Drugs 35 (Suppl , 5): 27-33 (1988)

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Left Ventricular Hypertrophy andAntihypertensive Therapy

Franz H. Messerli, Shmuel Oren and Ehud GrossmanDepartment of Internal Medicine, Section on Hypertens ive Diseases, Ochsner Clinicand Alton Ochsner Medical Foundation, New Orleans

Summary Cardiac adaptation to long-standing arterial hypertension consists of lef] ventricularhypertrophy (L VH). usually ofthe concentric type. i.e. an increase in wall thickness at theexpense ofchamber volume. L VH can no longer be considered only as a simple adaptivemyocardial process; it drastically increases the risk of sudden death and cardiovascularmorbidity and mortality, irrespective ofthe levels ofarterial pressure. Patients with L VHhave more premature ventricular contractions than patients without L VH or normotensivesubjects, which indicates that LVH per se increases ventricular ectopic activity .

Antihypertensive therapy should not only lower blood pressure, but also prevent ori mprove end-organ damage and therefore allow left ventricular mass to regress. Althoughthey lower blood pressure, certain antihypertensive agents such as the thiazide diureticsand arteriolar dilators (hydralazine, minoxidil) have little or el'en a detrimental effect onLVH. In contrast, other agents such as angiotensin-converting enzyme (ACE) inhibitors,fJ-blockers, antiadrenergic drugs. and certain calcium antagonists decrease left ventricularmass in parallel with arterial pressure. Recent evidence has shown that a decrease in leftventricular mass induced by certain antihypertensive drugs suppresses ventricular ectopicactivity by 85%. In contrast. left ventricular mass and ventricular ectopic activity remainunchanged or may even increase in patients treated with diuretics. It is not known whetherthe risk ofsudden death can be decreased and the ominous prognosis of LVH altered bysuch specific antihypertensive therapy.

1. Cardiac Adaptation to Hypertension

Adaptation.of cardiac anatomy in hypertensi vepatients may occur as concentric hypertrophy, ec­centric hypertrophy, predominant septal hypertro­phy, or any combination of these (Drayer et al.1983). The pathogenic mechanisms underlying thedifferent forms of left ventricular hypertrophy(LVH) are not yet clear. Devereux et al. (1983,1987) have shown that the classic form of concen­tric LVH (i.e. increased relative wall thickness) andincreased peripheral resistance are interrelated in

hypertension, whereas conditions with volumeoverload such as pregnancy. anaem ia, renal failureand , most commonly, obesity result in eccentricLVH (i.e. chamber dilatation and unchanged ra­dius to wall thickness ratio) [Messerli 1983]. Sav­age et al. (1979) found predominant septal LVH(i.e. ventricular septal-to-Ieft ventricular free-wallthickness ratio ~ 1.3) in 4% of their hypertensivesubjects, and it is not known whether this abnor­mality represents a genetically transmitted. abor­tive variant of hypertrophic cardiomyopathy or an

Left Ventricular Hypertrophy, Antihypertensive Treatment

atypical form of left ventricular wall thickeningsecondary to arterial hypertension.

Data from the Framingham study show that theprevalence of LVH detected by electrocardiogra­phy was more common in men than in women androse with age (Kannel et al. 1969). Age and dura­tion of hypertension have been reported to in­crease left ventricular mass for a given level of ar­terial pressure (Devereux et al. 1983), and it hasbeen suggested that the effectsof both age and bodysurface area should be taken into account when­ever the effects of hypertension on echocardio­graphic measurements are assessed; by use of thisapproach it was found that more than 60% of sub­jects with mild to moderate hypertension had ab­normalities such as septal and posterior wall thick­ening and increased ventricular mass (Savage et al.1979).

Although arterial pressure has been shown to bea major determinant of LVH, few people withhypertension ultimately develop this condition(Devereux et al. 1987). The weak correlation be­tween arterial pressure and left ventricular masssuggests that other hypertrophogenic factors maybe important. Included in these are sex, age, race,humoral factors such as the activity of the sym­pathetic nervous system and the renin-angiotensinsystem, whole blood viscosity, intravascular vol­ume (obesity), and perhaps the aetiology of hyper­tension (Dreifus 1984; Frohlich 1983; Messerli1983).

Data from the Framingham study indicate that,according to electrocardiographic evidence, LVHis not a benign compensatory process but an in­dependent risk factor for congestive heart failure,coronary artery disease, and sudden death (Gordon& Kannel 1971 ; Kannel 1983; Kannel et al. 1969),and subsequent investigations revealed that evenin its early stages LVH, as identified by echocar­diographic criteria, also increased the risk for car­diovascular morbid events (Casale et al. 1986;Kannel et al. 1986).

