SPECIAL

REPORT

Resolved and unresolved issues in the prevention and treatment of coronary artery disease: A workshop consensus statement Victor Dzau, MD, Eugene Braunwald, participating

MD, and participants.

Boston, Mass.,

and

centers

Coronary artery disease is a major cause of mortality and morbidity in the industrialized world. Until relatively recently, research in this area focused primarily on the management of patients with overt disease, but there has been an increasing emphasis on the identification and early detection of factors that predispose to the development and progression of coronary artery disease. As a result, research efforts are no longer directed solely toward management but toward early detection and prevention as well. Coronary artery disease develops through the chain of events depicted in Fig. 1. The presence of certain

This article is based on the consensus reached by participants at a workshop entitled, “Frontiers of cardiovascular therapy and cardiac protection: Resolved and unresolved issues,” held January 8-10, 1989 and subsequently updated. Cochairmen: Eugene Braunwald, MD, and Victor Dzau, MD, Boston, Mass. Participants: Lewis C. Becker, MD, Baltimore, Md.; Roland C. Blants, MD, San Diego, Calif.; B. Greg Brown, MD, PhD, Seattle, Wash.; Kanu Chatterjee, MB, FRCP, San Francisco, Calif.; Aram V. Chobanian, MD, Boston, Mass.; A. Richard Christlieb, MD, Boston, Mass.; Robert J. Cody, MD, Columbus, Ohio; Jay N. Cohn, MD, Minneapolis, Minn.; John E. Deanfield, MD, MRCP, London, England; Curt D. Furberg, MD, PhD, Winston-Salem, N.C.; Valentin Fuster, MD, New York, N.Y.; Lee Goldman, MD, Boston, Mass.; Sidney Goldstein, MD, Detroit, Mich.; Dewitt Goodman, MD, New York, N.Y.; Sidney 0. Gottlieb, MD, Baltimore, Md.; Charles H. Hennekens, MD, Boston, Mass.; Donald Hunninghake, MD, Minneapolis, Minn.; William B. Kannel, MD, MPH, Boston, Mass.; J. Ward Kennedy, MD, Seattle, Wash.; Robert A. Kloner, MD, PhD, Los Angeles, Calif.; Beverly H. Lorell, MD, Boston, Mass.; Joe M. McCord, PhD, Mobile, Ala.; Joel Morganroth, MD, Philadelphia, Pa.; Bertram Pitt, MD, Detroit, Mich.; Leopold0 Raij, MD, Minneapolis, Mimi.; Robert Roberts, MD, Houston, Texas; Jean-Lucien Rouleau, MD, FRCP, Montreal, Canada; Edmund H. Sonnenblick, MD, Bronx, N.Y.; Herman A. Tyroler, MD, Chapel Hill, N.C.; Paul M. Vanhoutte, MD, PhD, Houston, Texas; Michael A. Weber, MD, Long Beach, Calif.; Harry Wesseling, MD, PhD, Groningen, The Netherlands; Harvey D. White, MB, ChB, FRACP, Auckland, New Zealand; James T. Willerson, MD, Houston, Texas; and David 0. Williams, MD, Providence, R.I.

risk factors elicits changes in the heart and vasculature, some of which may initially be beneficial but may be maladaptive or become pathologic when they progress. An example is left ventricular hypertrophy (LVH), which develops in response to an increased work load placed on this chanber. Eventually ventricular wall remodeling occurs with increased muscle mass and cardiac dilatation, ultimately resulting in heart failure. Similarly coronary vascular obstruction and myocardial ischemia are the ultimate consequences of the proliferative response of the coronary vasculature caused by increased intravascular pressure, serum lipid elevations, and other factors. The ischemic state elicits further changes in the ventricle, which culminate in congestive heart failure and end-stage heart disease. Despite the notable strides that have been made in recent years in understanding the pathogenesis of coronary artery disease, this field is still at an early stage. Challenges continue to exist at each level in the chain of events leading to end-stage heart disease. The purpose of this review is to summarize what is currently known and what remains unknown about each of the physiologic processes involved in the pathogenesis of end-stage heart disease. It is recognized that not all topics can be addressed or discussed in depth. Nevertheless, the information presented, which is the product of the considerations of a number of talented investigators, should provide guidelines for future research that will have an impact on the clinical care of patients with or at risk for cardiovascular disease. Part I of the review focuses on cardiovascular risk factors and their sequelae. Part II examines coronary artery disease and its complications.

The workshop on which this article grant from Bristol-Myers-Squibb

PART I: CORONARY

Received

for publication

Aug.

is based was supported Corporation, Princeton,

6, 1990;

accepted

Reprint requests: Eugene Braunwald, MD, vard Medical School, Brigham and Women’s ton, MA 02115. 411127327

1244

Sept.

Department Hospital,

by an educational N. J. 7, 1990. of Medicine, Har75 Francis St., Bos-

RISK FACTORS

A number of risk factors for coronary disease have been identified, including abnormal serum lipid levels, hypertension, LVH, diabetes, and smoking. Serum lipid abnormalities. There is now general

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121

Number

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Part

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1

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Coronary Thrombosis f Myocardial lschemla

Arrhythmia & Loss of Muscle

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Sudden

Death

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Hibernation 1 Ventricular Dilatation

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f Atherosclerosts LVH

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2

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Risk Factors (CHOL. TBP, DM, Insulin Resistance) Platelets, Fibnnogen, etc.

Fig.

1245

\

Silent 4

issues in coronary disrasr

1.

Chain of events involved

agreement that moderate to severe elevations in serum cholesterol, specifically low-density lipoprotein (LDL) cholesterol, are causally related to the development of atherosclerosis and coronary heart disease (CHD) and that lowering of total and LDL cholesterol levels will reduce coronary risk.‘-” In fact, actual regression of atherosclerotic lesions has been reported with lipid-lowering therapy.“-6 Consequently the need for such therapy in patients with abnormally high serum lipid levels is clearly recognized. The report of the adult treatment panel of the National Cholesterol Education Program (NCEP) provides physicians with specific guidelines for the classification, evaluation, and treatment of these high-risk patients.7 However, to achieve the greatest impact on the overall problem of CHD in the most cost-effective manner, it would be highly desirable to adopt a public health or population-based lipid intervention strategy. Detailed recommendations for a population-based strategy have been provided recently by the NCEP.s-I0 Dietary intervention is regarded as the primary and initial approach to cholesterol lowering, but a need exists for greater dissemination of the dietary recommendations that have been formulated for reducing cholesterol levels. Educational programs directed toward the general public and dietary counseling for high-risk persons are both advised. To adequately implement these measures, better education of physicians in the areas of nutrition and dietary counseling is required. Serum lipid elevations are known to interact with various other atherogenic risk factors, which include

in coronary

artery disease.

hypertension, diabetes, obesity, and cigarette smoking. Consequently the risk status of an individual is best predicted by a synthesis of the risk factors present in a composite estimate. The usefulness of such multivariate risk profiles has been demonstrated in epidemiologic studies.” Unresolved issues (Table I). The NCEP defines individuals at high risk for development of CHD as those with LDL cholesterol levels greater than 159 mg/dl. For patients with established CHD, or with two or more other major CHD risk factors (one of which can be male sex), LDL cholesterol levels I 130 mg/dl warrant therapy. The minimum goal of therapy for such patients is to reduce the LDL cholesterol level to less than 130 mg/dl. However, there are data to suggest that for patients with documented CHD, a much lower LDL cholesterol level might be beneficial. Hence many experts now believe that patients with CHD should be treated to reduce LDL cholesterol levels to well below 130 mg/dl. The levels that warrant therapy and the goal of therapy in such patients need to be established. The NCEP guidelines are recommended for all adults regardless of age. Concern has been expressed by some as to whether the guidelines should be modified in the elderly. An expert panel of the NCEP is currently preparing guidelines for the classification and treatment of high blood cholesterol levels in children and adolescents. In contrast to LDL cholesterol, high-density lipoprotein (HDL) cholesterol has been found to protect against the development of CHD, but the fundamental mechanism responsible for this protective effect is not yet fully understood. In addition, the role

1246 Table

Dzau, Braunwald, et al. I. Unresolved

issues related

American

to serum lipid

April 1991 Heart Journal

abnormalities

I.

