Introduction: Recent perspectives on hypertension and the heart

SYMPOSIUM ON THE HEART IN HYPERTENSION Robert

C. Tarazi, MD, FACC, Guest Editor

Introduction: Recent Perspectives on Hypertension and The Heart ROBERT C. TARAZI,

MD, FACC

Cleveland, Ohio

The first descriptions of hypertension stemmed from pathologic studies of cardiac hypertrophy in renal disease. Despite these letters of credence and the intuitive analyses of Bright and Mahomedl and despite the importance of hypertension as a cause of cardiac disease,s there has been a long period of estrangement from hypertension by cardiologists in both research and practice. The causes of that apparent lack of interest were many. On a superficial level, but one with marked practical impact, were the pressures of bedside teaching. Hypertension as a source of exciting clinical signs is a pale competitor for valvular or congenital heart disease; measuring blood pressure is obviously not as stimulating as deciphering an arrhythmia. More important, there was little sense of urgency in a mostly asymptomatic disease at a time when medical practice was more attuned to crisis management than to long-term prevention and to treatment of apparently well adults. Of particular significance, also, was the little stimulus to cardiac studies from high blood pressure research. Because cardiac output was thought to be normal in most cases, the essential fault in hypertension was related to alterations in peripheral resistance, and studies of the heart were not thought likely to contribute much of fundamental significance. High blood pressure research focused on factors that influenced vessels or overfilled them; as such, it appeared to be divorced from the preoccupations of cardiologists and from the intense efforts that went into the studies of cardiac performance and hypertrophy. From the Research Division, The Cleveland Clinic Foundation, Cleveland, Ohio. The studies referred to in this review were supported in part by Grant 6835 from the National Heart, Lung, and Blood institute, Bethesda, Maryland, and grants from The John A. Hartford Foundation and the U. Whitaker Fund. Manuscript received June 8, 1979, accepted June 15, 1979. Address for reprints: Robert C. Tarazi, MD, Research Division, The Cleveland Clinic Foundation, Cleveland, Ohio 44106

Cardiogenic Hypertension Role of increased cardiac output: Interest was revived in a possible “role of the heart in hypertension”3 when investigations in the past decade described a high cardiac output in patients with labile hypertension4 renal arterial disease5 and primary aldosteronism6 as well as in a subtype of severe essential hypertension.7 Various types of experimental hypertension also appeared to be initiated by an increase in cardiac output.3,s However, these reports were mostly based on determinations of cardiac output and therefore left unresolved the problem of active cardia? participation in hypertension. The description of a high output in a hypertensive state does not define the role of increased flow in the production of high arterial pressure nor does it allow the conclusion that this hypertension is cardiogenic.g That term was introduced by Freis’O to describe hypertension due to primary increases in cardiac action. However, in many patients with high output hypertension, the heart is merely responding to increased blood volume or to venoconstriction and central relocation of blood.‘l More important, it was repeatedly shown that prevention of the increase in output in experimental conditions did not prevent the development of hypertensi0n.s The controversies surrounding the importance of cardiac output in the initiation of hypertension have been animated and fruitful. They have often focused on the problem of autoregulation and dealt little, if at all, with a specific cardiac role in the disease. In the traditional models of Borst128 and of Guyton,lzb hypervolemia and increased cardiac output were projected as key factors in the initiation of hypertension. However, an emerging trend appears to favor a primary role for increased vascular resistance even in volume-dependent hypertension.13 However, these discussions, although very important in the understanding of circulatory control, are really not germane to the definition of car-

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diogenic hypertension. An increased output is indeed found in many instances of spontaneous or experimental hypertension, :~%ll but, contrary to past opinions,” the role of the heart in hypertension cannot be defined in terms of cardiac output alone. This does not mean that a primary increase in cardiac performance cannot participate in the development of some types of hypertension 11,14or affect their clinical evo1ution.l” Studies with long-term stellate stimulation or prolonged intracoronary dobutamine infusion have shown that hypertension can be initiated by a primary increase in cardiac inotropism. The initial increase in cardiac output produced by those stimuli was not related to fluid overload. However, the role of the heart in these types of hypertension was defined not by this initial rise in output but rather by the fact that the stimulus was primarily directed to the heart. Cardiovascular

