/
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Congestive Heart Failure in Coronary Artery Disease TSUNG 0. CHENG, M.D., Washington, DC.
Congestive heart failure (CHF) affects approximately 1% of the United States population and its incidence continues to increase. Next to hypertension, coronary artery disease (CAD) is the second most frequent cause of CHF. Important distinction should be made between systolic dysfunction and diastolic dysfunction in CAD. The diagnostic and therapeutic challenges posed by both have sthnulated much investigation into the pathophysiologic mechanisms involved and have led to innovative pharmacologic interventions to forestall progression of the disease. The challenge in the 1990s is prevention. In the meantime, results of completed and ongoing randomixed controlled trials will determine the most effective forms of therapy, which will not only improve symptoms but also hopefully extend survival
PREVALENCE ongestive heart failure (CHF) is increasing in prevalence in the United States (Figure 1) [l]. Despite a decline in mortality from cardiovascular disease over the last four decades [2], CHF remains a major cause of morbidity and mortality, afflicting 4 million patients and killing 400,000 patients each year, more than 1,000 a day [3]. It is the only cardiovascular disorder that is increasing in prevalence and constitutes the most common cause for hospitalization to medical services in patients over 65 years of age [3,4]. According to the Framingham study, coronary artery disease (CAD) is the second most common cause of CHF, next to hypertension [5]. However, in the near future, CAD will become the major cause of CHF in view of the increasing emphasis on early treatment of hypertension and effectiveness of antihypertensive therapy. The two factors accounting for the growing prevalence of CHF in CAD seem to be the increasing average age of the population and
C
From the Division of Cardiology, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, D.C. Requests for reprints should be addressed to Tsung 0. Cheng, M.D., Division of Cardiology, Department of Medicine, The George Washington University Medical Center, 2150 Pennsylvania Avenue, N.W., Washington, DC. 20037. Manuscript submitted March 15. 1991, and accepted in revised form July 2. 1991.
the longer survival of persons with CAD. The aging of the population is certainly an important factor, since the prevalence of CHF approximately doubles for each succeeding decade from the fourth to the eighth decade of life [6]. CHF used to be considered rare in CAD, the more common manifestations of which were angina pectoris and myocardial infarction [7]. However, with more accurate diagnosis and more effective management, patients with angina and/or myocardial infarction are treated sooner and better and survive longer. These changes in the epidemiologic nature of CAD would lead to a higher prevalence of patients with chronic CAD in the population and thus more cases of CHF. PATHOPHYSIOLOGY CAD can cause or appear as CHF through one or more of 12 mechanisms (Table I) [7]. Most of these are direct consequences of acute or chronic obstructive diseases of the coronary arteries (e.g., acute myocardial infarction, acute reversible ischemia, and ischemic cardiomyopathy) or complications of myocardial infarction (e.g., right ventricular dysfunction, cardiogenic shock, acute mitral regurgitation, ventricular septal or free wall rupture, and ventricular aneurysm), while others represent related phenomena (e.g., coexistent diseases and iatrogenesis) or an incorrect diagnosis (e.g., pseudoheart failure). While the readers of this journal are referred to my original article [7] for a detailed discussion of each mechanism, current discussion will concentrate on three important modern concepts. Infarct Extension, Infarct Expansion, and Left Ventricular Remodeling Hutchins and Bulkley [8] were the first to draw attention to the difference between myocardial infarct extension (histologically more recent foci of contraction band necrosis around an infarct) and infarct expansion (acute dilatation and thinning of the area of infarction not explained by additional myocardial necrosis). Whereas infarct extension results in an actual increase in the total mass of infarcted tissue, infarct expansion causes an increase in the functional size of an infarct by increasing infarct segment length without increasing the overall mass of the infarct [9]. Both infarct extension and infarct expansion are events early in the course of acute myocardial infarction with serious immediate and long-term consequences.
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CONGESTIVE HEART FAILURE IN CAD / CHENG TABLE I Mechanisms
of Congestive
Heart Failure
in CoronaryArtery Disease*
Acute myocardial infarction Acute reversible ischemia Right ventricular dysfunction Cardiogenic shock Acute mitral regurgitation Ventricular septal perforation Cardiac free wall rupture lschemic cardiomyopathy Ventricular aneurysm Coexisting disease latrogenesis Pseudo-heart failure *Modified from Cheng171.
Figure congestive National produced
1. Age-adjusted
annual hospital discharge rates for heart failure from U.S. hospitals, 1973 to 1986, Hospital Discharge Survey, by sex-race group. (Rewith permission from [l].)
