Br Heart J (Supplement) 1994; 72: 24-32

Role of ACE inhibitors in hypertension with leftventricular hypertrophy

A Mark Richards, M Gary Nicholls, Ian G Crozier

Left ventricular hypertrophy in hypertension isan independent predictor for sudden death,ventricular arrhythmias, myocardial ischaemia,coronary heart disease, and heart failure. `-9These relations have proved true whether thehypertrophy is detected by electrocardiographyor by the much more sensitive technique ofechocardiography. It seems logical thatregression of left ventricular hypertrophywould be beneficial, but, as yet, few clinicaldata support this contention beyond a limitedexperience from the Framingham study. Anti-hypertensive treatments might differ in theirability to promote regression of left ventricularhypertrophy independently of their bloodpressure lowering effect. There is a powerfultheoretical basis suggesting that inhibition ofangiotensin converting enzyme (ACE), withconsequent reduction in plasma and tissueconcentrations of angiotensin II, may besuperior in promoting regression of leftventricular hypertrophy. Studies in animalmodels of hypertension and meta-analyses oftrials of drug treatment in human hypertensionare not entirely concordant, but overall theysupport a major role for ACE inhibitors inreducing left ventricular hypertrophy.

Left ventricular hypertrophy as riskfactorThe two widely used techniques for detectingleft ventricular hypertrophy are electrocardio-graphy and echocardiography. Echocardio-graphy is by far the more sensitive, detectinghypertrophy in 14% and 18% of men andwomen respectively in the subjects of theFramingham heart study. By contrast,electrocardiographic features of left ventricularhypertrophy were present in only 2/9% of menand 1-5% ofwomen in this population.'0 Moststudies using echocardiographic criteria for leftventricular hypertrophy apply the conventionsof the American Society of Echocardiography.These define abnormally increased leftventricular mass as the population mean plus2 SD. Echocardiography has provided a non-invasive means of estimating left ventricularmass with a close correlation to values atnecropsy.'114 In uncomplicated essentialhypertension left ventricular mass on echo-cardiography satisfied criteria for hypertrophy(over 125 g/m2) in 27% of patients.'5 In thesame study cardiovascular events occurred ina higher proportion of patients with leftventricular hypertrophy than in those without(26% v 12%, P < 0-0 1). Cardiovascular deathwas 28 times more common in the group withleft ventricular hypertrophy (14% v 0-5%,P < 0 00 1), all cause mortality being eight

times more common ( /6% v 2%, P < 0.01).Patients with normal left ventricular geometrysuffered no cardiac death and only 1 1%suffered a morbid event in contrast with thosewith concentric hypertrophy, who had amortality of 21% and a morbidity of 31%. Ina larger population of more than 3000 peopleover 40 who were free of overt clinicalcardiovascular disease and were followed upfor four years, 208 cardiovascular end organevents occurred, including 37 cardiovasculardeaths and 124 deaths from all causes.9 Therelative risk of cardiovascular death wassignificantly increased for every 50 g- incre-ment in left ventricular mass (relative risk 1-73for men and 2-12 for women). For all causesof death the corresponding relative risks were1-49 in men and 2-01 in women. In amultivariate analysis the adverse prognosticsignificance of increased left ventricular masswas independent of age, diastolic bloodpressure, pulse pressure, antihypertensivetreatment, smoking, presence or absence ofdiabetes, presence or absence of obesity, lipidprofile, and electrocardiographic evidence ofleft ventricular hypertrophy.

Recent studies using electrocardiographiccriteria for detecting left ventricular hyper-trophy confirm earlier indications that electro-cardiographic hypertrophy is an independentindicator of both cardiovascular and all causemortality. In a population of nearly 5000patients undergoing coronary angiographyover 13 years electrocardiographic evidence ofleft ventricular hypertrophy was present in5.2%. 16 Five year survival in this group wassignificantly less than in those without leftventricular hypertrophy (81 9% v 90-2%,P < 0 001). This effect of hypertrophy wasindependent of coronary artery disease in thateven in the presence of normal coronaryangiograms, electrocardiographic left ven-tricular hypertrophy was associated with areduced five year survival (81 0% v 87.7%,P < 0 0 1). Dunn et al analysed data from theGlasgow blood pressure clinic from nearly4000 patients over a mean follow up period ofmore than six years and found that leftventricular hypertrophy was present byelectrocardiographic criteria in 34.5% of menand 21 5% of women.'7 All cause mortality inthis population was 27-6 per 1000 patientyears for men with a normal electrocardiogramcompared with 43-2 per 1000 patient years inthose with left ventricular hypertrophy seenelectrocardiographically. In addition, thosewho also had "strain" in addition to othercriteria for left ventricular hypertrophy on

electrocardiography had a further increase inmortality to 56-9 per 1000 patient years. This

Departments ofMedicine andCardiology,Princess MargaretHospital,Christchurch, NewZealandA M RichardsM G NichollsI G CrozierCorrespondence to:Dr A M Richards,Cardio-Endocrinology, 3rdFloor, Princess MargaretHospital, Cashmere Road,Christchurch, New Zealand.

