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Management of Patients with Hypertension and Angina Pectoris
Management of Patients with Hypertension and Angina Pectoris
DAVID E. BUSH, M.D. BERNADINE HEALY BULKLEY, M.D. Baltimore, Maryland
From the Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland. This study was supported by Ischemic Heart Disease Specialized Center for Research, P50-HL-17655-05 and Training Grant 5-T32-HL-07227 from the National Institutes of Health, Public Health Service, Department of Health, Education, and Welfare, and the Peter Belfer Laboratory for Myocardial Research, Baltimore, Maryland. Dr. Bush is supported in part by a fellowship from the American College of Chest Physicians, Park Ridge, Illinois. Requests for reprints should be addressed to Dr. Bernadine Healy Bulkley, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21205.
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Management of patients with concomitant hypertension and angina pectoris mandates that the physician pay attention to the underlying pathophysiology. The heart, when exposed to years of hypertension, becomes "remodeled." Overall mass is enlarged, the walls are thickened, and initial cavity volume remains normal or relatively small. Left ventricular end-diastolic pressure rises in the setting of a hypertrophic noncompliant ventricle; coronary resistance and coronary perfusion pressure are increased; and coronary vascular reserve, even with widely patent coronary arteries, is decreased. Long-standing hypertension-a risk factor for coronary atherosclerosis-is often accompanied by epicardial coronary stenoses that aggravate these coronary abnormalities. In managing the patient with hypertension and angina pectoris, it is important to determine whether the angina occurs in the setting of hypertensive hypertrophic disease alone or coexists with coronary arterial stenoses. Also important to therapy is whether the ventricle is of normal size with good function or decompensated with dilatation and diminished function. The latter two anatomic considerations, namely, epicardial coronary patency and left ventricular cavity size, will influence the choice of an anti-ischemic regimen. For example, diuretic and nitrate therapy can be hazardous, and digitalis unnecessary, in the setting of a nondilated hypertrophic ventricle with hyperdynamic function. On the other hand, the combined use of beta blocking agents plus calcium antagonists is particularly effective in lowering blood pressure and in improving coronary blood flow. Finally, this combination has been shown to be rapidly effective and to have prolonged benefit in this setting. The choice of these latter agents is also affected by the underlying state of the ventricle. Calcium channel blocking agents without significant negative inotropic effect, such as nifedipine and nitrendipine, would be suitable in patients with decompensated ventricular function and dilated left ventricular cavities. Both of these drugs have been shown to increase cardiac output and contractility via a reflex effect and to have little or no direct negative inotropic effect. In contrast, verapamil has a direct negative inotropic effect. The final choice of agents must be tailored to the needs of the individual patient, and the physician also has to determine the role of specific agents in the natural history of hypertensive heart disease. A wide variety of drugs are available for the treatment of hypertension and angina pectoris. Essential hypertension increases cardiac oxygen requirements by increasing the workload of the heart and, over time and
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Figure 1. Shown is a heart with hypertrophic hypertensive cardiomyopathy with coexisting coronary artery disease. On the left is a postmortem angiogram showing the thick walls, small ventricle, and coronary artery lesions. Also on the left is a transverse section through both ventricles. Such hypertrophied ventricles typically have diastolic filling abnormalities, and congestive heart failure develops on that basis rather than in response to poor systolic function.
