verhoging van de

bovenbloeddruk) géén normaal fysiologisch ouderdomsverschijnsel is.

In de hoofdstukken 6 en 7 worden twee manieren uitgelegd voor

verbeterde opsporing van veranderingen aan het hart als gevolg van de

hoge bloeddruk. Hoofdstuk 6 gaat over het hartfilmpje ofwel het

electrocardiogram (ECG). Al lang is bekend dat met het ECG een te dikke

hartspier of linker ventrikelhypertrofie (LVH) opgespoord kan worden.

Deze methode is echter niet erg gevoelig, patiënten kunnen LVH hebben

terwijl het ECG normaal is. Een tweede nadeel van deze methode is dat

alleen het �goed/fout� fenomeen oftewel de aan- of afwezigheid van LVH

kan worden vastgesteld, terwijl in werkelijkheid de mate van

hartspierverdikking een continu gegeven is. In dit hoofdstuk wordt een

model gepresenteerd welke wél een continue maat geeft als inschatting

van de mate van verdikking van de hartspier. Deze methode neemt naast

het ECG ook andere factoren mee, zoals het geslacht en de lichaamsbouw.

CHAPTER

- 240 -

De uitkomst van dit model bleek vrij goed overeen te komen met de

meting van de hartspierdikte volgens het echocardiogram.

Hoofdstuk 7 gaat over een verbeterde methode van de echocardiografie.

Hiermee kan een vrij betrouwbare schatting worden gemaakt van de

hartspierdikte of de linker ventrikelmassa. Voor wetenschappelijk

onderzoek is deze continue maat het meest optimaal, maar in de dagelijkse

klinische praktijk wordt vaak een �goed/fout� afweging gevraagd: wel of

geen hypertrofie (LVH). Nadeel is dat dan alleen de top van afwijkingen

wordt gezien. Een antwoord hierop is het onderscheiden van een

tussengroep van personen die al wel een relatief te dikke spierwand van

de linker kamer hebben, zonder dat de criteria voor LVH bereiken.

Patiënten met deze tussengroep, genaamd concentrische remodeling,

blijken óók een verhoogd risico op hart- en vaatziekten te hebben. Een

probleem is dat deze groep lastig te onderscheiden is door de

ingewikkeldheid van de onderliggende berekeningen. Als oplossing voor

dit probleem wordt in dit hoofdstuk een nomogram gepresenteerd, een

grafiek waarmee op eenvoudige wijze de verschillende vormen van

hartspierverdikking bepaald kunnen worden.

De gevolgen van geïsoleerd systolische hypertensie voor het hart worden

nader bekeken in hoofdstuk 8. Daarin blijkt dat bij het merendeel van

nieuw ontdekte patiënten met geïsoleerd systolische hypertensie het hart

een toegenomen dikte heeft. Slechts een klein deel van de ISH-patiënten

vertoont echte hypertrofie (LVH) van de linker hartkamer, maar een vrij

groot deel blijkt relatief toegenomen wanddikte te hebben of concentrische

remodeling. Deze afwijkende vormen komen net zo vaak voor bij ISH-

patiënten als bij patiënten met diastolische hypertensie, en veel vaker dan

bij ouderen met normale bloeddrukken. Dit duidt erop dat de gevolgen

van ISH net zo ingrijpend zijn als die van de �gewone� diastolische

hypertensie.

De hoofdstukken 9 en 10 bevatten de resultaten van twee onderzoeken

naar de effecten van behandeling van ISH met verschillende

bloeddrukverlagende medicijnen. In hoofdstuk 9wordt het effect van een

�moderne� bloeddruk-verlager, de angiotensine-converting enzyme

(ACE)-remmer quinapril, vergeleken met het effect van de �ouderwetse�

plastablet triamtereen/hydrochlorothiazide. Beide middelen bleken in

deze middellange studie (6 maanden) in staat te zijn om de bloeddruk van

deze patiënten even goed te verlagen. Beide middelen gaven een

vergelijkbare verlaging van de mate van linker ventrikelhypertrofie en de

rekbaarheid van de lichaamsslagader. Het was verondersteld dat de ACE-


- 241 -

remmer quinapril hierin meer effectief zou zijn, omdat het angiotensine

juist een van de factoren lijkt te zijn die een rol speelt bij deze afwijkingen.

Er waren wel verschillen in de resultaten ten gunste van quinapril op de

soepelheid van de linker kamer en de rekbaarheid van kleinere

bloedvaten, maar deze waren niet eenduidig.