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association of electrocardiographic left ven-tricular hypertrophy with increased mortalitywas independent of age, blood pressure, andsmoking.The mechanism linking left ventricular

hypertrophy with increased morbidity andmortality is uncertain. Possibilities include amismatch of blood supply to tissue mass,leading to comparatively ischaemic subendo-cardial tissue. Basal myocardial oxygendemand may be increased because ofincreased wall mass and some increase in wallstress. There may be increased susceptibilityto ventricular arrhythmia, which may berelated to an increased component of fibroustissue within the myocardium. Coronaryreserve is reduced, leading to a loweredthreshold for induction of ischaemia in thepresence of stressors such as exercise and shortterm falls or rises in blood pressure.Thus, left ventricular hypertrophy is an

undeniably undesirable feature in hyper-tension, and it seems logical that regression ofhypertrophy might improve prognosis.However, clinical data to support thiscontention are sparse. Only one study hasprovided prospective evidence of the benefitsof regression of left ventricular hypertrophy.Data from the Framingham study showed afall of 25% in cardiovascular mortality in asubgroup with reduction in electrocardio-graphic left ventricular hypertrophy comparedwith a similar group without such regressionduring follow up of over four years.'8Furthermore, in 166 patients with hyper-tension followed up for five years cardio-vascular events occurred in only 6% of thosewhose left ventricular mass decreased or wasunchanged compared with 16% withincreased left ventricular hypertrophy.'9

Mechanisms underlying left ventricularhypertrophyCardiac myocytes hypertrophy in response toincreased wall stress (tension), as occurs inhypertension. This hypertrophy of individualcells in turn results in left ventricular wallhypertrophy, which tends to reduce unit walltension as predicted by the La Place equation(T = p X r/2L, where T = ventricular walltension, P = left ventricular pressure, r = ven-tricular radius, and L = ventricular wallthickness). Increased tension is a directstimulus to myocyte hypertrophy both inisolated tissue preparations20 and in intacthearts.2' These effects of tension on myocytesmay be mediated by mechanotransducer ionchannels, possibly by modifying intracellularpH or the concentration of intracellularmessengers such as cyclic AMP, which in turnincrease messenger RNA and proteinproduction. Myocardial stretch may alsoincrease messenger RNA directly bydeforming the nucleus.22 Other evidencesuggests, however, that additional neuro-humoral factors modify the hypertrophicresponse to tension. Cardiac structure isinfluenced not only by haemodynamic loadbut also by diverse neurohumoral factors,

including the renin-angiotensin system, ot andL adrenergic stimulation, and thyroxine.Different forms of antihypertensive treatmentmay therefore differ in their ability to promoteregression of left ventricular hypertrophy,depending on their effects on neurohumoralfactors in addition to their ability to lowerblood pressure.

Angiotensin II and cardiac hypertrophyAngiotensin II may contribute to leftventricular hypertrophy through a range ofdifferent mechanisms. Firstly, it may make asignificant contribution to total peripheralvascular resistance and hence to ventricularafterload in many forms of hypertension.Secondly, angiotensin II may indirectlystimulate myocyte hypertrophy by interactingwith the sympathetic nervous system toaugment sympathetic tone.22 Thirdly,angiotensin II has a direct trophic effect onmammalian myocytes, both as a circulatinghormone and probably also through a localcardiac renin-angiotensin system.23 Fourthly,angiotensin II can stimulate fibroblastproliferation24 25 and hence the formation ofcollagen. Angiotensin II stimulates DNA andRNA turnover in isolated myocytes,26 andprotein synthesis is augmented within hours ofexposure to angiotensin II.21-28 These effectsseem to be modulated by protein kinase C,cytosolic calcium, and activation of growthmodulating proto-oncogenes.23 29 30The relative importance of haemodynamic

