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Unloading the Heart in Congestive Heart Failure
Unloading the Heart in Congestive Heart Failure
JAY N. COHN, M.D. Minneapolis, Minnesota
Depressed contractile performance of the heart In congestive heart failure is aggravated by Increases In preload and afterload related in part to arterial and venous constriction. Vasodilator drugs have a salutary effect on left ventricular performance by reducing aortic impedance and/or Increasing venous capacitance resulting in an increase in stroke volume and a lowering of filling pressure. Vasodilators may act by counteracting the heightened neurohumoral vasoconstriction tone In heart failure (Inhibition of the sympathetic nervous system, Inhibition of the renin-angiotensin system) or by more directly affecting vascular smooth muscle tone (direct vasodilators, calcium antagonists). The Immediate effects of these drugs on restIng hemodynamics must be supplemented by knowledge of their effects on the circulatory response to exercise and of their efficacy during long-term administration before a rational choice can be made as to the Ideal agent or combimltlon of agents to use In the long-term management of congestive heart failure.
Damage to the left ventricular myocardium impairs myocardial contractility and depresses the performance of the left ventricle. This abnormal performance of the heart may be manifested at rest by a dilated chamber, a reduced ejection fraction, an elevated filling pressure, and/or a reduced cardiac output. Even more striking, however, is the abnormality of left ventricular performance noted during exercise. As opposed to the normal response to exercise, which is characterized by an increase in ejection fraction and an increaee in cardiac output with little if any change in ventricular filling pressure, the abnormal left ventricle responds to exertion with an attenuated increase in cardiac output and an inappropriate increase in ventricular filling pressure. When the left ventricular dysfunction limits exercise tolerance, the diagnosis of heart failure can be made. PRELOAD AND IMPEDANCE
From the Department of Medicine, Cardiovascular Division, Univl'lrsity of Minnesota Medical School, Minneapolis, Minnesota. Request for reprints should be addressed to Dr. Jay N. Cohn, University of Minnesota Hospital, ac>x 488, Minneapolis, Minnesota 55455.
Although depressed contractile force of heart muscle is at the root of the problem in congestive heart failure, the performance of the pump is intimately related to its loading conditions as well. Preload, or the end-diastolic fiber length, normally contributes directly to myocardial contractile force. In heart failure, the preload is often increased as a result of reduced systolic emptying, increased blood volume, and a central shift of circulating volume by virtue of reduced compliance of the venous capacitance system [1). This increased preload may have some salutary effect on cardiac performance; however, in heart failure, the left ventricle functions on a relatively flat Frank-Starling curve. Therefore, the augmentation in performance by virtue of this diastolic loading is only modest [2]. Furthermore, this increased preload is achieved at the expense of circulatory congestion with its attendant symptoms, and with an associated increase in ventricular end-diastolic volume, myocardial wall stress, and myocar-
August 20, 1984
The American Journal of Medicine
67
CONVERTING ENZYME INHIBITION-COHN
TABLE I
Relative Venodilator Effects of Arteriolar Dilators Used in Congestive Heart Failure Venous Effect Minoxidil Hydralazine Nifedipine Phentolamine Nitroprusside Captopril, enalapril Prazosin Nitrates
0 0/1 + 1+ 1+ 2+ 2+ 3+ 4+
dial oxygen consumption [3]. The net effect of an uncontrolled increase in preload may, therefore, be deleterious rather than beneficial in patients with heart failure. The load on the left ventricle during ejection, or afterload, also is an important determinant of left ventricular performance. In the normal heart, increases in afterload are well tolerated with remarkably little change in cardiac output [4]. In contrast, the heart with intrinsic myocardial disease responds poorly to increases in afterload by a progressive decline in stroke volume and cardiac output. The afterload, or wall stress during ejection, is influenced by the ventricular chamber radius and pressure generation. An increased aortic impedance in congestive heart failure places an afterload burden on the left ventricle because left ventricular pressure increases rapidly during ejection and because the reduced stroke volume limits the reduction in chamber diameter during systole. A major factor accounting for increased preload and impedance in congestive heart failure is activation of neurohumoral mechanisms. Activation of the sympathetic nervous system is manifested