Myocardial infarct expansion, with resultant left ventricular dilatation and remodeling [lo], occurs in 35% to 45% of anterior transmural myocardial infarctions and to a lesser extent in infarctions at other sites [9]. Infarct expansion and left ventricular remodeling have an adverse effect on infarct structure and function for several reasons. Functional infarct size is increased because of infarct segment lengthening, and expansion results in overall ventricular dilatation. Thus, patients with expansion of an infarct have poorer exercise tolerance, more symptoms of CHF, and greater early and late mortality than those without expansion. Infarct rupture and late aneurysm formation are two additional structural consequences of infarct expansion. Experimental and clinical data suggest that the incidence and severity of expansion can be modified by interventions (see below). Stunned and Hibernating Myocardium Until recently, it was generally assumed that left ventricular dysfunction in patients with CAD was always due to myocardial infarction. Viable myocytes were presumed to be normally contractile, whereas infarcted myocytes were not. However, it is now apparent that viable myocytes that were rendered ischemic may demonstrate relatively prolonged alterations in function, and that these alterations may contribute to overall left ventricular dysfunction. Two such altered states of viable myocytes include the “stunned myocardium” [ll] and the “hibernating myocardium” [12,13]. Stunned myocardium, as described by Braunwald and Kloner [11,14], refers to viable myocardium that has beensalvaged by coronary reperfusion, yet exhibits prolonged but transient postischemic contractile 410
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dysfunction, lasting hours to days. Hibernating myocardium, as described by Bahimhla [12], refers to ischemic myocardium (that is supplied by a stenotic coronary artery) in which the cells remain viable but contractility is chronically depressed. The depressed contractile function may actually be a protective mechanism whereby the left ventricle down-regulates its function to reduce its oxygen demand in the setting of reduced oxygen supply. Although stunned myocardium occurs as an acute event following reperfusion, hibernating myocardium represents chronic left ventricular dysfunction that may persist from months to years. There are other important differences between stunned myocardium and hibernating myocardium (Table II). It is extremely important to recognize myocardial stunning for the clinicians who, when confronted with a patient with a poorly contractile ventricle after relief of ischemia, do not assume incorrectly that it has been irreversibly damaged, but instead treat the stunned myocardium appropriately [ 151. The most important clinical circumstance encountered nowadays is in the patient with acute myocardial infarction in whom reperfusion has been achieved by means of either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA). One should remember that complete recovery of function after relief of ischemia sometimes takes days or even weeks. One should also keep in mind that myocardial stunning is not limited to systolic dysfunction but involves diastolic dysfunction as well [16,17]. Systolic and Diastolic Dysfunction In recent years, clinicians and physiologists alike have re-examined the concepts about the pathophysiology of CHF. It has been reported that as many as one third of patients with CHF have normal resting systolic ventricular function but abnormal diastolic function [18]. Although many of the patients with CHF resulting from CAD have systolic dysfunction [7], there is a significant number of pa-
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TABLE II
Stunned Myocardium Versus Hibernating Myocardium* StunnedMyocardium Origin of term Occurrence Onset Duration Mechanism Ventriculography and positron emission tomography Interrelation Clinical relevance
HibernatingMyocardium
Braunwald & Kloner (1982) After relief of ischemia Acute Hours to days Free radical generation, abnormal calcium homeostasis, excitation-contraction uncoupling Abnormal contractility in the presence of adequate blood flow and adequate or even increased metabolic activity
Rahimtoola (1985) During low flow Chronic Months to years Down-regulation of cardiac function to reduce oxygen demand in response to reduced supply Abnormal contractility in the presence of reduced blood flow and preserved metabolic activity
Areas of hibernating and stunned myocardium may coexist in the same heart Functional improvement may be gradual after recovery from unstable angina or coronary spasm and after successful thrombolysis or coronary angioplasty
May undergo postischemic stunning before full recovery Dysfunction is reversible following coronary artery bypass graft surgery in chronic angina or even in ischemic cardiomyopathy
*Adapted from Kloneret al U41.
tients with CAD in whom left ventricular dysfunction is predominantly diastolic [19,20]. These patients have a normal left ventricular ejection fraction; yet they have impaired diastolic relaxation and filling or even overt pulmonary and/or systemic venous congestion. As a matter of fact, diastolic dysfunction in CAD often precedes systolic dysfunction [21]. Myocardial ischemia and increased calcium loading have been implicated in the genesis of increased left ventricular stiffness [21]. The most common clinical manifestations of CHF, e.g., peripheral edema and pulmonary congestion, therefore may be associated as much with diastolic as with systolic dysfunction. Thus, the concept of diastolic dysfunction as a mechanism underlying CHF is similar to the description of “backward failure” as originally proposed by Hope [22] in 1832. Similarly, “forward failure,” expounded in 1913 by Mackenzie [23], can be equated to systolic dysfunction. Although backward failure and forward failure hypotheses, two seemingly opposite views that led to lively controversy during the first half of this century, were later reconciled to be both present in most patients with CHF, now the pendulum once again swings in the direction whereby diastolic dysfunction can occur without systolic dysfunction [24]. Treatment for diastolic dysfunction in CAD is quite different from that for systolic dysfunction (see below).
MANAGEMENT Conventional Medical Therapy of CHF in CAD The last quarter of a century has witnessed several major advances in our understanding of the mechanisms and therapy of CHF due to a.ll causes including CAD. In the mid-1960s, potent new diuretics revolutionized the management of patients with CHF and fluid retention. In the mid-197Os, the concept of vasodilator therapy gained widespread acceptance. In the mid-19809, newer inotropic agents and angiotensin-
I = lnotropic
I
Left Ventricular
Filling
Agent
.