load as opposed to the renin-angiotensinsystem and other trophic hormones in thedevelopment of left ventricular hypertrophyhas not been defined. The prevalence of leftventricular hypertrophy is high in essentialhypertension in humans. The relation betweenblood pressure and indices of left ventricularmass are often statistically weak, but thereseems little doubt that cardiac afterload initself is a major determinant of left ventricularmass. This contention is supported by the factthat mean 24 hour blood pressure values fromcontinuous ambulatory measurements relatemore closely to left ventricular hypertrophythan do casual clinic blood pressuremeasurements. Furthermore, integrated bloodpressures over 30 years were more clearlyrelated to left ventricular mass geometry thanwere contemporary blood pressures in theFramingham heart study.3' With acquisition offull data over a long time to give an integratedmeasure of blood pressure and thus cardiacafterload, the relation with left ventricularmass will become more clear.

Nevertheless, other factors must be co-determinants. Positive statistical associations,which may or may not reflect cause and effect,have been noted between left ventricular massand numerous indices, including dietary intakeof sodium,32 33 body weight34 35 or bodybuild,36 blood viscosity,37 plasma cate-cholamine concentrations,38 and increasingage.39 In essential hypertension the degree ofactivation of the circulating renin-angiotensinsystem has been positively related, albeit rather

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weakly, to left ventricular hypertrophy.40-42However, other reports are contradictory. Forexample, Russell et al reported that electro-cardiographic left ventricular hypertrophy wasless common in high renin than in normalrenin essential hypertension.43 Hammond et alfound that in patients with sustained hyper-tension low rather than high plasma reninactivities were associated with left ventricularhypertrophy on echocardiography.44 Suzukiet al found that left ventricular mass andrelative wall thickness were similar in patientswith unilateral renovascular (high renin)hypertension and in patients matched for age,sex, and blood pressure who had primary (lowrenin activity) aldosteronism.45 The treatmentof primary aldosteronism results in regressionof left ventricular hypertrophy despite risingconcentrations of renin and angiotensin 11.46Hence, activation of the circulating renin-angiotensin system is not an essential factor forexpression of left ventricular hypertrophy inhypertension.The role of the cardiac tissue renin-

angiotensin system in patients with leftventricular hypertrophy is unknown.Alderman et al found that in patients with

hypertension, renin profiles (obtained byplotting plasma renin activity against urinaryexcretion of sodium) were independentlyassociated with subsequent risk of myocardialinfarction.47 Other workers found no suchassociation between plasma renin activity andmyocardial infarction in normotensive men.48This raises the question of whether the asso-ciation of activation of the renin-angiotensinsystem and coronary events in essentialhypertension is mediated by promotion of leftventricular hypertrophy.A further link between the renin-

angiotensin-aldosterone system and cardio-vascular risk has appeared in recent studiesindicating that a particular deletion poly-morphism in the angiotensin convertingenzyme gene is associated with the risk ofmyocardial infarction, ischaemic cardio-myopathy, congestive cardiomyopathy, andhypertrophic cardiomyopathy.49-52 The asso-ciation was particularly strong in patients withhypertrophic cardiomyopathy with a strongfamily history of sudden death.52 The DDpolymorphism seems to act as an independentrisk factor. This polymorphism is related toenhanced plasma activity of ACE.Presumably, this may correlate with increasedplasma or tissue concentrations of angiotensinII, although this latter point remainsuncertain. Hence, in vitro, in vivo, and clinicaldata link the renin-angiotension system withleft ventricular hypertrophy and increasedcardiovascular morbidity. This raises thequestion whether ACE inhibition may beespecially effective in promoting regression ofleft ventricular hypertrophy and improvingcardiovascular prognosis.

Animal studiesLowering blood pressure by ACE inhibition inspontaneously hypertensive rats (and other

animal models of hypertension) results inregression of left ventricular hypertrophy.53 54

Several workers have attempted to determinewhether this is purely a pressure dependentphenomenon or whether ACE inhibitors haveadditional effects related to reduction inangiotensin II concentrations or to changes inother humoral agents.