by an increase in plasma norepinephrine concentration to levels that average more than three times normal [5]. Activation of the renin-angiotensin system is manifested by an increase in plasma renin activity that is quite variable in heart failure but that may reach exceedingly high levels (greater than 100 ng/ml per hour) [5,6]. The antidiuretic hormone-vasopressin system also is activated as evidenced by levels of plasma arginine vasopressin that average about twice normal [7]. Activation of these endogenous vasoconstrictor systems, therefore, may contribute in large part to the arteriolar constriction that raises peripheral resistance and impedance to left ventricular ejection as well as to the venoconstriction that shifts blood centrally and increases cardiac preload. These systems may also result in changes in the renal circulation that contribute to the sodium retention that plays a role in the expanded plasma volume in this syndrome [8]. Given the multiplicity of factors that apparently contribute to the depressed cardiac performance and the symptoms of congestive heart failure, it is not surprising that a variety of therapeutic interventions have been devised. The efficacy of vasodilator drugs in acutely improving the 68
August 20, 1984
The American Journal of Medicine
performance of the left ventricle attests to the adverse circulatory effects of the vasoconstrictor mechanisms detailed. Indeed, these drugs by reducing impedance and/or reducing preload could interrupt a vicious cycle of progressive vasoconstriction leading to progressive impairment of left ventricular performance that may be characteristic of the advanced stages of congestive heart failure. Since each of the vasodilator drugs available for study appears to act by somewhat unique mechanisms and may exert effects on differing vascular segments, the hemodynamic response to each of these drugs may vary. These variations may apply not only to differing vascular effects on the series components of an individual vascular bed but also to varying effects on different regional beds. CLASSIFICATION OF VASODILATORS One possible classification of the vasodilator drugs is on the basis of their vascular sites of action. The most simplified classification is based on the relative effects on the venous capacitance vessels and the arterial resistance vessels. As depicted in Table I vasodilator drugs have widely differing relative effects on these two vascular segments, from drugs that have almost an exclusive effect on the arterial side of the circulation to those whose predominant action is on the venous capacitance bed. The acute hemodynamic effect of a drug with a prominent venous action is quite different from that of a drug with a predominant arterial action. Resting cardiac filling pressure decreases in response to venodilation whereas cardiac output increases in response to arterial dilation. Another way to classify the vasodilators is on the basis of their mechanism of action. In that regard we identify at least four clinically useful classes of compounds: (1) inhibitors of the sympathetic nervous system; (2) inhibitors of the renin-angiotensin system; (3) direct muscle relaxers; and (4) calcium antagonists or calcium entry blockers. Striking differences in regional distribution of flow might result from use of drugs with different mechanisms of action. Interference by some of the qrugs in the compensatory neurohumoral mechanisms in heart failure also can profoundly influence the overall circulatory response both at rest and during exercise. Furthermore, direct cardiac effects of some of the agents might augment or counteract the beneficial pump function effects of vasodilation. INHIBITION OF THE SYMPATHETIC NERVOUS SYSTEM Drugs may interfere with the sympathetic nervous system at several different sites. Centrally acting inhibitors, such as clonidine and guanabenz, may block vasoconstriction, but they also inhibit sympathetic drive to the heart. The net effect of these drugs is that the resultant negative inotropic effect limits the increase in cardiac output that might otherwise be anticipated from the relaxation of adrenergic-mediated vasoconstriction [9]. Sympathetic inhibition also may be achieved more peripherally. Alpha adrenoceptor blockade with drugs such as prazosin, trimazosin,
CONVERTING ENZYME INHIBITION-COHN
