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Circulatory abnormalities and compensatory mechanisms in heart failure
Circulatory Abnormalities and Compensatory Mechanisms in Heart Failure FELIX BURKART, M.D., W.
KIOWSKI,
M.D.,
Base/, Switzerland
Knowledge of the basic alterations of central hemodynamics in congestive heart failure has failed to explain many aspects of this important syndrome. Increasing attention has recently been paid to compensatory and adaptive mechanisms occurring after the initial insult. Thus, new insights have been gained into the pathophysiology of contraction of hypertrophied myocardium and changes of adrenergic receptors in the myocardium due to chronically increased cardiac sympathetic tone. The role of the renin-angiotensin-aldosterone system in early and advanced congestive heart failure has been further elucidated, and the role of the vasodilating atria1 natriuretic peptide is undergoing further definition. New results further clarify the mechanisms leading to breathlessness and muscular fatigue in congestive heart failure, with emphasis shifting from the traditional concept of the importance of increased filling pressures to changes to the peripheral circulation and exercising muscles. Although progress has been made in understanding of the pathophysiology of congestive heart failure, many aspects are still poorly understood and await clarification.
From the Division of Cardiology, University Hospttal Basel. Basel, Switzerland. Requests for reprints should be addressed to Felix Burkart, M.D., University Hospital Basel, Department of Internal Medicine, Division of Cardiology, Petersgraben 4, CH-4031 Basel, Switzerland.
T
he pathophysiology of congestive heart failure is complex and the amount of new data pertaining to this problem attests not only to its unbroken attraction to researchers in basic sciences and clinical medicine, but also to the fact that many essential aspects of congestive heart failure are still poorly understood.
REGIONALHEMODYNAMICCHANGESIN HEART FAILURE Heart function is determined by contractility, preload, and afterload. When cardiac output decreases, a chain of reflexes and compensatory mechanisms sets in to restore a normal hemodynamic situation. The phase of cardiocirculatory compensation is characterized by mostly normal global pump performance at rest and a stabilization of heart rate at a higher level. In the compensated phase of congestive heart failure, the cardiac response to exercise is usually abnormal and the reduced cardiac output is redistributed in a characteristic way [I]. A normal individual performing moderate exercise distributes 70-80% of the cardiac output to the exercising skeletal muscle. Vasoconstriction may occur in the renal bed; however, renal flow does not decrease due to an increased perfusion pressure with moderate exercise. The response of the patient with moderate compensated heart failure is different. Cardiac output fails to rise normally with exercise and proportionally less flow is delivered to the exercising skeletal muscle, as marked cutaneous, renal, and splanchnic vasoconstriction occurs [2]. This pattern is more prominent in patients with severe heart failure, in whom reduced cardiac output is redistributed at rest away from the cutaneous, renal, and splanchnit beds, with relative preservation of coronary and cerebral flow [a]. Whereas preload influences stroke volume in normal subjects, a change of the filling pressure alters stroke volume only in a small way in severe heart failure. Conversely, stroke volume is largely independent of afterload in normal subjects, whereas in heart failure patients, even slight reductions result in an improvement of the effective cardiac forward volume. Whatever the insult leading to the development of congestive heart failure may be, the heart and
May 29, 1991. The American Journal of Medicine
Volume 90 (suppl 56)
56-19s
SYMPOSIUM
ON IBOPAMINE / BURKART and KIOWSKI
circulation have only limited means to adapt to and compensate for it. The mechanisms considered to be most effective and important are ventricular hypertrophy and neurohumoral changes.