Dostal and Baker infused angiotensin II intonormotensive Sprague-Dawley rats forbetween 7 and 14 days.55 Left ventricular massincreased substantially. The specific angio-tensin I receptor blocker losartan preventedthis increase in left ventricular hypertrophy.When blood pressure was maintained in thenormal range by concurrent administration ofhydralazine with the angiotensin II, this didnot prevent the induction of hypertrophy. Inaddition, in the first seven days of angiotensinII infusions many animals showed no rise inblood pressure and yet the left ventriclebecame hypertrophied. Infusion of angiotensinII during ACE inhibition (with perindopril) inspontaneously hypertensive rats not onlyprevented the antihypertensive effect of theACE inhibitor but also resulted in thedevelopment of greater heart weights than inanimals not receiving an ACE inhibitor.56Whereas captopril and dihydralazine wereequally effective in preventing a rise in bloodpressure in spontaneously hypertensive rats,only the former limited cardiac hypertrophy.57ACE inhibition in two kidney, one cliprenovascular hypertension prevented the de-velopment of left ventricular hypertrophy58and can lead to regression of established leftventricular hypertrophy,59-62 whereas alterna-tive antihypertensive agents failed to do so63;minoxidil may actually induce ventricularhypertrophy in the renovascular model.6' TheACE inhibitor quinapril prevented left ven-tricular hypertrophy associated with inter-mittent hindquarter compression in dogs.Minoxidil failed to do so, despite its ability tolower blood pressure.64 These data suggestthat angiotensin promotes left ventricularhypertrophy by mechanisms independent ofits effects on blood pressure.

In contrast with these findings, Mooser et alstudied relations between cardiac and renalhypertrophy and the circulating renin-angio-tensin system in a low renin model of hyper-tension (desoxycorticosterone acetate-salt)and in the renin dependent two kidney, oneclip model.65 Although the two models showedthe expected difference in circulating renin-angiotensin activity, the degree of leftventricular hypertrophy was similar in bothhypertensive models, despite a trend to some-what greater hypertension in the high reninmodel. Hence, left ventricular hypertrophy isrelated to increased ventricular load ratherthan to any independent effect of plasma-borne angiotensin II. Linz et al comparedconverting enzyme blockade with ramipriland angiotensin II receptor blockade withDUP 753 in an aortic banding model ofhypertension in the rat.66 They found that theACE inhibitor could prevent cardiac hyper-trophy without much effect on blood pressure,

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while the angiotensin II receptor blocker didreduce blood pressure but was less effective inreducing cardiac hypertrophy. Further studiesby this group indicated that ramipril was ableto prevent left ventricular hypertrophy andmyocardial fibrosis without blood pressurereduction over a one year period in rats.67 Bothantihypertensive and non-antihypertensivedoses were similarly effective in preventingcardiac hypertrophy and myocardial fibrosis.In rats with the volume expanded model ofhypertension (desoxycorticosterone acetate-salt) ACE inhibition failed to reduce bloodpressure or reverse left ventricular hyper-trophy.68 By contrast, in rats rendered hyper-tensive by renal ablation and high salt intakeperindopril prevented the usual increase in leftventricular weight, though circulating renin andangiotensin II values are low in this model, anddid not attenuate the rise in arterial pressure.69These studies suggest that a humoral effectindependent of both reductions in bloodpressure and suppression of angiotensin II maybe responsible for at least part of the ability ofconverting enzyme inhibitors to induceregression of left ventricular hypertrophy.

Quinapril, an ACE inhibitor with high tissuepenetrance, did not prevent increases in leftventricular mass in rats with supravalvar aorticstenosis when given immediately aftersurgery.70 It did induce an 80% regression ofestablished hypertrophy of the left ventriclewhen given six weeks after the operation. Incontrast, Zierhut et al observed no effects oframipril on the development of left ventricularhypertrophy (or cellular hypertrophy) in ratswith stenosis of the aortic arch.7'Thus animal data provide mixed messages.

Angiotensin II may be able to induce leftventricular hypertrophy independent of itspressor effects, although data from differentgroups are conflicting.55 65 67 71 ACE inhibitioncan clearly prevent left ventricular hypertrophyor induce regression of left ventricularhypertrophy in hypertensive rats, and thiseffect may be at least partially independent ofreductions in blood pressure and involveadditional humoral mechanisms-for example,bradykinin-beyond simple reduction inangiotensin II concentrations. Clearly, furthercareful controlled experiments in a range ofspecies with left ventricular hypertrophy ofvaried aetiology are needed to clarify furtherthe role of ACE inhibition in regression of leftventricular hypertrophy.

Studies in human hypertensionThe findings of the review by Liebson72 andthe meta-analyses by Cruickshank et al73 andDahlof et al74 7 are essentially consistent insuggesting that ACE inhibition causes agreater regression of left ventricular hyper-trophy for a given fall in blood pressure thando other simple drug treatments; ACEinhibition may be as effective in this regard ascombination treatments. However, all theauthors appropriately point out severalweaknesses in the database from which thesepossible conclusions are derived.