In hoofdstuk 10worden de resultaten van een lange-termijn studie (2

jaar) bij ISH gepresenteerd. Het effect van behandeling met een andere

ACE-remmer: lisinopril, wordt vergeleken met het effect van een niet-

werkzaam middel (placebo). De belangrijkste bevinding van deze studie is

dat de rekbaarheid van de lichaamsslagader in de met lisinopril

behandelde patiënten duidelijk verbetert, terwijl de resultaten (verder)

verslechteren in de placebo groep. De resultaten na twee jaar lisinopril-

behandeling benaderen die van controlepersonen met een normale

bloeddruk. Dit betekent dat de toegenomen stugheid van de grote

lichaamsslagaders, het belangrijkste kenmerk van geïsoleerd systolische

hypertensie, hersteld lijkt te kunnen worden. De dikte van de hartspier

verbetert met lisinopril tot bijna-normale waarden, maar laat ook een

verbetering zien in de placebo-groep. Hetzelfde geldt voor de gewone

bloeddruk, die zowel in de lisinoprilgroep als in de placebogroep daalt.

Mogelijke verklaringen hiervoor zouden kunnen zijn het placebo-effect,

dieetveranderingen of variaties in de metingen. De resultaten van de

ambulante 24-uurs bloeddrukmetingen laten wèl een verschil tussen beide

groepen zien, met een duidelijke verlaging in de lisinopril-groep terwijl de

metingen in de placebo-groep min of meer onveranderd blijven.

De twee studies in deze hoofdstukken behoren tot de eerste studies naar

effecten van behandeling op hart en bloedvaten in patiënten met ISH.

CHAPTER

- 242 -

DISCUSSIE EN IMPLICATIES VOOR DE TOEKOMST

ISH als risicofactor voor hart- en vaatziekten

De resultaten van dit proefschrift, samen met de bekende resultaten over

de gunstige effecten van behandeling van ISH, geven aan dat de oude

opvatting dat een systolisch verhoogde bloeddruk minder belangrijk is en

niet behandeld hoeft te worden, onterecht is en verworpen dient te

worden. ISH is een sterke en belangrijke risicofactor voor hart- en

vaatziekten, en de effecten van behandeling zijn zeker zo gunstig als de

behandeling van te hoge onder-bloeddruk. Zoals gebleken in dit

proefschrift vertonen personen met ISH duidelijk afwijkingen in de zin van

stuggere grote slagaders, en toegenomen dikte van de hartspier. Deze

veranderingen aan hart en bloedvaten lijken met langdurige behandeling

herstelbaar te zijn.

Met het accepteren van ISH als te behandelen risicofactor ontstaat er

een aantal praktische problemen en punten van discussie. Deze zullen

hierna besproken worden. Het eerste punt is de betekenis voor de

dagelijkse praktijk, met het probleem van opsporen en behandelen van

deze nieuwe groep patiënten. Richtlijnen voor de behandeling van ISH

worden gegeven, inclusief kosten-baten analyses van deze behandeling.

Tevens worden de verschillende mogelijkheden besproken waarmee

personen die een relatief hoger risico lopen dan anderen geselecteerd

kunnen worden. Tenslotte volgt een overzicht van de bekende resultaten

van de verschillende bloeddruk-verlagende medicijnen bij ISH.


Voor referenties: zie Hoofdstuk 3 1

- 243 -

ISH in de dagelijkse paraktijk

De hoge mate van voorkomen van ISH, en het aantal nieuwe gevallen

dat na relatief korte tijd kan worden aangetroffen, geven een probleem

voor de dagelijkse praktijk. De personen met ISH moeten vaak

gecontroleerd en behandeld worden, wat al leidt tot een verdubbeling van

het aantal ouderen met hoge bloeddruk in de huisartsenpraktijk. Daarnaast

zouden ook ouderen met nog normale of licht verhoogde

bovenbloeddrukken frequent gecontroleerd moeten worden, gezien het

risico op snel ontstaan van hypertensie, zoals ook geadviseerd wordt in de

recente richtlijnen van het Nederlandse Huisartsengenootschap

(NHG). Een oplossing voor dit praktische probleem is hetWalma ‘97 1)

inschakelen van de doktersassistente voor het doen van de

bloeddrukmetingen. Niet alleen kan hiermee hoge bloeddruk worden

opgespoord, maar tevens is gebleken dat zo patiënten met hoge bloeddruk

goed ingesteld en gecontroleerd kunnen worden met hulp van

behandelingsprotocollen. Zo�n aanpak zou ook centraal, viaSmilde [thesis] ‘79

huisartsenlaboratoria kunnen worden uitgevoerd, in het kader van

algemene risicofactorenmanagement. Een andere oplossing voor actieve

opsporing van hoge bloeddruk is het regelmatig verrichten van

bevolkingsonderzoekingen, zoals ook aan het huidige proefschrift ten

grondslag ligt, maar zulke onderzoeken vergen veel tijd en inspanning.

ISH: wie te behandelen?