HYPERTROPHY Imposition of a pressure or volume overload on the myocardium increases the wall stress of the involved ventricle and leads to hypertrophy. Although there is some controversy about the initiating factor causing hypertrophy, there is good evidence to suggest that the increased wall stress in itself, and not associated factors such as increased sympathetic stimulation, leads to hypertrophy [3]. Cardiac hypertrophy is generally viewed as a compensatory process that normalizes wall stress. After complete normalization of wall stress due to increased wall thickness, hypertrophy usually stabilizes [4,5]. Pressure overload in general leads to more pronounced hypertrophy, compared to volume overload. Measurements of the contractile state of hypertrophied myocardium have been previously performed on right ventricular myocardium from animal models subjected to pressure overload. Based on such experiments, it was postulated that overloaded hypertrophied myocardium has an inherent defect of contractility [6]. This simple view is no longer accepted. Rather, the functional consequences of cardiac overloading arise from the combined result of type, degree, and duration of overloading; species studied; and, particularly, chamber affected. Thus, it has been shown that the right ventricle is particularly sensitive to pressure overloading, with demonstrable decreases of contractility even before clinical failure ensues [7]. The abnormalities are still reversible before the development of overt failure. Once failure has ensued, it is no longer reversible [8]. In contrast, the left ventricle appears to tolerate both pressure and volume overload for a considerable time before abnormalities of contraction can be detected [9]. The differences between the functional consequences, particularly of pressure overloading, between right and left ventricles are not fully understood but may be the consequence of the normal anatomic function of the ventricles. The right ventricle has been compared to a thin-walled volume and the left ventricle to a thick-walled pressure pump [lo]. Therefore, pressure overload constitutes a qualitative change for the right ventricle, but a quantitative change for the left ventricle. Data obtained in vitro with human myocardium also lead one to question the opinion that the hypertrophied and failing heart has an intrinsic defect of
.5B-20s
May 29, 1991
The American Journal of Medicine
contraction. Feldman et al. [ll] demonstrated in in vitro experiments that trabecular muscle from the hearts of heart transplant recipients with end-stage heart failure developed the same peak isometric tension after stimulation by calcium, acetylstrophanthidin, and forskolin as trabecular muscle from donor hearts. However, the response was less for /3-adrenergic stimulation by isoproterenol, or for inhibition of phosphodiesterase activity by milrinone. Data from Fowler et al. [12] also suggest similar results, since the response to intravenous calcium of the left ventricle, in terms of changes in the maximal rate of rise of ventricular pressure in patients with severely depressed left ventricular function, was similar to that of patients with relatively normal left ventricular function. However, the response to /3-adrenergic stimulation with dobutamine was less in patients with more advanced heart failure. Even though the concept of depressed contractile function in failing myocardium must be seen in a different light, a number of abnormalities associated with hypertrophy and failure at the myocardial and cellular level of the cardiocyte have been studied. 1. The increased mass and work load of hypertrophied myocardium require an increased blood supply. Myocardial blood flow is usually normal at rest, but the vasodilator reserve seems to be diminished during stress in most forms of hypertrophy [13,14]. 2. One of the most consistent findings, also noted in the study by Feldman et al. [ll] in hearts from heart transplant recipients, is a prolongation of the action potential, together with prolongation of the contraction and increased time, until complete relaxation has occurred [15]. It has been argued that this may be due to increased size of the cardiocytes, which may lead to a decrease in the proportion of electrically effective cell surface for calcium entry p.er unit cell volume [16]. Alternatively, this finding may be explained by an inhibition of calcium uptake by, and/or release from, the sarcoplasmic reticulum in patients with heart failure [17]. 3. The production of cyclic adenosine monophosphate (CAMP) by hypertrophied and failing cardiocytes has also received a great deal of attention. The contractile response of failing myocardium to p-adrenergic stimulation by isoproterenol is subnormal [11,12]. Since the response to direct stimulation of the catalytic unit of adenylate cyclase by forskolin remained unchanged [ll], the reduced response to isoproterenol probably can be attributed to a deficient P-adrenoceptor-mediated CAMP production. This contention is supported by data
Volume 90 (suppl 58)
SYMPOSIUM
demonstrating a down-regulation of the number of p-adrenergic adrenoceptors in the failing myocardium [12]. This effect was pronounced for the P-adrenoceptor, leading to a preponderance of the Pa-adrenoceptors, upon whose stimulation the failing myocardium seems to depend to a greater degree than does normal myocardium [HI. A defect of p-adrenoceptor-mediated sympathetic support may be an important factor for the depressed cardiac function in human congestive heart failure. 4. An altered myosine-adenosine triphosphatase composition of the failing myocardium has been described in a rat model [19,20], with a shift of the isoforms of this enzyme toward a slower, less active form. This effect seems to be species specific and probably irrelevant in heart failure patients, since myocardium in normal human subjects already contains mostly the V3 isoform of the enzyme.