The available analyses must be interpretedwith four points in mind.

(1) Most studies of drug reversal of leftventricular hypertrophy in hypertension areuncontrolled.

(2) The number of patients in each study isgenerally small.

(3) In most studies the mean degree of leftventricular hypertrophy present is not great,and results may thus be distorted by inclusionof large numbers of patients who will not showregression of left ventricular hypertrophysimply because the condition is not present.

(4) It is possible that there are many studieswith negative results that have not beenpublished.

Liebson reviewed over 60 clinical studiesusing echocardiographic measurement of leftventricular mass. On average, only 10-15subjects were included in each study. Hepointed out the lack of studies in patients withclearly established disease-that is, clearcutmoderate or severe left ventricular hyper-trophy with complications such as coronarydisease-and highlighted the need for a studywhich followed up a substantial number ofpeople over a long treatment period. Ninetyper cent of studies had a follow up period ofless than one year. The longest running studywith the largest number followed up in a singlestudy (68 patients followed up for five years)was published by Schlant et al in 1982.76At the time of Liebson's review in 1990 only

three of 66 studies available for analysisincluded a placebo group. Only three studiesused ACE inhibition as the primary treatment,and this included only 35 patients. Not-withstanding these clear limitations, ACEinhibitors and calcium channel antagonistsmore reliably induced reduction of leftventricular mass than 1 blockade (where itoccurred in 50%), diuretics (much less than50%), or peripheral vasodilators (less than50°/). This review also reported that there wasno evidence of a loss of left ventricularcontractile systolic function with regression ofleft ventricular hypertrophy. Nearly all thepatients recruited into these studies had nounderlying significant heart disease other thanpossible mild to moderate left ventricularhypertrophy. Clearly, it is important todetermine whether regression of left ven-tricular hypertrophy produced major mech-anical disadvantages in patients who havealready sustained major cardiac ischaemicevents or have other associated cardiac lesionsbeyond the hypertrophy.The first reports indicating regression of left

ventricular hypertrophy in hypertensiontreated with ACE inhibitors appeared in theearly 1980s. Typically they included a smallnumber of patients followed up for fairly briefperiods of time without a control group forcomparison. For example, Fouad et alfollowed up 10 patients treated with enalaprilover 3-7 months using both radionuclide andechocardiographic measurements of leftventricular mass and function; six out of sevenpatients showed regression of left ventricularhypertrophy, and left ventricular function

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remained excellent.77 Dunn et al followed upeight patients treated with enalapril for only 12weeks and found a significant reduction in leftventricular mass index and no impairment ofleft ventricular contractility.78 Nakashima et alstudied seven patients receiving enalapril andundergoing echocardiography and radio-nuclide studies at baseline, at 5 days, and afterone, three, and seven months of treatment.79Left ventricular mas was reduced significantlyat three and seven months by 10% and 12%respectively. At the time these three smallstudies and several others were published inthe early 1 980s only methyldopa and ablocking drugs had been reported as inducingregression of left ventricular hypertrophy whenused as a single treatment in hypertension.80-83Previously, when combination treatment hadbeen seen to induce regression of leftventricular hypertrophy, the combinationalmost always included a sympatholytic agentor a a blocker.84-86Few data are available comparing the effects

of different ACE inhibitors. Garavaglia et alstudied 30 patients with mild to moderatehypertension receiving captopril, lisinopril, orenalapril for 10-12 weeks.87 Left ventricularmass was reduced in all three groups but rathermore with enalapril (29%) than with either ofthe two other agents (1 4% and 12% res-pectively). But the number of subjects in eachgroup was small (8-12) and baseline values forleft ventricular mass were greatest in theenalapril group. Grandi et al found thatcaptopril and perindopril had similar effects onboth blood pressure and left ventricular mass.88Hence, as yet, there are no unequivocal dataindicating that any particular ACE inhibitor orclass of ACE inhibitors is superior to anotherin terms of the ability to induce regression ofleft ventricular hypertrophy.Although numerous studies indicate that

regression of left ventricular hypertrophy doesnot lead to any impairment in left ventricularsystolic contractile function during treat-ment,77-79 most studies do not address thequestion of whether the "regressed" ventricleis more prone to dysfunction with thechallenge of acute increments in bloodpressure without the mechanical advantage ofhypertrophy, which reduces unit wall stress.One of the few studies to address this pointwas conducted by Schmieder et al, whoperformed an open study in 14 subjectsreceiving 1 blockade (five), calcium anta-gonists (two), or converting enzyme inhibitors(four).89 A further three received a com-bination of 13 blocker and diuretic. Leftventricular mass was significantly reducedfrom 274 (24) g to 239 (18) g over an averageof 19 months of treatment. After this period oftreatment drugs were removed for four weeks,during which blood pressure returned topretreatment values. Echocardiography indi-cated that the ventricles performed normallydespite the loss of left ventricular mass. As inmany other studies, patients in this study hadminimal baseline increases in mean posteriorwall thickness or interventricular septalthickness, indicating that probably half the