Pressure
Figure 2. Effects of inotropic agents, vasodilators, and diuretics, alone or in combination, on left ventricular function in congestive heart failure. (Reproduced with permission from Parmley WW. Pathophysiology and current therapy of congestive heart failure. J Am Coil Cardiol 1989; 13: 771-85.)
converting enzyme (ACE) inhibitors were introduced. Alone or in combination, the three D’s-diuretics, dilators, and digitalis or digitalis-like drugs-are usually effective not only in relieving the symptoms of CHF but also in improving the hemodynamic status (Figure 2). Unfortunately, despite these advances, most patients with CHF remain disabled and die of their underlying disease. It is therefore obvious that strategy for future investigation of the management of CHF needs to incorporate a different approach based on some of the modern concepts discussed in the Pathophysiology section. Prevention of Infarct Expansion and Left Ventricular Dilatation Infarct expansion begins in the early postinfarction period; therefore it seems possible that intervention applied early in the postinfarction period might prevent infarct expansion. Neither diuretics nor digitalis preparations seem to be very effective in this regard [25]. Recently, efforts have been concentrated on the early use of ACE inhibitors following
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myocardial infarction to forestall left ventricular remodeling, limit progressive left ventricular dilatation, and thus prevent CHF [26-301. The cardioprotective effect of captopril, which like glut&Gone, a well-recognized free radical scavenger [31], also contains a sulfhydryl group, has been further attributed to its capacity to act also as a free radical scavenger [32,33]; there is recently published evidence for enhanced free radical activity in CHF secondary to CAD 134,351. In addition, experimental studies in rats [36] showed the ACE inhibitors to reduce intimal proliferation and thus be of possible benefit in reducing or preventing coronary atherosclerosis and in preventing restenosis after PTCA [7]. The preliminary results from both animal experiments and human trials pointing to a potentially beneficial effect of treatment with ACE inhibitors in the prevention of left ventricular dilatation were so encouraging that several large multicenter studies were carried out subsequently. One of these has just been completed. The Veterans Administration Heart Failure Trial II study [37] demonstrated a significant lower 2-year mortality and a borderline lower 4-year mortality in patients, most of whom were in New York Heart Association class II and III, treated with enalapril than in patients treated with combined hydralaxine-isosorbide dinitrate therapy. The other two larger multicenter studies are the Studies of Left Ventricular Dysfunction (SOLVD) [38], which include patients with an ejection fraction equal to or less than 35% treated with enalapril versus placebo, and the Survival and Ventricular Enlargement (SAVE) study [7], which compares the effect of captopril with placebo in patients with left ventricular dysfunction after myocardial infarction. The treatment arm of the SOLVD trial also showed that the addition of enalapril to conventional therapy significantly reduced mortality and hospitalization for heart failure in patients with chronic CHF and low ejection fractions [38]. The results of the SAVE study should be available by early 1992. In addition to these studies, the effect on mortality of ACE inhibitors administered early following myocardial infarction is currently being evaluated in several large multicenter studies: the CONSENSUS-2 study with enalapril, and the Chinese and ISIS-4 studies with captopril [39]. Phosphodiesterase Inhibitors The initial enthusiasm for the phosphodiesterase inhibitors, for example, amrinone, milrinone, enoximone, and others, as newer inotropic agents based on reports of short-term hemodynamic improvement has largely been replaced now by controversy and skepticism as to their long-term effects on survival and the safety of these agents. The study results of the Prospective Randomized Mihinone Survival 412
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Evaluation (PROMISE) showed that oral milrinone has a deleterious effect on the survival of patients with advanced CHF when given with a diuretic, digoxin, and an ACE inhibitor [40]. A multicenter trial of oral enoximone in patients with moderate to moderately severe CHF showed not only a lack of benefit compared with placebo but also a worse survival rate [41]. Therefore, enoximone, and probably other phosphodiesterase inhibitors, have a limited role in the management of chronic CHF [42]. Patency of Infarct-Related Artery and Left Ventricular Dilatation The advent of thrombolytic reperfusion (and/or acute PTCA) for acute myocardial infarction, as well as the observation in the study by Pfeffer et al [26] in humans, raises the question of the possible role that patency of the infarct-related artery may play in preventing or ameliorating left ventricular dilatation. Although some investigators [43-46] showed that late ventricular dilatation following acute myocardial infarction may be largely prevented by early successful thrombolytic reperfusion, others [10,47,43] found no difference in the prevalence of left ventricular dilatation and/or CHF between successful and unsuccessful thrombolysis or between early and late thrombolysis. Therefore, at present, the importance of infarct-related artery perfusion, the time at which this needs to be present in order to limit ventricular dilatation, and the mechanism whereby it may limit ventricular dilatation are unresolved and under active investigation [49]. Treatment of Left Ventricular Diastolic Dysfunction Conventional therapy directed at improving systolic performance of the left ventricle has little place in the management of CHF due to diastolic dysfunction. Indeed, arterial vasodilators and inotropic agents, including digitalis, should be avoided [50]. Left ventricular diastolic dysfunction in CAD is best managed with fi-blockers, calcium channel blockers, or both. P-blockers slow the heart rate and improve the balance between myocardial oxygen supply and demand and, indirectly, they may increase the myocardial relaxation rate. Myocardial ischemia and increased calcium loading have been implicated in the genesis of increased left ventricular stiffness; consequently, the calcium channel blockers should improve left ventricular diastolic function [21]. Although diuretics are effective in reducing pulmonary and systemic venous congestion, care must be taken to avoid excessive preload reduction. Because of the steep (stiff) diastolic pressure-volume curve, large changes in diastolic pressure can be achieved with only modest changes in volume. Nitrates are useful preload-reducing agents, and they have the additional benefit of pro-
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30
-
25
-
20
-
15
-
10
-
1.31
1.59
1.78
Figure
4. Cumulative incidence of congestive heart failure (CHF) by prior history (Hx) and by treatment group in the first 30 days of myocardial infarction in patients from the Beta-Blocker Heart Attack Trial. (Reproduced with permission from [53].)