with the development of hypertrophy, by increasing the amount of myocardium to be perfused. When coronary artery disease is present, th~ capacity of the heart to respond to an increased workload is diminished. In addition, hypertension is reGqgnizect as a major risk factor for coronary heart disease and may accelerate its development. Selection of a drug regimen that will offer the highe~t therapeutic efficacy when these two common conditions coexist requires attention to the underlying pathophysiology of these disorders. HYPERTENSION AND ITS EFFECTS ON THE HEART
Blood pressure is determined by the product of two factors: cardiac output and peripheral resistance. Hypertension can result from an increase in either or both. In the most common form of hypertension-essential or primary hypertension-an increase in peripheral resistance is the predominant factor. As blood pressure increases, so does wall tension in the heart and in the cardiovascular arteries. The exact sequence of events coupling increases in wall tension to the biochemical process that leads to the development of hypertrophy has yet to be identified. A chronic increase in systolic wall tension appears to be a major factor responsible for cardiac hypertrophy in essential hypertension (1-3]. Other influences such as neurohumoral factors, metabolic status, and genetics may modulate the level of hypertrophy resulting from increases in cardiac load [4]. Thus, in response to chronic elevations in wall tension, the heart is remodeled [5]. Two different types of cardiac remodeling are observed in response to increased load and depend on whether the load is primarily due to increased pressure or increased volume [3]. In response to pressure overload, the ventricle remodels by increasing wall thickness while maintaining a normal or smaller than normal cavity size. This results in an increased ratio of myocardial mass to cavity volume and serves to normalize wall stress. When faced with a chronic volume overload, the heart increases both the ventricular wall thickness and the cavity volume. In most cases, this serves to maintain a relation of myocardial
mass to cavity volume that is similar to the ratio in a normal heart. In response to chronic hypertension, the heart generally remodels as for a pressure overload with an appropriate increase in the myocardial mass to cavity volume so that wall stress remains near normal. Some intriguing recent data suggest that obesity may play a role in the hypertrophic response of the heart to hypertension [6]. It has been postulated that in some patients with hypertension, a degree of hypertrophy adequate to normalize wall stress either cannot be maintained or does not occur; as a result, a dilated cardiomyopathy ensues [7,8] (Figures 1 and 2). The major determinants of myocardial oxygen demand are wall tension, heart rate, and contractility. In a ventricle working under an increased load, hypertrophy that increases the thickness of the ventricular wall relative to the cavity volume should reduce wall stress by the law of Laplace. Provided the other determinants of myocardial oxygen demand were not adversely affected, cardiac hypertrophy could represent a useful adaptation to chronic demands for increased function [3]. However, in association with coronary artery disease, hypertrophic cardiomyopathy may adversely affect the disease process by altering the myocardial supply-demand relationship. This association is supported by the finding that som~ patients with either primary or secondary left ventricular hypertrophy experience angina peetoris and electrocardiographic changes of myocardial ischemia in the presence of normal coronary arteries [9, 10]. Studies have demonstrated a marked reduction in coronary reserve in patients with left ventricular hypertrophy secondary to hypertension and angiographically normal coronary arteries [11 ]. It has been postulated that the reason for this reduced reserve is an inability of the myocardial capillaries to adequately supply hypertrophic myocytes [12,13]. Also, elevated left ventricular and diastolic pressure impairs the transmural perfusion gradient from epicardium to endocardium. Abnormalities in cardiac diastolic function are also observed in the presence of hypertensive hypertrophic cardiomyopathy. These alterations are characterized by a
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Figure 2. Shown here is a heart from a patient who died with a dilated cardiomyopathy. Although the mass of the heart is enlarged as is the heart in Figure 1, its major impairment was hypodynamic systolic function.