and indoramin does not depress cardiac function and therefore leads to considerable improvement in pump function and cardiac output [1 0]. Still uncertain is whether these drugs are capable of sustaining adrenoceptor blockade during long-term administration [11) and how this alpha blockade influences the regional distribution of cardiac output and the response to exercise, which normally stimulates alpha-adrenoceptor vasoconstriction of nonexercising vascular beds. Drugs may also inhibit the sympathetic nervous system by blocking catecholamine synthesis or by depressing release by presynaptic mechanisms, including dopaminergic stimulation [12). The precise localization of these actions in terms of cardiac versus . peripheral effects and exercise response has not been fully clarified. Beta-adrenoceptor blockade would be expected to inhibit the cardiac response to sympathetic stimulation but not the vasoconstrictor response. In that regard, this approach to therapy should not improve pump dysfunction but might aggravate it. Despite this theoretic contraindication, some studies have suggested a long-term beneficial effect of beta blockade in certain patients with heart failure [13]. It is unlikely that this reported response can be attributed predominantly to unloading of the heart. INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM
Since angiotensin is a potent vasoconstrictor and the renin-angiotensin system often is activated in heart failure, inhibition of angiotensin effect is an attractive approach to induce vasodilation. Receptor blockade with saralasin and converting enzyme blockade with captopril and enalapril have been utilized with remarkable hemodynamic and clinical responses. Indeed, the beneficial longterm effect of this therapy has even been observed in patients whose plasma renin activity is not particularly high. Since angiotensin may be involved in facilitating norepinephrine release, interventions that suppress angiotensin action also may exert an anti-adrenergic effect [14]. The regional blood flow responses to these agents has already been subjected to study [15]. SMOOTH MUSCLE RELAXATION
Several drugs, including sodium nitroprusside, the nitrates, hydralazine, and minoxidil, relax vascular smooth muscle by what may be a direct effect. The various biochemical mechanisms involved in this process apparently are so diverse that these drugs may have strikingly different effects on arterial and venous smooth muscle and on regional vascular beds. In addition, concerns about tolerance to their vasodilator effects and rebound vasoconstriction after their withdrawal may be related to alterations in the cellular response to their pharmacologic effect or to reflex mechanisms that are activated to counteract the vasodilator effect [16, 17]. These smooth muscles relaxants do not appear to have negative inotropic effects. Indeed, a positive inotropic ef-
feet of hydralazine has been demonstrated in some studies. Furthermore, several new nonadrenergic inotropic drugs appear to have a concomitant vasodilator effect that may contribute to their hemodynamic effect [18-20). CALCIUM ANTAGONISTS
Drugs that inhibit transmembrane calcium transport in myocardium or vascular smooth muscle constitute a heterogeneous group of compounds that have in common a vasodilator effect. Some exert a concomitant negative inotropic effect that may have an adverse influence on left ventricular dysfunction. With others the negative inotropic effect is so slight that vasodilation is the most prominent mechanism. The vasodilator effect of these drugs appears to be more potent on the arterial than on the venous circulation so an increase in cardiac output is more prominent than a decrease in cardiac filling pressure. IMPLICATIONS REGARDING EXERCISE
The major symptom of heart failure is limitation of exercise tolerance because of breathlessness or fatigue. Unloading the failing left ventricle can augment its performance in the resting state, but does the improvement persist during exercise? Although dynamic exercise is generally viewed as a vasodilator stimulus because of the marked reduction in vascular resistance in exercising muscle beds, stimulation of the sympathetic nervous system ·and renin-angiotensin system may play a role in increasing vascular resistance in other beds to enhance flow redistribution to active muscles [21]. A vasodilator drug could thus have counterbalancing effects during exercise: inhibition of vasoconstriction could contribute to improved left ventricular stroke volume, but this could have an adverse effect on flow distribution and also precipitate hypotension. Data from studies in several laboratories have provided somewhat inconclusive results. It appears that a modest improvement in cardiac performance during submaximal exercise can be demonstrated after short-term intervention with a vasodilator, but this improvement is not as clear-cut as maximal exercise levels and the improved left ventricular performance is not translated into an immediate improvement in exercise tolerance [22-24]. In contrast, after long-term therapy with some vasodilator regimens, an improvement in exercise tolerance can be demonstrated [24-26]. These results make it clear that hemodynamic effects at rest, hemodynamic response to exercise, and exercise capacity must all be assessed both short-term and longterm in order to reach a valid conclusion about the therapeutic efficacy of a vasodilator interaction in heart failure. SELECTION OF VASODILATOR THERAPY