Risk of CHF from Antiarrhythmic Arrhythmia Suppression B/PM
M
LVEF > 0.30
LVEF < 0.30
NYHA I AND II
NYHA III AND IV
0
I+
0 o-i+
0 I+
2+
4+
I-B Tocainide Mexiletine
0 0
0 0
I-C Encainide Flecainide Propafenone
0 I+ I+
4+ 3+
II Beta Blockers
l+
3+
III Amiodarone
O-l+
I+
5'
Drug
Class
o-
EF: n=
44.35%
34-25%
470
277
a
DILTIAZEM
1270 PLACEBO
Figure
.z 25% 142
I Moricizine
m
3. Diltiazem-associated
increase in late congestive heart failure (CHF) is progressively larger as baseline ejection fraction (EF) is reduced, as shown for 2,159 patients with baseline measurement of EF in the Multicenter Diltiazem Postinfarction Trial. Number of patients with CHF (numerator) and total number in each subset (denominator) are displayed above each bar, and number of patients in given group is indicated below corresponding pair of bars. At top of figure, value for each group shows percent of patients with late CHF among those given diltiazem (D) divided by percent of patients with late CHF among those given placebo (P). (Reproduced with permission from [52].)
viding anti-ischemic therapy. Thus, fl-blockers, calcium channel blockers, and nitrates are the three essential ingredients in the treatment, and even prevention, of diastolic dysfunction in CAD [51]. Primum Non Nocere CHF may result not only from failure to institute an appropriate therapeutic agent but also from the very same drugs that were frequently prescribed for patients with CAD. For example, although diltiazem is effective in suppressing myocardial ischemia in patients with CAD, it can also increase the risk of CHF in those patients with impaired left ventricular function evident soon after infarction, as shown by the Multicenter Diltiaxem Postinfarction Trial (MDPIT)[52] analysis (Figure 3). Similarly, the Beta-Blocker Heart Attack Trial (BHAT) showed a two- to three-fold increase in the frequency of late
Drugs in the Cardiac Trial (CAST)
HCI
I-A Quinidine Procainamide Disopyramide
I+
Figure 5. Increased risk of congestive heart failure (CHF) associated with the use of various antiarrhythmic drugs, especially in those patients in New York Heart Association (NYHA) class III and IV and with left ventricular ejection fraction (LVEF) less than 30%, in the Cardiac Arrhythmia Suppression Trial. B = benign ventricular arrhythmia class; PM = potentially malignant ventricular arrhythmia class; M = malignant arrhythmia class. (Modified with permission from [56].)
CHF among patients with previous myocardial infarction, history of CHF before the index infarction, enlarged cardiothoracic ratio, use of digitalis, and other clinical indicators of left ventricular dysfunction (Figure 4) [53]. The traditional therapeutic combination of digitalis and diuretics used in chronic CHF may not only be inappropriate for use
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CONGESTIVE HEART FAILURE IN CAD / CHENG CORONARY ARTERY DISEASE QROWTH OF KNOWLEDQE
, ,R-“iM o*,.t* ca~lolcw
Figure 6. Growth of knowledge in coronary artery disease from 1780 to 1990 and beyond, being exponential in the last decade.
in acute cardiac failure complicating acute myocardial infarction but may even be detrimental. A normovolemic individual who develops acute myocardial infarction may develop acute pulmonary congestion from fluid redistribution from the vascular space to the lungs, resulting in relative hypovolemia [54]. Diuretic therapy may precipitate hypotension, which may be deleterious during acute myocardial infarction. The use of a long-acting inotropic agent such as digoxin for cardiac failure in acute myocardial infarction, which in most cases is transient, is also undesirable and may increase the incidence of sudden death [55]. Finally, among the antiarrhythmic drugs that were frequently prescribed for patients with CAD, most can cause CHF, especially in those in New York Heart Association class III and IV and with left ventricular ejection fraction less than 30% as shown in the Cardiac Arrhythmia Suppression Trial (CAST) (Figure 5) [56]. Therapy with antiarrhythmic drugs, especially class I drugs, in patients with CHF is also associated with an increased risk of sudden death [57].
CONCLUSION CHF remains a major public health problem. Next to hypertension, CAD is the second most common cause of CHF. Despite our increased knowledge of the mechanisms of CHF in CAD, improved techniques in diagnosing CHF earlier in the course of CAD, and expanded therapeutic armamentarium in managing patients with CHF due to CAD, most patients remain disabled and die from their disease. It is ironic that, although the therapies for such manifestations of CAD as angina pectoris, arrhythmias, and acute myocardial infarction have vastly improved in the past 20 years, our ability to manage major derangements of myocardial function has made relatively little progress. Although the contin414
October 1991 The American Journal of Medicine
ued search for better therapeutic measures, aimed at improvement of myocardial contractile function without adversely affecting the myocardial oxygen supply/demand balance, will fill a much needed gap in the management of patients with CAD complicated by CHF, the most effective form of treatment lies in prevention of CHF from developing in the first place. Since some of the complications of CAD resulting in CHF (Table I) are inevitable, attention should best be directed at prevention of the underlying condition that leads to the occurrence of CHF, namely, CAD itself. Decades of progress have witnessed many advances in our knowledge of CAD and management of its sequelae, but the challenge for us in the 1990s is the prevention of CAD (Figure 6).