prolonged left ventricular isovolumic relaxation period and impaired diastolic filling [14]. These abnormalities may also play a role in the increased coronary resistance commonly observed in this setting. In addition, hypertension is a known risk factor for the development of coronary atherosclerosis, which would serve to further compromise myocardial blood supply. PATHOPHYSIOLOGY OF ANGINA PECTORIS
Angina pectoris results when myocardial oxygen demand exceeds supply. Various combinations of events resulting in either an increase in myocardial oxygen requirements or a decrease in blood supply can cause angina. In many patients, angina is due to a decreased coronary blood supply resulting from atherosclerotic plaques narrowing the lumen of epicardial coronary blood vessels. In many patients, coronary vasospasm may also play a role in the development of angina. Vasospasm appears to be rare in patients with purely exertional angina, but it may be an important factor in patients with rest angina. Vasospasm has been demonstrated in approximately 15 percent of patients with exertional angina and in about 40 percent of patients with predominantly rest angina. Parasympathetic stimulation or alterations in prostaglandins-for example, platelet production of thromboxane A2 or decreased prostacyclin production in the vessel wall-may influence the pathogenesis of coronary spasm. Transient decreases in blood supply due to thrombosis or platelet aggregation could also be factors in the etiology of angina. CLINICAL ASSESSMENT OF THE PATIENT WITH HYPERTENSION AND ANGINA
In managing the patient with hypertension and angina, it is important to determine whether the angina is occurring in response to hypertensive hypertrophic disease alone or with coexisting coronary artery stenoses. Lowering the blood pressure will result in reduced cardiac work and thereby a reduction of myocardial oxygen demands regardless of the presence of coronary artery disease. Anti-
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hypertensive therapy should in general improve the ratio of myocardial demand to supply. In patients with angina and hypertrophic ventricles but without coronary disease, a decrease in angina can be expected by control of blood pressure. Reduction in the anginal symptoms in these patients is probably directly related to the control of blood pressure. It has been observed that, in experimental animals as well as in patients, control of blood pressure can reverse the hypertrophic changes associated with longstanding hypertension [15, 16]. The finding that normalization of blood pressure does not, in all instances, result in complete regression of hypertrophic cardiomyopathy may be an indication of additional factors in the pathogenesis of hypertrophy [17-191. It has been suggested that the degree of ventricular hypertrophy in hypertension may be more closely related to blood pressure [8]. Such findings suggest that regression of hypertrophic cardiomyopathy may be more likely with agents that directly lower peripheral resistance. In the setting of significant epicardial coronary artery stenosis, coronary reserve will not be uniform. Antihypert~nsive agents t~~t ~re also vasodilators, such as the calcium channel blockers, may provide an additional benefit for patier~ts with coronary atherosclerosis because they dilate epicardial coronary blood vessels and improve collateral flow to ischemic regions of the left ventricle. The assessment of ventricular size and performance is also relevant to therapy. It is particularly important to distinguish the hypertrophied ventricle that is of normal size with good or adequate function from the ventricle that is dilated with poor function. In patients with hypertrophic cardiomyopathy with thick ventricular walls and normalsized cavities, systolic performance is usually normal, although diastolic filling is often impaired, In such a case, it becomes important to maintain adequate diastolic filling. Agents that are likely to be most beneficial in this group of patients are those that reduce heart rate and therefore improve the diastolic filling period. Agents that substantially reduce preload-nitrates or diuretics, for example-
CALCIUM CHANNEL BLOCKERS SYMPOSIUM-BUSH and BULKLEY