NEUROHUMORALCHANGES Sympathetic Activity
Activation of the sympathetic nervous system in congestive heart failure results from unloading of arterial baroreceptors by reduced blood pressure or stroke volume. Increased efferent discharge of sympathetic neurons [21-231 leads to increased heart rate, contractility, and peripheral vasoconstriction. In principle these changes are appropriate for maintaining vital organ function; nevertheless, peripheral vasoconstriction also increases afterload with its detrimental effects on ventricular performance. Renin-Angiotensin-Aldosterone
System
The role of the renin-angiotensin-aldosterone system has been also thoroughly studied [24-261. Increased activity of this system and stimulation of antidiuretic hormone release through a central action of angiotensin II lead to volume retention, which is thought to be beneficial for the augmentation of cardiac performance, using the Frank-Starling mechanism. The peripheral vasoconstrictor effects of angiotensin II also lead to peripheral vasoconstriction; similar to increased sympathetic nervous system activity, they lead to increased afterload, with its potential for further deterioration of cardiac performance. The timing of activation of this system during development of heart failure is not clear, but recent studies in animal models [27] and in humans [28] suggest that it may only be activated acutely and during more advanced stages of heart failure. Much of the elevation seen in congestive heart failure may be due to the effects of eommonly prescribed diuretics. Peripheral resistance
ON IBOPAMINE / BURKART and KIOWSKI
may be directly dependent on angiotensin-mediated vasoconstriction in patients with advanced disease, while in patients with milder degrees of cardiac dysfunction, vasoconstriction may be rendered dependent by administration of diuretics. Atrial Natriuretic Peptide
Another humoral factor that has attracted attention is the atria1 natriuretic peptide (ANP) or factor [29]. ANP is secreted in response to atria1 distention or stretch. This has been documented in normal human subjects undergoing water immersion [30] or volume loading [28], and also in patients with acute atria1 distension due to atria1 fibrillation or supraventricular tachycardia [31]. This stimulatory pathway also seems to be operative in congestive heart failure patients in whom plasma ANP levels are elevated [32] and directly proportional to right atria1 filling pressures [33]. Nonetheless, its role in congestive heart failure remains to be defined.
DETERMINANTSOF EXERCISECAPACITY The main symptoms that patients experience and that subjectively limit exercise capacity are pulmonary congestion, breathlessness, and muscle fatigue. Even though congestion has lent its name to the clinical syndrome, it should be recognized that this symptom is no longer as prominent [34] because of the availability of modern drug therapy, such as diuretics, venodilators, nitrates, or mixed vasodilators such as the angiotensin-converting enzyme (ACE) inhibitors. Dyspnea is thought to result from stimulation ‘of pulmonary, juxtacapillary “‘J” receptors, brought on by pulmonary congestion and decreased lung compliance. Lipkin et al. [35] have shown that maximal oxygen consumption as an objective measure of exercise capacity did not correlate with maximal pulmonary capillary wedge pressure during exercise, even though patients stopped performing exercise in this partieular test due to dyspnea. Similarly, Fink et al. [36] found no increase in exercise capacity in congestive heart failure patients after acutely lowering their filling pressures either by ACE inhibition or dobutamine infusions. Bayliss et al. [37] could not find a relationship between an index of left ventricular filling pressure and exercise duration, either during control conditions or when the filling pressure was lowered chronically by captopril or prazosin. In contrast to acute heart failure, where dyspnea is clearly related to increased intrapulmonary pressure, other factors seem to influence this symptom to a great extent in chronic congestive heart failure.
May 29, 1991
The American Journal of Medicine
Volume 90 (suppl 56)
58-m
SYMPOStUM
ON IBOPAMINE / BURKART and KIOWSKI
-
There is some controversy concerning the underlying mechanisms of reduced muscle perfusion durin,q exercise. It is believed that the decreased vasodilator capacity of congestive heart failure patients is due to a defect of the resistance vessels, possibly due to increased stiffness arising from increased water and sodium contents [a]. This view is supported by an elegant study comparing leg hemodynamic changes during one-leg and two-leg exercise. LeJemtel et al. [38] showed that femoral vein blood flow during two-leg exercise did not increase any more compared with one-leg exercise. Since patients were able to increase maximal oxygen uptake during two-leg exercise over values achieved during one-leg exercise, limitation of cardiac output was considered not to be the cause of reduced vasodilator response during exercise. Although the importance of reduced nutritional flow to skeletal muscle is well recognized, the underlying mechanisms leading to muscle fatigue remain to be precisely defined. Also, the effects of therapy on these important determinants of exercise capacity will certainly receive more attention as our knowledge of that subject increases.