Specific populations A. Level of LDL-C that warrants treatment in patients with CHD and goals of treatments in such patients B. Guidelines for cholesterol lowering in particular subgroups, such as elderly, children, and adolescents II. HDL cholesterol A. Mechanism by which HDL-C protects against coronary artery disease 13. Role of HDL-C in patient evaluation and treatment C. Management of patients with low HDL-C in the absence of high LDL-C III. Other risk factors A. Risk factor status of apolipoproteins (e.g., apo A-I and B), lipoprotein(a) and ape(a), and triglycerides B. Role of hemostatic factors (e.g., fibrinogen and t-PA inhibitor) at risk factors and their use in evaluation and treatment of patients C. Treatment of borderline hypertriglyceridemia and familial combined hyperlipidemia D. Risk factor status of oxidized lipoproteins IV. Dietary intervention A, Desirable level of intake of fiber and various fatty acids B. Clinical relevance of dietary-induced reductions in HDL-C C. Existence and identification of hyper- and hyporesponders to dietary cholesterol and saturated fatty acids D. Techniques for obtaining greater cooperation in food design and labeling V. Pharmacologic intervention A. Long-term consequences (beneficial and adverse) of lipid-lowering drugs B. Role of combination drug treatment in lipid lowering C. Need for drugs with novel mechanisms of action VI. Regression of atherosclerosis A. Best study population in which to assess effect of lipid-lowering treatment on regression (or progression) of atherosclerosis B. Types of studies needed to demonstrate antiatherogenic effect of treatment on various arterial beds C. Role of coronary angioscopy for defining atherosclerotic disease D. Best arteriographic parameters for characterizing atherosclerotic progression/regression E. Best indices for following atherosclerotic regression F. Most effective imaging method for defining atherosclerotic disease G. Defining role of cholesterol, collagen, elastin, thrombus formation, hypertrophy, and dilatation in the pathophysiology of atherosclerosis VII. Interpretation of risk factors A. Relationship of total cholesterol, especially very low values, to all-cause mortality B. Applicability today to diverse populations of risk factors derived decades ago C. Factors that provide most accurate assessment of risk D. Most acceptable format for risk assessment in clinical practice VIII. Public policy and programs A. Best methods for informing physicians of NCEP guidelines and motivating them to implement these guidelines B. Cost-benefit aspects of NCEP and other possible guidelines C. Development, implementation, and evaluation of successful mass cholesterol screening programs

of HDL cholesterol levels in evaluation and treatment and the most appropriate approach to the management of individuals with low HDL cholesterol levels in the absence of elevated concentrations of LDL cholesterol remain to be defined. The NCEP has reviewed the issue of the role of HDL cholesterol in clinical practice in some detaillo The NCEP defines a level of HDL cholesterol < 35 mg/dl as a major CHD risk factor and recommends that HDL cholesterol levels be used in assessment of risk but not as a target of therapy. Because the risk factor status of a number of other serum lipids and lipoproteins, such as apolipoproteins, lipoprotein(a), and triglycerides, and hemostatic factors, such as fibrinogen and tissue plasminogen activator inhibitor-l, has not been established, the role that these parameters might optimally play

in evaluation and treatment is currently unknown. Specifically there is no consensus as to the optimum approach to the treatment of persons with elevated triglyceride levels, particularly those with borderline hypertriglyceridemia of 250 to 500 mg/dl, and those with familial combined hyperlipidemia. Another unresolved area is the clinical relevance of the observation that oxidized lipoprotein in the arterial wall is more atherogenic than the native LDL.12 It has been proposed that antioxidants such as probucol reduce the oxidized LDL and thereby attenuate the atherosclerotic process. However, the actual impact on coronary risk of the oxidized lipoproteins present in the arterial wall cannot be addressed clinically at present because of the absence of techniques for measuring them. Although dietary intervention is considered first-

Volume Number

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1

line therapy for elevated serum cholesterol levels, questions remain regarding the optimum levels of intake of specific saturated fatty acids, omega-3 and omega-6 polyunsaturated fatty acids, monounsaturated fatty acids, and fiber. The clinical significance, if any, of the reduction in cardioprotective HDL cholesterol levels that accompanies certain dietary interventions, such as a reduced intake of total fat and saturated fatty acids, also remains to be elucidated. More research is needed to determine the possible existence of hyper- and hyporesponders to alterations in dietary cholesterol and saturated fatty acids and to devise methods for identifying such persons. To aid subjects in implementing current and future dietary recommendations, techniques must be developed for obtaining greater cooperation from the food industry, from the Food and Drug Administration, and from other groups in food development and food labeling. Lipid-lowering drugs represent a supplement to dietary intervention for the management of patients with elevated serum lipid levels, but more information is needed on the long-term effects of these agents in general and of the various individual drugs available. Systemic surveillance of both beneficial and adverse long-term sequelae is required to obtain such information. The value of drug combinations, such as resins and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors or niacin in lipidlowering therapy must also be further defined. Another question relates to the potential value of various unique pharmacologic approaches to the prevention of atherogenesis. Some of these suggested approaches include the use of agents (e.g., oxysterol) that primarily promote production of HDL cholesterol.13 Others involve the use of drugs with a direct effect on the arterial wall, such as probucol.14 Although regression of atherosclerosis is known to occur, the patient population most appropriate for evaluating the impact of lipid intervention therapy and the types of clinical trials required to demonstrate the effectiveness of such treatment on the different arterial beds, such as the coronary, cerebral, and femoral circulation, await clarification. It is not currently known whether atherosclerotic lesions behave independently in different vessels in a given patient. It also remains unexplained why in the same patient some atherosclerotic lesions progress and others regress after lipid-lowering interventions. In the past, responses have been expressed on both a lesion and a patient basis. There is also no consensus as to the most effective imaging method for defining and quantifying atherosclerotic lesions and the best arteriographic parameters for characterizing progression or regression of advanced disease. Another

Unresolved

issues in coronary disease

1247

unresolved question relates to the pathophysiologic mechanisms of regression itself. The composition of atherosclerotic plaque is complex, consisting of cellular components (i.e., smooth muscle cells, fibroblasts, and macrophages) and noncellular constituents (i.e., esterified cholesterol, collagen, elastin, and fibrin). It is unclear which of these components regress with risk factor reduction. The development of better disease models that can address the role of genetic and environmental factors in the initiation, progression, and regression of lesions may provide additional insights. A reduction in total and LDL cholesterol levels would be expected to result in a decline in the incidence of coronary artery disease. The J-shaped all-cause mortality curve based on the large number of screenees for the Multiple Risk Factor Intervention Trial15 suggestsa possible relationship between low levels of total cholesterol and mortality that requires further clarification. It is possible with the use of diet and combinations of potent hypolipidemic agents to lower LDL cholesterol to extremely low levels (< 90 mg/dl). The risk-benefit relationships of such extensive cholesterol lowering are unknown, although it should be noted that families with very low total and LDL cholesterol levels are known to show unusual longevity. The risk profiles currently used in assessingcoronary risk were derived several decades ago in areas of the country such as Framingham, Massachusetts16 and Chicago, Illinois,17 with a high incidence of atherosclerotic disease, and the applicability of this information to various populations today is not clear. There is a need to identify those factors that will provide the most accurate, most generalizable assessment of risk and to identify the type of risk assessment instrument most acceptable to clinicians and other health workers in clinical practice. The various formats that have been suggested for risk assessment include handbooks, calculators, and computer software programs. Strategies for informing physicians of the NCEP guidelines and motivating them to implement these recommendations are clearly needed. Additional information is also required on the cost-benefit aspects of the adult treatment panel guidelines of the NCEP and the economic impact of other possible guidelines, such as compliance with lower recommended LDL cholesterol levels. Finally, techniques for developing, implementing, and evaluating mass cholesterol screening programs should be devised. Hypertension. Hypertension has four principal interrelated sequelae: coronary artery disease, cerebrovascular accidents, renal disease, and LVH. Because of the importance of LVH and its status as an

April

1240

Dzau, Braunwald, et al.