Een belangrijke vraag is, of iedereen met ISH met medicijnen behandeld

moet worden. Indien deze vraag met �ja� beantwoord zou worden dan

heeft dit grote consequenties, aangezien het leidt tot een verdubbeling van

gebruik van bloeddrukverlagende medicijnen, tot in totaal zo�n 20% van

alle ouderen van 60 jaar en ouder. Een argument vóór zo�n positief

antwoord is dat bewezen is dat zo�n behandeling van patiënten met ISH

positief is: er wordt een duidelijk aantal beroertes en andere hart- en

vaatziekten mee voorkomen. Er hoeven niet eens zo heel veel personen te

behandeld worden om één zo�n gebeurtenis te voorkomen (zie tabel 1.3),

zeker niet in vergelijking met de �jongere� (< 60 jaar) patiënten met

diastolische hypertensie. Hierbij moet wel worden aangetekend dat bij

jongeren de gemiddelde duur van de studies (tot zo�n 5 jaar) misschien te

kort voor een optimaal rendement. Toch is de conclusie dat behandeling

CHAPTER

- 244 -

van ISH effectief is in termen van reductie van het risico op hart- en

vaatziekten. Dit geldt overigens dus ook voor ouderen met gemengde of

systolo-diastolische hypertensie.

Een ander belangrijk punt van discussie is, of het wel loont om ouderen

met ISH te behandelen, oftewel is het kosten-effectief? Eerdere studies

hebben reeds aangetoond dat behandeling van hoge bloeddruk in ouderen

niet alleen kosten-effectief, maar zelfs kostenbesparend kan zijn. Jönsson’96

Een verklaring hiervoor is dat bij ouderen hart- en vaatziekten vaker

vóórkomen, wat het gemakkelijker maakt om deze te voorkómen. Het

onderzoek van Jönsson betrof ouderen met gemengde hoge bloeddruk,

maar waarschijnlijk mag worden aangenomen dat hetzelfde geldt voor

ISH.

Richtlijnen voor behandeling van ISH

De afgelopen jaren zijn verschillende richtlijnen verschenen voor de

behandeling van hoge bloeddruk in het algemeen. De belangrijkste hiervan

zijn die van de European Task Force, de Amerikaanse JNC-VI,Pyörälä’94 JNC’97

en ook de nationale NHG-richtlijnen, In al deze is ISH nuWalma’97

opgenomen als te behandelen aandoening. Met deze behandeling wordt

een medicamenteuze behandeling bedoeld, waarbij mogelijk een

uitzondering te maken is voor diegenen met een matig verhoogde

bovenbloeddruk, gemiddeld tussen 160 en 180 mmHg. In deze laatste

gevallen zou kunnen worden volstaan met niet-medicamenteuze

behandeling, zoals dieetmaatregelen (zoutbeperking, afvallen) en

leefregels (meer beweging). Echter, wanneer deze personen tevens andere

risicofactoren voor hart- en vaatziekten hebben, of wanneer de bloeddruk

verhoogd blijft ondanks de genoemde maatregelen (termijn 3- max. 6

maand), zal hiernaast ook medicamenteuze behandeling gestart dienen te

worden. Een andere reden om direct behandeling met medicijnen te

starten is bestaande aanwijzingen voor eindorgaanschade, zoals een te

dikke hartspier. Wel moet worden opgemerkt dat de veiligheid en

effectiviteit van zo�n gestratificeerde aanpak nog niet door vooropgezet

(prospectief) onderzoek bewezen is.

Voor wat betreft de mate van bloeddrukverlaging zou idealiter de

systolische bloeddruk genormaliseerd moeten worden, dat wil zeggen tot

beneden 140 mm Hg. Echter, dit zal vaak moeilijk haalbaar blijken, en ook

een te forse reductie kunnen betekenen voor diegenen met een hoge

uitgangsbloeddruk van bijvoorbeeld 200 mm Hg, met het risico van veel

bijwerkingen als duizeligheid en valpartijen, met alle complicaties van


- 245 -

dien. Een meer praktisch advies zou kunnen zijn te streven naar verlaging

tot onder de 160 mm Hg, met een verlaging van tenminste 20 mm Hg. Zo�n

verlaging lijkt haalbaar en ook relevant, gelet op de beschikbare resultaten

van de ISH-onderzoeken inclusief de grote ISH-trials (SHEP, SYST-EUR;

zie tabellen 1.1 en 1.2 in hoofdstuk 1).

Identificatie van personen met een verhoogd risico

Zoals hierboven uiteengezet is het belangrijk om de aanwezigheid van

andere risicofactoren voor hart- en vaatziekten mee te wegen, bij het

inschatten van het risico van de individuele patiënt met geïsoleerd

systolische hypertensie. Een persoon met ISH die ook nog eens rookt,

suikerziekte heeft en bij wie in de familie veel hart- en vaatziekten

voorkomen heeft natuurlijk een duidelijk hoger risico dan iemand met

alleen ISH. Voor een meer precieze berekening van het gecombineerde

risico op hart en vaatziekten bij de individuele patiënt zijn

computermodellen beschikbaar. Een andere werkwijze is het in éénAnderson’91

keer bepalen van het totale risicoprofiel door bijvoorbeeld

huisartsenlaboratoria, wat als voordeel heeft dat het risicoprofiel op grote

schaal en gestandariseerd kan worden vastgesteld. Zo�n cardiovasculaire

risicomanagement-service, waarbinnen ook bloeddrukcontroles kunnen

worden verricht, is momenteel in oprichting in Groningen.