ACKNOWLEDGMENT I am grateful manuscript.
to Dr. Robert Kloner for his helpful suggestions
concerning
this
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Congestive Heart Failure in Coronary Artery Disease TSUNG 0. CHENG, M.D., Washington, DC.
Congestive heart failure (CHF) affects approximately 1% of the United States population and its incidence continues to increase. Next to hypertension, coronary artery disease (CAD) is the second most frequent cause of CHF. Important distinction should be made between systolic dysfunction and diastolic dysfunction in CAD. The diagnostic and therapeutic challenges posed by both have sthnulated much investigation into the pathophysiologic mechanisms involved and have led to innovative pharmacologic interventions to forestall progression of the disease. The challenge in the 1990s is prevention. In the meantime, results of completed and ongoing randomixed controlled trials will determine the most effective forms of therapy, which will not only improve symptoms but also hopefully extend survival
PREVALENCE ongestive heart failure (CHF) is increasing in prevalence in the United States (Figure 1) [l]. Despite a decline in mortality from cardiovascular disease over the last four decades [2], CHF remains a major cause of morbidity and mortality, afflicting 4 million patients and killing 400,000 patients each year, more than 1,000 a day [3]. It is the only cardiovascular disorder that is increasing in prevalence and constitutes the most common cause for hospitalization to medical services in patients over 65 years of age [3,4]. According to the Framingham study, coronary artery disease (CAD) is the second most common cause of CHF, next to hypertension [5]. However, in the near future, CAD will become the major cause of CHF in view of the increasing emphasis on early treatment of hypertension and effectiveness of antihypertensive therapy. The two factors accounting for the growing prevalence of CHF in CAD seem to be the increasing average age of the population and
C
From the Division of Cardiology, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, D.C. Requests for reprints should be addressed to Tsung 0. Cheng, M.D., Division of Cardiology, Department of Medicine, The George Washington University Medical Center, 2150 Pennsylvania Avenue, N.W., Washington, DC. 20037. Manuscript submitted March 15. 1991, and accepted in revised form July 2. 1991.
the longer survival of persons with CAD. The aging of the population is certainly an important factor, since the prevalence of CHF approximately doubles for each succeeding decade from the fourth to the eighth decade of life [6]. CHF used to be considered rare in CAD, the more common manifestations of which were angina pectoris and myocardial infarction [7]. However, with more accurate diagnosis and more effective management, patients with angina and/or myocardial infarction are treated sooner and better and survive longer. These changes in the epidemiologic nature of CAD would lead to a higher prevalence of patients with chronic CAD in the population and thus more cases of CHF. PATHOPHYSIOLOGY CAD can cause or appear as CHF through one or more of 12 mechanisms (Table I) [7]. Most of these are direct consequences of acute or chronic obstructive diseases of the coronary arteries (e.g., acute myocardial infarction, acute reversible ischemia, and ischemic cardiomyopathy) or complications of myocardial infarction (e.g., right ventricular dysfunction, cardiogenic shock, acute mitral regurgitation, ventricular septal or free wall rupture, and ventricular aneurysm), while others represent related phenomena (e.g., coexistent diseases and iatrogenesis) or an incorrect diagnosis (e.g., pseudoheart failure). While the readers of this journal are referred to my original article [7] for a detailed discussion of each mechanism, current discussion will concentrate on three important modern concepts. Infarct Extension, Infarct Expansion, and Left Ventricular Remodeling Hutchins and Bulkley [8] were the first to draw attention to the difference between myocardial infarct extension (histologically more recent foci of contraction band necrosis around an infarct) and infarct expansion (acute dilatation and thinning of the area of infarction not explained by additional myocardial necrosis). Whereas infarct extension results in an actual increase in the total mass of infarcted tissue, infarct expansion causes an increase in the functional size of an infarct by increasing infarct segment length without increasing the overall mass of the infarct [9]. Both infarct extension and infarct expansion are events early in the course of acute myocardial infarction with serious immediate and long-term consequences.
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CONGESTIVE HEART FAILURE IN CAD / CHENG TABLE I Mechanisms
of Congestive
Heart Failure
in CoronaryArtery Disease*
Acute myocardial infarction Acute reversible ischemia Right ventricular dysfunction Cardiogenic shock Acute mitral regurgitation Ventricular septal perforation Cardiac free wall rupture lschemic cardiomyopathy Ventricular aneurysm Coexisting disease latrogenesis Pseudo-heart failure *Modified from Cheng171.
Figure congestive National produced
1. Age-adjusted
annual hospital discharge rates for heart failure from U.S. hospitals, 1973 to 1986, Hospital Discharge Survey, by sex-race group. (Rewith permission from [l].)