Messerli etal. (1984) demonstrated a higherprevalence of premature ventricular contractionsand more complex ventricular arrhythmias inpatients with LVH than in hypertensive patients

28

without LVH or in normal subjects, which indi­cates that LVH per se increases ventricular ectopicactivity. McLenachan et al. (1987) demonstratedthat non-sustained ventricular tachycardia is sig­nificantly more common in hypertensive patientswith quite severe LVH than in those without it.Their data suggest a close relationship between thedegree of cardiac hypertrophy and the prevalenceof such arrhythmias (Frohlich 1987). Levy et al.(1987), in the recent Framingham Heart Study in­volving 6,218 participants, corroborated these databy demonstrating a high prevalence of ventriculararrhythmia in patients with LVH compared withthose with normal hearts.

2. Clinical Correlates of Left VentricularHypertrophy Regression

Regression of concentric LVH and predomi­nant septal hypertrophy during antihypertensivetherapy has been reported by a variety of investi­gators (Drayer et al. 1983; Fouad et al. 1982; Schlantet al. 1977). Similarly, in overweight patients whohad mild hypertension, weight reduction withoutantihypertensive treatment decreased left ventric­ular mass, whereas antihypertensive treatment withmetoprolol without weight reduction had no effect(MacMahon et al. 1986).

Theoretically, a reduction of arterial pressure,by decreasing afterload, should reduce myocardialwall stress and lead to a decrease in muscle mass.However, experimental and clinical data docu­ment discrepancies between control of arterialpressure and regression of hypertrophy. Despiteequipotent blood pressure-lowering effects, not allantihypertensive agents will allow LVH even to re­gress. Moreover, regression can be obtained with agiven drug even though the antihypertensive re­sponse may be less pronounced than that producedby another drug (Fouad et al. 1982; Frohlich &Tarazi 1979; Haugland et al. 1986; Pfeffer et al.1979; Sen et al. 1974; Tarazi 1983).

Some studies have suggested that the larger theleft ventricular mass, the greater was the reductionby treatment (Drayer et al. 1983; Hill et al. 1979);however, other investigators showed ,that even in

Left Ventricular Hypertrophy, Antihypertensive Treatment

patients with 'normal' cardiac muscle mass beforetreatment, a reduction in left ventricular mass canbe obtained (Dunn et at. 1984;Rowlands et at. 1982;Ventura et at. 1985).

The factors determining these diverse responsesare still not clear. Tarazi and Fouad (1984) foundthat neither age nor duration of hypertension couldaccount for the difference in response. The degreeof left ventricular mass regression correlated moreclosely with average diurnal arterial pressure levelsthan with casual office readings.

According to Fouad et at. (1987) the two factorsthat are relevant in regression of LVH are the dur­at ion of treatment and the mechanism by whicharterial pressure is controlled. Modulating factorscan accelerate or interfere with regression of LVH,but a marked and sustained decrease of left ven­tricular afterload alone, if predominantly due to areduction of systemic resistance , could lead toregression of hypertrophy. It is clear, however, thatdrugs which reduce arterial pressure and systemicresistance without stimulating sympathetic andrenin activity are more likely to produce regressionof left ventricular mass (Fouad et at. 1982; Pegram& Frohlich 1983; Pegram et at. 1982; Sen 1983; Senet at. 1974; Tarazi & Fouad 1984). In humans, def­inite reduction in left ventricular mass was not seenin the first 30 days ofantihypertensive therapy, de­spite rapid arterial pressure control, but it becameevident within 8 to 12 weeks after sustained treat­ment (Fouad et at. 1987).Dunn et at. (1987) showedsignificant reduction of posterior and septal wallthickness after 4 weeks' treatment with atenolol;however, left ventricular mass decreased signifi­cantly only after 6 months' treatment.

3. Reversibility of LVH andAntihypertensive Therapy

The effects of various antihypertensive thera­pies on the left ventricular mass of patients withhypertension are shown in tables I, II and III.

3.1 Antiadrenergic Drugs

Antiadrenergic drugs such as methyldopa andreserpine significantly reduce LVH; reduction ofleft ventricular mass was shown even with a small

29

dose of methyldopa that had little or no haemo­dynamic effect. On the contrary, even at a dosethat produced haemodynamic effects similar tothose produced by methyldopa, clonidine does notseem to decrease hypertrophy in the spontaneouslyhypertensive rat until the dose is tripled (Fouad etat. 1982; Haugland et at. 1986; Pegram & Frohlich1983; Pegram et at. 1982).