It would seem rational to tailor vasodilator therapy on the basis of the predominant mechanism of vasoconstriction in an individual patient. This approach has not been as effective as might be hoped, perhaps because the relative August 20, 1984
The American Journal of Medicine
69
CONVERTING ENZYME INHIBITION-COHN
role of each of the vasoconstrictor mechanisms in an individual patient is not easily discernible, or perhaps because these vasoconstrictor mechanisms are not static in their activity but change continuously, especially in response to an intervention aimed at inhibiting one of the mechanisms. Consequently, the decision as to which of the variety of vasodilator drugs should be employed in an individual patient to most effectively counteract the vasoconstrictor mechanism often is made empirically. Despite the remarkable hemodynamic response that has been demonstrated in patients with congestive heart failure acutely treated on a short-term basis with a variety of vasodilator drugs, still lacking is convincing evidence that long-term therapy with these drugs can alter the natural history of the disease. The effect of unloading on exercise performance also remains controversial. Improved exercise tolerance has been demonstrated in several controlled clinical trials [25,26), but the improvement appears
to be delayed for several weeks and thus out of phase with the resting hemodynamic effects that are most prominent immediately. Some have attributed the improvement in part to a training effect. Increased exercise tolerance and diminution in symptoms appear to have been most dramatic in response to the long-term administration of a converting enzyme inhibitor [26). The concept of unloading the heart as therapy for heart failure now appears well established, but many issues remain unsettled. What is the appropriate time in the course of the disease to intervene? Which agent should be selected? Is combination vasodilator therapy the proper approach as it appears to be in the treatment of hypertension. Should inotropic drugs be used in combination with vasodilators? Fortunately, current interest in the syndrome and its treatment is so high that these and other unresolved issues are likely to yield to new data in the next few years.
REFERENCES 1.
Wood JE: The mechanism of the increased venous pressure with exercise in congestive heart failure. J Clin Invest 1962;
2.
Cohn JN, Franciosa JA: Vasodilator therapy of cardiac failure. N Engl J Med 1977; 297: 27-31, 254-258. Sonnenblick EH, Ross J Jr, Braunwald E: Oxygen consumption of the heart. New concept of its multifactorial determination. Am J Cardiol 1968; 22: 328-336. Cohn JN: Blood pressure and cardiac performance. Am J Med
41: 2020-2024. 3. 4.
16.
17.
1973; 55:351-561. 5.
6.
Levine TB, Francis GS, Goldsmith SR, Simon A, Cohn JN: Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982; 49: 1659-1666. Curtiss C, Cohn JN, Vrobel T, Franciosa JA: Role of the reninangiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978; 58: 763-
1983; 2: 872-878. 18.
19.
770. 7.
8. 9.
10.
Goldsmith SR, Francis GS, Cowley AW, Levine TB, Cohn JN: Increased plasma arginine vasopressin in patients with congestive heart failure. JACC 1983; 1: 1385-1390. Barger AC: The pathogenesis of sodium retention in congestive heart failure. Metabolism 1956; 5: 480-489. Giles TD, lteld BJ, Mautner RK, Rognoni PA, Dillenkoffer RL: Short-term effects of intravenous elonidine in congestive heart failure. Clin Pharmacol Ther 1981; 30: 724-728. Franciosa JA, Cohn JN: Hemodynamic effects of trimazosin in patients with left ventricular failure. Clin Pharmacol Ther
20.
21.
Packer M, Meller J, Gorlin R, Herman MV: Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure. Circulation
12.
Francis GS, Parks R, Cohn JN: The effects of bromocriptine in patients with congestive heart failure. Am Heart J 1983; 106:
13.
Swedberg K, Waagstein F, Hjalmarson A, Wallentin 1: Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancet 1979; II: 1374-1376. Zimmerman BG, Gomer SK, Liao JC: Acting angiotensin on vascular adrenergic nerve endings; facilitation of norepinephrine release. Fed Proc 1972; 31: 1344-1350. Levine TB, Olivari MT, Garberg V, Sharkey S, Cohn JN: Hemo-
49: 1152-1159. Franciosa JA, Cohn JN: Effect of isosorbide dinitrate on response to submaximal and maximal exercise in patients with congestive heart failure. Am J Cardiol 1979; 43: 1009-
23.
Franciosa JA, Cohn JN: Immediate effects of hydralazine-isosorbide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure. Circulation 1979; 59: 1085-1091. Franciosa JA, Goldsmith SR, Cohn JN: Contrasting immediate and long-term effects of isosorbide dinitrate on exercise capacity in congestive heart failure. Am J Med 1980; 69: 559-
1014.
