Nephrol Dial Transplant (1997) 12: 945951 NephrologyDialysis

TransplantationOriginal Article

ACE inhibitors captopril and enalapril induce regression of leftventricular hypertrophy in hypertensive patients withchronic renal failure

A. I. Dyadyk1, A. E. Bagriy1, I. A. Lebed2, N. F. Yarovaya1, E. V. Schukina1 and G. G. Taradin1

1Department of Postgraduate Therapy Training, Medical University; 2Diagnostic Center, Donetsk, Ukraine

Abstract chronic renal failure; diastolic function; left ventricularhypertrophyBackground. Left ventricular hypertrophy is frequently

noted in patients with moderate to severe chronic renalfailure not requiring dialysis. Recently, several studieshave shown reversal of myocardial hypertrophy in end-stage renal disease with long-term pharmacological Introductioncontrol of blood pressure, but it is unclear whether leftventricular mass regresses or normalizes with antihy- Cardiovascular disease is the leading cause of death inpertensive treatment of patients with earlier stages of end-stage renal failure, representing 4352% of overallchronic renal failure. mortality [13]. Indeed, cardiovascular mortality inMethods. Seventy-two undialysed patients with chronic patients on renal replacement therapy is 1020 timesrenal failure, chronic mild-to-moderate hypertension, more common than in the general population [47].and left ventricular hypertrophy were randomly Left ventricular hypertrophy is an independent factorassigned in a prospective study to either the captopril related to overall mortality in uraemic patients [811].(n=36) or enalapril group (n=36). Blood pressure In non-uraemic hypertensive patients with leftmeasurements, echocardiographic and Doppler para- ventricular hypertrophy, prolonged restoration ofmeters were evaluated before treatment and at 6 and normal loading conditions with most classes of antihy-12 months of therapy. pertensive drugs, excluding direct vasodilators andResults. During follow-up, six patients developed side- diuretics, leads to significant decrease in left ventriculareects including dry cough, taste disturbances, skin muscle mass index and left ventricular wall thicknessrash and gastric intolerance. In the captopril group and to improvement of left ventricular systolic andthere was a decrease in mean left ventricular mass diastolic function [12,13]. Regression of left ventricularindex by 12% after 6 months of treatment, which hypertrophy in end-stage renal disease has been demon-decreased by 20% after 12 months treatment. For strated after treatment with recombinant humanenalapril, the average reduction of myocardial mass erythropoietin [14,15] and after renal transplantationafter 6 months treatment was 14% and after 12 months [5,16]. Although recently, several experimental andtreatment, the decrease was 19%. In both treatment clinical studies have shown reversal of myocardialgroups there was significant improvement of left ventri- hypertrophy in end-stage renal disease with long-termcular filling dynamics. No deterioration of left ventricu- vigorous pharmacological control of blood pressurelar systolic function was observed. [1720], it is unclear whether left ventricular mass andConclusions. Our results confirm that antihypertensive left ventricular filling dynamics are improved by antihy-monotherapy with the ACE inhibitors, captopril and pertensive treatment of patients with earlier stages ofenalapril, in patients with chronic renal failure results chronic renal failure. Moreover, the impact of regres-in regression of left ventricular mass index associated sion of left ventricular hypertrophy on systolic functionwith a significant improvement in the diastolic function in this population remains controversial. Previous stud-of the left ventricle without a demonstrable deteriora- ies have reported no consistent improvement in lefttion in left ventricular systolic performance. ventricular systolic function in treated patients with

essential hypertension and end-stage renal failure, des-Key words: ACE inhibition; blood pressure control; pite a significant reduction in left ventricular mass

[12,13,18].We investigated whether long-term antihypertensive

treatment with captopril and enalapril decreases leftCorrespondence and oprint requests to: Prof. A. I. Dyadyk,Teatralniy prospect, 24, 18, Donetsk, 340050, Ukraine. ventricular mass and improves left ventricular systolic

1997 European Renal AssociationEuropean Dialysis and Transplant Association

A. I. Dyadyk et al.946

serial measurements of blood pressure, heart rate (electrocar-function and left ventricular filling dynamics in patientsdiogram), complete blood count tests, urinalysis, routinewith chronic renal insuciency and left ventricularserum chemistry analysis, and evaluation of echocardio-hypertrophy.graphic and Doppler parameters.