Er zijn ook nog andere manieren om het individuele risico van de patiënt

met ISH beter in te kunnen schatten. Eén ervan is het gebruik van 24-uurs

bloeddrukmetingen, zoals recent uitgebreid beschreven in het proefschrift

van Beltman. De resultaten van deze metingen blijken beter tethesis’96

correleren met de mate van eindorgaanschade dan de gewone

enkelvoudige bloeddrukmeting uit de spreekkamer, bovendien kunnen

met deze methode individuen onderscheiden worden die in de

spreekkamer wèl een hoge bloeddruk hebben, maar daarbuiten niet: de

�witte-jas hypertensie�. Of dit fenomeen nu wel of niet onschuldig is staat

echter nog steeds ter discussie. Daarnaast staan de normaalwaarden voor

de ambulante bloeddrukken nog minder duidelijk vast in vergelijking met

de spreekkamerbloeddruk, zeker voor de bovenbloeddruk. Een ander

probleem is dat met de meeste methodes van 24-uurs meting de gemeten

bovenbloeddruk veel lager is ten opzichte van de spreekkamer, wat

mogelijk komt door de andere manier van meten. Een laatste nadeel van

de ambulante bloeddrukmeting is dat deze in vergelijking vrij duur is.

CHAPTER

- 246 -

Een andere variant van bloeddrukmeten is de thuisbloeddrukmeting,

waarbij een patiënt met een eigen (automatische) bloeddrukmeter thuis

gedurende een aantal dagen regelmatig de bloeddruk meet. Deze meting is

goedkoper dan de ambulante meting, maar de voorspellende waarde van

deze methode voor het risico op hart- en vaatziekten is nog niet duidelijk,

terwijl de relatie van deze metingen met eindorgaanschade minder goed

lijkt te zijn dan die van ambulante metingen.

Er zijn nog meer alternatieven om het risico van de individuele patiënt

met ISH beter te kunnen inschatten, zoals bepalingen uit het bloed (ANF,

BNF, ACE-genotype) of de urine (micro-albuminurie), maar de waarde van

deze metingen moet nog bewezen worden. Over het risico en de mate van

schade aan de �eindorganen� zoals het hart en de bloedvaten, is meer

bekend ook uit dit proefschrift, en dit zal apart in de volgende paragraaf

behandeld worden.

Plaats van echocardiografie en andere eindorgaanschade-metingen

Echocardiogafie zal voorlopig de methode van keuze blijven om de

gevolgen van hoge bloeddruk te bepalen. Het is een gemakkelijk, niet

belastend onderzoek, en het hebben van afwijkingen is duidelijk

gerelateerd aan de prognose van de patiënt met hoge bloeddruk. Niet

alleen loopt deze een veel hoger risico op hart en vaatziekten bij het

hebben van evidente linker ventrikelhypertrofie (LVH), maar ook kan de

grote middengroep met een matig verhoogd risico: concentrische

remodeling worden opgespoord. Deze afwijkingen zijn nu eenvoudig te

bepalen met het nomogram zoals gepresenteerd in dit proefschrift. Voor

wat betreft het verband tussen het verlagen van een te hoge linker

ventrikelmassa en en reductie van het risico op hart- en vaatziekten moet

gesteld worden dat het absolute bewijs nog ontbreekt (vergt grootschalig

prospectief onderzoek), maar onderzoeken wijzen wel op eenDevereux’94

gunstig resultaat van reductie van LVH.Kannel’88, Muiesan’95

Een implicatie van dit duidelijke belang van de hartspiermassa zoals

gemeten met het echocardiogram zou zijn dat alle personen met ISH en

ook andere vormen van hoge bloeddruk zo�n echocardiografisch

onderzoek zouden moeten ondergaan, idealiter vóór de start van enige

behandeling. Hiermee kan beter het risico van de individuele patiënt

worden ingeschat, en eventueel ook de behandeling hierop worden

aangepast. Zo�n grootschalige toepassing betekent wel dat het

echocardiogram gemakkelijker onder het bereik van de huisarts moet


- 247 -

komen, bijvoorbeeld zonder automatische verwijzing naar de specialist.

Een voordeel ook qua kosten zou een �verkort� uitgevoerd echo-onderzoek

zijn. Anderzijds is specialistische supervisie van het echo welSheps’97

noodzakelijk, voor een correcte interpretatie van de metingen en van

eventueel gevonden afwijkingen in de functie van de hartspier en de

hartkleppen.