1979; 59: 531-539. 24.
100-106.
14.
15.
70
August 20, 1984
The American Journal of Medicine
Maskin CS, Sinoway L, Chadwick B, Sonnenblick EH, Le Jemtel TH: Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203, in patients with severe congestive heart failure. Circulation 1983; 67: 1065-1070. Uretsky BF, Generalovich T, Reddy PS, Spangenberg RB, Follansbee WP: The acute hemodynamic effects of a new agent, MDL 17,043, in the treatment of congestive heart failure. Circulation 1983; 67: 823-828. Petein M, Levine TB, Cohn JN: Hemodynamic effects of a new inotropic agent, MDL 19205, in patients with chronic heart failure. JACC (in press). Francis GS, Goldsmith SR, Ziesche SM, Cohn JN: Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure. Am J Cardiol 1982;
22.
1978; 23: 11-18. 11.
dynamic and clinical response to enalapril, a long acting converting enzyme inhibitor, in patients with congestive heart failure. Circulation (in press). Packer M, Meller J, Medina N, Yushak M, Gorlin R: Determinants of drug response in severe chronic heart failure. 1. Activation of vasoconstrictor forces during vasodilator therapy. Circulation 1981; 64: 506-514. Olivari MT, Carlyle PF, Levine TB, Cohn JN: Hemodynamic and hormonal response to transdermal nitroglycerin in normal subjects and in patients with congestive heart failure. JACC
566. 25.
26.
Levine TB, Franciosa JA, Cohn JN: Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure. Circulation 1980; 62: 35-41. Captopril Multicenter Research Group: A placebo-controlled trial of captopril in refractory chronic congestive heart failure. JACC 1983; 2: 755-763.
JAY N. COHN, M.D. Minneapolis, Minnesota
Depressed contractile performance of the heart In congestive heart failure is aggravated by Increases In preload and afterload related in part to arterial and venous constriction. Vasodilator drugs have a salutary effect on left ventricular performance by reducing aortic impedance and/or Increasing venous capacitance resulting in an increase in stroke volume and a lowering of filling pressure. Vasodilators may act by counteracting the heightened neurohumoral vasoconstriction tone In heart failure (Inhibition of the sympathetic nervous system, Inhibition of the renin-angiotensin system) or by more directly affecting vascular smooth muscle tone (direct vasodilators, calcium antagonists). The Immediate effects of these drugs on restIng hemodynamics must be supplemented by knowledge of their effects on the circulatory response to exercise and of their efficacy during long-term administration before a rational choice can be made as to the Ideal agent or combimltlon of agents to use In the long-term management of congestive heart failure.
Damage to the left ventricular myocardium impairs myocardial contractility and depresses the performance of the left ventricle. This abnormal performance of the heart may be manifested at rest by a dilated chamber, a reduced ejection fraction, an elevated filling pressure, and/or a reduced cardiac output. Even more striking, however, is the abnormality of left ventricular performance noted during exercise. As opposed to the normal response to exercise, which is characterized by an increase in ejection fraction and an increaee in cardiac output with little if any change in ventricular filling pressure, the abnormal left ventricle responds to exertion with an attenuated increase in cardiac output and an inappropriate increase in ventricular filling pressure. When the left ventricular dysfunction limits exercise tolerance, the diagnosis of heart failure can be made. PRELOAD AND IMPEDANCE
From the Department of Medicine, Cardiovascular Division, Univl'lrsity of Minnesota Medical School, Minneapolis, Minnesota. Request for reprints should be addressed to Dr. Jay N. Cohn, University of Minnesota Hospital, ac>x 488, Minneapolis, Minnesota 55455.
