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(Circulation. 1998;98:1987-1989.)
© 1998 American Heart Association, Inc.
Editorial |
Regression of Left Ventricular Hypertrophy in Patients With Hypertension
Blockade of the Renin-Angiotensin-Aldosterone System
From the Cardiology Division, University of Michigan Medical Center, Ann Arbor.
Correspondence to Bertram Pitt, MD, Cardiology Division, University of Michigan Medical Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0366.
Key Words: Editorials • hypertrophy • hypertension
Left ventricular hypertrophy in patients with hypertension is of importance because of its association with an increase in the incidence of heart failure and other cardiovascular events, such as myocardial infarction and sudden cardiac death. Not all antihypertensive agents, however, have been suggested to be equally effective in causing regression of left ventricular hypertrophy or preventing its progression.1 Although several classes of antihypertensive agents are effective in causing regression of ventricular hypertrophy, it is uncertain whether all strategies are equally effective and, more importantly, whether strategies equally effective in causing regression of ventricular hypertrophy will be equally effective in preventing the consequences of ventricular hypertrophy, such as myocardial infarction and sudden cardiac death.
The mechanism of ventricular hypertrophy in patients with hypertension is as yet uncertain; however, activation of the renin-angiotensin-aldosterone system (RAAS) as a result of myocardial stretch and other factors is recognized as playing an important role. Angiotensin II has been shown to stimulate various growth factors, cytokines, fibroblast activity, myocyte hypertrophy, and myocardial fibrosis. Strategies to prevent activation of the RAAS and/or its effects would therefore appear attractive in preventing ventricular hypertrophy and its consequences in patients with hypertension.
ACE inhibitors have been shown to cause a reduction in myocardial cytokines, growth factors, oxygen free radical production, collagen formation, and myocyte growth. They increase nitric oxide release and reduce morbidity, ischemic events, and mortality in patients with heart failure, including those with a history of hypertension. A meta-analysis of all antihypertensive agents has suggested that ACE inhibitors are the most effective class in causing regression of ventricular hypertrophy.2 The number of patients and length of follow-up in these studies, however, is limited, and any final answer to the question as to the effectiveness of ACE inhibitors compared with other means of blocking the RAAS and other classes of antihypertensive agent must await further larger-scale, longer-term studies. The mechanism by which ACE inhibitors cause regression and/or prevent the development of ventricular hypertrophy is important in predicting whether they will be the most effective means of preventing the effects of angiotensin II in patients with hypertension and ventricular hypertrophy. Experimental studies have shown that subhemodynamic doses of an ACE inhibitor are effective in preventing the development of ventricular hypertrophy and that this effect can be negated by the bradykinin B2 receptor antagonist HOE-140,3 suggesting that the mechanism by which ACE inhibitors prevent ventricular hypertrophy is in large part due to the prevention of bradykinin degradation rather than the accumulation of angiotensin II. Recent data, however, have cast doubt on the importance of bradykinin in preventing ventricular hypertrophy and therefore the contribution of bradykinin to the beneficial effects of ACE inhibitors in preventing ventricular hypertrophy. Ritchie et al4 showed in an isolated myocardial cell culture preparation that bradykinin does not cause regression of myocardial hypertrophy produced by angiotensin II. Only when cardiac muscle cells were coincubated with endothelial cells did bradykinin prevent angiotensin II–induced myocardial hypertrophy. The finding that endothelial cells are necessary for bradykinin to exert its antihypertrophic effects suggests that an endothelial factor such as nitric oxide may be of critical importance in the effectiveness of bradykinin in preventing ventricular hypertrophy. It is therefore important to point out that patients with essential hypertension often have evidence of endothelial dysfunction and/or other risk factors associated with endothelial dysfunction, such as hyperlipidemia, homocystinemia, diabetes mellitus, smoking, menopause, and/or advanced age. In these situations, nitric oxide may be destroyed by oxygen free radical production and/or the production of endothelial nitric oxide synthase may be impaired. Thus, although ACE inhibitor–induced bradykinin accumulation may be important in various experimental models of hypertension and ventricular hypertrophy, it is less certain that ACE inhibitor–induced bradykinin accumulation is as important in causing regression of ventricular hypertrophy in patients with hypertension. ACE inhibitor–induced accumulation of bradykinin has other important implications for predicting whether ACE inhibitors may be more or less effective than other means of inhibiting the RAAS and in preventing the cardiovascular events associated