Naast deze genoemde voordelen van het echocardiogram zijn er ook

enkele nadelen. Zo is bij zo�n 10-20% van de patiënten geen betrouwbare

meting mogelijk, door teveel storende invloeden van lucht (longpatiënten)

of vet (zwaarlijvigheid). Daarnaast lijkt er nogal wat variatie te bestaan

tussen de uitkomsten van metingen bij verschillende centra of

onderzoekers. Waarschijnlijk komt dit doordat er te weinig strict volgens

bestaande criteria gemeten wordt. Dit dient verbeterd te worden alvorens

echocardiografie op grote schaal gebruikt kan worden. Ten opzichte van de

andere mogelijkheden van eindorgaanschade-onderzoek heeft het

echocardiogram ook weer voordelen. Zo is het electrocardiogram wel

goedkoper, maar te veel gevallen van LVH worden er nog mee gemist,

waardoor het echo uiteindelijk toch beter scoort in kosten-

effectiviteit. Een ander onderzoek, magnetische resonantie-imagingDevereux‘87

of MRI, is nauwkeuriger in het meten van de dikte van de hartspier dan

het echocardiogram, en heeft daarbij ook minder last van lucht of vet, maar

dit onderzoek is weer veel duurder en niet toepasbaar op grote schaal.

Metingen van de soepelheid van de bloedvaten zullen niet direct een

standaard plaats verdienen in de dagelijkse praktijk van de patiënt met

ISH. Niet alleen zijn methoden zoals de bio-impedantie metingen vrij

ingewikkeld om dagelijks toe te passen, maar een belangrijk verschil met

echocardiografie is dat eventuele gevonden afwijkingen niet duidelijk

bewezen samen hangen met een verhoogd risico van de patiënt. Wel zijn

deze metingen goed bruikbaar voor onderzoek naar de oorzaken en

gevolgen van ISH en andere soorten van hoge bloeddruk, en over effecten

hierop van de verschillende soorten bloeddrukverlagende

geneesmiddelen.

CHAPTER

- 248 -

Keuze van bloeddrukverlagende medicijnen bij ISH

De discussie over welke soorten van bloeddrukverlagende

geneesmiddelen het meest geschikt zijn bij de behandeling van ISH is nog

niet gesloten. In het voordeel van de meest �simpele� geneesmiddelen, de

plastabletten of diuretica, pleit dat zij niet alleen het goedkoopst zijn, maar

tevens dat ze een bewezen gunstig effect hebben op het cardiovasculair

risico van de ISH-patiënt. In de eerste grote studie naar de effecten op

ziekte en sterfte bij ISH, de Systolic Hypertension in the Elderly Population

(SHEP)-trial, was het diureticum chlorthalidon het middel van eersteSHEP’91

keus. Een nadeel is dat nog weinig bekend is over hun werking op

structurele afwijkingen in het hart en de bloedvaten, hoewel ook in dit

proefschrift een verlaging van de bloeddruk met een diureticum

geassocieerd bleek te zijn met afname van de hartspiermassa.

Voor de tweede klassieke groep van bloeddrukverlagende

geneesmiddelen, de beta-blokkers, geldt dat weinig bekend is over de

effectiviteit bij de behandeling van ISH. Atenolol was het tweede middel

van keuze in de SHEP-studie, waarin uiteindelijk wel positieve resultaten

werden gevonden. Echter, in een andere grote studie naar ouderen met

hoge bloeddruk, de Medical Research Council in the elderly (MRC-II)MRC’92

trial waar ook ISH-patiënten in zaten, kon geen positief effect van de beta-

blokkers worden aangetoond, in tegenstelling tot diuretica. Ook is nog niet

veel bekend over het effect van beta-blockers op structurele afwijkingen

van hart en bloedvaten in ISH.

Als voordeel voor de derde groep van middelen, de calcium-

antagonisten, geldt het positieve effect dat gevonden werd voor het

langwerkende middel nitrendipine in de tweede grootschalige studie bij

ISH, de Systolic hypertension in Europe (SYST-EUR)-studie.Staessen’97

Behandeling in deze studie resulteerde in een duidelijke afname van het

aantal beroertes en sterfgevallen door hartziekten. Verder geldt althans in

theorie dat het intracellulair calcium ook betrokken is bij de regeling van

de contractie van de gladde spiercellen van de bloedvaten, en daarmee de

soepelheid van deze bloedvaten. Echter, studies met calcium-antagonisten

zijn onvoldoende gedaan om te kunnen vaststellen of deze middelen

inderdaad een positief effect hebben op structurele afwijkingen van hart en

bloedvaten in ISH.

Voor de laatste groep van bloeddruk-verlagende middelen, de

angiotensin-converting enzyme inhibitors of ACE-remmers, geldt dat er

wel studies beschikbaar zijn die een positief effect op structurele

afwijkingen van hart en bloedvaten in ISH beschikbaar zijn. Zoals


- 249 -

aangetoond in dit proefschrift, kan met ACE-remmers de hartspiermassa

verminderd worden, en tevens soepelheid van de grote lichaamsslagaders

verbeterd worden, zelfs tot bijna-normale waarden indien lang genoeg

behandeld wordt. Dit herstel van afwijkingen suggereert een gunstig effect

op de overleving van de ISH-patiënten. Echter, er is nog geen

grootschalige studie uitgevoerd met ACE-remmers die zo�n positief effect

op het risico op hart en vaatziekten in ISH aantoont. Wel was de ACE-

remmer enalapril het tweede middel van keuze in de SYST-EUR studie,

die een gunstig effect van behandeling liet zien.