may actually be hazardous in this group of patients, as such a reduction may actually aggravate diastolic filling abnormalities. Digitalis is also probably unnecessary and potentially harmful in this group of patients, since systolic function is usually not significantly impaired. In contrast, patients with hypertension and dilated ventricles with poor function are likely to benefit from agents that reduce after~ load without significant negative inotropic effects. To distinguish the hypertrophic ventricle with good left ventricular function from the dilated hypodynamic ventricle, one- or two-dimensional echocardiography is the single most useful test. With the echocardiogram, precise information on wall thickness and left ventr.icular cavity diameter are readily obtainable, as is an assessment of left ventricular function. When coronary artery disease is suspected, it may be difficult to interpr13t changes in the electrocardiogram at rest or during exercise. Exercise testing should not be performed in patients with angina and hypertension until adequate control of blood pressure has been achieved. In patients with markedly abnormal electrocardiograp~ic findings at rest, an exercise stress test can be performed with thallium 201 imaging, which allows a more precise interpretation of exercise-related electrocardiographic changes. Hypertension is a known risk factortor coronary disease, and the two diseases frequently coexist. -In patients with long-standing hypertension, the only way to establish the presence and severity of coronary disease is to perform coronary angiography. The decision to carry out this procedure, however, is only made when a patient is poorly responsive to antianginal medications or if an unstable coronary syndrome develops. ANTIHYPERTENSIVE MEDICATION IN THE PATIENT WITH ANGINA AND HYPERTENSION
Diuretics. These agents are considered to be the cornerstone of antihypertensive therapy. Thiazide diuretics are generally safe and effective for the treatment of hypertension. All diuretics produce their initial blood pressure response by reducing plasma volume via an increase in urinary sodium excretion. Long-term diuretic therapy sustains reductions in blood pressure by lowering peripheral resistance. ·When diuretics are administered to patients for the .tr~atment of hypertension, particular attention shollld be paid to the level of serum potassium in the presence of coexisting ischemic heart disease. Most diuretics will lower serum potassium to some degree. Many of these patients will also be receiving digitalis for the treatment of congestive heart failure. It is well known that hypokalemia in the presence of digitalis is associated with an increased risk for arrhythmic complications. There is also reason to suspect that diuretic-induced hypokalemia may be arrhythmogenic in. patients with ischemic heart disease who are not receiving digitalis. During an attack of angina, the level of circulating catecholamines is usually
increased. It has recently been reported that physiologic increases in circulating epinephrine levels can induce hypokalemia by stimulation of a beta2 receptor (20]. The ischemic myocardium is more sensitive to th.e arrhythmogenic effects of hypokalemia and elevated levels of catecholamines than is the nonischemic myocardium. Thus, during an attack of angina, the level of circulating catecholamines is elevated, and cellular hypokalemia may be induced. Diuretics; which also may ·chronically deplete potassium, might expose patients with angina to an increased risk for arrhythmic complications. Because of the effect of diuretics on ventricular function, they should also be used with caution in patients with hypertrophic ventricles and small or normal cavity size. In these patients, diastolic filling is often markedly abnormal, although systolic function remains normal. Any agent that will reduce preload may further impair diastolic filling. As with idiopathic hypertrophic cardiomyopathy, impaired filling and increased emptying of the hypertrophic ventricle may lead to increased left atrial pressure, pulmonary congestion, and, possibly, lowered cardiac output. Thus, paradoxically, preload reduction with either a diuretic or anitrate may precipitate or aggravate congestive heart failure. Beta Blockers. Beta-adrenergic blocking agents have been shown to be effective in the separate treatment of both angina and hypertension. Although the mechanism by which beta blockers reduce blood pressure is incompletely defined, the beneficial effects of these agents in angina are apparently related to their ability to reduce myoca~dial oxygen demand by decreasing heart rate, contractility, and blood pressure. Thus, this group of agents would seem to be a logical choice when the two conditions coexist. A wide variety of beta blockers are currently available. These compounds differ chemically, and there are differences in some of their pharmacologic effects as well. Pharmacologic properties of beta blockers that theoretically could be relevant to drug selection in the patient with hypertension and angina include cardioselectivity, partial agonist activity, and membrane stabilizing activity (21-23]. Cardioselectivity: There are two categories of beta receptors: beta1 receptors, which cause cardi~c stimulation and renin release, and beta2 receptors, which cause vasodilatation and bronchodilatation. Cardioselectivity refers to beta blockers that inhibit the beta 1 receptor to a greater degree than the beta2 receptor. In lheory, beta2 blockade of peripheral arterioles ·might allow vasoconstriction via unopposed alpha effects. Partial agonist activity: Another phrase to describe partial agonist activity is intrinsic sympathomimetic activity, which is defined as the mild sympathetic stimulation that occurs in the presence of certain beta blockers. Clinically, beta blockers with partial agonist activity demonstrate less resting bradycardia and less reduction of car-
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TABLE I
Approximated Relative Effects of Three Calcium Channel Blockers
Calcium Channel Blocker
Vascular Muscle
Cardiac Muscle
Inhibition of Conduction
Diltiazem Nifedipine Verapamil
+++ ++++ ++
++ + ++
++ + +++
diac output. It is not yet clear whether beta blockers with partial agonist properties are as effective for the treatment of hypertension and angina as those without this activity. They have theoretic benefit for the patient with congestive heart failure and a hypodynamic ventricle in the setting of hypertension. Membrane stabilizing activity: This property is demonstrated by certain beta blockers with the ability to produce local anesthesia and alter Phase 0 of the cardiac action potential. Although it has been suggested that membrane stabilizing activity has beneficial antiarrhythmic and antiplatelet effects, these effects may only be present in dosage ranges that are higher than those used clinically. In addition, agents without membrane stabilizing activity have also been shown to demonstrate antiarrhythmic properties. The significance of this effect has not yet been fully explored by clinical studies. The clinical importance of cardioselectivity, partial agonist activity, and membrane stabilizing activity are not fully understood. It has been shown, however, that some patients may experience an increase in angina while receiving beta blockers [24]. This effect is presumably due to an unopposed alpha-adrenergic vasoconstrictor effect on the coronary arteries, which has been shown to be blocked by nifedipine [25]. Thus, combining a vasodilator with a beta blocker would seem especially appropriate for patients with hypertension and exertional angina. In particular, patients with rest angina may benefit from the addition of a calcium channel blocker, either alone or in combination with a beta blocker [26]. Calcium Channel Blockers. Calcium channel blockers are effective in the medical treatment of variant and typical angina as well as hypertension [27]. These drugs also possess an ability to improve collateral flow to ischemic areas of the"myocardium [28,29]. Improved collateral flow should prove to be a cardioprotective benefit to patients with angina. Calcium channel blockers, as a class, act by inhibiting calcium movement across cell membranes, particularly in myocardium and vascular smooth muscle. These drugs have negative inotropic effects in cardiac and vascular smooth muscle, reduce impulse formation, and slow conduction through the sinoatrial and atrioventricular nodes. Increased peripheral resistance is found in
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most types of hypertension. Using vasodilators that act directly on arterial resistance vessels in the treatment of hypertension has a logical appeal. Calcium channel blockers may be particularly attractive as vasodilators in hypertensive patients due to their negative chronotropic action, which appears to limit reflex tachycardia in comparison with other vasodilators. In patients with secondary hypertrophic cardiomyopathy, calcium channel blockers may confer additional advantages: Improvements in diastolic function characterized by decreases in left ventricular and diastolic pressures, improved left ventricular distensibility, and enhanced left ventricular filling have been shown to occur with calcium blockers. Calcium channel blockers have a variety of chemical structures and exhibit differences in their effects on target tissues. Approximated relative effects of several calcium channel blockers are shown in Table I. These differences in tissue effects may be important in drug selection. For example, in patients with dilated, poorly functioning ventricles, concern has been expressed that the negative inotropic properties of some calcium channel blockers might be detrimental. Studies have shown, however, that calcium channel blockers can be given to patients with