REFERENCES 1. Flaim SF, Minteer WY: Ventrrcular volume overload alters cardiac output distributron in rats durrng exercise. J Appl Physiol 1980; 49: 482-90. 2. Zelis R, Flaim SF: Vasoconstrictor Mechanisms and the Effect of Nitrate Vasodilators in Chronic Heart Failure. Berlin: Springer Verlag, 1983; l-13. 3. Cooper G, Kent RL, Ubon CE, Thompson EW, Marino TA: Hemodynamic versus adrenergic control of cat rrght ventricular hypertophy. J Clin Invest 1985; 75: 140314. 4. Burger SB, Strauer BE: Left ventrrcular hypertrophy in chronic pressure load due to spontaneous essential hypertensron. Left ventricular function, left ventricular geometry, wall stress. In: Strauer BE, ed. The heart in hypertension. Berlin: SpringerVerlag, 1981; 13-36. 5. Meerson FZ: The myocardrum in hyperfunction, hypertrophy and heart failure. Circ Res 1969; 25: 1-16. 6. Spann JF Jr: Heart farlure and ventricular hypertrophy: Altered cardiac contractilsty and compensatory mechanrsms. Am J Cardrol 1969; 23: 504-9. 7. Cooper G, Savata R, Harrison C, Coleman HN: Mechanisms for the abnormal energetics of pressure-induced hypertrophy of cat myocardium. Circ Res 1973; 33: 213-23. 8. Cooper G, Marino TA: Complete reversibility of cat right ventricular chronic progressive pressure overload. Circ Res 1984; 54: 323-31. 9. Serizawa T, Mrrsky I, Carabello B, Alpert NR: Drastolic myocardral stiffness in gradually developing left ventricular hypettrophy in dog. Am J Physiol 1982; 242: H633-7. 10. Cooper G: Cardiocyte adaptation to chronically altered load. Annu Rev Physiol 1987; 49: 501-18. 11. Feldman MD, Copelas L, Gwathmay JK et al: Deficient production of CAMP: Pharmacological evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulatron 1987; 75: 331-9. 12. Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MW: Assessment of the beta-adrenergrc pathway In the intact farlrng human heart: Progressive receptor down-regulation and subsensrbllity to agonist response. Circulation 1986; 74: 1290302. 13. Bathe RJ, Vrobel TR, Ring WS, Emergy RW, Anderson RW: Regional myocardial
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May 29, 1991
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blood flow during exercise in dogs with chronic left ventrrcular hypertrophy. 1981; 48: 78-87.
Crrc Res
14. Wusten B, Buss DD, Heist H, Schaper W: Dilatory capacity of the coronary circulation and its correlation to the arterial vasculature rn the canrne left ventricle. Basic Res Cardrol 19n; 72: 636-50. 15. Aronson RS: Characteristics of action potentials of hypertrophied from rats with renal hypertension. Circ Res 1980; 47: 443-54.
