Is the Decrease in Arterial Pressure the Sole Factor for Reduction of Left Ventricular Hypertrophy? ROLAND E. SCHMIEDER, M.D., Numberg, Germany, FRANZ H. MESSERLI, M.D., New Orleans, Louisiana

The increasing evidence that identifies left ven- tricular hypertrophy (LVH) as a powerful prognostic factor leads to the question whether or not reduction of LVH is a desirable goal of antihypertensive therapy and, moreover, whether a decrease in arterial pressure per se is the only or the main determinant for reduc- tion of LVH. An analysis of the underlying pathogenic mechanisms suggests the presence of multiple interacting pathogenic factors in the development of LVH. Conversely, disparate rates of reduction of LVH with various antihy- pertensive drugs as well as conflicting results in different hypertensive patients point to the existence of blood pressure-independent factors influencing reduction of LVH.

From the Department of Medicine, University of Eriangen Nurnberg, Niirnberg, Germany, and the Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana, U.S.A.

Requests for reprints should be addressed to Franz H. Messerli, M.D., Ochsner Clinic, 1514 Jefferson Highway, New Orleans, Louisiana 70121.

I s decrease in arterial pressure the sole factor responsible for reduction of left ventricular hy-

pertrophy (LVH) in patients with essential hyper- tension? In order to analyze this question we first will discuss four separate pathophysiologic aspects of LVH: (a) characterization of the clinical and prognostic importance of LVH in essential hyper- tension; (b) analysis of the prognostic implications of a reduction of LVH; (c) the pathogenetic mecha- nisms accounting for development, maintenance, or reduction of LVH; and (d) the various pharmacolo- gic properties of antihypertensive drugs that possi- bly could explain discrepancies between reduction in arterial pressure and reduction in LVH with cer- tain antihypertensive drugs.

LEFT VENTRICULAR HYPERTROPHY: A RISK FACTOR IN ESSENTIAL HYPERTENSION?

The heart has been identified as a major target organ of hypertensive disease. More than two dec- ades ago, the Framingham study documented that hypertensive patients with electrocardiographic evidence of LVH were at a high risk for subsequent cardiovascular morbidity and mortality [l-3]. The 5-year mortality rate in men with echocar- diographically determined LVH was about 35% compared with lo-15% in men without echocar- diographically determined LVH. A sustained in- crease in afterload, such as occurs in essential hy- pertension, leads to an adaptive response of the left ventricle, and after a Byear period, about 50% of patients with systolic pressures >180 mm Hg will develop LVH [l]. The echocardiogram is a tool that is about lo-fold more sensitive than the electrocar- diogram for diagnosing LVH [4]. Thus, the preva- lence of echocardiographically determined LVH was documented to be as high as 50% in a popula- tion of elderly patients with mild essential hyper- tension [5]. Epidemiologic findings from the Fram- ingham cohort revealed that the signs of echocar- diographically determined LVH had a higher prog- nostic significance than electrocardiographic LVH for the development of coronary heart disease, irre- spective of all other well-known risk factors 161. Thus, in an echocardiographic study of 696 hyper- tensive patients ~62 years old who were followed

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for 27 months, those with echocardiographically determined LVH had a significantly higher occur- rence of new cardiac events and of atherothrom- botic brain infarction than those with normal left ventricular mass [7]. Although in most studies pa- tients with underlying coronary artery disease were excluded, echocardiographic epidemiologic studies did not allow ruling out a connection be- tween clinically silent coronary artery disease and subsequent morbidity and mortality in patients with LVH. However, a recent study from the Cook County Hospital (Illinois) documented that the pre- dictive power of LVH was independent of coronary artery disease. These investigators observed higher death rates in patients with echocar- diographically determined LVH, independent of angiographically defined coronary artery lesions and of ejection fraction [8]. The findings docu- mented that an increase in either septal or poste- rior wall thickness from 1.1 cm to 1.2 cm was associ- ated with an approximately two- to seven-fold in- crease in the risk of death 181.