people studied did not satisfy criteria for leftventricular hypertrophy. The question remainswhether regression of pronounced establishedleft ventricular hypertrophy with or withoutcomplicating coronary or other cardiac diseaserenders ventricles vulnerable to dysfunction inthe advent of short term changes in bloodpressure.

Schneeweiss et al have published one of thefew blinded comparative studies of asubstantial number of patients.90 Thirtypatients with hypertension were treated witheither cilazapril or hydrochlorothiazide for 10weeks. Within this time the ACE inhibitorinduced some regression of left ventricularhypertrophy but the thiazide agent did not,despite similar effects on blood pressure.

In one of the few studies that specificallyexamined patients with clearly established leftventricular hypertrophy 34 patients, all withpoorly controlled blood pressure despitetreatment with a 1 blocker and diuretic, hadeither captopril or minoxidil randomly addedto their treatment.9' Mean interventricularseptal thickness was 17-4 mm and 15-5 mmfor the captopril and minoxidil groups respec-tively. Posterior wall thickness was 14-5 mmand 14 1 mm respectively. Left ventricularmass index was 236 g/m2 and 212 g/m2 for thetwo groups. Thus severe left ventricularhypertrophy was present. Baseline bloodpressures were similar in the two groups. Leftventricular wall thickness and mass indexclearly declined in the group treated withcaptopril, whereas the opposite occurred inthose receiving minoxidil despite similarreductions in blood pressure. These datacontrast the effect of an ACE inhibitor againstminoxidil when both were combined with twoother antihypertensive agents. Nevertheless,the differences in response are quite striking.At least one study suggests that the ability of

ACE inhibitors to induce regression of leftventricular hypertrophy is independent ofcardiac innervation. Angermann et al reportedregression of left ventricular hypertrophy onechocardiography in 10 patients with hyper-tension after cardiac transplantation.92Treatment over one year with enalapril andfrusemide with or without verapamil reducedblood pressure substantially and significantlyreduced left ventricular mass.With the shortcomings of previous studies in

mind, Dahlof and Hansson comparedenalapril and hydrochlorothiazide in a doubleblind study of treatment with hypertension inmale patients who were previously untreated.93This was a double blind comparative trialwithout a placebo group. Twenty eightpatients were included. Treatment was main-tained for 14-18 months. Similar reductionsin blood pressure occurred with both drugs.Left ventricular mass fell progressively andsignificantly after 18 months of treatment withenalapril. In comparison, reductions in leftventricular mass with hydrochlorothiazidewere not significant. Neither drug had anadverse effect on systolic left ventricularfunction. Enalapril significantly reduced pos-terior left ventricular wall thickness, inter-

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ventricular septal thickness, and leftventricular mass. The authors concluded thatan ACE inhibitor is significantly more effectivethan a diuretic in reducing left ventricularmass. Before this study trials of ACE inhi-bition were confined to open studies usually inpreviously treated patients. Despite itsstrengths, the study by Dahlof and Hanssonstill includes only 28 patients, or 14 in eachstudy group, and once again mean baselinevalues for ventricular dimensions and masssuggest that much of the study group did nothave left ventricular hypertrophy. There isclearly still a major need for a carefullyconducted double blind comparative study (atrue placebo group is ethically prohibited)with follow up of at least one year of patientswith well established left ventricular hyper-trophy at baseline. Similarly, studies of thosewith hypertensive left ventricular hypertrophyand other established cardiac disease are alsorequired.Not all clinical trials examining the effect of

ACE inhibitors in hypertension with leftventricular hypertrophy have positive results.In view of the described frailties of thedatabase and the probability that studies withnegative results are not as readily published asthose with positive results, these contraryfindings cannot be ignored. Shahi et al studied20 previously untreated hypertensive patientsreceiving captopril with or without a diureticfor six months and found reduced bloodpressure (15/20) without change in left ven-tricular hypertrophy.94 However, mean base-line left ventricular dimensions were notobviously hypertrophic, although indices ofdiastolic function (criteria for selection to thestudy) were uniformly abnormal. Recently,Laufer et al found no change in left ventricularhypertrophy, despite sustained falls in bloodpressures, in patients treated with eithercaptopril or atenolol for 12 months (15thscientific meeting of the High Blood PressureResearch Council of Australia, Melbourne,December 1993).The conclusions of meta-analyses by