myocardium
16. Keung ECH, Keung C, Aronson RS: Passive electrical properties of normal and hypertrophied rat myocardium. Am J Physrol 1982; 243: H917-26. 17. Sordahl LA, McCollum WB, Wood WG, Schwarts A: Mitochondria and sarcoplasmic rehculum function in cardrac hypertrophy and failure. Am J Physiol 1973; 224: 497-502. 18. Bristow MR, Ginsburg R, Umans V, et ai: Beta,-and beta,-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: Coupling of both receptor subtypes to muscle contraction and selective beta-l-receptor downregulation in heart failure. Circulation 1986; 59: 297-309. 19. Lompre AM, Schwartz K, d’Albis A, et al: Myosin isoenzyme redistribution in chronic heart overload. Nature 1979; 282: 105-7. 20. Mercadier J, Bouveret P, Gorza L, et ai: Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ Res 1983; 53: 52-62. 21. Leimbach WN, Wallin G, Victor RG, Aylward PE, Sundlof G, Mark AL: Direct evidence from intraneural recordings for increased central sympathetic outhow in patrents with heart failure. Circulation 1986; 73: 913-9. 22. Hasking GJ, Esler MD, Jennings GL, Burton D, Korner PI: Noreprnephrine spillover to plasma In patients with congesbve heart farlure: Evidence of increased overall and cardiorenal sympathetic actlvrty. Circulation 1986; 73: 615-21. 23. Di Bona GF: The functions of the renal nerves. Rev Physiol Blochem Pharmacol 1982; 94: 76-88. 24. Curtiss C, Cohn JN. Vrobel T, Franciosa JA: Role of the renin-angrotensin system in the systemrc vasoconstriction of chronrc congestive heart failure. Circulation 1978; 58: 763-9. 25. Francis GS, Goldsmith SR, Levine B, Olivan MT, Cohn JN: The neurohumoral axis In congestive heart failure. Ann Intern Med 1984; 101: 370-7. 26. Drau VJ, Colucci WS, Hollenberg NK, Williams GH: Relatron of reninangiotensrn-aldosterone system to clinical state in congestive heart failure. Circulabon 1981; 63: 645-51. 27. Armstrong PW, Stopps TP, Ford SE, deBold AJ: Rapid ventricular pacing in the dog: Pathophysiology studres of heart failure. Circulation 1986; 74: 1075-84. 28. Yamajr T, lshibashr M, Takaku F: Atrial natriuretic factor in human blood. J Clin Invest 1985; 76: 1705-g. 29. DeBold Al, Borenstein HB, Veress AT, Sonnenberg H: A raprd and potent natriuretie response to intravenous Infection of atrral myocardial extract in rats. Lrfe Sci 1981; 28: 89-94. 30. Gerbes AL, Arendt RM, Schnizer W, et al: Regulation of atrial natriuretrc factor release in man: Effect of water immersron. Klin Wochenschr 1986; 64: 666-7. 31. Yamaji T, lshibashi M, Nakaoka H, lmataka K, Amono M, Fujii J: Possible role for atrral natriuretic peptlde in polyuria associated with paroxysmal atrral arrhythmras [letter]. Lancet 1985; 1: 1211. 32. Shenker Y, Sider RS, Ostafin EA, Grekin RJ: Plasma levels of immunoreactive atnal natriuretrc factor in healthy subjects and patients with edema. J Clan Invest 1985; 76: 1684-7. 33. Raine AEG, Erne P, Burgisser E, et al: Atrial natriuretic peptide and atrial pressure in patients with congestive heart farlure. N Engl J Med 1986; 315: 533-7. 34. Jafri SM, Lakier JB, Rosman HS, Goldstein S: Prevalence of congestion in chronic heart farlure. Chest 1986; 90: 311-2. 35. Lipkin DP, Canepa-Hauson R, Stephens MR, Poole-Wilson PA: Factors determining symptoms in heart failure: Comparrson of fast and slow exercise tests. Br Heart J 1986; 55: 439-45. 36. Fink LI, Wilson JR, Ferraro N: Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am J Cardiol 1986; 57: 249-53. 37. Bayliss J, Canepa-Hauson R, Norell MS, Poole-Wrlson PA, Sutton G: Vasodilation with captoprrl and prarosin in chronic heart failure: Double blind study at rest and on exercise. Br Heart J 1986; 55: 265. 38. LeJemtel TH, Maskin CS, Lucid0 D, Chadwick BJ: Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation 1986; 74: 245-51.