Therefore, LVH must be regarded as a powerful blood pressure-independent risk factor for cardio- vascular morbidity and mortality. What is less clear, however, is whether reduction of LVH will lower this risk and should therefore be considered a desirable therapeutic goal [9].

LEFT VENTRICULAR HYPERTROPHY: WHY IS IT A RISK FACTOR?

Supranormal systolic function secondary to an increase in left ventricular pump function and con- tractility has been reported in the early stages of essential hypertension [ 10,111. As hypertensive cardiovascular disease progresses, an increase in left ventricular (LV) mass occurs, but eventually this and other adaptive mechanisms no longer suf- fice to compensate for the increase in afterload. As a consequence, LV pump function becomes im- paired and contractility falls, leading to a sequence of events that ultimately will result in congestive heart failure [3,12,13]. Thus, the manifestations of congestive heart failure reflect an imbalance be- tween the imposed afterload, secondary to sus- tained hypertension, and an insufficient myocardial contractility reserve, despite the development of “compensatory” hypertrophy. The reduction in myocardial contractility is further aggravated by deposits of collagen throughout the myocardium that may interfere with contractile function [11,14].

In contrast to systolic dysfunction, which is a fairly late phenomenon, diastolic dysfunction has been shown to be one of the earliest manifestations of hypertensive heart disease and can be encoun- tered in patients who do not fulfill the criteria of

LVH. However, the extent of impairment of dia- stolic function has been documented to parallel the degree of LVH [15,16]. Initially, the reduced filling occurring in early diastole causes a compensatory increase in late diastolic filling accompanied by ac- celeration of late diastolic inflow [17]. With pro- gressive LVH, however, this compensatory late diastolic mechanism diminishes, the ventricle be- comes stiffer, and diastolic filling falls dramatically. In certain hypertensive patients, congestive heart failure has been shown to be due to impaired dia- stolic function in the presence of a normal systolic pump function [Ml.

LVH has been shown to induce or aggravate myocardial ischemia. Pathogenic factors leading to impairment in myocardial perfusion are a decrease in coronary reserve [19,20], an increase in end- diastolic pressure, and the development of micro- vascular disease in the coronary circulation, which has been shown to occur even in the absence of LVH [21,22]. In addition, the increase in muscle mass per se and the increase of hemodynamic bur- den demand more oxygen for myocardial perfusion. With progression of LVH, an inadequate adapta- tion of coronary vasculature has been observed, leading to a relative underperfusion [23,24]. In- deed, the rate of cardiac death and myocardial rein- far&ion have been documented to be increased 1.7- 2.1 times in the presence of LVH in the postmyo- cardial infarction patients [25].

A further cardiovascular consequence of LVH is the documented increase of arrhythmogenicity. Several studies have shown that hypertensive pa- tients with LVH and patent coronary arteries expe- rienced runs of ventricular tachycardia more fre- quently than patients without LVH [26-281. Re- sults from the Framingham study reinforced these findings by showing that the prevalence of all forms of ventricular arrhythmias was significantly higher in patients with echocardiographically determined LVH than in patients without LVH [29].

DOES RISK REDUCTION FOLLOW CARDIAC HYPERTROPHY REDUCTION?

Although numerous studies documented the clin- ical significance of LVH in essential hypertension, so far only two prospective studies have analyzed the possible prognostic significance of LVH reduc- tion. The data are preliminary and therefore do not give a final answer to the intriguing question whether reduction of LVH is a desirable therapeu- tic goal. Recently, data were presented on the prognostic significance of changes in LV mass in hypertensive patients. Cardiovascular events (car- diac death, myocardial infarction, stroke, angina pectoris, or coronary revascularization) were re-

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ported to occur more frequently in patients with persisting LVH than in patients with reduction in LV mass [30,31]. In multivariate analyses, only age and reduction of LV mass were independently asso- ciated with clinical outcome. These provocative findings are supported by a multicenter East Euro- pean study that followed 232 patients with LVH over 7 years. Cardiovascular events were observed in nearly 50% of all hypertensive subjects whose LV wall thickness increased by 2 mm (G. Heine- mann, personal communication). In contrast, car- diovascular events were found in 35% of hyperten- sive patients with unchanged LV wall thickness (? 2 mm) but only in 10% of hypertensive patients whose LV wall thickness decreased by 2 mm. These data, therefore, suggest that reduction of LV mass improves the outcome in essential hypertension.