Myocardial infarct expansion, with resultant left ventricular dilatation and remodeling [lo], occurs in 35% to 45% of anterior transmural myocardial infarctions and to a lesser extent in infarctions at other sites [9]. Infarct expansion and left ventricular remodeling have an adverse effect on infarct structure and function for several reasons. Functional infarct size is increased because of infarct segment lengthening, and expansion results in overall ventricular dilatation. Thus, patients with expansion of an infarct have poorer exercise tolerance, more symptoms of CHF, and greater early and late mortality than those without expansion. Infarct rupture and late aneurysm formation are two additional structural consequences of infarct expansion. Experimental and clinical data suggest that the incidence and severity of expansion can be modified by interventions (see below). Stunned and Hibernating Myocardium Until recently, it was generally assumed that left ventricular dysfunction in patients with CAD was always due to myocardial infarction. Viable myocytes were presumed to be normally contractile, whereas infarcted myocytes were not. However, it is now apparent that viable myocytes that were rendered ischemic may demonstrate relatively prolonged alterations in function, and that these alterations may contribute to overall left ventricular dysfunction. Two such altered states of viable myocytes include the “stunned myocardium” [ll] and the “hibernating myocardium” [12,13]. Stunned myocardium, as described by Braunwald and Kloner [11,14], refers to viable myocardium that has beensalvaged by coronary reperfusion, yet exhibits prolonged but transient postischemic contractile 410
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dysfunction, lasting hours to days. Hibernating myocardium, as described by Bahimhla [12], refers to ischemic myocardium (that is supplied by a stenotic coronary artery) in which the cells remain viable but contractility is chronically depressed. The depressed contractile function may actually be a protective mechanism whereby the left ventricle down-regulates its function to reduce its oxygen demand in the setting of reduced oxygen supply. Although stunned myocardium occurs as an acute event following reperfusion, hibernating myocardium represents chronic left ventricular dysfunction that may persist from months to years. There are other important differences between stunned myocardium and hibernating myocardium (Table II). It is extremely important to recognize myocardial stunning for the clinicians who, when confronted with a patient with a poorly contractile ventricle after relief of ischemia, do not assume incorrectly that it has been irreversibly damaged, but instead treat the stunned myocardium appropriately [ 151. The most important clinical circumstance encountered nowadays is in the patient with acute myocardial infarction in whom reperfusion has been achieved by means of either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA). One should remember that complete recovery of function after relief of ischemia sometimes takes days or even weeks. One should also keep in mind that myocardial stunning is not limited to systolic dysfunction but involves diastolic dysfunction as well [16,17]. Systolic and Diastolic Dysfunction In recent years, clinicians and physiologists alike have re-examined the concepts about the pathophysiology of CHF. It has been reported that as many as one third of patients with CHF have normal resting systolic ventricular function but abnormal diastolic function [18]. Although many of the patients with CHF resulting from CAD have systolic dysfunction [7], there is a significant number of pa-
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TABLE II
Stunned Myocardium Versus Hibernating Myocardium* StunnedMyocardium Origin of term Occurrence Onset Duration Mechanism Ventriculography and positron emission tomography Interrelation Clinical relevance
HibernatingMyocardium
Braunwald & Kloner (1982) After relief of ischemia Acute Hours to days Free radical generation, abnormal calcium homeostasis, excitation-contraction uncoupling Abnormal contractility in the presence of adequate blood flow and adequate or even increased metabolic activity
Rahimtoola (1985) During low flow Chronic Months to years Down-regulation of cardiac function to reduce oxygen demand in response to reduced supply Abnormal contractility in the presence of reduced blood flow and preserved metabolic activity
Areas of hibernating and stunned myocardium may coexist in the same heart Functional improvement may be gradual after recovery from unstable angina or coronary spasm and after successful thrombolysis or coronary angioplasty
May undergo postischemic stunning before full recovery Dysfunction is reversible following coronary artery bypass graft surgery in chronic angina or even in ischemic cardiomyopathy
*Adapted from Kloneret al U41.
tients with CAD in whom left ventricular dysfunction is predominantly diastolic [19,20]. These patients have a normal left ventricular ejection fraction; yet they have impaired diastolic relaxation and filling or even overt pulmonary and/or systemic venous congestion. As a matter of fact, diastolic dysfunction in CAD often precedes systolic dysfunction [21]. Myocardial ischemia and increased calcium loading have been implicated in the genesis of increased left ventricular stiffness [21]. The most common clinical manifestations of CHF, e.g., peripheral edema and pulmonary congestion, therefore may be associated as much with diastolic as with systolic dysfunction. Thus, the concept of diastolic dysfunction as a mechanism underlying CHF is similar to the description of “backward failure” as originally proposed by Hope [22] in 1832. Similarly, “forward failure,” expounded in 1913 by Mackenzie [23], can be equated to systolic dysfunction. Although backward failure and forward failure hypotheses, two seemingly opposite views that led to lively controversy during the first half of this century, were later reconciled to be both present in most patients with CHF, now the pendulum once again swings in the direction whereby diastolic dysfunction can occur without systolic dysfunction [24]. Treatment for diastolic dysfunction in CAD is quite different from that for systolic dysfunction (see below).
MANAGEMENT Conventional Medical Therapy of CHF in CAD The last quarter of a century has witnessed several major advances in our understanding of the mechanisms and therapy of CHF due to a.ll causes including CAD. In the mid-1960s, potent new diuretics revolutionized the management of patients with CHF and fluid retention. In the mid-197Os, the concept of vasodilator therapy gained widespread acceptance. In the mid-19809, newer inotropic agents and angiotensin-
I = lnotropic
I
Left Ventricular
Filling
Agent
.