3.2 Diuretics

Diuretics usually do not reduce left ventricularmass, except in isolated cases (Fouad et at. 1987;Tarazi & Fouad 1984); however, the addition ofsmall doses of methyldopa to diuretics leads to sig­nificant reduction ofleft ventricular mass with littlechange in arterial pressure (Fouad et at. 1982; Pe­gram & Frohlich 1983; Wollam et at. 1983). Drayeret at. (1983) showed significant decrease in dia­stolic septal thickness and relative wall thicknessbut no change in poster ior wall thickness duringlong term antihypertensive treatment with hydro­chlorothiazide and methyldopa.

3.3 Arterial Vasodilators

Arterial vasodilators such as hydralazine, min­oxidil and postsynaptic a-blockers such as prazosindid not decrease LVH despite adequate arterialpressure control (Fouad et at. 1987; Frohlich 1987;Haugland et at. 1986). Exceptions were reportedwhen a vasodilator was used in combination witha iJ-blocker or methyldopa (Fouad et at. 1987; Tar­azi & Fouad 1984).

3.4 iJ-Blockers

Initial studies with iJ-blockers gave controver­sial results (Fouad et at. 1987; Tarazi & Fouad1984), but it is now clear that their use leads to adecrease in LVH. Corea et at. (1983) showed sig­nificant reduction in left ventricular wall thicknessand mass index after 18 months' monotherapy withatenolol, and the reduction in mass index corre­lated with the magnitude of pressure reduction, notwith pretreatment mass. Rowlands et at. (1982), and

Left Ventricular Hypert roph y, Ant ihypertensive Treatment

Table I. Regression of left ventricular hypertrophy in patients treated with some antihypertensive drugs

Reference Drug Duration of Change in Reduction in

treament LV mass BP (mm Hg)(months) (%)

Antiadrenerg ics

Fouad et al. (1982) Clonidine no change

Tarazi & Fouad (1984) Reserpine decrease"

Wollam et at. (1983) Methyldopa 3 -13.6 30/22

Diuretics

Drayer et al. (1983) Hydrochlorothiazide 1.5 no change 7/4Wollam et al. (1983) Hydrochlorothiazide 18 no change 36/29

Vasodilators

Fouad et al. (1987) Hydralazine no change

Haugland et al. (1986) Prazosin no change

Tarazi & Fouad (1984) Hydralazine no change

Ii-Blockers

Corea et al. (1983) Atenolol 18 - 16.9 32/27Dunn et al. (1987) Atenolol 6 -11 .8 27/6Trimarco et al. (1984) Acebutolo l 6 -6.1 29/15Wikst rand (1987) Metop rolol 12 - 15.0

a Decrease not quantified.

Abbreviations: LV = left ventricular ; BP = blood pressure.

30

Table II. Regression of left ventricular hypertrophy in patients treated with calcium antagonists or angiotensin-convert ing enzyme(ACE) inhibitors

Reference

ACE inhibitors

Dunn et al. (1984)

Garavaglia et al. (unpublished)

Ventura et at, (1985)

Calcium antagonists

Amodeo et al. (1986)DeSimone et al. (1984)

Drayer et al. (1986)Ferrara et al. (1985)Giles et al. (1986)McLea'y et al. (1983)

Muiesan et al. (1986)Schmieder et al. (1987)

Drug

Enalapril

Lisinopril

Captopril

Diltiazem

Nifedipine

NitrendipineNitrendipine

Nitrend ipine

Nifedip ineNifedip ineVerapamil

Duration oftreatment(months)

333

323333

Change inLV mass

(%)

-19.5

-12

-14

-10.3

no changeno change- 3.4no change

-7-13.3

-6

Reduction in

BP (mm Hg)

22/18

17/12

20/12

15/9

12/1417/11

16/10

35/2328/1822/13

Abbreviations: LV = left ventricular; BP = blood pressure .

Left Ventricular Hypertrophy, Antihypertensive Treatment

Table III. Regression of left ventricular hypertrophy in patients treated with combinations of antihypertensive drugs

31

Reference Drugs Duration of Change intreatment LV mass(months) (%)

Drayer et al. (1986) Nitrendipine + HCTZ no changeNitrendipine + propranolol no change

Fouad et at. (1982) Methyldopa + HCTZ 9 - 30Fouad et at, (1987) Methyldopa + hydralazine decrease"Tarazi & Fouad (1984) Hydralazine + propranolol decrease"Wollam et al. (1983) Methyldopa + HCTZ 18 - 17:5

Reduction in BP(mmHg)

6/3

46/27

a Decrease not quantified.Abbreviations: LV = left ventricular; BP = blood pressure; HCTZ = hydrochlorothiazide .

more recently Dunn et al. (1987), demonstrated re­duction of posterior and septal wall thickness andcardiac mass with atenolol treatment, the formereven in patients with no evident increase in leftventricular mass or wall thickness. Metoprolol hasalso been shown to decrease mass (Wikstrand 1987).Using the cardioselective drug acebutolol , Tri­marco et al. (1984) showed decreases in left ven­tricular posterior wall and ventricular septal thick­ness and estimated left ventricular mass, althoughthe diminution in wall thickness occurred only afterprolonged (~ 8 months) therapy . In other studiesthe combination ofpropranolol and hydralazine invarying ratios achieved significant reversal of hy­pertrophy (Fouad et al. 1987; Hill et al. 1979).