Cruickshank et al73 and Dahlof et al74 75 mustbe considered in light of the limitations of thedatabase as already described. Cruickshank et alanalysed data from 104 published studies.73Of these, only eight were randomised andplacebo controlled. Twenty two were ran-domised and were comparisons of active treat-ments, and most (74) were uncontrolledstudies. The analysis used all data andcompared results in each treatment subgroupwith its own baseline data, yielding a total of147 sets of data for comparisons over time.Interestingly, the authors found that change inheart rate and the degree of left ventricularhypertrophy at baseline was not significantlyassociated with outcome, and these cofactorswere dropped from analyses. A clear possibleflaw in this form of analysis resides in the factthat if the vast majority of study participantsdid not have true left ventricular hypertrophy,the full predictive effect of baseline leftventricular hypertrophy may be "diluted" andbecome statistically inapparent. On average,

the change in blood pressure (irrespective ofthe form of drug treatment) and the durationof treatment were related to the change in leftventricular mass.When we wrote this review, the number of

studies fulfilling* criteria for inclusion in themeta-analysis and the total number of patientsincluded in trials of treatment with ACEinhibition had risen (compared with the 1990review by Leibson72) to 23 studies including321 patients receiving either captopril orenalapril. However, in the total patient pool of2107 patients only 76 were in placebo groups.The mean duration of treatment with ACEinhibitors was 7 0 months, the maximumbeing 12 months. The mean reduction inmean arterial pressure with ACE inhibitionwas 22 mm Hg, which was greater than anyother single group other than combinationdrug treatment, although this distinction wasnot significant. Left ventricular mass indexanalysed for all active treatment fell signifi-cantly. This was not true for the placebogroup, but the numbers taking placebo weresmall, reducing the statistical power of thissubanalysis.There were significant differences between

active drug classes in change in left ventriculardimensions and mass. When the effects of thefall in blood pressure and duration of treat-ment were taken into account, the distinctionsbetween drugs in terms of change in leftventricular wall thickness were lost, but aneffect on change in left ventricular mass indexwas preserved. By multivariate analysis thechange in left ventricular mass index differedbetween drugs, this distinction being inde-pendent of the degree of left ventricularhypertrophy, the degree of blood pressurereduction, and time receiving treatment. ACEinhibitors reduced left ventricular mass morethan vasodilators or dihydropyridine calciumantagonists or 1 blockers. The effect of ACEinhibitors was comparable with that ofmethyldopa. Among drug groups, the relationbetween change in blood pressure and changein left ventricular mass was most pronouncedfor j blockers. The duration of studies usingcalcium antagonists tended to be short (4-1months on average), thus possibly disadvan-taging calcium antagonists in analysis, butwhen similarly brief ACE inhibitor studieswere compared with calcium antagoniststudies a superior effect of ACE inhibition inleft ventricular mass reduction was stillobserved.

Currently, the recent meta-analysis byDahlof et al represents the current state ofknowledge on the relative strength ofantihypertensive drugs in regression of leftventricular hypertrophy.74 7 This meta-analysis considers studies published from 1977up to the end of 1990, which gave dataconcerning reversal of left ventricularhypertrophy assessed by echocardiography.Studies were included in the analysis if allrecruited patients had essential (as opposed tosecondary or malignant) hypertension; ifpatients were treated with drugs (rather thangiven non-pharmacological treatment); if

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patients underwent standardised echocardio-graphy; if patients were all accounted for(studies with a fall out rate > 30% wereexcluded); and if the data had been publishedin "reputable" journals with peer review or"similar editorial processes." The analysisincluded 14 studies of ACE inhibitors with anaverage study group size of 11 2-that is, atotal of 157 patients. Thus it is more selectivethan that by Cruickshank et al published in thesame year, which included a slightly smallernumber of studies (104 v 109) but a greaternumber of patients receiving ACE inhibitors(321 v 157).73 Overall, 2357 patients wereincluded in analysis. Twenty eight per cent ofthese were previously untreated. Studies withACE inhibition included only 11% previouslyuntreated patients. Diuretic studies included55%, calcium antagonists 22%, and P3 blockers20%. This disparity would tend to bias thestudy against indicating a superior effect forACE inhibitors rather than otherwise (seebelow).