Pressure
Figure 2. Effects of inotropic agents, vasodilators, and diuretics, alone or in combination, on left ventricular function in congestive heart failure. (Reproduced with permission from Parmley WW. Pathophysiology and current therapy of congestive heart failure. J Am Coil Cardiol 1989; 13: 771-85.)
converting enzyme (ACE) inhibitors were introduced. Alone or in combination, the three D’s-diuretics, dilators, and digitalis or digitalis-like drugs-are usually effective not only in relieving the symptoms of CHF but also in improving the hemodynamic status (Figure 2). Unfortunately, despite these advances, most patients with CHF remain disabled and die of their underlying disease. It is therefore obvious that strategy for future investigation of the management of CHF needs to incorporate a different approach based on some of the modern concepts discussed in the Pathophysiology section. Prevention of Infarct Expansion and Left Ventricular Dilatation Infarct expansion begins in the early postinfarction period; therefore it seems possible that intervention applied early in the postinfarction period might prevent infarct expansion. Neither diuretics nor digitalis preparations seem to be very effective in this regard [25]. Recently, efforts have been concentrated on the early use of ACE inhibitors following
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myocardial infarction to forestall left ventricular remodeling, limit progressive left ventricular dilatation, and thus prevent CHF [26-301. The cardioprotective effect of captopril, which like glut&Gone, a well-recognized free radical scavenger [31], also contains a sulfhydryl group, has been further attributed to its capacity to act also as a free radical scavenger [32,33]; there is recently published evidence for enhanced free radical activity in CHF secondary to CAD 134,351. In addition, experimental studies in rats [36] showed the ACE inhibitors to reduce intimal proliferation and thus be of possible benefit in reducing or preventing coronary atherosclerosis and in preventing restenosis after PTCA [7]. The preliminary results from both animal experiments and human trials pointing to a potentially beneficial effect of treatment with ACE inhibitors in the prevention of left ventricular dilatation were so encouraging that several large multicenter studies were carried out subsequently. One of these has just been completed. The Veterans Administration Heart Failure Trial II study [37] demonstrated a significant lower 2-year mortality and a borderline lower 4-year mortality in patients, most of whom were in New York Heart Association class II and III, treated with enalapril than in patients treated with combined hydralaxine-isosorbide dinitrate therapy. The other two larger multicenter studies are the Studies of Left Ventricular Dysfunction (SOLVD) [38], which include patients with an ejection fraction equal to or less than 35% treated with enalapril versus placebo, and the Survival and Ventricular Enlargement (SAVE) study [7], which compares the effect of captopril with placebo in patients with left ventricular dysfunction after myocardial infarction. The treatment arm of the SOLVD trial also showed that the addition of enalapril to conventional therapy significantly reduced mortality and hospitalization for heart failure in patients with chronic CHF and low ejection fractions [38]. The results of the SAVE study should be available by early 1992. In addition to these studies, the effect on mortality of ACE inhibitors administered early following myocardial infarction is currently being evaluated in several large multicenter studies: the CONSENSUS-2 study with enalapril, and the Chinese and ISIS-4 studies with captopril [39]. Phosphodiesterase Inhibitors The initial enthusiasm for the phosphodiesterase inhibitors, for example, amrinone, milrinone, enoximone, and others, as newer inotropic agents based on reports of short-term hemodynamic improvement has largely been replaced now by controversy and skepticism as to their long-term effects on survival and the safety of these agents. The study results of the Prospective Randomized Mihinone Survival 412
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Evaluation (PROMISE) showed that oral milrinone has a deleterious effect on the survival of patients with advanced CHF when given with a diuretic, digoxin, and an ACE inhibitor [40]. A multicenter trial of oral enoximone in patients with moderate to moderately severe CHF showed not only a lack of benefit compared with placebo but also a worse survival rate [41]. Therefore, enoximone, and probably other phosphodiesterase inhibitors, have a limited role in the management of chronic CHF [42]. Patency of Infarct-Related Artery and Left Ventricular Dilatation The advent of thrombolytic reperfusion (and/or acute PTCA) for acute myocardial infarction, as well as the observation in the study by Pfeffer et al [26] in humans, raises the question of the possible role that patency of the infarct-related artery may play in preventing or ameliorating left ventricular dilatation. Although some investigators [43-46] showed that late ventricular dilatation following acute myocardial infarction may be largely prevented by early successful thrombolytic reperfusion, others [10,47,43] found no difference in the prevalence of left ventricular dilatation and/or CHF between successful and unsuccessful thrombolysis or between early and late thrombolysis. Therefore, at present, the importance of infarct-related artery perfusion, the time at which this needs to be present in order to limit ventricular dilatation, and the mechanism whereby it may limit ventricular dilatation are unresolved and under active investigation [49]. Treatment of Left Ventricular Diastolic Dysfunction Conventional therapy directed at improving systolic performance of the left ventricle has little place in the management of CHF due to diastolic dysfunction. Indeed, arterial vasodilators and inotropic agents, including digitalis, should be avoided [50]. Left ventricular diastolic dysfunction in CAD is best managed with fi-blockers, calcium channel blockers, or both. P-blockers slow the heart rate and improve the balance between myocardial oxygen supply and demand and, indirectly, they may increase the myocardial relaxation rate. Myocardial ischemia and increased calcium loading have been implicated in the genesis of increased left ventricular stiffness; consequently, the calcium channel blockers should improve left ventricular diastolic function [21]. Although diuretics are effective in reducing pulmonary and systemic venous congestion, care must be taken to avoid excessive preload reduction. Because of the steep (stiff) diastolic pressure-volume curve, large changes in diastolic pressure can be achieved with only modest changes in volume. Nitrates are useful preload-reducing agents, and they have the additional benefit of pro-
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30
-
25
-
20
-
15
-
10
-
1.31
1.59
1.78
Figure
4. Cumulative incidence of congestive heart failure (CHF) by prior history (Hx) and by treatment group in the first 30 days of myocardial infarction in patients from the Beta-Blocker Heart Attack Trial. (Reproduced with permission from [53].)
