Glinicai Investigator

Clin Investig (1992) 70: S 87-S 92

© Springer-Verlag 1992

Therapeutic effect on left ventricular hypertrophy by different antihypertensive drugs W. Motz and B.E. Strauer Universit~it Diisseldorf, Medizinische Klinik und Poliklinik B, Abteilung Kardiologie, Angiologie, Pneumologie

Summary. Left ventricular hypertrophy (LVH) constitutes a powerful independent risk factor in hypertensive heart disease. Although initially the wall stress, i.e., left ventricular afterload, remains normal, the coronary reserve is diminished due to disturbances in the microcirculation. This is also shown in the commonly present silent ischemia episodes in Holter monitoring. LVH also causes ventricular dilation and heart failure. Apart from systolic wall stress LVH is modulated by the trophic effects of the sympathetic nervous system and angiotensin II and genetic factors. Long-term antihypertensive treatment must therefore focus on regression of both LVH and the microvascular abnormalities. A step approach for the treatment of the LVH has been recommended on the basis of the experience of this working group with calcium antagonists and ACE inhibitors, whereas the place of fl-blockers is as yet unclear. Preliminary data indicate that coronary flow rescue can also be improved after chronic antihypertensive treatment. Key words: Left ventricular hypertrophy - Hypertension - Coronary heart disease - Antihypertensive treatment

The Framingham study has shown that once left ventricular hypertrophy is present either in the electrocardiogram or echocardiography, it constitutes a powerful independent risk factor for coronary artery disease, stroke, and heart failure [1]. Investigations in patients with left ventricular pressure or volume overload showed that despite extremely marked myocardial hypertrophy, left ventricular function is not impaired as long as systolic wall stress, i.e., left ventricular afterload, is not

increased [2, 3]. As a result of the increase in wall thickness, the systolic wall tension remains normal - at least initially - despite excessively high systolic ventricular pressures [2-5]. At the same time, the myocardial oxygen consumption of these hypertrophied hearts per unit weight of myocardium remains normal [2, 3]. However, when progressive ventricular dilation leads to an increase in wall stress, the left ventricular ejection fraction decreases in inverse proportion to the increase in wall stress [2, 3, 5]. An increase in myocardial energy consumption per unit weight of myocardium corresponding to the increase in wall tension, i.e., in afterload, then ensues [2, 3]. In hypertensive cardiac hypertrophy the coronary reserve is already appreciably reduced even in the absence of any stenosis of epicardial coronary arteries [2, 3]. Probably as a result of media hypertrophy [6] of the coronary resistance vessels [7-9] - an adaptive structural process analogous to myocardial hypertrophy - the minimal coronary resistance after intravenous administration of dipyridamole is increased by about 30% [2, 3, 10]. The coronary reserve of the hypertensive heart, which is a ratio of coronary resistance at rest to minimal resistance after maximal coronary dilation, is correspondingly reduced. Thus, even in patients with hemodynamically compensated hypertension and a normal coronary angiogram, there is already a predisposition toward myocardial ischemia. The clinical manifestation of the reduced coronary reserve is anginal pain in the hypertensive patient with a normal coronary angiogram. Recently, it has been demonstrated that in the Holter electrocardiogram, ST-segment depression events were found in about 50% of hypertensive patients without left ventricular hypertrophy, indicating the presence of myocardial ischemia despite smooth epicardial coronary arteries [11].