Table II. Unresolved issues related coronary artery disease

American

to hypertension

and

1. Mechanism responsible for promotion of atherosclerosis by hypertension 2. Importance of home vs office vs 24-hour blood pressure measurements in predicting coronary risk 3. Clinical significance of metabolic abnormalities associated with blood pressure-lowering medications 4. Reason(s) why control of mild hypertension does not reduce CHD 5. Most appropriate clinical trial design for demonstrating potentially beneficial effect of antihypertensive treatment on coronary artery disease 6. Optimum degree of blood pressure lowering, particularly for prevention of coronary artery disease 7. Role of nonpharmacologic therapy in management of hypertension 8. Effect of antihypertensive drugs other than diuretics and beta blockers on mortality and morbidity in hypertension

independent risk factor, this topic is addressed separately. Hypertension and coronary disease. Epidemiologic studies have clearly established the role of elevated blood pressure as a major risk factor for CHD.15 The presence of other concurrent risk factors, particularly hypercholesterolemia and glucose intolerance, which tend to be more common in patients with hypertension than in the normotensive population,16-18greatly increases the incidence of coronary artery disease. The higher rate of hypercholesterolemia and glucose intolerance in subjects with hypertension who were receiving blood pressurelowering medication as compared with those who remained untreated18s ig suggests that some drugs used in the management of hypertension may themselves unfavorably influence coronary risk factors.20921However, the metabolic effects of treatment are largely dependent on the individual agent selected. For example, diuretics may increase serum levels of total cholesterol, LDL cholesterol, glucose, and uric acid and decrease serum potassium concentrations, whereas beta blockers may lower HDL cholesterol levels. In contrast, metabolic alterations generally do not occur with the use of angiotension-converting enzyme (ACE) inhibitors and calcium antagonists, although inhibition of ACE may be associated with potassium conservation. Results of clinical trials in patients with moderate to severe hypertension have shown convincingly that pressure-related events such as stroke and congestive heart failure can be reduced substantially by treatment with blood pressure-lowering drugs.22 Results of studies that examined the effect of treatment in patients with mild to moderate hypertension have

Heart

1991 Journal

been less consistent. Analysis of pooled data from 10 randomized studies involving approximately 43,000 patients indicates that the treatment of mild to moderate hypertension reduces the all-cause mortality rate by about 10%. 23This benefit is attributable primarily to a reduction in pressure-related events. The effect of treatment of less severe forms of hypertension on CHD, however, is equivocal. Urzresolued issues (Table II). An important problem in the field of hypertension is the definition of hypertension. In a given individual, a single blood pressure measurement taken at one point in time may not reflect the true stresses in the vascular system in how they are played out over 24 hours. Features useful in identifying subjects with hypertension at risk of cardiovascular complications and the appropriateness of office versus 24-hour blood pressure monitoring in quantifying that risk are currently undefined. Lability is another very important factor that has yet to be dealt with. Moreover, the rise in blood pressure in relation to various forms of stress may have different impacts on the circulation. The specific mechanism by which elevated blood pressure accelerates or predisposes to atherosclerosis remains unknown, as do the interactive mechanisms responsible for the accelerated development of CHD in patients with hypertension with other risk factors such as diabetes mellitus. The clinical significance of the metabolic abnormalities associated with antihypertensive medications is uncertain, although there is concern that changes in serum lipid, glucose, and electrolyte levels may increase the risk of the development of CHD and arrhythmias. 24*25Such effects may explain why treatment of milder forms of hypertension with drugs having these effects has failed to have an impact on the risk of CHD. It is also possible that the design of the clinical trials might have influenced the outcome, for example, duration of treatment, low event rate, presence of other risk factors, and appropriate experimental control group. The optimum degree of blood pressure lowering, particularly for the prevention of coronary artery disease, is also unresolved. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure advises that blood pressure be reduced to less than 140/90 mm Hg,26 but the appropriateness of this recommendation has not been confirmed clinically. The role of nonpharmacologic treatment in the control of hypertension also remains undefined and largely untested. The impact on mortality and morbidity of ACE inhibitors and calcium antagonists, two classes of drugs now recommended as first-step antihypertensive therapy, has yet to be addressed in large-scale clinical trials.

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Unresolved

1

Treatment of moderately or severely elevated blood pressure reduces the rate of the deterioration of renal function associated with hypertension.22 The presence of hypertension increases the risk of progression of primary renal disease and appears to contribute to the development of glomerulosclerosis.27+ 28 An apparent link also exists between blood pressure and renal impairment in the diabetic population. The rate of deterioration of renal function in patients with diabetes correlates with the blood pressure level, and patients with insulin-dependent diabetes and coexisting hypertension almost invariably exhibit renal dysfunction.2g Microalbuminuria is predictive of the eventual development of chronic renal failure in these patients.30 Experimentally induced hypertension in animals is associated with an increase in glomerular capillary hydrostatic pressure and a reduction in the glomerular ultrafiltration coefficient.31, 32 The increased glomerular capillary pressure has been shown in animal models to be a risk factor for progression to glomerulosclerosis, although its importance in humans is less clear. Various growth factors have been shown to stimulate proliferation of mesangial cells in vitro,33 suggesting a potential role of these substances in the cause of hypertensive renal disease. Heparin and calcium antagonists have been found to inhibit the stimulatory effectof growth factors.34-36 Unresolved issues (Table III). It is not known why chronic renal failure is many times more prevalent in the black population with hypertension compared to the white population.27, 37,38 More severe blood pressure elevations in black patients is one suggested explanation, although other fundamental differences, possibly related to genetic or environmental factors, may also be involved. Another issue still to be resolved in the area of hypertension and renal disease is the optimum goal of blood pressure reduction in patients in whom these conditions coexist. More aggressive treatment aimed at lowering blood pressure to a greater extent than in other patients with hypertension may be advisable in this population. The role of multiple therapeutic approaches, such as combined pharmacologic therapy and dietary intervention, in the management of hypertensive renal disease is another unresolved treatment-related issue. Possible differences in the impact of the various antihypertensive medications on renal function remain to be identified. The importance of the effects of these agents on glomerular capillary pressure also requires clarification. ACE inhibitors, which reduce both systemic and glomerular capillary pressure, decrease the incidence of glomerulosclerosis in rat Hypertension

and renal

disease.

issuesin coronary disease I 249

III. Unresolved issuesrelated to hypertension and renal disease Table

1. Reason(s) for higher prevalence of chronic renal failure in black patients with hypertension 2. Goal of blood pressure reduction in patients with hypertension and renal disease 3. Role of multiple approaches to treatment in patients with hypertension and renal disease 4. Effects of various antihypertensive medications on renal function 5. Importance of effects of antihypertensive medications on glomerular capillary hypertension 6. Optimum approach to treatment of patients with hypertension and diabetes, with and without chronic renal failure 7. Potential benefits and complications of dietary interventions on renal and cardiovascular complications of patients with hypertension and diabetes 8. Importance of renal growth factors in hypertensive renal disease 9. Importance of endothelial derived relaxing and constricting factors in regulation of glomerular function

models.32, 3g However, the clinical applicability of this observation has not been established. Furthermore, the effects on glomerular capillary pressure and the progression of glomerulosclerosis by other hypertensive agents need further definition. The relationship of renal growth factors to mesangial cell changes in patients with hypertension and the impact of substances that inhibit these growth factors on the course of chronic renal failure are currently unknown. Likewise the role of endotheliumderived relaxing factor and the tndothelium-dependent contracting factor endothelin on the regulation of glomerular function remains to be established.40 Diabetes mellitus and coronary heart disease. It is well established that diabetes mellitus is a major risk factor for the development of coronary artery disease. Patients with diabetes are predisposed to pathologic lesions of the microvasculature and accelerated atherosclerosis of large arteries. Most of the morbidity and mortality associated with diabetes relates to complications of systemic vascular disease, that is, myocardial infarction, stroke, and renal failure. Patients with diabetes often have coexisting risk factors such as hypertension, low HDL cholesterol, elevated triglycerides, obesity, and platelet dysfunction. Results of epidemiologic studies suggest that the presence of diabetes potentiates the deleterious effects of these other risk factors for CHD. Unresolved issues (Table IV). The mechanisms responsible for the microvascular and macrovascular diseases in diabetes are not completely understood. It is particularly important to elucidate the pathophysiologic mechanisms involved in the accelerated development of coronary artery disease in patients

1250

Dzau, Braunwald,

Table IV. Unresolved nary artery disease

et al.

issues related

American

to diabetes

and coro-

1. Mechanism for accelerated development of CHD in patients with diabetes 2. Design of practical clinical trial to assess effect of control of diabetes on coronary artery disease 3. Nature of relationship of microalbuminuria to development of CHD in patients with diabetes 4. Reason for loss in women with diabetes of relative protection of female sex against CHD 5. Role of insulin in development of hypertension in patients with diabetes 6. Role of treatment of hypertension and of other risk factors in slowing progression of CHD in diabetes mellitus 7. Identification of optimum pharmacotherapy in treatment of hypertension in patients with diabetes

with diabetes. Microalbuminuria, defined as a urinary albumin excretion of approximately 15 mg/day, is predictive of the development of coronary artery disease in patients with diabetes,4l but the precise nature of this relationship has yet to be clarified. The reason why the relative protection against CHD observed in premenopausal women is lost in premenopausal diabetic women is likewise unresolved. More clinical trials are necessary to further define the effect of different dietary regimens, new technologies for the control of glucose, and pharmacologic interventions on the development of vascular disease in patients with diabetes. Patients with noninsulin-dependent diabetes and diastolic hypertension have an elevated level of fasting and postpradial insulin,42 but the role of insulin in the development of hypertension in these patients has not been determined. It has been suggested that insulin may promote hypertension by increasing renal tubular sodium reabsorption43 or by stimulating catecholamine release.443 45 It is postulated that a primary abnormality of insulin metabolism may define a subset of patients with increased risk factors for coronary artery disease (i.e., hypertension, glucose intolerance, low HDL cholesterol, and elevated triglycerides). It remains to be determined whether these patients have an altered natural history in the development of coronary artery disease or whether they respond differently to risk factor modification. Recognition of such subsets of patients may be of clinical utility since certain antihypertensive agents or diabetic diet regimens may adversely influence the risk profile. Indeed ACE inhibitors appear to increase the sensitivity of glucose metabolism to the effect of insulin, whereas diuretics decrease insulin sensitivity.20 Antihypertensive therapy has been found to slow