Although depressed contractile force of heart muscle is at the root of the problem in congestive heart failure, the performance of the pump is intimately related to its loading conditions as well. Preload, or the end-diastolic fiber length, normally contributes directly to myocardial contractile force. In heart failure, the preload is often increased as a result of reduced systolic emptying, increased blood volume, and a central shift of circulating volume by virtue of reduced compliance of the venous capacitance system [1). This increased preload may have some salutary effect on cardiac performance; however, in heart failure, the left ventricle functions on a relatively flat Frank-Starling curve. Therefore, the augmentation in performance by virtue of this diastolic loading is only modest [2]. Furthermore, this increased preload is achieved at the expense of circulatory congestion with its attendant symptoms, and with an associated increase in ventricular end-diastolic volume, myocardial wall stress, and myocar-
August 20, 1984
The American Journal of Medicine
67
CONVERTING ENZYME INHIBITION-COHN
TABLE I
Relative Venodilator Effects of Arteriolar Dilators Used in Congestive Heart Failure Venous Effect Minoxidil Hydralazine Nifedipine Phentolamine Nitroprusside Captopril, enalapril Prazosin Nitrates
0 0/1 + 1+ 1+ 2+ 2+ 3+ 4+
dial oxygen consumption [3]. The net effect of an uncontrolled increase in preload may, therefore, be deleterious rather than beneficial in patients with heart failure. The load on the left ventricle during ejection, or afterload, also is an important determinant of left ventricular performance. In the normal heart, increases in afterload are well tolerated with remarkably little change in cardiac output [4]. In contrast, the heart with intrinsic myocardial disease responds poorly to increases in afterload by a progressive decline in stroke volume and cardiac output. The afterload, or wall stress during ejection, is influenced by the ventricular chamber radius and pressure generation. An increased aortic impedance in congestive heart failure places an afterload burden on the left ventricle because left ventricular pressure increases rapidly during ejection and because the reduced stroke volume limits the reduction in chamber diameter during systole. A major factor accounting for increased preload and impedance in congestive heart failure is activation of neurohumoral mechanisms. Activation of the sympathetic nervous system is manifested by an increase in plasma norepinephrine concentration to levels that average more than three times normal [5]. Activation of the renin-angiotensin system is manifested by an increase in plasma renin activity that is quite variable in heart failure but that may reach exceedingly high levels (greater than 100 ng/ml per hour) [5,6]. The antidiuretic hormone-vasopressin system also is activated as evidenced by levels of plasma arginine vasopressin that average about twice normal [7]. Activation of these endogenous vasoconstrictor systems, therefore, may contribute in large part to the arteriolar constriction that raises peripheral resistance and impedance to left ventricular ejection as well as to the venoconstriction that shifts blood centrally and increases cardiac preload. These systems may also result in changes in the renal circulation that contribute to the sodium retention that plays a role in the expanded plasma volume in this syndrome [8]. Given the multiplicity of factors that apparently contribute to the depressed cardiac performance and the symptoms of congestive heart failure, it is not surprising that a variety of therapeutic interventions have been devised. The efficacy of vasodilator drugs in acutely improving the 68
August 20, 1984
The American Journal of Medicine
performance of the left ventricle attests to the adverse circulatory effects of the vasoconstrictor mechanisms detailed. Indeed, these drugs by reducing impedance and/or reducing preload could interrupt a vicious cycle of progressive vasoconstriction leading to progressive impairment of left ventricular performance that may be characteristic of the advanced stages of congestive heart failure. Since each of the vasodilator drugs available for study appears to act by somewhat unique mechanisms and may exert effects on differing vascular segments, the hemodynamic response to each of these drugs may vary. These variations may apply not only to differing vascular effects on the series components of an individual vascular bed but also to varying effects on different regional beds. CLASSIFICATION OF VASODILATORS One possible classification of the vasodilator drugs is on the basis of their vascular sites of action. The most simplified classification is based on the relative effects on the venous capacitance vessels and the arterial resistance vessels. As depicted in Table I vasodilator drugs have widely differing relative effects on these two vascular segments, from drugs that have almost an exclusive effect on the arterial side of the circulation to those whose predominant action is on the venous capacitance bed. The acute hemodynamic effect of a drug with a