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ARTERIAL HYPERTENSION[

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Fig. 1. Causes of arterial hypertensionin the myocardium[left ventricular (LV) hypertrophy] and in the coronary circulation (functional and structural alterations of the small intramural resistancevessels).Both left ventricularhypertrophyand microangiopathy predisposeto congestiveheart failure

Fig. 2. Different effects of various antihypertensivetreatment regimenson left ventricularmusclemass

Because arterial hypertension is an important risk factor for coronary artery disease, patients with hypertensive heart disease are often found to have concomitant coronary artery disease [1, 2, 12]. However, coronary artery disease is a separate nosologic entity and should therefore be distinguished from hypertensive heart disease, even if clinical symptoms such as angina pectoris are often similar or even identical in both diseases. Provided the course is sufficiently protracted, left ventricular hypertrophy is followed almost regularly by ventricular dilation and heart failure. Preventive drug therapy or reversal of hypertensive cardiac hypertrophy are thus almost synonymous with causal therapy of hypertensive heart failure. Because the impaired coronary regulatory capacity due to functional or structural alterations of the small coronary arteries predisposes toward symptomatic or silent myocardial ischemia [11], drug therapy should also aim at improving coronary reserve through regression of abnormalities within the coronary microcirculation. Accordingly, longterm treatment of the hypertensive heart has to focus on regression of both left ventricular hypertrophy and microvascular abnormalities (Fig. 1).

given methyldopa in addition to ongoing diuretic treatment, some showed a significant reduction in muscle mass unrelated to pressure, without further reduction of blood pressure [16]. During therapy with enalapril [17, 18], dihydropyridines [19, 20], prazosin [21], and clonidine [21], the reduction in blood pressure was paralleled by regression of cardiac hypertrophy. The spectrum of action of antihypertensive pharmacotherapy on myocardial hypertrophy thus ranges from complete absence of effect, through a largely pressure-related decrease in muscle mass (enalapril, dihydropyridines, prazosin), to a pressure-unrelated reversal of myocardial hypertrophy (methyldopa). This discrepancy between the extent of reduction in arterial blood pressure and the regression of myocardial hypertrophy suggests that, apart from arterial blood pressure, the degree of left ventricular hypertrophy is also governed by other factors such as sympathetic tone [22], influence of the renin-angiotensin-aldosterone system [23], and structural changes in the myocardium [24] (Fig. 2).

Reversalof left ventricularhypertrophy Clinical studies have shown that not all forms of antihypertensive therapy lead to regression of myocardial hypertrophy. After chronic treatment with diuretics no reversal of cardiac hypertrophy was demonstrated, even though arterial blood pressure was reduced to normotensive levels [13, 14]. Treatment with the phatalazine derivate trimazosin, a substance related to hydralazine, likewise produced no regression of cardiac hypertrophy despite decreasing blood pressure [15]. Of patients

Influenceof the sympatheticnervoussystem on myocardialhypertrophy Increases in heart rate and myocardial contractility as a result of pressure and volume overload could be mediated through sympathetic innervation of the heart [25]. Laks [26] described norepinephrine as a myocardial hypertrophy hormone, because chronic infusion of subhypertensive doses of norepinephrine in the dog led to left ventricular hypertrophy. Simpson [27] was able to show that norepinephrine stimulates the growth of isolated cultured myocardial cells through c~-receptors. Despite effecting a marked reduction in blood pressure, diur-

$89 etics do not lead to regression of cardiac hypertrophy [13, 14], but they do stimulate the sympathetic nervous system [28]. Because catecholamines appear to play a t r o p h i c role in the development of hypertrophy, the increased sympathetic tone could be responsible for the failure of diuretic therapy to produce reversal of hypertrophy [13, 14, 26]. As already mentioned, trimazosin, a substance related to hydralazine, also leads to stimulation of the sympathetic nervous system. This substance was also unable to induce regression of hypertrophy under clinical conditions [15]. On the other hand, a decrease in the level of circulating norepinephrine as a result of additional administration of methyldopa [16] was paralleled by a pressureunrelated decrease in left ventricular muscle mass without a further reduction in blood pressure. A further indication of the trophic role of the sympathetic nervous system is provided by the finding that treatment with clonidine was followed by a marked decrease in left ventricular muscle mass in relation to the reduction in blood pressure [21]. Treatment with fl-adrenergic antagonists should also encourage regression of hypertrophy because of their blockade of myocardial fl-receptors. Wikstrand et al. [29], however, were only able to demonstrate very protracted regression of hypertrophy after 12 months' treatment with metoprolol, whereas other investigators described regression of cardiac hypertrophy after treatment with fi-receptor blockers [30-32]. The intrinsic sympathomimetic activity appears to play an important role in the reversal of cardiac hypertrophy during treatment with fi-adrenergic antagonists. Treatment for 12 months with acebutolol, a fl-blocker with intrinsic sympathomimetic activity, did not produce any regression of cardiac hypertrophy, but when therapy in the same patients was switched to atenolol, a fi-blocker without intrinsic sympathomimetic activity, there was regression of cardiac hypertrophy while blood pressure remained at comparable levels [30]. The controversial role of the fi-adrenergic antagonists in the clinical therapeutic reversal of cardiac hypertrophy could also be due to the fact that the norepinephrine-mediated growth of isolated myocytes can only be prevented by blockade of cq-receptors and not of fi-receptors [27].