April 1991 Heart Journal

the rate of progression of renal dysfunction in patients with diabetes,46> 47 but the optimum approach to the treatment of diabetes, with and without chronic impairment of renal function, is not clear. The potential benefits and the possible complications of dietary interventions such as protein restriction on the renal and the cardiovascular complications of diabetes are under investigation. Left ventricular hypertrophy. As previously mentioned, LVH is another of the complications of untreated hypertension. Data from the Framingham study show that LVH is also an independent risk factor for sudden death and congestive heart failure, particularly in the elderly. LVH is a form of ventricular remodeling characterized by changes in the size, shape, qualitative and quantitative composition, and cellular disposition of the ventricular wall. LVH represents an adaptive response to chronic pressure overload that allows augmentation of left ventricular work while maintaining normal systolic wall stress and shortening.48 Pressure overload hypertrophy, however, eventually results in the progressive impairment of diastolic distensibility of the left ventricle, manifested by an elevation of left ventricular filling pressure relative to diastolic volume. LVH has a multifactorial etiology. It is not attributable solely to mechanical factors such as systolic and diastolic load; direct trophic effects of neurohumoral factors such as norepinephrine and angiotensin II are also probably involved.4gy 5o An age-related loss of myocytes that necessitates compensatory enlargement of remaining cells contributes further to the development of LVH. LVH is clearly a major independent risk factor for many types of cardiovascular disease. A number of clinical studies have demonstrated that echocardiographic evidence of increased left ventricular mass is predictive of mortality, coronary events, stroke, congestive heart failure, and total cardiovascular events.51-54 Regression of LVH can be achieved with pharmacologic therapy di,rected at control of load, neurohormonal factors, or both. Drugs that have been shown to decrease left ventricular muscle mass include centrally acting sympatholytic agents such as methyldopa, clonidine, and guanabenz, peripherally acting alpha-adrenergic blockers such as prazosin and terazosin, and ACE inhibitors such as captopril and enalapril.55-5g There have been conflicting reports of the ability of calcium channel antagonists and betaadrenergic blockers to cause regression of LVH.58, 5g Although direct-acting vasodilators do not appear to cause regression of LVH in patients with mild to

Volume Number

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moderate hypertension, significant reductions in left ventricular mass have been reported in patients with severe hypertension and marked cardiomegaly treated with the vasodilator minoxidil.60 Unresolved issues (Table V). The relationship between the physiologic adaptation to an increased load and the pathologic changes of LVH is not clear. It is possible that the pathologic state represents a quantitative failure of adaptation rather than a qualitative alteration. The specific factors that trigger the development of LVH, the events that lead to cellular enlargement, and the impact of genetic makeup, age, and the duration and severity of pressure overload on LVH are also unknown. It is recognized that LVH resulting from pressure overload and LVH induced by exercise, such as is seen in athletes, differ with respect to the type of hypertrophy and the biochemical alterations that are produced.61 There is, however, no definitive explanation for these differences. The significance of the changes in connective tissue that occur as part of the left ventricular remodeling proces@ is also unclear. A number of problems exist with respect to the animal models of LVH used in experimental studies. It is not known how well these models truly reflect events in humans. In addition, differences in the type, extent, and duration of the load imposed and the age of the animals tested may also influence the results obtained. The unknown impact of aging and the presence of concomitant disorders such as coronary artery disease on LVH in humans further complicate the interpretation of research findings. It is not clear which cells benefit from load reduction or neurohumoral interventions directed toward the regression of LVH. There is some concern that drug-induced regression may represent primarily a reduction in the size of healthy contractile myocytes leaving behind diseased cells and fibrous tissue.58 The impact of LVH regression on mortality, myocardial ischemia, systolic and diastolic function, arrhythmias, peripheral vascular disease, and clinical symptoms is also unknown. Hypertrophy of smooth muscle cells in the peripheral vasculature is another complication of chronically elevated blood pressure,63, 64 but it remains to be determined whether this response occurs parallel to LVH. Similarly it is not known whether regression of LVH is associated with similar effects in the arterial circulation. PART II: CORONARY DISEASE AND ITS COMPLICATIONS Myocardial ischemic syndromes. The presence and

severity of active myocardial ischemia is emerging as an important factor in the prognosis of patients with

Unresolved Table V. Unresolved hypertrophy

issues in coronary issues related

disease

125 1

to left ventricular

1. Relationship between physiologic and pathologic changes of LVH 2. Factors that trigger LVH 3. Effect of genetic background, age, and load severity and duration on LVH 4. Differences between LVH induced by pressure overload and exercise-induced LVH 5. Significance of connective tissue changes in LVH 6. Effect of age, type and duration of increased load, species, and presence of other diseases on experimental studies of LVH 7. Identification of cells that benefit from regression of LVH 8. Impact of LVH regression on mortality, systolic and diastolic function, arrhythmias, and peripheral vascular disease 9. Effect of regression on various components of LVH (e.g., myocytes, connective tissue)

coronary artery disease. 65,66 This association between ischemia and cardiovascular prognosis is apparent in patients with known coronary artery disease, as well as in asymptomatic persons and those with stable and unstable angina, myocardial infarction, and peripheral vascular disease. Options for the treatment of ischemia, which is the functional expression of severe obstructive coronary artery disease, include pharmacologic therapy with nitrates, calcium antagonists, beta-adrenergic blockers, and mechanical revascularization by percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG). These interventions are effective in the management of patients with symptomatic and asymptomatic ischemia. Objective methods are now available for assessing myocardial ischemia, both inside and outside the hospital. Ambulatory ECG monitoring indicates that the characteristics of ischemia during activities of daily life differ from those of ischemic episodes during conventional exercise tests and that ischemia is frequently asymptomatic. Ischemic episodes recorded in an ambulatory setting may occur at relatively low levels of heart rate and under circumstances involving minimum hemodynamic stress. Triggers for out-of-hospital ischemia also differ, and disease activity tends to be highly variable with time, even in patients who are stable symptomatically. Such variability suggests the need for a redefinition of stability based not solely on the occurrence of angina pectoris but rather on the presence of total ischemic activity, sometimes referred to as the “total ischemic burden.” The pathophysiology of ischemia during dsily life is more variable and less closely related to an increase in myocardial oxygen demand than ischemia precipitated during exercise stress

1252 Table

Dzau, Braunwald, et al. VI. Unresolved issuesrelated to myocardial ischemia

of active myocardial ischemia in population as a 1. Prevalence whole and in patients with coronary artery disease between symptomatic and asymptomatic is2. Relationship chemia in pain perception during ischemia, 3. Reason for differences both between patients and in same person 4. Relationship between ischemic activity and events in atherosclerotic plaque 5. Relationship between events in epicardial coronary artery and ischemic activity outside the hospital between ischemic activity and clinical complica6. Association tions of CHD I. Best assessment measures for identifying patients with coronary artery disease at high risk 8. Features of ischemia (frequency, duration, pattern) useful in identifying high-risk patients with coronary artery disease frequency of evaluation of ischemia for opti9. Recommended mum risk assessment of relationship between coronary artery disease and 10. Nature sudden cardiac death of terminal event in patients with sudden cardiac 11. Nature death 12. Indications for treatment of asymptomatic ischemia end points for treatment of asymptomatic is13. Therapeutic chemia 14. Optimum approach to treatment of ischemia

tests. A more important factor in the genesis of outof-hospital episodes of ischemia may be a transient decrease in coronary flow, which now appears to be involved in the pathophysiology of many individual ischemic episodes across the entire range of coronary syndromes.65* 66 The clinical features of the various ischemic syndromes may be caused by and reflect events in the coronary atherosclerotic plaque. For example, plaque disruption and coronary thrombosis are regarded as important factors in acute unstable myocardial ischemic syndromes (acute myocardial infarction and unstable angina). 67 Dysfunction or disruption of the vascular endothelium is also being recognized as an important factor, even in patients with chronic stable angina.68* 6g This is likely to be the basis for both disturbed vasomotion and control of coronary flow in response to physiologic stresses and the variable pattern of ischemic activity seen in several studies of “stable patients.” Coronary artery disease is regarded as an important contributor to sudden cardiac death, as reflected in its presence in the majority of the victims of sudden death.70 Complex plaques and thromboses are also frequently detected in these patients. The presence of ventricular arrhythmias and left ventricular dysfunction has been shown to increase the risk of sudden cardiac death.