Reflexes

All of the foregoing considerations have dealt with cardiac pumping as a determinant of arterial pressure, but the heart may well have another role in hypertension. Emerging evidence indicates that it can be a source of potent pressor reflexes. ~8~7 In retrospect, it does not appear likely that physiologic monitoring of arterial pressure would be limited to only one or two vascular areas. The large differentials in pressure across the heart and great vessels as well as cardiac sensitivity to alterations in venous return or in resistance to ejection suggest that important information could be generated from these areas to help control the circulation. Chemoreflexes from the heart have been described by Comroe17 and James et al.ls among others; they can be stimulated by anoxia or by specific receptors to veratrum or serotonin. If the blood can be likened to a computer tape, the heart and lung vessels would be important strategic sites to decode messages. To date, cardiac reflexes have been related clinically only to some types of paroxysmal hypertension, 17,1g,20 particularly those that are associated with coronary insufficiency or that follow bypass surgery. Whether they have an ongoing function in chronic hypertension remains to be determined. It is conceivable that some hyperkinetic states alter arterial pressure as much by altered neural input from a disordered cardiac action as by their increased rate of blood flow. Along the same speculative lines, it has been suggested that the antihypertensive effect of beta adrenergic blockade could be related in part to a reflex toning down of sympathetic activity secondary to less forceful distortion of some cardiovascular receptors. Cardiac

Hypertrophy

in Hypertension

A rapidly developing area is the study of the cardiac hypertrophy of hypertension and its reversal by some antihypertensive measures. A simple mechanistic view of the relation between increased pressure load and ventricular hypertrophy is, in my opinion, no longer tenable.21 Many factors can modulate the hypertrophic response to a rising arterial pressure or to maintained hypertension. Of those discussed elsewhere in this

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Symposium,s2 the rate of pressure rise, the influences of associated diseases and the subtle effects of malnutrition or alcoholism are of particular importance clinically. Still to be fully elucidated are the reasons for the frequency of cardiomegaly among hypertensive patients from Africa”s or from lower socioeconomic classes.24 The practical implications of these observations are obvious; they include not only a better understanding of cardiovascular hypertrophic responses but also the possibility of reversing structural lesions by antihypertensive therapy. 21 Results from different centers2527 suggest a significant difference among various antihypertensive drugs as regards their potential for reversing cardiac and vascular hypertrophy. Reversal of hypertrophy appears linked to blood pressure control by drugs that reduce or at least do not stimulate adrenergic activity.“l This can be seen in the results of Sen et a1.25 in cardiac hypertrophy of spontaneously hypertensive rats, in those of Yamori26 in cerebral and mesenteric arteries of the same model and in’those of Foidart et al.27 in vessels of renovascular hypertensive rats. Results obtained in experimental models of hypertension: These have added an important practical aspect to the long-standing controversy regarding the efficiency of a hypertrophied heart. Reversal of hypertrophy by blood pressure control is demonst,rably possible, but if hypertrophy is not really deleterious, why attempt to reverse it? If its reversal is indicated, what would be the influence on cardiac performance a process that leads to a smaller muscle mass with increased collagen concentrations?25 Some answers to these questions are beginning to be outlined, but much more is needed for definitive solutions. Of particular importance is the need to differentiate carefully between the intertwining effects of a decrease in blood pressure, a reduction of myocardial mass, a relative increase in collagen and possible associated myocardial disease.28*2g Biochemical studies of myocardial changes in hypertension: Such studies have opened new avenues for therapeutic intervention. The evolution of cardiac hypertrophy with aging in spontaneously hypertensive rats was found to be associated with different rates of myosin and collagen synthesis.30 Attempts to reduce collagen synthesis by different drugs, such as colchicine, penicillamine and beta aminoproprionitrile, have been successful both in the heart31 and in vessels32v33 of different experimental models of increased afterload. Long-term treatment with reserpine also reduced collagen content of mesenteric vessels in renal hypertensive rats.27 Although the myocardial concentration of collagen did not appear to influence significantly cardiac function curves2s or velocity of papillary muscle contraction31 it would probably interfere with myocardial compliance. More important, perhaps, collagen content of vessel walls is said to play an important role in vascular complications of hypertension.32 Thus, new fields for therapeutic intervention in hypertension and in myocardial disease could conceivably be opened up if future studies would substitute present speculations and if ways could be developed to influence selectively