Effect of renin-angiotensin-aldosterone system on myocardial hypertrophy Because antihypertensive treatment with an angiotensin-converting enzyme (ACE) inhibitor, in con-

trast to diuretic treatment [13, 14], leads to regression of cardiac hypertrophy [17, 18], it is possible that the elevated levels of angiotensin II regularly found during diuretic treatment also have a trophic effect. The increase in circulating renin with diuretic treatment is certainly not relevant to the development of left ventricular hypertrophy, because regression of cardiac hypertrophy takes place during ACE inhibitor treatment despite regularly raised renin levels. Devereux et al. [33] also found that in hypertensives there is no correlation between the extent of left ventricular hypertrophy and the plasma renin level. Left ventricular hypertrophy as a consequence of clipping the abdominal aorta can be completely prevented through treatment with an ACE inhibitor [23]. This suggests a strong trophic role of angiotensin II and the corresponding atrophic effects of inhibiting the cardiac angiotensin system. In cardiovascular hypertrophy tissue ACE expression and activity is increased and local angiotensin generation accelerated. Schunkert et al. [34] have demonstrated an increased ACE m R N A expression and enhanced angiotensin conversion in the hypertrophied ventricle. Measured ACE activity was significantly higher in the hypertrophied left ventricle compared with control ventricles. However, in the non-hypertrophied right ventricle ACE activity was not increased. This indicates that the stimulus for increased ACE expression is related to the stretch of the cardiac myocytes in response to the increased wall tension and not mediated by systemic factors. The hypothesis that hypertensive remodeling of the heart is, at least partially, mediated by an increased local angiotensin activity is further supported by proto-oncogene induction [35].

Genetic determination of myocardial hypertrophy When left ventricular hypertrophy is diagnosed in the echocardiogram or ventriculogram, an additional pathologic, genetically determined form of hypertrophy such as hypertrophic obstructive or hypertrophic non-obstructive cardiomyopathy can never simply be ruled out. Pronounced asymmetric septal hypertrophy is, however, also seen in about 14% of hypertensives [36], so that asymmetric left ventricular hypertrophy is not specific for hypertrophic cardiomyopathy with or without obstruction. On account of its larger radius of curvature, the ventricular septum appears to hypertrophy earlier and more markedly in response to an increased systolic pressure load than does the posterior or anterior wall. The higher regional concentration

$90 of catecholamines in the ventricular septum might also be a possible explanation for the high prevalence of septal hypertrophy in hypertensives [37]. Because essential arterial hypertension is genetically determined, the capacity of the heart to respond with hypertrophy might also be, at least in part, genetically determined. Accordingly, the process of left ventricular hypertrophy in response to a hypertensive ventricular load could be genetically enhanced. Every case of hypertensive cardiac hypertrophy could contain an individually varying genetic component, which might help to explain the varying responses of the myocardium to antihypertensive treatment in different patients.