prominent venous action is quite different from that of a drug with a predominant arterial action. Resting cardiac filling pressure decreases in response to venodilation whereas cardiac output increases in response to arterial dilation. Another way to classify the vasodilators is on the basis of their mechanism of action. In that regard we identify at least four clinically useful classes of compounds: (1) inhibitors of the sympathetic nervous system; (2) inhibitors of the renin-angiotensin system; (3) direct muscle relaxers; and (4) calcium antagonists or calcium entry blockers. Striking differences in regional distribution of flow might result from use of drugs with different mechanisms of action. Interference by some of the qrugs in the compensatory neurohumoral mechanisms in heart failure also can profoundly influence the overall circulatory response both at rest and during exercise. Furthermore, direct cardiac effects of some of the agents might augment or counteract the beneficial pump function effects of vasodilation. INHIBITION OF THE SYMPATHETIC NERVOUS SYSTEM Drugs may interfere with the sympathetic nervous system at several different sites. Centrally acting inhibitors, such as clonidine and guanabenz, may block vasoconstriction, but they also inhibit sympathetic drive to the heart. The net effect of these drugs is that the resultant negative inotropic effect limits the increase in cardiac output that might otherwise be anticipated from the relaxation of adrenergic-mediated vasoconstriction [9]. Sympathetic inhibition also may be achieved more peripherally. Alpha adrenoceptor blockade with drugs such as prazosin, trimazosin,
CONVERTING ENZYME INHIBITION-COHN
and indoramin does not depress cardiac function and therefore leads to considerable improvement in pump function and cardiac output [1 0]. Still uncertain is whether these drugs are capable of sustaining adrenoceptor blockade during long-term administration [11) and how this alpha blockade influences the regional distribution of cardiac output and the response to exercise, which normally stimulates alpha-adrenoceptor vasoconstriction of nonexercising vascular beds. Drugs may also inhibit the sympathetic nervous system by blocking catecholamine synthesis or by depressing release by presynaptic mechanisms, including dopaminergic stimulation [12). The precise localization of these actions in terms of cardiac versus . peripheral effects and exercise response has not been fully clarified. Beta-adrenoceptor blockade would be expected to inhibit the cardiac response to sympathetic stimulation but not the vasoconstrictor response. In that regard, this approach to therapy should not improve pump dysfunction but might aggravate it. Despite this theoretic contraindication, some studies have suggested a long-term beneficial effect of beta blockade in certain patients with heart failure [13]. It is unlikely that this reported response can be attributed predominantly to unloading of the heart. INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM
Since angiotensin is a potent vasoconstrictor and the renin-angiotensin system often is activated in heart failure, inhibition of angiotensin effect is an attractive approach to induce vasodilation. Receptor blockade with saralasin and converting enzyme blockade with captopril and enalapril have been utilized with remarkable hemodynamic and clinical responses. Indeed, the beneficial longterm effect of this therapy has even been observed in patients whose plasma renin activity is not particularly high. Since angiotensin may be involved in facilitating norepinephrine release, interventions that suppress angiotensin action also may exert an anti-adrenergic effect [14]. The regional blood flow responses to these agents has already been subjected to study [15]. SMOOTH MUSCLE RELAXATION
Several drugs, including sodium nitroprusside, the nitrates, hydralazine, and minoxidil, relax vascular smooth muscle by what may be a direct effect. The various biochemical mechanisms involved in this process apparently are so diverse that these drugs may have strikingly different effects on arterial and venous smooth muscle and on regional vascular beds. In addition, concerns about tolerance to their vasodilator effects and rebound vasoconstriction after their withdrawal may be related to alterations in the cellular response to their pharmacologic effect or to reflex mechanisms that are activated to counteract the vasodilator effect [16, 17]. These smooth muscles relaxants do not appear to have negative inotropic effects. Indeed, a positive inotropic ef-
feet of hydralazine has been demonstrated in some studies. Furthermore, several new nonadrenergic inotropic drugs appear to have a concomitant vasodilator effect that may contribute to their hemodynamic effect [18-20). CALCIUM ANTAGONISTS
Drugs that inhibit transmembrane calcium transport in myocardium or vascular smooth muscle constitute a heterogeneous group of compounds that have in common a vasodilator effect. Some exert a concomitant negative inotropic effect that may have an adverse influence on left ventricular dysfunction. With others the negative inotropic effect is so slight that vasodilation is the most prominent mechanism. The vasodilator effect of these drugs appears to be more potent on the arterial than on the venous circulation so an increase in cardiac output is more prominent than a decrease in cardiac filling pressure. IMPLICATIONS REGARDING EXERCISE