Subjects and methods Echocardiographic and Doppler measurements

Echocardiographic studies were obtained before treatmentPatient populationand at 6th and 12th months after the individual doses ofstudied drugs were reached.Seventy-two patients (34 men and 38 women, mean age 43.7

M-mode echocardiographic examination was performedyears, range 2461 years) with moderate to severe chronicwith two-dimensional monitoring using ATL Ultramark-9renal failure not requiring dialysis (mean serum creatinineduplex echocardiograph (Advanced Technologies Labor-0.49 mmol/l, range 0.32 to 0.54 mmol/l ) were enrolled in theatories, Bellevue, WA, USA) with a 2.5-mHz transducer.study. Renal failure was due to primary glomerulonephritisLeft ventricular internal dimensions, interventricular septal(46 patients with mesangioproliferative and 26 patients withthickness and posterior wall thickness were measured accord-mesangiocapillary glomerulonephritis). Enrolled patients hading to the recommendations of the American Society ofa chronic mild to moderate hypertension (defined as a restingEchocardiography by the same observer ( I.A.L.) who wassitting diastolic blood pressure between 95 and 116 mmHgblinded to the patients clinical status, treatment assignment,in the untreated state), and had not been taking antihyper-and phase of study. Each parameter value was averaged overtensive or other cardiovascular drugs for at least 3 monthsthree cardiac cycles. Left ventricular mass was estimated bybefore the study.the Devereux-modified American Society of Echocardiog-Patients were included only if they met echocardiograph-raphy cube formula and was divided by the body surfaceically defined criteria for left ventricular hypertrophy (in menarea to derive the left ventricular mass index [22].134 g/m2 and in women 110 g/m2, as described below).

Left ventricular systolic function was assessed by examin-Exclusion criteria included significant valvular or coronarying the left ventricular shortening fraction derived from theheart disease, cardiac arrhythmia or conduction defects, orstandard equation. Left ventricular diastolic filling para-technically uninterpretable two-dimensional echocardiogram.meters were estimated with pulsed Doppler examinations toNone of the patients had echocardiographic regional wallobtain peak velocity of early (E) and late diastolic fillingmotion abnormalities or a left ventricular shortening fraction(A), and the ratio (E/A) of early to late diastolic flowless than 25%. Other secondary causes of hypertension werevelocity was calculated.ruled out by clinical examination and routine biological tests.

Enrolled patients gave written informed consent for studyparticipation; both the study protocol and the consent form Statistical analysiswere approved by the Institutional Review Board.

Results are expressed as meansSD. Comparisons of para-meters of cardiac structure and function at baseline withStudy designthose during treatment were performed by one-way analysisof variance with repeated measurements. Comparisons ofThe 72 recruited patients were randomly assigned to one ofstudied parameters between A and B groups were performedtwo treatment groups: group A (n=36) were given captoprilby using Students t test for unpaired observations. Simpleand group B (n=36) enalapril. The study design consistedlinear regression analysis was performed to correlate changesof three phases: a single-blind placebo phase, a 6- to 8- weekin left ventricular mass with changes in left ventricularphase of drug titration and a 12-month maintenance phase.shortening fraction or in diastolic filling parameters duringA complete medical history was obtained and a physicaltreatment. A P value less than 0.05 was considered signific-examination, complete blood count, urinalysis, routine serumant [23].chemistry analysis, electrocardiogram, echocardiographic

and Doppler examinations and thoracic radiographs wereperformed. All blood pressure readings were made by the

Resultssame investigator, who used the same calibrated mercurysphygmomanometer throughout the study.