Structural changes in hypertrophied myocardium In the course of cardiac hypertrophy, marked structural changes take place in the myocardium, which might no longer be amenable to the molecular processes involved in regression of hypertrophy. The progressive increase in myocardial connective tissue in the course of the hypertrophy might be a particular hindrance to potential regression processes [25, 38]. Investigations in patients with valvular aortic stenosis after aortic valve replacement showed that, on account of collagen persistence, regression of myocardial hypertrophy can be accompanied by a relative increase in the amount of connective tissue [39]. Thus, myocardial fibrosis may be responsible for failure to achieve reversal of hypertrophy.

Differential treatment of hypertensive heart disease Because of the later development of myocardial failure, from the cardiac point of view, antihypertensive treatment in hemodynamically compensated left ventricular hypertrophy is largely preventive in character. The aim of the therapeutic measures is to reverse both myocardial hypertrophy and disease of the small coronary arteries. Improvement of left ventricular function is not a goal in this form of hypertrophy, in which ventricular function is in the normal or upper normal range [2, 3]. With regard to ventricular geometry, this form of hypertrophy is characterized by a high mass-to-volume ratio and normal systolic wall stress, i.e., afterload [2, 3]. Antihypertensive treatment in this form of hypertrophy should use substances that are capable of reversing the cardiac hypertrophy. As a first step, an ACE inhibitor or, alternatively, a calcium channel blocker should be administered. If none of these substances alone leads to normotension

or regression of cardiac hypertrophy, a combination of these two substance groups - ACE inhibitor and calcium channel blocker - is indicated as a second step. If combination therapy does not lead to regression of the cardiac hypertrophy either, addition of a sympatholytic substance such as methyldopa or clonidine is indicated as a third step. This stepped-care approach to the treatment of hypertensive cardiac hypertrophy inevitably differs from a treatment schedule designed primarily to control hypertension with a minimum of side effects and good subjective tolerance. Since diuretics effectively reduce blood pressure but are not very effective with regard to reversal of hypertrophy, their role in the treatment of hypertensive cardiac hypertrophy is only a minor one. However, substances such as ACE inhibitors and calcium channel blockers are antihypertensives of choice in the treatment of the hypertensive heart. If the coronary angiogram is normal and the resting electrocardiogram or results of the exercise tolerance test are abnormal, hypertensive disease of the small coronary arteries must be assumed to be the cause of the anginal symptoms. Hypertensive small-vessel disease can be diagnostically confirmed by measurement of the coronary reserve [2, 3, 10]. Improvement of symptoms can be achieved with antianginal substances such as flreceptor blockers, calcium channel blockers, and nitrates. In this form of hypertensive cardiac disease, reversal of myocardial hypertrophy as treatment of the underlying disease should also be attempted. Thus, the primary form of treatment for this type of hypertensive heart disease is again the stepped-care approach of cardiac hypertrophy, which should be combined primarily with antianginal substances such as fl-blockers and nitrates for symptomatic relief. In addition to reversing hypertrophy, drug therapy should also aim at regressing the structural and functional abnormalities of the small coronary resistance arteries. It is known that coronary reserve was enhanced after administration of hydralazine in spontaneously hypertensive rats without a parallel reversal of myocardial hypertrophy [40]. The calcium channel blocker felodipine led to a reversal of media hypertrophy in coronary resistance vessels [41]. After therapy with the ACE inhibitor lisinopril, coronary reserve was enhanced along with a regression of both media hypertrophy and myocardial fibrosis [42]. It was found that other ACE inhibitors induced a reduction in arterial medial thickness [43, 44]. Mall and coworkers [45] found a reduction in the volume density of myocardial