depressed left ventricular function [30-33]. Nifedipine may be particularly useful in this group of patients since its powerful vasodilating effects may actually work to improve cardiac function. Calcium channel blockers and beta blockers both have useful effects in the treatment of hypertension and angina, and they work by different mechanisms. Their use in combination, therefore, might be desirable in many instances, particularly in patients with coexisting hypertension and angina. There has been concern that the use of beta blockers and calcium channel blockers together might markedly reduce left ventricular contractility and heart rate. T.he combination of nifedipine and propranolol, however, has been shown to be safe in patients with concomitant hypertension and angina. In patients with depressed ventricular function, however, especially in the presence of dilated cardiomyopathy, caution in the combined use of calcium channel blockers and beta blockers seems prudent. In such patients, nifedipine, which has fewer myocardial depressant effects than verapamil, might be advantageous, especially when it is to be used in combination with a beta blocker [34]. Other Antihypertensive Agents and Nitrates. In addition to diuretics, calcium blockers, and beta blockers, several other classes of antihypertensive agents are available for the treatment of hypertension. Such drugs include sympathetic blockers, which may act either by central mechanisms (for example, methyldopa, clonidine) or peripherally (for example, reserpine, guanethidine). Vasodilators such as hydralazine and minoxidil and converting enzyme inhibitors such as captopril are also useful in the treatment of hypertension. Insofar as hypertension aggra-
CALCIUM CHANNEL BLOCKERS SYMPOSIUM-BUSH and BULKLEY
vates angina by increasing the workload of the heart, any therapy that reduces blood pressure should be beneficial. As beta blockers and calcium blockers each have direct therapeutic efficacy in the treatment of hypertension and angina,· their use in patients in whom these conditions coexist is particularly attractive. Nitrates are useful in the treatment of angina of all causes. Nitrates are not, however, particularly effective in the management of chronic hypertension. CARDIOVASCULAR RISK IN ANTIHYPERTENSIVE THERAPY
The question of whether antihypertensive therapy favorably affects all the diseases with which hypertension is an associated risk factor has not been answered. Several large cooperative studies have shown that antihypertensive therapy does reduce the incidence of stroke, renal failure, and heart failure, but they do not show statistically significant decreases in deaths related to coronary events [35,36]. Further concern has been raised by results from the Multiple Risk Factor Intervention Trial in which patients with multiple risk factors for atherosclerosis were assigned to either a special regimen of stepped-care therapy or to standard community health services [37]. In this study, no significant differences were found in overall coronary deaths between the two groups. Even more disturbing was the finding that in the special-care group, coro-
nary deaths were actually higher among hypertensive patients with resting electrocardiographic abnormalities. It has bee.n postulated that in these patients, many of whom presumably had underlying coronary disease, diuretic therapy may have been a factor in the higher mortality in the special-care group. · The recent report of the· Lipid Research Clinic Primary Prevention Trial showed that treatment of primary hypercholesterolemia with cholestyramine reduced the incidence of coronary heart disease [38]. These findings raise questions as to whether drugs that alter lipoprotein profiles by increasing triglyceride and total cholesterol levels (such as occurs with thiazides), reduce high-density lipoprotein cholesterol levels (as with beta blockers), or reduce the ratio of high-density lipoprotein cholesterol to total cholesterol (as is the case with methyldopa, reserpine, furosemide, and spironolactone) may actually increase the risk of coronary artery disease in patients receiving these drugs. Prazosin is an agent that is known not to have those effects. Another question is whether ri!)k factors associated with initiation of atherosclerosis are the same ones responsible for its progression. Results of studies evaluating primary risk factors as factors in the progression of coronary heart disease have yielded mixed results [39-42]. These questions, which may have a significant impact on the management of patients with hypertension and angina, await further clarification.