Further evidence for an improved prognosis in hypertensive heart disease following reduction of LVH comes from studies that examined changes in systolic and diastolic function after reduction of LVH [32-341. In patients treated for 19 months for mild and moderate hypertension, antihypertensive therapy was discontinued after LV mass had been significantly reduced. Within 4 weeks, afterload was noted to return to pretreatment levels. Yet, despite the re-exposure of the left ventricle to an increased afterload, there was an improvement in LV performance, ejection fraction, fractional fiber shortening, velocity of circumferential fiber short- ening, as well as in myocardial contractility esti- mated by end-systolic wall stress/end-systolic vol- ume index [32]. Similarly, Trimarco et al [33] showed that after a 3-week washout period after treatment with angiotensin-converting enzyme (ACE) inhibitors and calcium-entry blockers, the contractile response of the left ventricle, judged by the correlation between fractional shortening and end-systolic stress, returned to pretreatment lev- els. By that time, LV mass was 16% lower, whereas mean arterial pressure was only 6% lower than be- fore treatment [33]. Antihypertensive therapy with ACE inhibitors caused a reduction in LV mass and collagenous elements in experimental models with consecutive improvement of LV filling [35]. Im- proved diastolic filling after therapy with /3 block- ers and calcium antagonists was also found [34,36,37]. Yet, other studies have observed no improvement in LV filling under antihypertensive therapy [38,39]. Altogether, results remain contro- versial with regard to diastolic function, and one should also take into account that all antihyperten- sive agents have their own hemodynamic and phar- macologic properties and can directly influence car- diac function. Recent studies analyzing determi- nants of diastolic dysfunction in hypertensive pa-

tients suggested that in essential hypertension, parameters for diastolic function are more depen- dent on LV cavity size and heart rate than on LVH and such clinical parameters as age, systolic pres- sure, diastolic pressure, or obesity [40].

Clearly, further prospective studies are needed to demonstrate that reduction of LVH is accompa- nied by improvement of systolic and diastolic func- tion and to determine whether pharmacologically induced reversal of the hypertrophic process can reduce the increased risk associated with LVH.

IS BLOOD PRESSURE THE SOLE FACTOR RESPONSIBLE FOR LVH?

Numerous studies have suggested that in addi- tion to the pressure load, other factors participate in or permit determination of the degree of LVH in response to hypertensive disease as well as the de- gree of its reversal after control of arterial pres- sure. The wide range of factors associated with development of increasing LV mass in clinical and experimental forms of hypertension is shown in Figure 1. The actual roles of these factors in the pathogenesis of LVH are discussed as follows.

LVH is primarily understood to be the result of hemodynamic factors that overload the myocar- dium. Persisting systemic pressure overload in- duces an immediate biochemical response of the myocardium to increase protein synthesis and thereby to initiate the adaptive structural process of LVH; as a consequence of the structural changes of the myocardium, increased wall stress returns to normal values, thereby serving to maintain cardiac pump function [13,41&l. However, increased pressure overload of the left ventricle, reflecting increased blood pressure and total peripheral re- sistance, does not represent the sole hemodynamic factor that participates in the development of LVH. A faster heart rate and increased LV contractility (potentially reflecting increased sympathetic drive to the heart) have also been reported to be related to the development of LVH in essential hyperten- sion [433. Yet, although hypertrophy seems to com- pensate for pressure overload, several questions remain. For example, why are there patients with extremely high pressures who show little or no evi- dence of cardiac enlargement? And mutatis mutan- dis, why do some patients with marked LVH have only minimally elevated pressures [44]? The disso- ciation of pressure and hypertrophy in these partic- ular patient groups has strongly promoted the search for additional factors that may also account for the development of LVH in essential hyperten- sion.