Volume 90 (suppl 56)
KIOWSKI,
M.D.,
Base/, Switzerland
Knowledge of the basic alterations of central hemodynamics in congestive heart failure has failed to explain many aspects of this important syndrome. Increasing attention has recently been paid to compensatory and adaptive mechanisms occurring after the initial insult. Thus, new insights have been gained into the pathophysiology of contraction of hypertrophied myocardium and changes of adrenergic receptors in the myocardium due to chronically increased cardiac sympathetic tone. The role of the renin-angiotensin-aldosterone system in early and advanced congestive heart failure has been further elucidated, and the role of the vasodilating atria1 natriuretic peptide is undergoing further definition. New results further clarify the mechanisms leading to breathlessness and muscular fatigue in congestive heart failure, with emphasis shifting from the traditional concept of the importance of increased filling pressures to changes to the peripheral circulation and exercising muscles. Although progress has been made in understanding of the pathophysiology of congestive heart failure, many aspects are still poorly understood and await clarification.
From the Division of Cardiology, University Hospttal Basel. Basel, Switzerland. Requests for reprints should be addressed to Felix Burkart, M.D., University Hospital Basel, Department of Internal Medicine, Division of Cardiology, Petersgraben 4, CH-4031 Basel, Switzerland.
T
he pathophysiology of congestive heart failure is complex and the amount of new data pertaining to this problem attests not only to its unbroken attraction to researchers in basic sciences and clinical medicine, but also to the fact that many essential aspects of congestive heart failure are still poorly understood.
REGIONALHEMODYNAMICCHANGESIN HEART FAILURE Heart function is determined by contractility, preload, and afterload. When cardiac output decreases, a chain of reflexes and compensatory mechanisms sets in to restore a normal hemodynamic situation. The phase of cardiocirculatory compensation is characterized by mostly normal global pump performance at rest and a stabilization of heart rate at a higher level. In the compensated phase of congestive heart failure, the cardiac response to exercise is usually abnormal and the reduced cardiac output is redistributed in a characteristic way [I]. A normal individual performing moderate exercise distributes 70-80% of the cardiac output to the exercising skeletal muscle. Vasoconstriction may occur in the renal bed; however, renal flow does not decrease due to an increased perfusion pressure with moderate exercise. The response of the patient with moderate compensated heart failure is different. Cardiac output fails to rise normally with exercise and proportionally less flow is delivered to the exercising skeletal muscle, as marked cutaneous, renal, and splanchnic vasoconstriction occurs [2]. This pattern is more prominent in patients with severe heart failure, in whom reduced cardiac output is redistributed at rest away from the cutaneous, renal, and splanchnit beds, with relative preservation of coronary and cerebral flow [a]. Whereas preload influences stroke volume in normal subjects, a change of the filling pressure alters stroke volume only in a small way in severe heart failure. Conversely, stroke volume is largely independent of afterload in normal subjects, whereas in heart failure patients, even slight reductions result in an improvement of the effective cardiac forward volume. Whatever the insult leading to the development of congestive heart failure may be, the heart and
May 29, 1991. The American Journal of Medicine
Volume 90 (suppl 56)
56-19s
SYMPOSIUM
ON IBOPAMINE / BURKART and KIOWSKI
circulation have only limited means to adapt to and compensate for it. The mechanisms considered to be most effective and important are ventricular hypertrophy and neurohumoral changes.