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Grossman W, Jones D, McLaurin LP: Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 1975; 56: 56-64. Meerson FZ: Development of modern components of the mechanism of cardiac hypertrophy. Circ Res 1974; 35(suppl II): 58-63. Grossman W: Cardiac hypertrophy: useful adaptation or pathologic process? Am J Med 1980; 69: 576-583. Frohlich ED, Tarazi RC: Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy? Am J Cardiel 1979; 44: 959-963. Folkow B: Cardiovascular structural adaptation; its role in the initiation and maintenance of primary hypertension. Clin Sci · Mol Med 1978; 55: 3s-22s. Messerli FH, Sundgaard-Rijse K, Reisin Ed, et al: Dimorphic cardiac adaptation to obesity and arterial hypertension. Ann Intern Med 1983; 99: 757-761. Strauer BE: Ventricular function and coronary hemodynamics in h}tpertensive heart disease. Am J Cardiel 1979; 44: 999-
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Devereux RB, Savage DO, Sachs I, Laragh JH: Relation of hemodynamic load to left ventricular hypertrophy and performance in hypertension. Am J Cardiol1983; 51: 171~176. Harris CN, Aranow WS, Parker DP, Kaplan MA: Treadmill stress ·in left ventricular hypertrophy. Chest 1973; 63: 353-357. Pasternac A, Bourassa MG: Pathogenesis of chest pain in patients with cardiomyopathies and normal coronary arteries. lnt J Cardiel 1983; 3: 273-280. Opherk D, Gerhard M, Zebe H, et al: Reduction of coronary
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reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation 1984; 69: 1-7. Roberts JT, Weam JT: Quantitative changes in the capillarymuscle relationship in human hearts during normal growth and hypertrophy. Am Heart J 1941; 21: 617-633. Linzbach AJ: Heart failure from the point of view of quantitative anatomy. Am J Cardiel 1960; ?: 370-382. Sanderson JE, Gibson DG, Brown OJ, Goodwin JF: Left ventricular filling in hypertrophic cardiomyopathy: an angiographic study. Br Heart J 1977; 39: 661-670. Kobayashi K, Tarazi RC: Effect of nitrendipine on coronary flow and ventricular hypertrophy in hypertension. Hypertension · 1983; 5(supplll): 45-51. Khatri I, Gottdiener J, Notargiacomo A, FreisE: Effect of therapy on left ventricular function in hypertension. Clin Sci 1980; 59: 435s-439s. Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE: Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa: lack of association with blood pressure control. Am J Cardiel 1982; 49: 795-801. · Mujais SK, Fouad FM, Tarazi RC: Reversal of left ventricular hypertrophy with captopril: heterogeneity of response among hypertensive patients. Clin Cardiel 1983; 6: 595-602. Devereux RB, Pickering TG, Harshfield GA, et al: Left ventricular hypertrophy in pati~nts with hYPertension: importance of blood pressure response. to regularly recurring stress. Circulation 1983; 68: 470-476. Brown MJ, Brown DC, Mu~hY MB: Hypokalemia from be~-
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receptor stimulation by circulating epinephrine. N Engl J Med 1983; 309: 1414-1419. Frishman WH: The beta-adrenoceptor blocking drugs. lnt J Cardiol 1982; 2: 165-178. Louis WJ, McNeil JJ, Jarrott B, Drummer OH: Beta-adrenoceptor blocking drugs: current status and the significance of partial agonist activity. Am J Cardio11983; 52: 104A-112A. Taylor SH: Intrinsic sympathomimetic activity: clinical fact or fiction? Am J Cardiol 1983; 52: 16D-26D. Kern MJ, Ganz P, Horowitz JD, et al: Potentiation of coronary vasoconstriction by beta-adrenergic blockade in patients with coronary artery disease. Circulation 1983; 67: 1178-1185. Tilmant PY, Lablanche JM, Thieuleux FA, Dupuis BA, Bertrand ME: Detrimental effect of propranolol in patients with coronary artery spasm countered by combination with diltiazem. Am J Cardiol 1983; 52: 230-233. Gerstenblith G, Ouyang P, Achuff SC, et al: Nifedipine in unstable angina: a double-blind randomized trial. N Engl J Med 1982; 306: 885-889. Nayler WG, Horowitz JD: Calcium antagonists: a new class of drugs. Pharmacol Ther 1983; 20: 203-262. Gross CJ, Warltier DC, Hardman HF: Comparative effects of two slow channel calcium entry blockers, FR 34235 and nifedipine, on true coronary collateral blood flow. J Cardiovasc Pharm 1984; 6: 61-67. Jolly SR, Hardman HF, Gross GJ: Comparison of two dihydropyridine calcium antagonists on coronary collateral blood flow in acute myocardial ischemia. J Pharmacol Exp Ther 1981; 217: 20-25. Ludbrook PA, Tiefenbrunn AJ, Reed FR, Sobel BE: Acute hemodynamic responses to sublingual nifedipine: dependence on left ventricular function. Circulation 1982; 65: 489-498. Ferlinz J, Citron PD: Hemodynamic and myocardial performance characteristics after verapamil use in congestive heart failure. Am J Cardiol1983; 51: 1339-1345. Lorell BH, Paulus WJ, Grossman W, Wynne J, Cohn PF: Modification of abnormal left ventricular diastolic properties by ni-