with ventricular hypertrophy. Bradykinin has been shown to be cardioprotective in several experimental models. For example, in a model of myocardial infarction, ACE inhibitors have been shown to significantly reduce infarct size. The addition of the bradykinin B2 antagonist HOE-140 negates this effect,5 suggesting that the major effect of ACE inhibitors after myocardial infarction is due to bradykinin accumulation rather than angiotensin II receptor stimulation. In other models of experimental myocardial infarction, however, angiotensin II type I receptor blocking agents (AT1RBAs) have been shown to be as effective as an ACE inhibitor in preventing ventricular remodeling,6 suggesting that angiotensin II receptor stimulation may be of greater importance than bradykinin accumulation. Bradykinin accumulation may in fact, under certain circumstances, be detrimental. Bradykinin has been shown to cause prejunctional sympathetic neuronal release of norepinephrine7 as well as norepinephrine release from the human atria. In a direct comparative study in an isolated muscle preparation, an ACE inhibitor was shown to increase norepinephrine spillover, which could be blocked by HOE-140, whereas an AT1RBA decreased norepinephrine spillover.8 In an isolated ischemic heart model, an ACE inhibitor was found to increase norepinephrine release and the incidence of ventricular arrhythmias, which could be blocked by HOE-140, whereas an AT1RBA decreased norepinephrine release and the propensity for ventricular arrhythmias.9
AT1RBAs have been suggested to be as effective as ACE inhibitors in lowering blood pressure and are finding increasing clinical application. They have the advantage over ACE inhibitors and several other classes of antihypertensive agents in that they are relatively free of side effects. There has, however, been some doubt as to their effectiveness in preventing ventricular hypertrophy. The study by Thürmann et al10 suggesting that the AT1RBA valsartan is more effective than atenolol in decreasing left ventricular mass index in untreated patients with hypertension and echocardiographically proven left ventricular hypertrophy is therefore of importance in predicting whether AT1RBAs will be beneficial in reducing cardiovascular events in patients with hypertension and left ventricular hypertrophy. Whether or not valsartan is truly more effective than atenolol or other ß-adrenergic blocking agents in causing regression of left ventricular hypertrophy, however, will require further study in a larger number of patients in whom equivalent blood pressure control is achieved. In the study by Thürmann et al,10 the reduction in systolic blood pressure achieved by valsartan was 16 mm Hg, compared with 11 mm Hg in the atenolol group, and the reduction in diastolic pressure was similar in the 2 groups, 11 and 10 mm Hg, respectively. Comparative studies such as this are of value only in determining the relative effectiveness of different agents when there is a more complete evaluation of the dose-response relationship of each agent. The more important finding in the study by Thürmann et al10 is that an AT1RBA, valsartan, was effective in causing a reduction in left ventricular mass index from baseline in patients with hypertension. Recent studies suggest that losartan11 and irbesartan12 also appear to be effective in causing regression of ventricular hypertrophy in patients with hypertension. All of these studies, however, are of relatively small size and short duration. The question as to the mechanism by which AT1RBAs cause regression of left ventricular hypertrophy is of importance for the development of further therapeutic strategies and as a basis for predictions as to whether they will prove to be as effective as ACE inhibitors in reducing ventricular hypertrophy and the cardiovascular events associated with ventricular hypertrophy. In a recent, relatively small study comparing the effectiveness of an ACE inhibitor and an AT1RBA, the AT1RBA was found to be more effective than the ACE inhibitor in causing regression of ventricular hypertrophy.13 One possibility for such a finding, if confirmed in larger studies, is that AT1RBAs block non–ACE-dependent as well as ACE-dependent angiotensin II formation. Although the functional importance of non–ACE-dependent angiotensin II formation in the myocardium remains uncertain, there is increasing evidence suggesting a role of chymase-induced vascular angiotensin II formation. Another question relates to whether AT1RBAs prevent ventricular hypertrophy by blocking the effects of angiotensin II on the AT1 receptor or whether the increase in plasma renin levels and angiotensin II levels found after AT1RBA, resulting in unopposed stimulation of AT2 and or other angiotensin II receptors such as AT1–7, contributes to their effectiveness. In models of experimental myocardial hypertrophy, the ratio of cardiac AT2/AT1 receptors appears to be increased, which could increase the relative importance of AT2 receptor stimulation. The relative importance of these mechanisms may determine whether AT1RBAs will be used alone or in combination with an ACE inhibitor, which might diminish the contribution of angiotensin II formation and hence AT2 receptor stimulation. It is of interest in this regard to find, in an experimental