Overall, active treatment of any kindreduced left ventricular mass by 1 1 .9% (95%confidence interval 10 1% to 13 7%), togetherwith a fall in mean arterial pressure of 14f9%(14-0% to 15-8%). ACE inhibitors reducedleft ventricular mass by 15% (9 9% to 20.1/%),P blockers by 8% (4/8% to 11 2%), calciumantagonists by 8-5% (5.1% to 11.8%)/, anddiuretics by 11.3% (5.6% to 17.0%). Meanfall in left ventricular mass was 44.7 g withACE inhibitors, 22-8 g with I blockers, 26-9g with calcium antagonists, and 21L4 g withdiuretics. All agents other than diureticsreduced left ventricular wall thickness whilediuretics predominantly reduced ventriculardiameter.Only three studies in the meta-analysis were

randomised, double blind, and exclusivelystudied previously untreated patients. Exam-ination of data solely from previouslyuntreated patients indicated greater averageeffects than in previously treated patients. Leftventricular mass was reduced by 15-2%(11-3% to 18.8%) and mean arterial pressureby 17.2% (15.6% to 18-8%). In previouslyuntreated patients mean reduction in leftventricular mass associated with ACEinhibition was 16.9% (11/6% to 22.2%). Thismean value was greater than that observed inany other subgroup, with the exception of thepatients included under "all other mono-therapies." The latter presumably includedthose treated with lesser used drugs and non-pharmacological treatments. This subgroupincluded some 300 patients who achieved amean percentage reduction in left ventricularmass of 17% (9/2% to 23-8%). The subgroupincluded under "all combination therapies"also performed similarly to that under ACEinhibitors, with a reduction in left ventricularmass of 16-4% (12-6% to 20/2%). The meanpercentage reduction in mean arterial pressurewas greater for ACE inhibition than any othersubgroup (16.3% (3/6%)). These distinctionsbetween ACE inhibitors and other activetreatments were not, however, significant inthis meta-analysis. Furthermore, when co-

A

ACE inhibitors

,B BlockersCalcium 1111111uantagonists

Diuretics

-25 -20 -15 -10 -5

B

ACE inhibitors

fi BlockersCalcium 111111111antagonists I

Diuretics

-25 -20 -15 -10Regression

1 I L1 i1Placebo

l-0 5 10 15

-5 0 5 10

Progression15

A: The unadjusted change in percentage of left ventricularmass with 95% confidence interval for placebo, ACEinhibitors, /3 blockers, calcium antagonists, and diuretics.B: The adjusted change in percentage of left ventricularmass with 95% confidence interval (ANCOVA) for ACEinhibitors, ,3 blockers, calcium antagonists, and diuretics.

variate analysis was applied to compensate fordifferences between studies in mean baselineindices of cardiac structure and in duration offollow up, the adjusted percentage change inleft ventricular mass showed clear overlap inconfidence intervals between ACE inhibitors,a blockers, calcium antagonists, and diuretics(figure). Thus, although this meta-analysisprovides strong suggestive evidence, based ontrends, of an enhanced effect of ACEinhibition on regression of left ventricularhypertrophy, the data are by no meansconclusive. The authors' cautious interpreta-tion, "We hypothesize that ACE inhibitors aremore effective than other first-line therapies inreducing [left ventricular] mass. However, thistheory and its possible prognostic implicationsneed to be evaluated in controlled prospectivetrials," seems appropriate.

ConclusionsIn hypertension ACE inhibitors have theor-etical advantages in terms of their neutral orbenign effect on glucose and lipid metabolism;the possible protective effects against recurrentmyocardial infarction in patients who have hadan infarction; their possible special efficacy inpreserving renal function in diabetes; and theirsafety and value when other conditions, such

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Role of ACE inhibitors in hypertension with left ventricular hypertrophy

as asthma or heart failure, coexist withhypertension. Current data suggest that ACEinhibitors are probably superior to otherantihypertensive agents in promoting regres-sion of left ventricular hypertrophy. However,carefully designed, blinded, randomised trialscomparing ACE inhibitors with other agentsfor at least 12 months in previously untreatedpatients with established left ventricularhypertrophy are still required before thisadded advantage can be unequivocally addedto the growing list of therapeutic benefitsoffered by ACE inhibitors. Additional studiesshould focus on groups with hypertension withleft ventricular hypertrophy and otherestablished cardiac disease.

Mrs Barbara Griffin provided expert secretarial help.

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