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the synthesis of different types of cardiovascular proteins. Hemodynamic factors: To the extent that hypertension is a hemodynamic abnormality, careful study of cardiac factors might lead to better understanding of the heart’s participation in circulatory control and of its reaction to abnormal loads. Cross-fertilization among different disciplines is already bearing significant fruits for both patients with hypertension and those with cardiac disease. Thus, until recently, little was known of coronary blood flow in hypertension. Marcus et a1.34have pioneered in this field by demonstrating a reduced coronary reserve in hypertensive models. As renewed interest stimulates research, questions multiply, an obvious one among others being the effect of hypertension on coronary dynamics and collateralization after an infarct. Humoral factors: In another area, the close interrelation between humoral factors and hemodynamic effects that characterize hypertension research has already been in increased understanding of some aspects of cardiac decompensation.35*36 Secondary aldosteronism was shown to play an important role in heart failure,35 and studies of plasma renin activity revealed a wide pattern of abnormalities in patients with failure.36 Stimulation of the renin-angiotensin-aldosterone system by cardiac decompensation could play an important role in both its hemodynamic and volume abnormalities. Davis35 has stressed the importance of elevated aldosterone levels for the salt and water retention of heart failure and for resistance to diuretic ther-

apy. Angiotensin II could be a factor in the elevated peripheral resistance seen in many forms of low output cardiac failure.37 Thus, interference with the renin cascade by converting enzyme inhibition seemed a logical approach to the treatment of resistant heart failure37v38;it could help alleviate both its metabolic and its hemodynamic derangements. Captopril has been shown in hypertensive patients to lower peripheral resistance without increasing preload3g and to help control secondary aldosteronism. 4o Early results in resistant heart failure in normotensive patients seem promising, but the true potential of that new approach remains to be evaluated. In this Symposium, reviews of recent advances have helped answer some questions and have uncovered many more. The role of the heart in hypertension has emerged as much more important and complex than previously thought. Better care for patients will evolve from this continued dynamic interaction between fundamental and clinical research. Hypertension has proved to be one of the more frequent and important causes of cardiac disability; a thoughtful approach to its problems will be more fruitful in the long run than cook-book recipes. Cardiologists have an important contribution to make in this respect. Acknowledgment I gratefully acknowledge the generous help of the Cleveland Clinic International Center and of Merck Sharp & Dohme in making this Symposium possible. The constant and selfless help of Kathy Akiya has been invaluable.

References 1. Pickering G: Systemic arterial hypertension. In, Circulation of the Blood, Men and Ideas. New York, Oxford University Press, 1946, p 492-504 2. Kannell WB: Role of blood pressure in cardiovascular morbidity and mortality. Prog Cardiovasc Dis 175-24, 1974 3. Ledingham JM, Cohen RD: Role of the heart in the pathogenesis of renal hypertension. Lancet 2:979-981, 1963 4. Julius S, Conway J: Hemodynamic studies in patients with borderline blood pressure elevation. Circulation 38:282-288, 1968 5. Frohlich ED, Ulrych M, Tarasi RC, Dustan HP, Page IH: A hemodynamic comparison of essential and renovascular hypertension: cardiac output and total peripheral resistance: supine and tilted patients. Circulation 35:289-297, 1967 6. Tarazi RC, lbrahim MM, Bravo EL, Dustan HP: Hemodynamic characteristics of primary aldosteronism. N Engl J Med 289: 1330-1335,1973 7. lbrahim MM, Tarazi RC, Dustan HP, Bravo EL, Gifford RS Jr: Hyperkinetic heart in severe hypertension: a separate clinical hemodynamic entity. Am J Cardiol 35667-674, 1975 8. Ferrario CM, Page IH: Current views concerning cardiac output in the genesis of experimental hypertension. Circ Res 43:821-831, 1978 9. Duslan HP, Tarazi RC: Cardiogenic hypertension. Ann Rev Med 29:485-493, 1978 10. Freis ED: Hemodynamics of hypertension. Physiol Rev 40:27-54, 1960 11. Tarari RC, lbrahim MM, Dustan HP, Ferrario CM: Cardiac factors in hypertension. Circ Res 34:Suppl l:l-213-221, 1974 12a. Borst JGG: Hypertension explained by Starling’s theory of circulation hemostasis. Lancet 1:677-682, 1963 12b. Guyton AC, Coleman TG: Quantitative analysis of the pathophysiology of hypertension. Circ Res 24, 25: Suppl 1:1-l-19,