Both the adrenergic and the renin-angiotensin- aldosterone systems have been thought to influence

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cardiac structural adaptation in certain subsets of hypertensive patients [45-521. Experimental evi- dence is available that increased exposure to norep- inephrine, even in suppressor amounts, may induce development of LVH. Both norepinephrine, the natural hormonal substance, and isoproterenol, a synthetic specific beta-adrenergic receptor agonist, have been shown to cause myocardial hypertrophy [48-501. Conversely, centrally acting antiadrener- gic agents as well as beta-adrenoceptor blockers reduce LV mass, even when arterial pressure is not completely controlled [53,54].

Modification of structural cardiac adaptation by the activity of the renin-angiotensin-aldosterone system may occur through inappropriately elevated angiotensin II levels. Angiotensin II has been shown to stimulate synthesis of DNA, RNA, and proteins in myocardial muscle cells [51,52]. Dietary salt intake, identified as a strong determinant of cardiac structural adaptation, has been linked to LVH by the dependence of sodium homeostasis on the renin-angiotensin-aldosterone system [42,55]. Other neuroendocrine and metabolic factors have been related to the pathogenesis of LVH. Thus, growth hormone and parathyroid hormone were suggested as determinants of LV mass [56]. Abnor- mal glucose tolerance as well as insulin resistance, both characterized by increased serum insulin lev- els, have been associated with an increased LV mass in essential hypertension, independently of the level of arterial pressure

Figure 1. Factors associated with development of increasing ventricular mass in clinical and experimental forms of hypertension. LVH = left ventricular hypettrophy.

7,581. Another al-

tered metabolic state is that of hyperuricemia. An increased risk of cardiac enlargement has been as- sociated with elevated serum uric acid levels [59].

Another important pathogenetic factor that must be considered a modulator of LVH is obesity. He- modynamic studies have revealed that obese pa- tients are characterized by an increased total blood volume and cardiac output as well as by cardiac en- largement. The latter reflects structural adaptation in obesity to both volume and pressure overload [60,61]. Age is a further clinical determinant that has been related to increased cardiac mass. Al- though resting systolic ventricular function is usu- ally well maintained throughout senescence, a slight decline in cardiac index of about 25 mL/min/ m2/year has been found in various invasive studies 162,631. Echocardiographically, this decline in sys- temic flow has been found to be characterized by an increase in LV wall thickness and LV mass without change in chamber volume [64]. Altogether, the increase of arterial pressure throughout life, the decrease of arterial compliance with age, and the decrease in the number of contractile myocardial fibers may explain the development of age-related LVH. Sex and race have also been described as modulating factors in cardiac adaptation in patients with essential hypertension [65,66]. At any given level of arterial blood pressure, women exhibit smaller LV dimensions than men. Sex differences in LV structure are more pronounced between pre- menopausal women and men and tend to disappear

Infarction Congestive heart failure Sudden death

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TABLE I Impact of Antihypertensive Therapy on Blood Pressure and Left Ventricular Mass Classified According to Their Pharmacologic Properties

Antihypertensive Agent

BP;;;;ing Impact on LVH Comments

Vasodilators =I? Stimulation of the SNS Diuretics f =* and renin-angiotensin system Calcium antagonists

t Intracellular signals modiied

a blocker f: Peripheral blockade of myocardial growth fl blocker ACE inhibitors Antiadrenergics i

i ’ signals by norepinephrine, neuronal SNS activity, and angiotemin II

Central blockade of SNS activity to the heart 1 BP = blood pressure; LVH = left ventricular hypertrophy; SNS = sympathetic nervous system; 1 decrease; = no change; T increase. *Overall effect is presented, although not uniformly reported for all drugs of this pharmacologic class.

after menopause. Animal studies demonstrated that sex differences in cardiac size could be abol- ished by orchiectomy and restored after testoster- one replacement and associated the observed changes with hormonal differences [6’i’].