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fibrosis, a decrease in arterial medial volume, and an increase in the length density of capillaries with either nifedipine or moxonidine [45]. However, caution should be exercised in extrapolating to man from these experimental findings in regard to the prevention and reversal of structural remodeling in genetically determined hypertension in rats. References 1. Levy D, Garrison R J, Savage DD, Kannel WB, Castelli WP (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 332:1561-1566 2. Strauer BE (1979) Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve. Am J Cardiol 44:730 740 3. Strauer BE (1980) Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol 44:999 1006 4. Ford EF (1985) Heart size. Circ Res 39:297-303 5. Grossmann W, Jones D, McLaurin LP (1975) Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56-64 6. Folkow B (1975) Cardiovascular structural adaption: its role in the initiation and maintenance of primary hypertension. Clin Sci Mol Med 48:205s-214s (The fourth Volhard lecture) 7. James TN (1977) Small arteries of the heart. Circulation 56:~14 8. Furuyama M (1962) IIistometrical investigations of arteries in reference to arterial hypertension. Yohoku J Exp Med 76:388-414 9. Klepzig M, Eisenlohr H, Steindi S, Schmiebusch H, Strauer BE (1986) Mediahypertrophie bei Koronargef/iBen spontan hypertoner Ratten (abstract). Z Kardiol (Suppl 1) 75:32 10. Vogt M, Motz W, Strauer BE (1989) Coronary flow reserve in arterial hypertension. Scand J Clin Lab Invest (Suppl 196) 49 : %15 11. Scheler S, Motz W, Strauer BE (1989) Transiente Myokardischfimien bei Hypertonikern. Z Kardiol 78 : 19%203 12. Wallace JM (1975) Hemodynamic lesions in hypertension. Am J Cardiol 36 : 670-684 13. Motz W, Klepzig M, Stellwaag M, Strauer BE (1987) Regression der Herzhypertrophie unter Saluretika (abstract). Klin Wochenschr (Suppi 165) 65:176 14. Wollam GL, Hall DW, Porter VD, Douglas MB, Unger D J, Blumenstein BA, Cotsonis GA, Knudtson ML, Felner JM, Schlant RC (1983) Time course of regression of left ventricular hypertrophy in treated hypertensive patients. Am J Med (Suppl) 75:100A-110A 15. Drayer JIM, Garding JM, Weber MS, Aronow WS (1983) Cardiac muscle mass during vasodilatation therapy of hypertension. Clin Pharmacol Ther 33 : 72%732 16. Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE (1982) Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa. Lack of association with blood pressure control. Am J Cardiol 49:795-801 17. Motz W, Strauer BE (1988) Riickbildung der hypertensiven Herzhypertrophie durch chronische Angiotensin-Konversionsenzymhemmung. Z Kardiol 77 : 53-60 18. Nakashima Y, Fouad FM, Tarazi RC (1984) Regression of left ventricular hypertrophy from systemic hypertension by enalapril. Am J Cardiol 53:1044-1049