Voor de andere, nieuwere klassen van bloeddrukverlagende

geneesmiddelen, zoals angiotensine-II antagonisten en centraal werkende

atihypertensiva, geldt over het algemeen dat te weinig resultaten

beschikbaar zijn om reeds een oordeel te kunnen vellen over hun

effectiviteit in de behandeling van ISH.

In het licht van deze discussie over effectiviteit van de verschillende

groepen van bloeddrukverlagende geneesmiddelen is een ander punt

misschien wel minstens net zo belangrijk. Dit is dat de mate van verlaging

van de bloeddruk op zich waarschijnlijk net zo belangrijk is als welk

geneesmiddel hiervoor gekozen wordt. Dit leidt tot de stellingname dat

�bij behandeling van hoge bloeddruk het doel van behandeling zwaarder weegt danmet welk middel dit gebeurt�. Deze stelling lijkt ondersteund te worden door

de resultaten van een grootschalig vergelijkend onderzoek in patiënten

met een matig verhoogde onderbloeddruk of diastolische hypertensie, de

Treatment Of Mild Hypertension Study (TOMHS). In deze studieNeaton’93

werd aangetoond dat met diverse soorten geneesmiddelen vergelijkbare

resultaten konden worden bereikt in de zin van bloeddrukverlaging en

tevens een afname van de hartspierdikte. Deze effecten verschilden niet

van die bereikt met strenge dieetmaatregelen, ook daarmee kon

bloeddrukverlaging bereikt worden en verlaging van de hartspierdikte.

Samenvattend kan gesteld worden dat de keuze van behandeling bij

ISH-patiënten in eerste instantie erop gericht moet zijn om een adequate

verlaging van de verhoogde bloeddruk te bereiken. Naast de effectiviteit

kunnen hierin ook andere aspecten, zoals kosten (goedkoopste: diuretica)

en bijwerkingen worden meegenomen. Natuurlijk geldt altijd dat

aanwezigheid van andere ziekten of aandoeningen reden kan zijn om tot

een andere therapiekeuze te komen.

De conclusie ...

CHAPTER

- 250 -

Verhoogde bovenbloeddruk of geïsoleerd systolische hypertensie (ISH) is

een aandoening die behandeld dient te worden, zoals ook wordt

geadviseerd in de recente internationale en nationale richtlijnen. Het is de

meest voorkomende vorm van hoge bloeddruk op oudere leeftijd.

Patiënten met ISH hebben een toegenomen hartspierdikte en een

afgenomen rekbaarheid van de grote lichaamsslagaders, welke kunnen

worden hersteld met langdurige behandeling met bloeddrukverlagende

geneesmiddelen. De ernst van de afwijkingen is vergelijkbaar met die als

gevolg van de �gewone� verhoogde onderdruk of diastolische hypertensie.

De hoge mate van vóórkomen, en het snel optreden van nieuwe gevallen

van ISH in de oudere bevolking vormen een belangrijk probleem in de

dagelijkse praktijk, zeker gezien het feit dat deze bevolkingsgroep sterk zal

groeien. Studies zullen moeten worden gedaan om na te gaan of een

gedifferentieerde behandeling, afgestemd niet alleen op de hoogte van de

bloeddruk maar tevens op de aanwezigheid van andere risicofactoren voor

hart- en vaatziekten, en op de aanwezigheid van gevolgen van de hoge

bloeddruk zoals linker ventrikelhypertrofie, de meest optimale en veilige

aanpak is. Indien ISH effectief behandeld wordt, zal dit leiden tot een

duidelijke afname van belangrijke aandoeningen als beroertes,

hartaanvallen en hartfalen, alle aandoeningen met een hoge kans op

overlijden en invalidering, en met een sterke beinvloeding van de kwaliteit

van leven van de oudere patiënt.


- 251 -

LAW NR. XII:

IF THE RADIOLOGY RESIDENT AND

THE BMSBOTH SEE A LESION ON THE

CHEST X-RAY, THERE CAN BENO LESION THERE

ANKWOORD

- 253 -


DANKWOORDDANKWOORDDANKWOORDDANKWOORD

Dit proefschrift mag dan onder één naam gepubliceerd worden, maar het

was er nooit in de huidige vorm gekomen zonder de medewerking van velen,

op verschillende wijzen. Een aantal van hen wil ik hier persoonlijk bedanken.