EFFlCACY OF ANTIHYPERTENSIVE TREATMENT ON THE COURSE OF LVH IN ESSENTIAL HYPERTENSION

If elevated blood pressure levels are believed to represent the sole factor of LVH in hypertension, pharmacologic agents capable of lowering arterial pressure should be expected to prevent or diminish LVH. However, clinical and experimental studies showed that not all antihypertensive drugs reduce LVH [9,68]. Antihypertensive treatment with diu- retics does not consistently reduce LVH despite their significant blood pressure-lowering effects [69]. Antihypertensive therapy with vasodilators has been documented to have no influence on the reduction of LV mass [70,71]. In contrast, centrally acting antiadrenergics, p-blockers, calcium antago- nists, ACE inhibitors, and peripheral a-antagonists have been documented to diminish LVH [9,68,‘72- 781. The varying efficacy of the different antihyper- tensive regimens is illustrated in Table I. Thus, not all antihypertensive agents are equal in reducing LVH, despite an equipotent antihypertensive ef- fect. Specific effects of antihypertensive drugs on either the renin-angiotensin-aldosterone system or the sympathetic nervous system may to some extent explain this variability. This line of thinking is supported by the fact that ACE inhibitors and calcium antagonists diminish both norepinephrine receptor concentrations (B,) and angiotensin II plasma levels [79,80]. In contrast, treatment with hydralazine or trimazosin may increase norepineph- rine B,, and angiotensin II plasma levels [81].

Administration of ACE inhibitors (perindopril, captopril, enalapril) has consistently been reported

to produce a reduction in LV mass of >lO% [78,82]. The strong impact of ACE inhibitors on LVH and the opposite effects of vasodilators and diuretics (both known to stimulate the renin-angiotensin system) on LV mass suggest that stimulation of neurohumoral systems plays an important role in the pathogenesis of LVH. Animal studies depicting a positive correlation between plasma renin activity and cardiac mass in spontaneously hypertensive rats underline this hypothesis [83,84]. Similarly, methyldopa and propranolol have been documented to lead to a parallel reduction in plasma renin activ- ity and LVH, whereas therapy with minoxidil caused an increase in LVH and plasma renin activ- ity [85].

A possible further advantage of ACE therapy in the question of LVH reduction may be the absence of an increase in heart rate, as occurs with dihydro- pyridine calcium antagonists and other vasodila- tors.

Overall, differences in patient cohorts and meth- odologic factors may account for the diversity of the results obtained. Randomized, well-controlled tri- als comparing the capability of various antihyper- tensive agents in reducing LVH are nonexistent. Differences in age, sex distribution, pretreatment with antihypertensive agents, degree of LVH pres- ent at study onset, duration of study, lack of ran- domization, concomitant weight changes, reduced dietary salt intake, and exercise profiles may ac- count for some of the controversy. However, most evidence suggests that reduction of LVH is related to the drug class.

CONCLUSIONS Altogether, clear evidence is available that LVH

in essential hypertension is a risk factor for future cardiovascular morbidity and mortality. However, a variety of confounding factors in the pathogenesis of LVH and the disparate efficacy of various antihy-

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pertensive drug regimens in reducing LVH despite their equally effective blood pressure control clearly suggest that blood pressure elevation is not the sole determinant of LVH and that blood pres- sure reduction is not the sole factor in reducing LVH. Although LVH can be reduced by a variety of antihypertensive drugs, it is not known whether or not such a reduction will improve morbidity and mortality associated with this entity.

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4E-348 April 27, 1992 The American Journal of Medicine Volume 92 (suppl 4B)