The major symptom of heart failure is limitation of exercise tolerance because of breathlessness or fatigue. Unloading the failing left ventricle can augment its performance in the resting state, but does the improvement persist during exercise? Although dynamic exercise is generally viewed as a vasodilator stimulus because of the marked reduction in vascular resistance in exercising muscle beds, stimulation of the sympathetic nervous system ·and renin-angiotensin system may play a role in increasing vascular resistance in other beds to enhance flow redistribution to active muscles [21]. A vasodilator drug could thus have counterbalancing effects during exercise: inhibition of vasoconstriction could contribute to improved left ventricular stroke volume, but this could have an adverse effect on flow distribution and also precipitate hypotension. Data from studies in several laboratories have provided somewhat inconclusive results. It appears that a modest improvement in cardiac performance during submaximal exercise can be demonstrated after short-term intervention with a vasodilator, but this improvement is not as clear-cut as maximal exercise levels and the improved left ventricular performance is not translated into an immediate improvement in exercise tolerance [22-24]. In contrast, after long-term therapy with some vasodilator regimens, an improvement in exercise tolerance can be demonstrated [24-26]. These results make it clear that hemodynamic effects at rest, hemodynamic response to exercise, and exercise capacity must all be assessed both short-term and longterm in order to reach a valid conclusion about the therapeutic efficacy of a vasodilator interaction in heart failure. SELECTION OF VASODILATOR THERAPY
It would seem rational to tailor vasodilator therapy on the basis of the predominant mechanism of vasoconstriction in an individual patient. This approach has not been as effective as might be hoped, perhaps because the relative August 20, 1984
The American Journal of Medicine
69
CONVERTING ENZYME INHIBITION-COHN
role of each of the vasoconstrictor mechanisms in an individual patient is not easily discernible, or perhaps because these vasoconstrictor mechanisms are not static in their activity but change continuously, especially in response to an intervention aimed at inhibiting one of the mechanisms. Consequently, the decision as to which of the variety of vasodilator drugs should be employed in an individual patient to most effectively counteract the vasoconstrictor mechanism often is made empirically. Despite the remarkable hemodynamic response that has been demonstrated in patients with congestive heart failure acutely treated on a short-term basis with a variety of vasodilator drugs, still lacking is convincing evidence that long-term therapy with these drugs can alter the natural history of the disease. The effect of unloading on exercise performance also remains controversial. Improved exercise tolerance has been demonstrated in several controlled clinical trials [25,26), but the improvement appears
to be delayed for several weeks and thus out of phase with the resting hemodynamic effects that are most prominent immediately. Some have attributed the improvement in part to a training effect. Increased exercise tolerance and diminution in symptoms appear to have been most dramatic in response to the long-term administration of a converting enzyme inhibitor [26). The concept of unloading the heart as therapy for heart failure now appears well established, but many issues remain unsettled. What is the appropriate time in the course of the disease to intervene? Which agent should be selected? Is combination vasodilator therapy the proper approach as it appears to be in the treatment of hypertension. Should inotropic drugs be used in combination with vasodilators? Fortunately, current interest in the syndrome and its treatment is so high that these and other unresolved issues are likely to yield to new data in the next few years.
REFERENCES 1.
Wood JE: The mechanism of the increased venous pressure with exercise in congestive heart failure. J Clin Invest 1962;
2.
Cohn JN, Franciosa JA: Vasodilator therapy of cardiac failure. N Engl J Med 1977; 297: 27-31, 254-258. Sonnenblick EH, Ross J Jr, Braunwald E: Oxygen consumption of the heart. New concept of its multifactorial determination. Am J Cardiol 1968; 22: 328-336. Cohn JN: Blood pressure and cardiac performance. Am J Med
41: 2020-2024. 3. 4.
16.
17.
1973; 55:351-561. 5.
6.
Levine TB, Francis GS, Goldsmith SR, Simon A, Cohn JN: Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982; 49: 1659-1666. Curtiss C, Cohn JN, Vrobel T, Franciosa JA: Role of the reninangiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978; 58: 763-
1983; 2: 872-878. 18.
19.
770. 7.
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