HYPERTROPHY Imposition of a pressure or volume overload on the myocardium increases the wall stress of the involved ventricle and leads to hypertrophy. Although there is some controversy about the initiating factor causing hypertrophy, there is good evidence to suggest that the increased wall stress in itself, and not associated factors such as increased sympathetic stimulation, leads to hypertrophy [3]. Cardiac hypertrophy is generally viewed as a compensatory process that normalizes wall stress. After complete normalization of wall stress due to increased wall thickness, hypertrophy usually stabilizes [4,5]. Pressure overload in general leads to more pronounced hypertrophy, compared to volume overload. Measurements of the contractile state of hypertrophied myocardium have been previously performed on right ventricular myocardium from animal models subjected to pressure overload. Based on such experiments, it was postulated that overloaded hypertrophied myocardium has an inherent defect of contractility [6]. This simple view is no longer accepted. Rather, the functional consequences of cardiac overloading arise from the combined result of type, degree, and duration of overloading; species studied; and, particularly, chamber affected. Thus, it has been shown that the right ventricle is particularly sensitive to pressure overloading, with demonstrable decreases of contractility even before clinical failure ensues [7]. The abnormalities are still reversible before the development of overt failure. Once failure has ensued, it is no longer reversible [8]. In contrast, the left ventricle appears to tolerate both pressure and volume overload for a considerable time before abnormalities of contraction can be detected [9]. The differences between the functional consequences, particularly of pressure overloading, between right and left ventricles are not fully understood but may be the consequence of the normal anatomic function of the ventricles. The right ventricle has been compared to a thin-walled volume and the left ventricle to a thick-walled pressure pump [lo]. Therefore, pressure overload constitutes a qualitative change for the right ventricle, but a quantitative change for the left ventricle. Data obtained in vitro with human myocardium also lead one to question the opinion that the hypertrophied and failing heart has an intrinsic defect of
.5B-20s
May 29, 1991
The American Journal of Medicine
contraction. Feldman et al. [ll] demonstrated in in vitro experiments that trabecular muscle from the hearts of heart transplant recipients with end-stage heart failure developed the same peak isometric tension after stimulation by calcium, acetylstrophanthidin, and forskolin as trabecular muscle from donor hearts. However, the response was less for /3-adrenergic stimulation by isoproterenol, or for inhibition of phosphodiesterase activity by milrinone. Data from Fowler et al. [12] also suggest similar results, since the response to intravenous calcium of the left ventricle, in terms of changes in the maximal rate of rise of ventricular pressure in patients with severely depressed left ventricular function, was similar to that of patients with relatively normal left ventricular function. However, the response to /3-adrenergic stimulation with dobutamine was less in patients with more advanced heart failure. Even though the concept of depressed contractile function in failing myocardium must be seen in a different light, a number of abnormalities associated with hypertrophy and failure at the myocardial and cellular level of the cardiocyte have been studied. 1. The increased mass and work load of hypertrophied myocardium require an increased blood supply. Myocardial blood flow is usually normal at rest, but the vasodilator reserve seems to be diminished during stress in most forms of hypertrophy [13,14]. 2. One of the most consistent findings, also noted in the study by Feldman et al. [ll] in hearts from heart transplant recipients, is a prolongation of the action potential, together with prolongation of the contraction and increased time, until complete relaxation has occurred [15]. It has been argued that this may be due to increased size of the cardiocytes, which may lead to a decrease in the proportion of electrically effective cell surface for calcium entry p.er unit cell volume [16]. Alternatively, this finding may be explained by an inhibition of calcium uptake by, and/or release from, the sarcoplasmic reticulum in patients with heart failure [17]. 3. The production of cyclic adenosine monophosphate (CAMP) by hypertrophied and failing cardiocytes has also received a great deal of attention. The contractile response of failing myocardium to p-adrenergic stimulation by isoproterenol is subnormal [11,12]. Since the response to direct stimulation of the catalytic unit of adenylate cyclase by forskolin remained unchanged [ll], the reduced response to isoproterenol probably can be attributed to a deficient P-adrenoceptor-mediated CAMP production. This contention is supported by data
Volume 90 (suppl 58)
SYMPOSIUM
demonstrating a down-regulation of the number of p-adrenergic adrenoceptors in the failing myocardium [12]. This effect was pronounced for the P-adrenoceptor, leading to a preponderance of the Pa-adrenoceptors, upon whose stimulation the failing myocardium seems to depend to a greater degree than does normal myocardium [HI. A defect of p-adrenoceptor-mediated sympathetic support may be an important factor for the depressed cardiac function in human congestive heart failure. 4. An altered myosine-adenosine triphosphatase composition of the failing myocardium has been described in a rat model [19,20], with a shift of the isoforms of this enzyme toward a slower, less active form. This effect seems to be species specific and probably irrelevant in heart failure patients, since myocardium in normal human subjects already contains mostly the V3 isoform of the enzyme.