19. Strauer BE, Mahmoud MA, Bayer F, Bohn J, Motz U (1984) Reversal of left ventricular hypertrophy and improvement of cardiac function in man by nifedipine. Eur Heart J (Suppl F) 5 : 53-60 20. Vogt M, Kreutz KU, Motz W, Strauer BE (1989) Hypertrophieregression nach Nitrendipin: Einflul3 auf systolische und diastolische Funktion. Z Kardiol 78:469-477 21. Strauer BE, Bayer F, Brecht HM, Motz W (1985) The influence of sympathetic nervous activity on regression of cardiac hypertrophy. J Hypertens (Suppl 4) 3 : $39 $44 22. Tarazi RC, Sen S, Saragoca M, Kairrallah P (1982) The multifactorial role of catecholamines in hypertensive cardiac hypertrophy. Eur Heart J (Suppl 3):A103-A110 23. Kromer EP, Riegger GA (1988) Effects of long-term angiotensin converting enzyme inhibition on myocardial hypertrophy in experimental aortic stenosis in the rat. Am J Cardiol 62:161 163 24. Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bakey RI (1988) Collagen remodeling of the pressure overloaded, hypertrophied nonhuman primate myocardium. Circ Res 62:757 765 25. Ostman-Smith I (1981) Cardiac sympathetic nerves as the final common pathway in the induction of adaptive cardiac hypertrophy. Clin Sci 61:265-272 26. Laks MN (1976) Norepinephrine the myocardial hypertrophy hormone? Am Heart J 91:674-675 27. Simpson P (1983) Norepinephrine-stimulated hypertrophy of cultered rat myocardial cell is an alpha-t-adrenergic response. J Clin Invest 72:732-738 28. Lake CR, Ziegler MG, Coleman MD, Kopin IJ (1979) Hydrochlorthiazide-induced sympathetic hyperactivity in hypertensive patients. Clin Pharmacol Ther 26:428-432 29. Wikstrand J, Trimarco B, Ricciardelli B, DeLuca N, Volope M (1984) Reversal of cardiovascular changes during antihypertensive treatment: functional consequences and time course of reversal as judged from clinical studies. Hypertension 6 :III: III-348-III-367 30. Sau F, Seguro C, Merano G, Cherchi A (1986) Atenolol but not acebutolol reverses left ventricular hypertrophy secondary to arterial hypertension (abstract). J Am Coll Cardiol (Suppl) 7:A186 31. Rowlands DB, Glover DR, Stallard TJ, Littler WA (1982) Control of blood pressure and reduction of echocardiographically assessed left ventricular mass with once-daily timolol. Br J Clin Pharmacol 14:89-95 32. Corea L, Bentivoglio M, Verdecchia P, Providenza M, Motolese M (1984) Left ventricular hypertrophy regression in hypertensive patients treated with metoprolol. J Clin Pharmacol 22:363 370 33. Devereux RB, Savage DD, Drayer JIM, Laragh JH (1982) Left ventricular hypertrophy and function in high, normal and low-renin forms of essential hypertension. Hypertension 4:524-531 34. Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH (1990) Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. J Clin Invest 86:19131920 35. Naftilan AJ, Pratt RE, Dzau VJ (1989) Induction of platelet-derived growth factor A chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest 83 : 1419-1424 36. Strauer BE (1983) Hypertensive heart disease. Springer, Ber1in Heidelberg New York, pp 37-46 37. Safar ME, Benessiano JR, Hornsyk AL (1982) Asymmetric septal hypertrophy and borderline hypertension. Int J Cardiol 2:103 108

$92 38. Motz W, Strauer BE (1989) Left ventricular function and collagen content after regression of hypertensive hypertrophy. Hypertension 13 : 43-50 39. Hess OM, Ritter M, Schneider J, Grimm K, Turina M, Krayenb/.ihl HP (1984) Diastolic stiffness and myocardial structure in aortic valve disease before and after valve replacement. Circulation 69: 865 885 40. Anderson PG, Bishop SP, Digerness SB (1989) Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats. Circ Res 64:1127-1136 41. Strauer BE (1990) Significance of coronary circulation in hypertensive heart disease for development and prevention of heart failure. Am J Cardiol 65: G34-G41 42. Brilla CG, Janicki JS, Weber KT (1991) Cardioreparative effects of lisinopril in rats with genetic hypertension and left ventricular hypertrophy. Circulation 83:1771 1779 43. Clozel J-P, Kuhn H, Hefti F (1989) Effects of chronic ACE inhibition on cardiac hypertrophy and coronary vascular

reserve in spontaneously hypertensive rats with developed hypertension. J Hypertens 7:267-275 44. Michel JB, Levy BI (1990) Vascular effects of ACE inhibition by perindopril. Drugs (Suppl 1) 39 : 39-42 45. Mall G, Greber D, Gharebhagi H, Wiest G, Mattfeldt T, Ganten U (1991) Myokardprotektion und Hypertrophieregression bei spontan hypertensiven Ratten durch Nifedipin und Moxonidin-Stenologische Untersuchungen. In: Ganten D, Mall G (eds) Herz-Kreislauf-Regulation, Organprotektion und Organsch/iden. Schattauer, Stuttgart, pp 19-106 Priv.-Doz. Dr. W. Motz Medizinische Klinik und Poliklinik B Abteilung Kardiologie, Angiologie, Pneumologie Universitfit Dfisseldorf Moorenstrasse 5 W-4000 Dfisseldorf 1, FRG