During the placebo phase, eligible patients received one Characteristics of the study population on entryplacebo tablet per day for 12 weeks. Patients with a sitting

There was no significant dierence between the twodiastolic blood pressure of 95116 mmHg after the placebophase were eligible for further participation in the study. groups at baseline (Table 1). There was a slight dier-

During the titration phase, the initial doses of captopril ence between the two groups with respect to leftand enalapril were 6.25 and 2.5 mg/day respectively [21 ]. ventricular mass index, which did not reach statisticalThe dosage was increased every 2weeks by 6.25 or 2.5 mg significance.increments, respectively, until goal BP, defined as a sittingdiastolic BP of

ACE inhibitors in chronic renal failure 947

Table 1. Baseline clinical and echocardiographic characteristics of Eect of treatment on cardiac structurethe two patient groups

In both groups left ventricular end-diastolic dimensionssignificantly decreased after the 6 months treatment.Group A Group BThese dimensions continued to decrease in the enalaprilpatients after 12 months therapy, and remainedAge (years) 4310 4412unchanged in the captopril group (between 6 and 12(2461) (2559)

Sex (M5F) 13515 10512 months) (Tables 2, 3).Blood pressure (mmHg) After 6 months of treatment with captopril, there

Systolic 17418 18224 was a 7% decrease in interventricular septal thickness,(138218) (142222)as well as a 12% decrease in left ventricular mass indexDiastolic 1076 1068(all P

A. I. Dyadyk et al.948

Table 2. M-mode echocardiographic measurements, Doppler parameters of left venticular filling, and laboratory data before and duringtreatment of patients in group A

Group A

Baseline 6 months treatment 12 months treatment

Systolic BP (mmHg) 17418 15014* 14613*Diastolic BP (mmHg) 1076 936* 916*Heart rate (beats/min) 787 779 788Haemoglobin (g/l ) 9011 8910 8914Creatinine (mmol/l ) 0.480.07 0.480.10 0.490.11IVS thickness (cm) 1.40.2 1.20.2* 1.10.2* **LVEDD (sm) 5.10.7 4.90.7* 4.90.6*LVMI (g/m2 ) 14724 13027* 12024* **LVSF (%) 336 347 376*LV filling:

E (sm/s) 549 598* 648* **A (sm/s) 669 628* 598* **E/A 0.80.2 0.90.1* 1.10.2* **

Values are axpressed as meansSD.Abbreviations: BP, blood pressure; IVS, interventricular septum; LVEDD, left ventricular end-diastolic diameter; LVMI, left ventricularmass index; LVSF, left ventricular shortening fraction; E, peak early filling velocity; A, peak late filling velocity; E/A, ratio of peak earlyfilling velocity to peak late filling velocity.*P

ACE inhibitors in chronic renal failure 949

vascular risk in both uraemic and non-uraemic popula- both. In the present study, the decrement in leftventricular hypertrophy was not correlated with thetions, the prevention of hypertrophy, its early

detection, and reduction of left ventricular mass index reduction in the systolic and diastolic blood pressure.In agreement with our findings, other clinical andat early stages of chronic renal failure appear to be

promising for the reduction of cardiovascular events experimental studies have shown that the left ventricu-lar mass correlated poorly with blood pressure levelin patients with chronic uraemia [4,27,29,30].

In the last few years a growing number of experi- during both the development and the reversal of hyper-tensive left ventricular hypertrophy [13,37]. However,mental and clinical reports have analysed the structural

left ventricular changes during ACE-inhibition in several studies reported the crucial role of a decreasein blood pressure diminishing in the reduction of lefturaemia. The results are controversial. Rambausek

et al. [31] have described left ventricular hypertrophy ventricular mass in end-stage renal disease, as well asin essential hypertension [17,29,35]. The disparity indevelopment and progression in uraemic animals des-

pite blood pressure normalization by ACE inhibitors. the reported findings may be attributable to the dier-ent antihypertensive drugs used in these studies, andThese results are in accordance with recent findings of

Roithinger et al. [32], who concluded that the ACE to interstudy dierences in methods of blood pressuremeasurements (casual blood pressure versus 24-hinhibitor lisinopril, at a dose which left the blood

pressure unchanged throughout the study period, was ambulatory blood pressure monitoring).not able to induce reduction of left ventricular mass.