NEUROHUMORALCHANGES Sympathetic Activity
Activation of the sympathetic nervous system in congestive heart failure results from unloading of arterial baroreceptors by reduced blood pressure or stroke volume. Increased efferent discharge of sympathetic neurons [21-231 leads to increased heart rate, contractility, and peripheral vasoconstriction. In principle these changes are appropriate for maintaining vital organ function; nevertheless, peripheral vasoconstriction also increases afterload with its detrimental effects on ventricular performance. Renin-Angiotensin-Aldosterone
System
The role of the renin-angiotensin-aldosterone system has been also thoroughly studied [24-261. Increased activity of this system and stimulation of antidiuretic hormone release through a central action of angiotensin II lead to volume retention, which is thought to be beneficial for the augmentation of cardiac performance, using the Frank-Starling mechanism. The peripheral vasoconstrictor effects of angiotensin II also lead to peripheral vasoconstriction; similar to increased sympathetic nervous system activity, they lead to increased afterload, with its potential for further deterioration of cardiac performance. The timing of activation of this system during development of heart failure is not clear, but recent studies in animal models [27] and in humans [28] suggest that it may only be activated acutely and during more advanced stages of heart failure. Much of the elevation seen in congestive heart failure may be due to the effects of eommonly prescribed diuretics. Peripheral resistance
ON IBOPAMINE / BURKART and KIOWSKI
may be directly dependent on angiotensin-mediated vasoconstriction in patients with advanced disease, while in patients with milder degrees of cardiac dysfunction, vasoconstriction may be rendered dependent by administration of diuretics. Atrial Natriuretic Peptide
Another humoral factor that has attracted attention is the atria1 natriuretic peptide (ANP) or factor [29]. ANP is secreted in response to atria1 distention or stretch. This has been documented in normal human subjects undergoing water immersion [30] or volume loading [28], and also in patients with acute atria1 distension due to atria1 fibrillation or supraventricular tachycardia [31]. This stimulatory pathway also seems to be operative in congestive heart failure patients in whom plasma ANP levels are elevated [32] and directly proportional to right atria1 filling pressures [33]. Nonetheless, its role in congestive heart failure remains to be defined.
DETERMINANTSOF EXERCISECAPACITY The main symptoms that patients experience and that subjectively limit exercise capacity are pulmonary congestion, breathlessness, and muscle fatigue. Even though congestion has lent its name to the clinical syndrome, it should be recognized that this symptom is no longer as prominent [34] because of the availability of modern drug therapy, such as diuretics, venodilators, nitrates, or mixed vasodilators such as the angiotensin-converting enzyme (ACE) inhibitors. Dyspnea is thought to result from stimulation ‘of pulmonary, juxtacapillary “‘J” receptors, brought on by pulmonary congestion and decreased lung compliance. Lipkin et al. [35] have shown that maximal oxygen consumption as an objective measure of exercise capacity did not correlate with maximal pulmonary capillary wedge pressure during exercise, even though patients stopped performing exercise in this partieular test due to dyspnea. Similarly, Fink et al. [36] found no increase in exercise capacity in congestive heart failure patients after acutely lowering their filling pressures either by ACE inhibition or dobutamine infusions. Bayliss et al. [37] could not find a relationship between an index of left ventricular filling pressure and exercise duration, either during control conditions or when the filling pressure was lowered chronically by captopril or prazosin. In contrast to acute heart failure, where dyspnea is clearly related to increased intrapulmonary pressure, other factors seem to influence this symptom to a great extent in chronic congestive heart failure.
May 29, 1991
The American Journal of Medicine
Volume 90 (suppl 56)
58-m
SYMPOStUM
ON IBOPAMINE / BURKART and KIOWSKI
-
There is some controversy concerning the underlying mechanisms of reduced muscle perfusion durin,q exercise. It is believed that the decreased vasodilator capacity of congestive heart failure patients is due to a defect of the resistance vessels, possibly due to increased stiffness arising from increased water and sodium contents [a]. This view is supported by an elegant study comparing leg hemodynamic changes during one-leg and two-leg exercise. LeJemtel et al. [38] showed that femoral vein blood flow during two-leg exercise did not increase any more compared with one-leg exercise. Since patients were able to increase maximal oxygen uptake during two-leg exercise over values achieved during one-leg exercise, limitation of cardiac output was considered not to be the cause of reduced vasodilator response during exercise. Although the importance of reduced nutritional flow to skeletal muscle is well recognized, the underlying mechanisms leading to muscle fatigue remain to be precisely defined. Also, the effects of therapy on these important determinants of exercise capacity will certainly receive more attention as our knowledge of that subject increases.
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Volume 90 (suppl 56)