1969 13. Tarazi RC: Hemodynamic role of extracellular fluid in hypertension. Circ Res 38: Suppl ll:ll-72-11-83, 1976 14. Liard JF: Hypertension induced by prolonged intracoronary administration of dobutamine in conscious dogs. Clin Sci Mol Med 54:153-160, 1978 15. Tarari RC, Ferrarlo CM, Dustan HP: The heart in hypertension. In, Hypertension: Physiopathology and Treatment. New York, McGraw-Hill, 1977, p 738-754 16. Peterson DF, Brown AM: Pressor reflexes produced by stimulation of the afferent fibers in the cardiac sympathetic nerves of the cat. Circ Res 28:605-610, 1971 17. Comroe JH Jr: Location and function of the chemoreceptors of the aorta. Am J Physiol 127:176-191, 1939 18. James TN, lsobe JH, Urlhaler F: Analyses of components in a cardiogenic hypertensive chemoreflex. Circulation 52:179-192, 1975 19. Horwitz 0, Sjoerdsma A: Some interrelationships between elevation of blood pressure and angina pectoris. Proc Councilon High Blood Pressure Research 13:39-48, 1964 20. Tarazi RC, Estafanous GF, Fouad FM: Unilateral stellate block in the treatment of hypertension after coronary bypass surgery. Am J Cardiol 42:1013-1018. 1978 21. Tarazi RC: Reversal of cardiac hypettrophy. Possibility and clinical implications. In, Left Ventricular Hypertrophy in Hypertension. Royal Society of Medicine, International Congress and Symposium Series 9. London, Academic Press and Royal Society of Medicine, 1979, p. 55-65 22. Frohlich ED, Tarazi RC: Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy? Am J Cardiol 44:959-963, 1979 23. Falase AO: Cardiomegaly of unknown origin among Nigerian adults.

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Role of hypertension in Its aetiology. Br Heart J 39:671-679, 1977 Cohn JN, Limas CJ, Guiha NH: Hypertension and the heart. Arch Intern Med 133:969-979, 1974 Sen S, Tarazi RC, Bumpus FM: Cardiac hypertrophy and antihypertensive therapy. Cardiovasc Res 11:427-433, 1977 Yamori Y: Pathogenesis of spontaneous hypertension as a model for essential hypertension. Jpn Circ J 41:259-266, 1977 Foidart JM, Rorive GL, Nusgens BV, Lapiere CM: The relationship between blood pressure and aortic collagen metabolism in renal hypertensive rats. Clin Sci Mol Med 55:27s-29s. 1978 Ferrarlo CM, Spech M, Tarazi RC, Doi Y: Cardiac pumping ability in rats with experimental renal and genetic hypertension. Am J Cardiol 43:979-985, 1979 Pfeffer J, Pfeffer MA, Ftetcher P, Braunwald E: Alterations of cardiac performance in rats with established spontaneous hypertension. Am J Cardiol 43:994-998, 1979 Sen S, Tarazi RC, Bumpus FM: Age, hypertension and protein synthesis in SHR. In, Spontaneous Hypertension; Its Pathogenesis and Complications. DHEW Publication No. (NIH) 77-l 179, 1977, p 59-63 Bing OHL, Fanburg BL, Brooks WW, Matsushita S: The effect of the lathyrogen /%aminoproprionitrile (BAPN) on the mechanical properties of experimentally hypertrophied rat cardiac muscle. Circ Res 431632-637, 1978 Hollander W: Hypertension, antihypertensive drugs and athero-

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sclerosis. Circulation 48:1112-i 123, 1973 33. Ooshima A, Fuller G, Cardinale G, Spector S, Udenfriend S: Increased collagen synthesis in the cardiovascular system of hypertensive rats and its reversal by antihypertensive agents. Pharmacologist 16:604, 1974 34. Marcus ML, Mueller TM, Kerber RE, Abboud FM: Regional left ventricular perfusion in hypertrophied ventricles during maximal vasodilation (abstr). Circulation 54: Suppl ll:ll-43, 1976 35. Davjs JO: Mechanisms of salt and water retention in cardiac failure. In, The Myocardium: Failure & Infarction. New York, HP Publishing, 1975, p 80-89 36. Brown JJ, Davies DL, Johnson VW, Lever AF, Robertson JIS: Renin relationships in congestive cardiac failure, treated and untreated. Am Heart J 80:329-342, 1970 37. Curtiss C, Cohn JN, Vrobel T, Franciosa JA: Role of the reninangiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 58:763-770, 1978 38. Gavras H, Faxon DP, Berkoben J, Brunner HR, Ryan TJ: Angiotensin converting enzyme inhibition in patients with congestive heart failure. Circulation 58:770-776, 1978 39. Cody RJ, Tarazi RC, Bravo EL, Fouad FM: Haemodynamics of orally-active converting enzyme inhibitor (Xl 14225) in hypertensive patients. Clin Sci Mol Med 55453-459, 1978 40. Bravo EL, Tarazi RC: Converting enzyme inhibition with an orally active compound in hypertensive man. Hypertension 1:39-46, 1979

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