Risk of CHF from Antiarrhythmic Arrhythmia Suppression B/PM
M
LVEF > 0.30
LVEF < 0.30
NYHA I AND II
NYHA III AND IV
0
I+
0 o-i+
0 I+
2+
4+
I-B Tocainide Mexiletine
0 0
0 0
I-C Encainide Flecainide Propafenone
0 I+ I+
4+ 3+
II Beta Blockers
l+
3+
III Amiodarone
O-l+
I+
5'
Drug
Class
o-
EF: n=
44.35%
34-25%
470
277
a
DILTIAZEM
1270 PLACEBO
Figure
.z 25% 142
I Moricizine
m
3. Diltiazem-associated
increase in late congestive heart failure (CHF) is progressively larger as baseline ejection fraction (EF) is reduced, as shown for 2,159 patients with baseline measurement of EF in the Multicenter Diltiazem Postinfarction Trial. Number of patients with CHF (numerator) and total number in each subset (denominator) are displayed above each bar, and number of patients in given group is indicated below corresponding pair of bars. At top of figure, value for each group shows percent of patients with late CHF among those given diltiazem (D) divided by percent of patients with late CHF among those given placebo (P). (Reproduced with permission from [52].)
viding anti-ischemic therapy. Thus, fl-blockers, calcium channel blockers, and nitrates are the three essential ingredients in the treatment, and even prevention, of diastolic dysfunction in CAD [51]. Primum Non Nocere CHF may result not only from failure to institute an appropriate therapeutic agent but also from the very same drugs that were frequently prescribed for patients with CAD. For example, although diltiazem is effective in suppressing myocardial ischemia in patients with CAD, it can also increase the risk of CHF in those patients with impaired left ventricular function evident soon after infarction, as shown by the Multicenter Diltiaxem Postinfarction Trial (MDPIT)[52] analysis (Figure 3). Similarly, the Beta-Blocker Heart Attack Trial (BHAT) showed a two- to three-fold increase in the frequency of late
Drugs in the Cardiac Trial (CAST)
HCI
I-A Quinidine Procainamide Disopyramide
I+
Figure 5. Increased risk of congestive heart failure (CHF) associated with the use of various antiarrhythmic drugs, especially in those patients in New York Heart Association (NYHA) class III and IV and with left ventricular ejection fraction (LVEF) less than 30%, in the Cardiac Arrhythmia Suppression Trial. B = benign ventricular arrhythmia class; PM = potentially malignant ventricular arrhythmia class; M = malignant arrhythmia class. (Modified with permission from [56].)
CHF among patients with previous myocardial infarction, history of CHF before the index infarction, enlarged cardiothoracic ratio, use of digitalis, and other clinical indicators of left ventricular dysfunction (Figure 4) [53]. The traditional therapeutic combination of digitalis and diuretics used in chronic CHF may not only be inappropriate for use
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CONGESTIVE HEART FAILURE IN CAD / CHENG CORONARY ARTERY DISEASE QROWTH OF KNOWLEDQE
, ,R-“iM o*,.t* ca~lolcw
Figure 6. Growth of knowledge in coronary artery disease from 1780 to 1990 and beyond, being exponential in the last decade.
in acute cardiac failure complicating acute myocardial infarction but may even be detrimental. A normovolemic individual who develops acute myocardial infarction may develop acute pulmonary congestion from fluid redistribution from the vascular space to the lungs, resulting in relative hypovolemia [54]. Diuretic therapy may precipitate hypotension, which may be deleterious during acute myocardial infarction. The use of a long-acting inotropic agent such as digoxin for cardiac failure in acute myocardial infarction, which in most cases is transient, is also undesirable and may increase the incidence of sudden death [55]. Finally, among the antiarrhythmic drugs that were frequently prescribed for patients with CAD, most can cause CHF, especially in those in New York Heart Association class III and IV and with left ventricular ejection fraction less than 30% as shown in the Cardiac Arrhythmia Suppression Trial (CAST) (Figure 5) [56]. Therapy with antiarrhythmic drugs, especially class I drugs, in patients with CHF is also associated with an increased risk of sudden death [57].
CONCLUSION CHF remains a major public health problem. Next to hypertension, CAD is the second most common cause of CHF. Despite our increased knowledge of the mechanisms of CHF in CAD, improved techniques in diagnosing CHF earlier in the course of CAD, and expanded therapeutic armamentarium in managing patients with CHF due to CAD, most patients remain disabled and die from their disease. It is ironic that, although the therapies for such manifestations of CAD as angina pectoris, arrhythmias, and acute myocardial infarction have vastly improved in the past 20 years, our ability to manage major derangements of myocardial function has made relatively little progress. Although the contin414
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ued search for better therapeutic measures, aimed at improvement of myocardial contractile function without adversely affecting the myocardial oxygen supply/demand balance, will fill a much needed gap in the management of patients with CAD complicated by CHF, the most effective form of treatment lies in prevention of CHF from developing in the first place. Since some of the complications of CAD resulting in CHF (Table I) are inevitable, attention should best be directed at prevention of the underlying condition that leads to the occurrence of CHF, namely, CAD itself. Decades of progress have witnessed many advances in our knowledge of CAD and management of its sequelae, but the challenge for us in the 1990s is the prevention of CAD (Figure 6).
ACKNOWLEDGMENT I am grateful manuscript.
to Dr. Robert Kloner for his helpful suggestions
concerning
this
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