Allereerst mijn �maatje� in het Friese veld, Frank Beltman. Beste Frank,

zonder jouw organisatietalent en computerkennis was het begin van het

onderzoek beslist veel moeizamer verlopen. Daarnaast heb ik genoten van

onze discussies, zowel op het medische als op het politieke vlak onder het

genot van een biertje. Ik ben blij dat je je draai gevonden hebt, met

Annechien en in het huisartsenvak, al denk ik dat je het daar vast niet bij zult

laten: we zullen vast nog wel van je horen in de wetenschap of in de politiek.

Mijn eerste promotor, Henk Lie, wil ik graag bedanken voor zijn snelle en

scherpe begeleiding van dit proefschrift. Korte momenten waren vaak genoeg

om snel en helder de lijnen uit te zetten, en mede daardoor is het huidige

proefschrift een fraai afgerond geheel geworden. Hij heeft cardiologie

Groningen stevig op de wetenschappelijke landkaart gezet. Ik ben blij dat hij

mij heeft willen begeleiden (zal ik echt de laatste zijn?), ondanks zijn vertrek

naar Amsterdam. Tevens dank ik hem voor het in mij gestelde vertrouwen

door mij toe te laten tot de opleiding Cardiologie, die ik hoop af te ronden

onder zijn opvolger, professor Harry Crijns.

Mijn tweede promotor, Betty Meyboom, wil ik bedanken voor haar

gedreven en inspirerende begeleiding. Beste Betty, jij wist altijd goed de

betekenis van dit onderzoek voor de eerste lijn aan te geven. Daar zal ook

altijd de behandeling van hypertensie moeten blijven, in samenwerking met

de expertise uit de tweede lijn. Als dit proefschrift ook die geest uitdraagt,

dan is dat mede jouw succes.

CHAPTER

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Mijjn derde �last but not least� promotor is Pieter de Graeff. Beste Pieter, jij

bent naast andere zaken met name textueel erg belangrijk geweest voor het

huidige resultaat. Jouw opmerking in de eindfase dat �mijn schrijven

aanmerkelijk verbeterd was� deed mij erg veel plezier, maar is tegelijkertijd

een compliment aan jezelf. De opmerking dat ik gezien de omvang van dit

boekje �wat megalomane trekjes vertoonde� vergeet ik echter net zo min! Ik

hoop dat we nog veel zullen samenwerken in de toekomst.

De professoren De Jong, Thien, en van Zwieten dank ik voor hun bereidheid

zitting te nemen in de leescommissie, waarbij speciaal mijn dank voor het

minitieus nakijken van professor Thien van het oorspronkelijke manuscript.

Mijn eerste co-promotor en begeleider, Dr. Jo May, is méér dan alleen

begeleider van dit onderzoek geweest de afgelopen jaren. Beste Jo, jij nam mij

reeds onder jouw supervisie toen ik als keuze-coassistent op C2Va begon. Ik

was blij dat je toen al wat grijze haren had want anders had je die vast

gekregen van mijn �hemelbestormendheid� destijds. Ik bewonder je integriteit

en je klinische kunde zeer, en ik hoop dat ik daar nog veel van mag

profiteren.

Mijn tweede promotor, Dr. Andries Smit, is minstens net zo belangrijk

geweest voor het tot stand komen van het huidige boekje. Beste Andries, bij

jou heb ik geleerd rustig af te wachten en te luisteren: het mag wel eens even

duren, maar wat er dan uitkomt is bijna zonder uitzondering uiterst scherp en

zinnig. De stellingen zijn dankzij jou ook flink aangescherpt. Daarnaast heb ik

ook erg veel waardering voor je persoonlijke begeleiding, ik kon ook goed bij

jou terecht als het om bredere zaken als toekomstplannen ging.

Graag bedank ik ook hierbij de andere �heren� van de Stichting

Hypertensiedienst. Dr. Havinga, Dr. Schuurman en Dr. van der Veur. Beste

Tjeerd, jij hebt reeds meermaals jouw organisatietalent bewezen, en ook het

bevolkingsonderzoek in Achtkarspelen waarop dit boekje gebaseerd is had

hier niet zonder gekund. Beste Frits en Enno, jullie medewerking bestond niet

alleen uit het inbrengen van het Huisartsenlaboratorium, maar was net zo

goed onmisbaar in het uitvoeren van het bevolkingsonderzoek in de zin van

automatisering en public relations. Onder jullie leiding lijkt er geen eind te

komen aan de expansie van het Huisartslaboratorium: veel succes ermee en

mogelijk dat we elkaar in dat verband nog eens vaker zullen tegenkomen. De

onderzoeken in Friesland hadden ook nooit uitgevoerd kunnen worden

zonder de �meiden� van het Huisartslaboratorium. Daarom mijn dank aan

Maaike van der Werff en Ria Homan en al die anderen.