3.5 ACE Inhibitors

The ACE inhibitors captopril, enalapril andIisinopril decrease left ventricular mass in hyper­tensive patients with and without LVH after shortterm treatment (Dunn et al. 1984; Gara vaglia et al.unpublished; Ventura et al. 1985). The mechanismfor this reduction in left ventricular mass seems tobe mainly ventricular afterload reduction; how­ever, inhibition of angiotensin II-dependent myo­cardial protein synthesis and perhaps decreases inangiotensin-mediated adrenergic outflow may alsocontribute to this process. '

3.6 Calcium Antagonists

Antihypertensive therapy with calcium antag­onists has also been shown to allow regression ofLVH. A reduction of left ventricular mass as wellas relative wall thickness was observed after 8 to12 weeks' effective treatment with verapamil in asustained-release formulation and after 4 weekswith diltiazem (Amodeo et al. 1986; Schmieder etal. 1987). Previous studies have shown regressionof muscle mass with nifedipine and nitrendipine(Ferrara et al. 1985; Kobayashi & Tara zi 1983;Massie et al. 1984; McLeay et al. 1983; Motz et al.1983; Muiesan et al. 1986), whereas others dem­onstrated effective lowering of arterial pressurewithout any significant decrease in left ventricularmass (DeSimone et al. 1984; Giles et al. 1986).Drayer et al. (1986) did not show significant changein left ventricular mass in patients receiving ni­trendipine monotherapy or combination therapywith nitrendipine and propranolol. The reductionof mass seems primarily to be caused by afterloadreduction , although a lowered concentration ofintracellular calcium ions, which are necessary forprotein synthesis , or a reduced sensitivity to angio­tensin II, which initiates protein synthesis in card­iac muscle, may conceivably contribute to this re­duction of cardiac mass.

Left Ventricular Hypertrophy, Antihypertensive Treatment

4. Regression of LVH - Beneficial orDetrimental?

Most studies report that in humans, left ven­tricular performance remained unchanged by re­duction of left ventricular mass after antihyperten­sive therapy. However, these studies do not clearlydissociate the effects of blood pressure reductionfrom those of LVH regression, since all were car­ried out in hypertensive patients who were still onmedication. Trimarco et al. (1984) showed in­creases in ejection fraction and velocity of circum­ferential fibre shortening in hypertensive patientstreated with acebutolol and in whom a parallel de­crease in left ventricular mass occurred. However,the authors excluded the possibility that the im­provement in left ventricular performance mightbe a result of the reversal of hypertrophy, since nodifference was detected between those patients whoshowed a reduction in left ventricular mass andthose who did not.

Tarazi and Fouad (1984) and Fouad et al. (1987)have revealed that the relationship between leftventricular end-systolic stress and left ventricularfractional shortening was unchanged during reduc­tion in left ventricular mass, which confirmed thatregression of hypertrophy was not associated withdeterioration of left ventricular performance.

In a recent study, Schmieder et al. (in press) dis­continued antihypertensive medication for 4 weeksin patients on long term therapy in order to re­examine left ventricular function and contractilityafter regression of LVH. Even though arterial pres­sure had returned to pretreatment levels, left ven­tricular mass remained reduced and myocardialcontractility, ejection fraction, fractional fibreshortening and velocity of circumferential fibreshortening improved. This preliminary study sug­gests that regression of myocardial hypertrophy ap­pears to be beneficial and not detrimental to car­diac pump performance.

Recent evidence indicates that regression of leftventricular mass induced by calcium antagonistssuppresses ventricular ectopic activity by 85%. Eventhough diuretics produced a parallel lowering of'ar­terial pressure, they did not affect left ventricular

32

mass or ventricular ectopic activity (Nunez et al.unpublished) . Although these preliminary resultslook promising, it is still not known whether thedecrease of the left ventricular mass by antihyper­tensive therapy will influence the inherent morbid­ity and mortality of LVH.

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Author 's address: Dr Franz H. Messerli, Ochsner Clinic, 1514Jefferson Highway, New Orleans, LA 70121 (USA).