American

April 1991 Heart Journal

Unresolved issues (Table VI). The prevalence of active myocardial ischemia in the population as a whole and in subsets of patients with coronary artery disease, the relationship between symptomatic and asymptomatic ischemia, and the reason for differences in perception of pain during ischemia among patients and even in the same person at different times are among the important unresolved issues related to myocardial ischemia. The association between ischemic activity and events occurring in atherosclerotic plaque, as well as events in epicardial coronary arteries, such as endothelial disruption/ dysfunction, platelet aggregation, and thrombosis, also requires further investigation. Clarification of the role of ischemia in the precipitation of the complications of coronary artery disease is also needed. At this time it is not known whether transient episodes of ischemia alone are damaging to the heart or ischemia is merely a marker of instability in the proximal epicardial coronary arteries that leads to complications. Evidence suggests that ischemia damages the heart directly, but this issue has not been resolved conclusively. The methods for the assessment of ischemia and its features, for example, frequency, duration and pattern, most useful in identifying high-risk patients need to be determined. Serial monitoring over time may be necessary to obtain the best results. However, the frequency of evaluation required for adequate assessment of risk and optimum patient management must also be defined. Despite the presence of coronary artery disease in a high percentage of patients who experience sudden cardiac death, the nature of the relationship between coronary artery disease and sudden death is unclear. The identification of the precise cause will be important in determining whether strategies for preventing coronary death should be directed toward the management of arrhythmias, ischemia, or both. There are a number of unresolved issues related to the treatment of ischemia, including indications for the treatment of asymptomatic ischemia. Although frequent and severe ischemia, whether symptomatic or asymptomatic, appears to identify patients at relatively high risk of death and serious cardiovascular events, it is not at all clear whether treatment of ischemia will reduce this risk. In other words, it is not known if ischemia is deleterious, per se (in which case its abolition or reduction would be desirable), or if ischemia is merely a marker for future untoward events, in which case elimination or reduction of ischemia may have little effect on prognosis. Finally, it is possible that both situations may apply, and

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ischemia may exert an adverse effect and also be a marker for poor prognosis. Once the indications for the treatment of ischemia are established, therapeutic end points must be defined. At this time it is not known whether symptomatic relief is sufficient or more aggressive therapy directed toward the relief of the asymptomatic component of the disease is needed. The optimum approach to treatment must also be determined. If ischemia is found to be the direct cause of some of the complications of coronary artery disease, it is not known if suppression of ischemia by medical therapy will prove beneficial or if revascularization is necessary. If this latter approach is required, the most appropriate form of revascularization, PTCA versus CABG in various subgroups of patients, must be identified. Coronary

thrombosis

and acute myocardial

infarction

Plaque disruption and thrombosis. Plaque disrup-

tion is frequently the underlying event preceding all acute coronary syndromes. Rupture or fissuring of an atherosclerotic plaque may be followed by adherence of platelets to the vessel wall, subsequent platelet aggregation, and thrombus formation.67, 71 Unresolued issues (Table VII). Small plaques with a high fat content appear to be the most susceptible to rupture,71 but it is not known whether imaging techniques will prove useful in identifying such plaques. Evidence obtained experimentally and at autopsy suggests that macrophages present in fatty plaques contribute to digestion and rupture of plaque. However, the mechanism responsible for this digestive action remains to be established. Shear forces may also trigger plaque rupture, although again the precise mechanism remains unknown. An exciting unresolved issue in the area of plaque disruption is the potential for reversal of atherosclerotic plaques by means of cholesterol reverse transport. It has been suggested that the infusion of HDL may induce the regression of experimentally induced atherosclerotic plaques.i”T 73 This area clearly needs future intensive study. In addition, the effect of a selective increase in HDL on the regression of human disease and on the disruption of plaques is not known. Thrombus formation after plaque rupture may contribute to progression of stenotic lesions.74 However, whether such progression occurs by thrombotic mechanisms, nonthrombotic mechanisms, or both has not been resolved. In experimental animal models, the accumulation of thromboxane A2 and serotonin appears to contribute to development of thrombus at sites of endothelial injury and thromboxane and serotonin receptor antagonists and monoclonal antibodies to the platelet glycoprotein IIb/IIIa re-

Table and

VII. Unresolved thrombus

issues in coronary disease

issues

related

to plaque

1253

disruption

formation

I.

Plaque disruption A. Ability of quantitative imaging techniques to identify plaques likely to rupture B. Ability of qualitative imaging techniques to identify plaques likely to rupture C. Mechanism for plaque digestion by macrophages D. Mechanism for plaque rupture by shear forces E. Possible reversal of fatty plaque II. Thrombus formation A. Role of thrombotic and nonthrombotic mechanisms progression of stenosis B. Factors contributing to development of fixed thrombi response to plaque ulceration and labile thrombi response to fissuring of plaque C. Mechanisms for vasoconstriction associated with thrombus formation D. Reason for thrombogenicity of surface of residual thrombus E. Means for preventing thrombus formation, particularly the part in proximity to damaged vessel wall, which most resistant to prevention and treatment

in in in

is

ceptor have potent antithrombotic properties in the presence of coronary stenoses.75 Preliminary results of a study evaluating the effect of antithrombotic therapy on atherosclerotic progression support the concept that thrombosis (with subsequent fibrotic organization) plays a role in progressive atherosclerotic narrowing.76 The degree of plaque rupture appears to determine whether a thrombus will be labile or fixed.“7 Ulcerations tend to result in fixed thrombi and myocardial infarction, whereas fissures are more likely to precipitate labile thrombi and unstable angina; the factors responsible for these differences, however, remain to be elucidated. In addition, experimental and clinical data are emerging, which suggest that increased plasma levels of epinephrine, lipoprotein(a), and plasminogen activator inhibitors may favor the thrombogenic response after plaque rupture. Further details of such mechanisms remain to be elucidated. Thrombus formation also leads to acute plateletdependent vasoconstriction.67, 75 Intermittent vasoconstriction related to the loss of endothelial cells may also be induced by this event. However, other more specific, as yet unidentified, mechanisms are also believed to exist. Thrombi may lyse spontaneously or in response to thrombolytic therapy. The surface of the residual thrombus remaining after reperfusion is extremely thrombogenic; although exposure of thrombin may play a role, the factors responsible for this phenomenon have not been established. Another unresolved issue relates to the optimum approach for the pre-

1254 Table

Dzau, Braunwald, et al. VIII.

Unresolved

issues related

American

to thrombolytic

ther-

apy I.

Patient selection A. Value of thrombolysis in stable inferior myocardial infarction B. Value of thrombolysis in unstable angina C. Effectiveness of thrmbolysis in the elderly D. Effectiveness of late thrombolysis (>6 to 24 hours) in patients with and without ischemic pain E. Effectiveness of thrombolysis in patients with cardiogenie shock treated within first 4 hours II. Lytic agents A. Thrombolytic agent of choice in various patient groups B. Effect of combined use of various thrombolytic agents C. Degree of lytic activity of fibrin-specific thrombolytic agents D. Effectiveness of simplified methods of administration of thrombolytic agents, such as bolus injection and selfadministration III. Additional strategies A. Effectiveness of prehospital thrombolytic therapy B. Role of adjunctive therapy with antithrombotics, beta blockers, and free radical inhibitors in thrombolysis C. Identification of patients likely to benefit from additional methods of revascularization such as PTCA D. Best method of patient stratification for ensuring most appropriate form of intervention

vention of thrombus formation. Possible strategies include a combination of anticoagulants and lowdose aspirin, thrombin inhibitors, and blockade of specific receptors and ligands for platelet adhesion and aggregation. Thrombolytic therapy. As a result of the recognition of the role of thrombosis in the precipitation of acute myocardial infarction, thrombolytic therapy has now been established as a useful modality for the treatment of acute infarction. Clinical trials have demonstrated clearly that intravenous thrombolytic therapy reduces infarct size and mortality in patients with anterior myocardial infarction, provided treatment is initiated within approximately 6 hours after is most the onset of symptoms. 77 Thrombolysis effective when started within 1 to 2 hours after the onset of infarction. Results of the ISIS-II trial indicate that concomitant administration of low-dose aspirin enhances the effects of thrombolysis with intravenous streptokinase. I8 An overall 42 % reduction in the 35-day cardiovascular mortality rate was achieved in patients who received this combination, and a 60% reduction was noted in the subgroup treated within the first hour of infarction. The benefits of streptokinase on vascular mortality, while attenuated by increasing intervals between the onset of symptoms and randomization, were apparent for those randomized up to 24 hours after the onset of symptoms. Current evidence indicates that PTCA,