model of ventricular hypertrophy, that an AT1RBA as monotherapy was effective in preventing ventricular hypertrophy but that the simultaneous administration of an AT2RBA negated the effects of the AT1RBA alone.14 There is increasing evidence suggesting that stimulation of the AT2 receptor has antihypertrophic as well as apoptotic effects and can cause the release of nitric oxide. The combination of an AT1RBA and an ACE inhibitor has been shown to be more effective than either strategy alone in reducing blood pressure and hypertrophy in spontaneously hypertensive rats.15 A recent study in patients, however, suggests that the addition of an ACE inhibitor to an AT1RBA had no advantage in regard to regression of ventricular hypertrophy.16 The combination of an ACE inhibitor and an AT1RBA would most likely be associated with a greater incidence of side effects than an AT1RBA alone. There is in fact evidence of an increase in side effects, such as cough, when an AT1RBA is added to therapy in patients with hypertension who had been maintained on an ACE inhibitor.17
Blockade of angiotensin II, whether by inhibition of its formation by an ACE inhibitor or by blockade of the effects of angiotensin II on the AT1 receptor, may also be effective in causing regression of ventricular hypertrophy by preventing the formation of aldosterone. Aldosterone has been shown to be important in ventricular hypertrophy and in causing myocardial fibrosis.18 Aldosterone has also been suggested to block extraneuronal uptake of norepinephrine from the myocardium19 and thus could contribute to the increase in cardiac failure and sudden cardiac death associated with activation of the RAAS and ventricular hypertrophy. Inhibition of angiotensin II formation and/or of its effects on the AT1 receptor by an ACE inhibitor and an AT1RBA have not proved effective in completely suppressing the formation of aldosterone, because mechanisms other than the formation of angiotensin II, such as serum potassium, are important in its regulation. Thus, to effectively prevent the consequences of activation of the RAAS in the pathophysiology of left ventricular hypertrophy and its clinical consequences, we may need to consider the use of an aldosterone receptor blocking agent in combination with an ACE inhibitor and/or an AT1RBA.
Although Thürmann et al10 suggest that an AT1RBA is more effective than a ß-adrenergic receptor blocking agent in causing regression of ventricular hypertrophy, there is reason to consider the combination of an ACE inhibitor and/or an AT1RBA with a ß-adrenergic receptor blocking agent in preventing the development and/or consequences of ventricular hypertrophy. ß-Adrenergic receptor blocking agents may in part decrease serum renin levels and therefore provide better suppression of the RAAS than an ACE inhibitor and/or an AT1RBA alone, as well as by directly blocking the effects of catecholamines on ventricular hypertrophy. The combination of an ACE inhibitor and a ß-adrenergic receptor blocking agent has been found to be more effective than an ACE inhibitor alone in causing a reduction in mortality and cardiovascular events in patients with heart failure due to systolic left ventricular dysfunction and in patients after infarction. Other combinations of an ACE inhibitor and/or an AT1RBA, such as with a thiazide or a calcium channel blocking agent, are also in clinical use in patients with hypertension and could be useful in the regression of ventricular hypertrophy and prevention of its clinical consequences. The study by Thürmann et al10 and of other AT1RBAs in causing regression of left ventricular hypertrophy11 12 suggest that AT1RBAs, in view of their low side-effect profile and effectiveness, will most likely play a role in future strategies to prevent the progression of left ventricular hypertrophy in patients with hypertension. However, we will need to await the results of larger-scale clinical trials before reaching any conclusions in regard to their relative clinical effectiveness in reducing cardiac events associated with ventricular hypertrophy. It should be emphasized that although angiotensin II is an important mechanism for left ventricular hypertrophy, it is not the only or perhaps even the most important mechanism. In an AT1-knockout mouse model, Harada et al20 were not able to prevent the development of left ventricular hypertrophy. This study suggests that the myocardium has alternative signaling mechanisms for the development of hypertrophy and holds promise for a new understanding of these signaling processes and new therapeutic approaches to prevent hypertrophy.
Clearly, we are only at an early stage in our understanding of the mechanisms of ventricular hypertrophy in patients with hypertension, the best strategy to prevent it, whether regression of ventricular hypertrophy is independent of blood pressure reduction, and whether all strategies causing regression of ventricular hypertrophy will be equally effective in preventing cardiovascular events.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Dr Pitt is a consultant to Merck (manufacturer of losartan), Warner Lambert (manufacturer of the ACE inhibitor quinapril), and Searle (manufacturer of the aldosterone receptor blocker aldactone).
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