Hans Hamer en Els Pieperwil ik bedanken niet alleen voor hun zeer grote

ANKWOORD

- 255 -

kennis, maar ook voor de liefde voor de echocardiografie die zij op mij

hebben overgebracht. Daarvoor ook dank aan het personeel van de

echokamer, toen en nu. Voor het quinapril-onderzoek was de medewerking

van het vaatlaboratorium onmisbaar: daarom dank aanMargreet, Wietze,

Bertha, Marian en Ray. Tevens wil ik Jaap Muntinga bedanken. Beste Jaap,

zonder jou had ik nog steeds niet het verschil tussen distensibiliteit en

compliantie geweten, en hadden hoofdstukken 2 en 5 er heel anders

uitgezien. Pieter-Jan de Kam van het TCC dank ik voor zijn hulp bij de

statistiek van de mega-bestanden, de discussies over �statistisch

verantwoord� en �klinisch relevant� waren vaak uitvoerig en verhelderend.

Grote dank ook voor Caro Kropveld, die een lang bestaand idee niet alleen

wist te realiseren, maar ook zo mooi wist uit te voeren dat nu waarschijnlijk

helemáál meer naar de omslag dan naar de inhoud van dit boekje wordt

gekeken.

Bij het gehele onderzoek zijn ook veel medisch studenten betrokken

geweest. Speciale dank daarbij aan Sybolt de Vries, die zoveel werk heeft

verricht aan het ECG-model dat het niet meer dan terecht was dat zijn naam

als eerste boven het artikel kwam.Willem Terpstra, ik ben erg blij dat je mijn

�opvolger� bent geworden. Ook dank aan al diegenen die ons bij het

vaatonderzoek of anderzins hebben geholpen: Sascha, Hanneke, Gerard,

Ronald, Trudeke, Truuke, Sibo, Roelf, Ingrid en al die anderen (circa 80!) die

bij de beide bevolkingsonderzoeken zelf hebben geholpen. Ik vond het altijd

erg plezierig om jullie te begeleiden en heb daar ook zelf een hoop van

opgestoken; ik hoop dat dit wederzijds was.

Zonder dat dit afbreuk doet aan de belangrijkheid zijn er nog een aantal

�losse� personen die mijn dank verdienen. Jobst en de andere assistenten

(opleiding en research) van Cardiologie voor de prima sfeer, de staf van de

cardiologie AZG voor mijn opleiding en de ruimte die ik kreeg om deze

promotie af te ronden. Daarvoor ook mijn dank aan de collega�s van de

vooropleiding Interne AZG (opleider destijds prof. Reitsma). Ook gaat grote

dank uit naar alle deelnemende huisartsen: in de gemeente Achtkarspelen en

het Marnegebied, Delfzijl, Bedum en Eelde/Paterswolde, zonder wie dit

onderzoek nooit had kunnen worden uitgevoerd. Hetzelfde geldt voor al die

patiënten die zo belangeloos meededen; voor de laatste twee groepen is dit

boekje eigenlijk nog het meest geschreven.

CHAPTER

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Voor het doen van onderzoek is het van eminent belang dat je juist ook niet

altijd met dat onderzoek bezig bent, maar goede vrienden hebt die je juist

met heel andere zaken bezig houden. Daarvoor mijn dank aan Bart S en Bart

H, Jan, Juliet en Frank, en Maaike en Marlies, en aan alle andere volleyballers,

kroegtijgers en tennissers van toen en nu.

Lieve Pa en Ma, niet alleen staan jullie altijd klaar als er iets moet gebeuren,

maar jullie gaven ons ook een grote mate van zelfstandigheid mee, wat niet

alleen voor dit onderzoek maar voor mijn hele opleiding erg belangrijk is.

Hopelijk blijven jullie nog lang in goede gezondheid bij ons. Mijn lieve broers

en zussen, en allen die daar bij horen, dank ik ook. We zien elkaar misschien

niet zo vaak, door de spreiding over het land, maar de band is er niet minder

om. Jullie zaten mij vroeger nog wel eens op mijn kop, maar het

doorzettingsvermogen wat daaruit voortgekomen is heeft mij nu wel tot hier

gebracht.

Tenslotte: mijn lieve Lisette. Jou tegenkomen was een waar geschenk: de

zekerheid en het plezier en de liefde die ik nog dagelijks ervaar met jou

verbaast me nog steeds. Ook jouw familie: Wim, Ineke en Mariska, is met

recht er één uit duizenden. De �bevalling� van dit boekje mag dan voor nu

even heel belangrijk zijn, het resultaat van jouw aanstaande bevalling zal het

onmiddelijk reduceren tot iets van veel mindere importantie: een

momentopname vastgelegd op papier.

ANKWOORD

- 257 -

Noot: The House of God (Samuel Shem): een fantastisch boek, deels

�jiddisch� absurdistisch en deels gelukkig achterhaald, maar toch ook

nog deels dagelijkse realiteit(!), en daarom verplichte kost voor alle

medisch studenten/co-assistenten.

CHAPTER

- 258 -

LAW NR. XIII:

THEDELIVERY OFMEDICALCARE IS TO DO ASMUCHNOTHING AS POSSIBLE

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