April 1991 Heart Journal

immediately or 18 to 48 hours after thrombolysis with tissue plasminogen activator (t-PA), does not decrease the likelihood of vessel reocclusion or reduce the size of the infarct.7g Unresolved issues (Table VIII). Although thrombolytic therapy is known to be beneficial in the management of Q wave anterior myocardial infarction, and probably also in patients with Q wave inferior myocardial infarction, its value in patients with non-Q wave infarction and in those with unstable angina or evolving myocardial infarction has not been clearly established. The effect of late thrombolysis (12 to 24 hours after the onset of symptoms) is also currently unresolved, as is the impact of thrombolysis on mortality in patients with cardiogenic shock treated within the first 4 hours. Recombinant tissue-type plasminogen activator (rt-PA) is superior to streptokinase in lysing coronary thrombi,80 but one large trial (GISSI-II), the design of which has been questioned, has shown that rt-PA is not superior to streptokinase in reducing mortality.81 The preferred thrombolytic agent for use both before and after hospitalization and the potential value of combinations of thrombolytic agents in improving the initial rate of reperfusion and preventing reocclusion are other unresolved issues. Increased lytic activity would appear to be a desirable feature of new thrombolytic agents, but such activity may increase the risk of bleeding complications, particularly hemorrhage into the central nervous system. Whether or not newer more fibrin-specific thrombolytic agents will provide effective thrombolysis without an increased risk remains to be determined. Alternative simplified methods of administration of thrombolytic agents, such as front-loading bolus injections2 and self-administration, may allow more effective, more rapid thrombolysis, but the value of such means of delivery has yet to be demonstrated. Early administration of thrombolytic therapy before hospitalization is another alternative treatment strategy being investigated. Phase I of the Seattle Myocardial Infarction, Triage, and Intervention Project established the feasibility of the initiation of thrombolysis by emergency medical technicians in the prehospital setting,83 and phase II of this investigation is now comparing the risks and benefits oftPA administration in the field and after arrival in the emergency room. Another area requiring further investigation is the role of adjuvant drugs, such as anticoagulants, antiplatelet agents, beta-adrenergic blockers, and free radical inhibitors and scavengers, as adjuncts to thrombolytic therapy. The benefits of establishing patency of an infarct-related coronary artery in the absence of myocardial salvage remain to be determined. The subsets of patients (if any) in

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1

whom early and late PTCA may be beneficial after thrombolysis have yet to be identified. In addition, there is a need for improved methods for stratification of patients with acute myocardial infarction to the most appropriate methods of intervention, for example, thrombolytic therapy, PTCA, CABG, and combinations of the therapies. Reperfusion injury. The reestablishment of coronary perfusion after coronary occlusion is associated with both irreversible necrosis and a reversible form of injury referred to as stunned myocardium.84 It is likely that stunned myocardium represents a functional form of reperfusion injury. Myocardial stunning, which is characterized by prolonged but ultimately reversible systolic and diastolic dysfunction,s4 has been produced consistently in animal models. Stunning has been demonstrated to occur in patients after spontaneous or pharmacologic thrombolysis or the relief of vasospasm in patients with unstable angina. The overall frequency and importance of this phenomenon in humans, however, is unknown. Both the generation of oxygen-derived free radicals and the transient overload of myocytes with calcium during early reflow are believed to be involved in the pathogenesis of myocardial stunning.85* 86 Free radical scavengers, such as superoxide dismutase with cat&se and the ACE inhibitor captopril, transient reperfusion with a low calcium solution, calcium channel blockers,s7 and maintenance of acidosis,88 which may prevent sodium/calcium exchange, have been shown to prevent or reduce myocardial stunning in the laboratory. Whether any of these approaches would be useful clinically is not known. Myocardial stunning is associated with certain metabolic abnormalities, such as a deficiency in production of highenergy phosphate, inappropriately high myocardial oxygen consumption, and the preferential metabolism of glucose rather than free fatty acids for energy production. These abnormalities, however, do not appear to be directly responsible for dysfunction. Necrosis caused by reperfusion (i.e., a lethal or irreversible reperfusion injury) has also been demonstrated in some animal models, although not as consistently as myocardial stunning. Exposure of isolated cells, myocardial tissue, or intact hearts to oxygen-derived free radicals produces injury similar to reperfusion necrosis, providing evidence for a role of these substances in the pathogenesis of such injury. In addition, generation of free radicals has been noted in ischemic reperfused or hypoxic reoxygenated myocardial tissue. Finally, neutrophils may participate in the pathogenesis of reperfusion necrosis.8g Unresolved issues (Table IX). The precise biochemical mechanism(s) responsible for myocardial

Table

issues in coronary

disease

1255

IX. Unresolved issues related to reperfusion injury

1. Mechanism of myocatdial stunning 2. Causes for spontaneous reversal of stunning 3. Species and sources of free radicals responsible for stunning and tepetfusion necrosis 4. Clinical importance of stunned myocatdium and tepetfusion necrosis 5. Methods for prevention of myocatdial stunning and tepetfusion necrosis in patients with acute coronary syndromes

stunning remain unresolved, although it is presumably related in some way to calcium activation of the myofilaments. The reason for the spontaneous recovery of the stunned myocardium is also unknown. Consequently it is difficult to formulate strategies for accelerating the recovery process. An important unresolved issue is the clinical significance of stunned myocardium and reperfusion-induced necrosis. The species and sources of the oxygen-derived free radicals involved in myocardial stunning and reperfusion necrosis remain unidentified. It is possible that free radicals are released from the coronary endothelium as a result of the xanthine oxidase reaction or arachidonate metabolism via the electron transport chain or from intravascular or extravascular leukocytes. Theoretically administration of free radical scavengers before reperfusion would appear to be of potential benefit, although the scavenger(s) of choice has not been determined. ACE inhibition

in acute myocardial

infarction.

Experimental data suggest that ACE inhibitors may be beneficial during the acute phase of myocardial infarction.g0-v2 Reductions in myocardial oxygen demand as a result of reductions in arterial pressure and left ventricular filling pressure have been demonstrated with ACE inhibitor therapy both in animal models and in humans. ACE inhibitors have also been shown to reduce acute left ventricular dilation and infarct expansion, which occur early after myocardial infarction.g3 In addition, similar to nitroglycerin, ACE inhibitors cause dilatation of epicardial coronary arteries. ACE inhibition also reduces reperfusion arrhythmias in experimental models, although the antiarrhythmic effect in humans is less clear. Another potential benefit of ACE inhibition in the setting of acute myocardial infarction is the reduction in catecholamine release that has been observed in isolated hearts.v4 Again, however, whether similar activity occurs in humans remains to be established. Activation of the renin-angiotensin-aldosterone system in patients with acute myocardial infarction, especially those with left ventricular failure,v5 suggests that ACE inhibitors may be effective in the management of this subgroup.

1256

Dzau, Braunwald, et al.

Table X. Unresolved issues related acute myocardial infarction 1.

2. 3. 4. 5. MI,

American

to ACE inhibition

in

Role of renin-angiotensin system in myocardium and significance of its increased activity in acute MI Safety of ACE inhibitors in acute MI Effect of ACE inhibitors on infarct size, reperfusion necrosis, and reperfusion arrhythmias Clinical importance of reperfusion arrhythmias Significance of sulfhydryl group present in some ACE inhibitors myocardial

infarction.