In contrast, the data in our study indicate that in Changes in diastolic function during treatmentpatients with chronic renal failure and moderate arter-ial hypertension, long-term treatment with the ACE The present study showed that regression of left ventri-

cular hypertrophy during antihypertensive treatmentinhibitors, captopril or enalapril, significantly loweredarterial pressure and reduced left ventricular hyper- of chronic renal failure patients with ACE inhibitors

captopril and enalapril is associated with significanttrophy. A significant dierence in respect of bloodpressure diminishing and reduction of left ventricular improvement in the diastolic function of the left vent-

ricle. In contrast with our findings, Roithinger et al.mass index between the two treatments was not evident.In agreement with our results, London et al. [11] [32] were unable to show improvement in diastolic

filling in patients with chronic renal failure receivingshowed that despite similar eects on blood pressurein patients with left ventricular hypertrophy and end- an ACE inhibitor.

It is speculated that reduction in left ventricularstage renal failure, a reduction in left ventricular massand volume was observed with ACE inhibition but not mass with antihypertensive treatment increases the

fibrosis/myocardial muscle fibre ratio, leaving the vent-with calcium-channel blockade.In the present study, left ventricular mass index was ricle less compliant and perhaps with worsened dia-

stolic function [12,13]. The data in this study, as wellfound to be reduced by 12 and 14% after 6 months oftreatment with captopril and enalapril respectively. as that of others, do not support this concept, since

regression of hypertrophy was accompanied byThe degree of left ventricular mass index reduction inour study was in agreement with some short-term improvement in left ventricular filling dynamics in all

reports [35].previous studies of ACE inhibitor treatment in patientswith essential hypertension and end-stage renal failure[11,24,33]. Changes in systolic function during treatmentThe time course of regression of left ventricularhypertrophy during antihypertensive therapy has been There has been some concern, based on a previous

experimental study, that regression of left ventricularevaluated in several studies. In some clinical reports areduction in posterior wall thickness and left ventricu- hypertrophy with antihypertensive treatment might

lead to a deterioration of left ventricular systolic per-lar mass index occurs as early as 4 weeks after thebeginning of treatment, with further reduction during formance [38]. However, this concern has not been

borne out by clinical studies that have shown eitherthe subsequent 14 months and no significant changethereafter for up to 1 year [13,34]. In contrast, several no change, or an improvement, in left ventricular

systolic function after regression of left ventricularstudies have clearly demonstrated that the magnitudeof the reduction in left ventricular mass index is related hypertrophy in essential hypertension, even when treat-

ment was withdrawn and blood pressure had increasedto the duration of treatment [35,36 ]. In our study, leftventricular mass index continued to decrease with again [35,36 ]. We have also demonstrated no deteriora-

tion in left ventricular systolic function after reductioncontinuous treatment with ACE inhibitors, and after12 months was 20 and 19% less than pretreatment of left ventricular mass with antihypertensive treatment

of patients with end-stage renal disease [18]. In thevalues for captopril and enalapril groups respectively.The data herein indicate that the period of 36 months present study, left ventricular shortening fraction was

unaltered in both groups after 6 months and signific-used in most previous studies is insucient to docu-ment the time course of left ventricular mass reduction. antly increased after 12 months of treatment. Our

findings of left ventricular shortening fractionIt is unclear whether the regression of left ventricularhypertrophy is due to a lowering of blood pressure or dynamics after regression of left ventricular hyper-

trophy confirm those of previous reports [18,35].to a direct eect of the drugs on the myocardium, or

A. I. Dyadyk et al.950

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Received for publication: 8.7.96Accepted in revised form: 9.1.97