UnresoZuecE issues (Table X). The role of the renin-angiotensin system in the heart is uncertain, and it is unclear whether the heightened activity of this system in acute myocardial infarction is detrimental or beneficial. The safety of ACE inhibitor therapy in acute myocardial infarction is another unresolved issue. There is some concern that these agents may cause an excessive reduction in arterial pressure, especially when used in conjunction with nitrates or other vasodilators. The impact of ACE inhibition on infarct size, reperfusion necrosis, and reperfusion arrhythmias in humans has not been determined, although beneficial effects have been demonstrated in animal studies.g1$ g5-g7It is unclear, however, whether reperfusion arrhythmias are of any clinical importance in patients with an acute myocardial infarction, There is some experimental evidence that ACE inhibitors containing a sulfhydryl group may have some advantage over agents without this group, particularly with respect to reducing reperfusion injury and improving coronary blood flow. g7,g8 These findings remain to be confirmed in humans. Post-myocardialinfarctionperiod.Patientswhohave

recovered from a myocardial infarction are at risk for further complications, which include reinfarction, congestive heart failure, and sudden death. The processes underlying the development of these secondary events begin shortly after an acute infarction. This section will examine certain aspects of the pathophysiologic processes that occur after infarction and various therapeutic modalities useful in secondary prevention after myocardial infarction. Post-myocardial infarction remodeling. After a myocardial infarction, both expansion of the infarct size and remodeling of the noninfarct zone are known to occur. These processes are progressive with time and contribute to the development of left ventricular dilatation, which increases ventricular wall stress and myocardial oxygen demand.%> loo The principal determinant of left ventricular dilatation is infarct size. However, transmural infarction is necessary for dila-

April 1991 Heart Journal

tation to occur. Furthermore, dilatation is greater with anterior than with inferior infarcti0ns.l’)’ The principal predictor of long-term survival after recovery from an acute myocardial infarction is ventricular function. Of the various indicators of ventricular function, end-systolic volume has been shown to be the most powerful predictor of survival, and superior to left ventricular ejection fraction,‘“g although the additional predictive power of end-systolic volume is apparent only when ejection fraction is reduced to less than 50%. Unresolued issues (Table XI). The time course of ventricular remodeling is not clearly understood. More information is also needed to determine whether there is an association between the patency status of the infarct-related artery and the development of left ventricular dilatation.lOIi It has been suggestedlo but not yet established that left ventricular dilatation can be attenuated by the late establishment of coronary patency. Secondary prevention. Postinfarction therapy with beta-adrenergic blockers appears to be a costeffective approach for improving survival. Pooled data from studies in which beta blocker therapy was initiated at the time of hospital discharge indicate a 25% relative reduction in the annual mortality rate during the first 3 years after infarction. Although calcium antagonists have proven efficacy in the treatment of angina pectoris, the effectiveness of these drugs in secondary prevention after myocardial infarction has been disappointing. Most clinical trials have shown minimum benefit in patients with Q wave infarction and perhaps a deleterious effect in some patient subsets. 1o,5,lo6 In contrast, patients with non-Q wave infarction appear to benefit from treatment with diltiazem.lo7 It remains to be resolved whether calcium antagonists will also be beneficial in patients with non-Q wave myocardial infarction treated with aspirin or thrombolytic therapy. It is well accepted that ventricular arrhythmias are an independent risk factor for death in patients who have recovered from a myocardial infarction. 108However, it remains to be proved whether suppression of asymptomatic ventricular ectopy improves survival in this patient population. The Cardiac Arrhythmia Suppression Trial was designed to address this question but was terminated prematurely because of the observation that treatment with the class IC antiarrhythmic agents flecainide and encainide resulted in an increase in mortality as compared with placebo.log These findings suggest a possible proarrhythmic effect of these agents that persists for months after the initiation of therapy. Aspirin has been shown to reduce the incidence of

Volume

121

Number

4, Part

Unresolved

1

“all important vascular events,” a term that includes nonfatal myocardial infarction, nonfatal stroke, and vascular death in patients with a previous myocardial infarction and in patients with a history of a cerebrovascular accident or unstable angina. Meta (overview)-analysis of 25 trials conducted with aspirin and other forms of antiplatelet therapy in such patients demonstrated a 25% reduction in “all important vascular events,” which includes statistically significant reductions of 32% in nonfatal myocardial infarction, 27 % in nonfatal stroke, and 15 % in vascular death.‘lO Aspirin has also been shown to reduce vascular events in patients with an evolving myocardial infarction. The reduction in “all important vascular events” in ISIS-II was 28%, which includes statistically significant reductions of 49 % in nonfatal reinfarction, 46% in nonfatal stroke, and 23% in vascular death. ACE inhibition may also be an important therapeutic modality for secondary prevention. Results of experimental studie&’ suggest that ACE inhibitors can prevent ventricular dilatation and improve survival in animals after an acute myocardial infarction. Indeed results of two recent clinical trials provide support for the attenuation of ventricular dilatation in humans by captopril. loor 112 An ongoing multicenter investigation, the Survival and Ventricular Enlargement study, is currently underway to examine the impact of an ACE inhibitor on postinfarction survival in humans. In addition, the Study of Left Ventricul Dysfunction (SOLVD) will also address the preceding question to some extent. Unresolved issues (Table XII). The role of other forms of intervention as secondary therapy after infarction is less clearly defined. Pooled results of randomized trials of secondary prevention with cholesterol reduction indicate a 1.9% decline in recurrent cardiac events for each 1% reduction in cholesterol levels.3 However, the number of patients involved in such trials has been relatively small, and further investigations are needed to more fully examine the impact of lowering cholesterol levels. If this apparent beneficial effect can be confirmed in large-scale trials, cholesterol reduction would appear to be a very costeffective approach to secondary prevention. The role of combining different classes of drugs in secondary prevention must also be evaluated. The mechanism responsible for the reduction in mortality and cardiac events in patients treated with beta blockers and aspirin is not yet understood. Consequently it is not known whether the use of these drugs in combination is associated with additive or synergistic effects. Unresolved issues regarding aspirin concern the

issues in coronary disease

1257

Table Xl. Unresolved issuesrelated to post-myocardial in-

farction remodeling 1. Time course of ventricular remodeling 2. Role of patency status of infarct-related of left ventricular dilatation

Table

after infarction artery as determinant

XII. Unresolved issuesrelated to secondarypreven-

tion 1. Role of cholesterol reduction in secondary prevention 2. Role of combination therapy (e.g., aspirin, beta blockade, ACE inhibition) in secondary prevention 3. Effect of ACE inhibitors on mortality after infarction in humans 4. Optimum time of onset of ACE inhibitor therapy 5. Effect of combined therapy with ACE inhibitor and thrombolysis 6. Effect of ACE inhibition when combined with late reperfusion

best dose, frequency of administration, or rate of release of aspirin or other platelet-active agents for achieving the optimum net benefit on reinfarction, stroke, and vascular death. To address this question, basic research findings are needed to determine the optimum regimen for controlling thromboxane while also sparing prostacyclin and minimizing the occurrence of side effects. The clinical relevance of prostacyclin sparing could also be further elucidated. In addition, clinical research is necessary to determine the optimum loading dose during evolving myocardial infarction to achieve the most rapid clinical antithrombotic effect. Another unresolved issue concerns the effect of adding anticoagulants to a regimen of aspirin therapy for patients during an evolving myocardial infarction. To address this question, large randomized trials of sufficient sample size are necessary to determine the relative net benefits of aspirin alone versus a combination of aspirin plus anticoagulant therapy. Although flecainide and encainide appear to be detrimental in post-myocardial infarction patients with ventricular premature contractions, it is still unclear whether other antiarrhythmic agents such as ethmozine, amiodarone, or sotalol can exert beneficial effects in these patients. In particular, it remains to be demonstrated whether antiarrhythmic therapy will benefit higher risk subsets of patients than those in the Cardiac Arrhythmia Suppression trial, such as those with left ventricular dysfunction and/or ventricular tachycardia. It is also unknown whether ACE inhibitors will decrease mortality in patients after myocardial infarction, although as previously mentioned a study is

1258 Table

Dzau, Braunwald, et al. XIII. Unresolved

issues related

American

to heart failure

1. Comprehensive definition of heart failure 2. Definition of arrhythmic death 3. Methods for quantifying clinical improvement in patients with heart failure 4. Factors responsible for symptoms in patients with left ventricular dysfunction 5. Explanation for status of ejection fraction, myocardial oxygen consumption, and ventricular tachycardia as independent markers of prognosis in heart failure 6. Status of neurohormonal stimulation as independent risk factor 7. Appropriate form of beta-adrenergic receptor manipulation, i.e., stimulation or blockade, in patients with heart failure 8. Factors that determine progression of left ventricular dysfunction 9. Impact of interventions that improve ejection fraction by divergent means on mortality 10. Impact of interventions that decrease ventricular arrhythmias on mortality 11. Optimum method for assessing effect of treatment of heart failure on quality of life

currently underway to examine this question. If these drugs are found to have a beneficial effect on survival, the optimum time for the initiation of therapy must be determined. Whether or not ACE inhibitors should be used in combination with a thrombolytic agent is another unresolved issue. Furthermore, it is not clear what effect if any ACE inhibition may have on late reperfusion achieved by either pharmacologic or mechanical means. Heart failure. Other than death resulting from arrhythmia, heart failure is the final expression in the chain of events in coronary artery disease (Fig. 1). Congestive heart failure after myocardial infarction is principally a defect in systolic function, and the present discussion is limited to that form. Heart failure is a complicated syndrome that involves both the heart and the periphery. The cardiac and peripheral aspects of heart failure interact and cannot be considered independently. Instead the mechanical, neurohormonal, metabolic, and local regulatory factors that contribute to this interaction must be taken into account. Because of the complexity of this interaction and the lack of a good animal model of heart failure, few issues regarding this clinical syndrome are currently fully resolved. The knowledge that we do have in this area might be more accurately categorized as “possibly resolved.” Neurohormonal activation, which has been observed both in animal models of heart failure and in patients withlmoderate and severe heart failure, is believed to represent a physiologic response to contractile dysfunction. ii3y 114 Certain drugs used in

April 1991 Heart Journal

treating heart failure, such as diuretics, exacerbate this response, 115 In addition to its role as a compensatory mechanism in heart failure, neurohormonal activation is also believed to contribute to the pathophysiology of heart failure, perhaps by influencing renal perfusion, sodium excretion, exercise tolerance, ventricular contractility, and the development of arrhythmias. The prognosis of advanced heart failure is poor. Several studies have reported that patients with class III-IV heart failure have approximately a 50% mortality rate within 1 year. ii69 Ii7 This overall prognosis appears to be related to the severity of heart failure and the degree of neurohormonal activation.l14 Left ventricular function, as reflected in left ventricular ejection fraction, has been shown to be a powerful predictor of survival in patients with heart failure.l’s Ventricular tachycardia is another potential independent risk factor for mortality, particularly sudden death. Despite its poor correlation with ejection fraction, impaired exercise tolerance, the principal clinical manifestation of heart failure, is also an independent predictor of mortality, especially mortality attributable to pump failure.ll* Vasodilators, including ACE inhibitors, not only improve hemodynamics in patients with heart failure but also relieve symptoms and prolong survival. The Veterans Administration Cooperative Study showed that the combination of hydralazine and a long-acting nitrate when added to digitalis and diuretics can improve survival in patients with advanced heart failure.l17 However, prazosin therapy was no better than placebo (plus digitalis and diuretics) in affecting life expectancy. The CONSENSUS trial showed that an ACE inhibitor (enalapril) significantly improved survival (by 31% ) at 1 year in patients with advanced heart failure who were receiving digitalis, diuretics, and vasodilators other than ACE inhibitors.‘16 It is also clear that ventricular arrhythmias are very common in patients with heart failure, and sudden death, presumably the result of ventricular fibrillation, may account for up to 50% of deaths in such patients. ACE inhibitors appear to reduce the frequency of ventricular ectopy in these patients.llg ACE inhibitors improve symptoms and exercise capacity and reduce hospital visits in patients with mild to moderate heart failure. When added to diuretics, captopril compares favorably with digoxin and diuretics and is better than diuretic therapy alone in these patients.120 Unresolved issues (Table XIII). One unresolved issue in the area of heart failure is the definition of this syndrome. Clinical trials to evaluate potential drug therapy generally define heart failure as a

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1

reduction in exercise tolerance and/or symptoms of exertional dyspnea and fatigue, but a more broadbased definition is needed. Arrhythmic deaths also require a clearer definition. Not all sudden deaths are caused by arrhythmias, and some method of precisely identifying arrhythmic deaths is required. This distinction is especially important for the evaluation of therapies with a selective action on arrhythmias. A third related unresolved issue is the best method of quantifying clinical improvement in heart failure. The factors responsible for symptoms in patients with left ventricular dysfunction have not been clearly established. Many patients with severely depressed left ventricular function are totally asymptomatic, whereas others exhibit overt heart failure.121 The reason why ejection fraction, exercise performance, and ventricular arrhythmias appear to be independent markers of prognosis in patients with heart failure is also unexplained. It is not known whether these three factors are truly independent markers or instead represent an integrated expression of the severity of the disease. The role of neurohormonal stimulation as an independent risk factor is also unknown. Because some of the drugs used in the management of heart failure, such as diuretics, dopamine, and dobutamine, cause neurohormonal stimulation, whereas others, such as ACE inhibitors, produce neurohormonal inhibition, this issue may have important clinical implications. In addition, resolution of this question may clarify whether the efficacy of ACE inhibitors in heart failure is attributable primarily to the hemodynamic benefits provided by these drugs, to the inhibition of the renin-angiotensin-aldosterone system, and/or to the sympathetic nervous system. The relative importance of the tissue versus circulating renin-angiotensin system in heart failure also needs elucidation. Related to this issue is the question of whether betaadrenergic receptors should be stimulated or blocked in patients with heart failure. Unresolved issues from a therapeutic standpoint are the role of beta-adrenergic agonists and nondigitalis inotropic agents in heart failure.122 Also unclear is the proper first-line drug (diuretics vs digitalis vs ACE inhibitor) or combination of drugs in the treatment of early heart failure. How early in the development of heart failure should these therapeutic agents be used? Finally, it is unclear whether any pharmacologic therapy in early or mild heart failure will alter life expectancy. Sequential data are currently insufficient to understand the natural history of heart failure. Results of controlled studies indicate that progressive deterioration of left ventricular ejection fraction does not

Table

XIV.

issues in coronary disease

1259

Future directions for research in the field of

heart failure 1. Identification left ventricular 2. Development lar dysfunction 3. Development progression 4. Evaluation of

of key factors that contribute to progression of dysfunction of strategies to prevent progression of ventricuof

strategies

combination

to

identify

patients

at

risk

of

therapy

necessarily occur in all patients who ultimately die of heart failure. However, the factors that determine whether or not ejection fraction will continue to decline remain undefined. The impact on mortaIity of interventions that improve ejection fraction, an important predictor of survival, is not known. There are no data showing that the newer inotropic agents prolong life, even though they improve left ventricular function, and there is some concern that the opposite may actually be true. 123 Likewise the influence on mortality of agents that reduce the frequency of ventricular arrhythmias has not been established. Although improvement in the quality of life is an important aspect of the management of heart failure, the best method of assessing the effect of treatment on this variable has not been identified. It has been shown that clinical impressions of improvement do not necessarily correlate with objective measures of improvement. Finally, a better understanding of the molecular mechanism of myocardial failure may provide new insights into the treatment of this condition. For example, the hypertrophic response of the heart to a pressure overload such as hypertension or after loss of myocardial mass such as myocardial infarction is one in which there is not only an increase in cell size (total protein) but also a change in the type of protein. There is significant reexpression of fetal proteins with a recapitulation of various fetal patterns. These fetal proteins, which include myosin, actin, and tropomyosin, appear to be altered to conserve energy. However, these fetal forms, which are different than the adult forms, may in some way, with prolonged exposure to a normal or increased work load, be more vulnerable to energy exhaustion and deterioration. Elucidation of the mechanisms responsible for the gene switching and factors that involve the cardiac growth response will require widespread application of the techniques of recombinant DNA and molecular biology. Results of this research are likely to provide an understanding of the pathogenesis of heart failure, as well as the design of specific drugs to enhance cardiac growth, and be applicable to the

1260

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American

prevention and treatment of cardiac failure. Hopefully in the future myocytes may be induced to replicate and undergo hypertrophy, which would represent a more appropriate adaptive and repair mechanism to cardiac disease. Future directions (Table XIV). These unresolved issues provide suggestions and guidelines for future research in the field of heart failure. A major objective of such research should be the prevention rather than the treatment of heart failure. Identification of the key factors that contribute to progression of heart failure, such as progressive ventricular dysfunction or the neurohormonal response to ventricular dysfunction, is of great importance. An understanding of these factors is critical to the formulation of strategies for the prevention of progressive dysfunction. Furthermore, techniques for the identification of patients at risk of progression are essential for targeting therapy to the population most in need of intervention. Finally, because heart failure is a multifactorial process, combination therapy with various drug classes, such as vasodilators, inotropic agents, diuretics, and antiarrhythmics, should be evaluated.

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SUMMARY

Advances in cardiovascular research during the past two decades have resulted in an improved understanding of the chain of events that lead to end-stage coronary artery disease. These developments have been paralleled by therapeutic advances that now make it possible to intervene at virtually every stage in the development of advanced cardiac disease, from asymptomatic persons at risk of developing coronary atherosclerosis to patients with endstage heart failure. By interrupting this chain of events, perhaps at multiple sites, it may be possible to prevent or slow the development of symptomatic heart disease and hopefully prolong life. Many opportunities exist for obtaining further information regarding the underlying pathophysiology, the fundamental mechanisms of action of interventions designed to prevent and/or treat the development of myocardial ischemia and cardiac failure and for effecting favorably the natural history of various forms of heart disease. We gratefully acknowledge Gibbons in the preparation

the helpful assistance of this manuscript.

of Dr.

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Gary

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