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fedipine in patients with hypertrophic cardiomyopathy. Circulation 1982; 65: 499-507. Aoki K, Kondo S, Sato K, et al: Hypotensive action of nifedipine (Ca2 + -Antagonist) and propranolol in acute trials and its long term therapy of hypertensive coronary heart disease patients. Jpn Heart J 1981; 22: 575-584. Winniford MD, Markham RV, Firth BG, Nicod P, Hillis LD: Hemodynamic and electrophysiologic effects of verapamil and nifedipine in patients on propranolol. Am J Cardiol 1982; 50: 704-710. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 1143. Helgeland A: Treatment of mild hypertension: a five-year controlled drug trial. The Oslo Study. Am J Med 1980; 69: 725732. Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results. JAMA 1982; 248: 1465-1477. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 251: 351-361. Moise A, Theroux P, Taeymans Y, et al: Clinical and angiegraphic factors associated with progression of coronary artery disease. JACC 1984; 3: 659-667. Bruschke AVG, Wijers THS, Kolsters W, Landman J: The anatomic evolution of coronary artery disease demonstrated by coronary arteriography in 256 nonoperated patients. Circulation 1981; 63:527-536. Nash DT, Gensini G, Esente P: Effect of lipid-lowering therapy on the progression of coronary atherosclerosis assessed by scheduled repetitive coronary arteriography. lnt J Cardiol 1982; 2: 43-55. Raichlen JS, Achuff SC, Bulkley BH, Pearson TA: Risk factors and angiographic progression of coronary artery disease. Circulation 1982; 66(supplll): 283.
DAVID E. BUSH, M.D. BERNADINE HEALY BULKLEY, M.D. Baltimore, Maryland
From the Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland. This study was supported by Ischemic Heart Disease Specialized Center for Research, P50-HL-17655-05 and Training Grant 5-T32-HL-07227 from the National Institutes of Health, Public Health Service, Department of Health, Education, and Welfare, and the Peter Belfer Laboratory for Myocardial Research, Baltimore, Maryland. Dr. Bush is supported in part by a fellowship from the American College of Chest Physicians, Park Ridge, Illinois. Requests for reprints should be addressed to Dr. Bernadine Healy Bulkley, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21205.
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Management of patients with concomitant hypertension and angina pectoris mandates that the physician pay attention to the underlying pathophysiology. The heart, when exposed to years of hypertension, becomes "remodeled." Overall mass is enlarged, the walls are thickened, and initial cavity volume remains normal or relatively small. Left ventricular end-diastolic pressure rises in the setting of a hypertrophic noncompliant ventricle; coronary resistance and coronary perfusion pressure are increased; and coronary vascular reserve, even with widely patent coronary arteries, is decreased. Long-standing hypertension-a risk factor for coronary atherosclerosis-is often accompanied by epicardial coronary stenoses that aggravate these coronary abnormalities. In managing the patient with hypertension and angina pectoris, it is important to determine whether the angina occurs in the setting of hypertensive hypertrophic disease alone or coexists with coronary arterial stenoses. Also important to therapy is whether the ventricle is of normal size with good function or decompensated with dilatation and diminished function. The latter two anatomic considerations, namely, epicardial coronary patency and left ventricular cavity size, will influence the choice of an anti-ischemic regimen. For example, diuretic and nitrate therapy can be hazardous, and digitalis unnecessary, in the setting of a nondilated hypertrophic ventricle with hyperdynamic function. On the other hand, the combined use of beta blocking agents plus calcium antagonists is particularly effective in lowering blood pressure and in improving coronary blood flow. Finally, this combination has been shown to be rapidly effective and to have prolonged benefit in this setting. The choice of these latter agents is also affected by the underlying state of the ventricle. Calcium channel blocking agents without significant negative inotropic effect, such as nifedipine and nitrendipine, would be suitable in patients with decompensated ventricular function and dilated left ventricular cavities. Both of these drugs have been shown to increase cardiac output and contractility via a reflex effect and to have little or no direct negative inotropic effect. In contrast, verapamil has a direct negative inotropic effect. The final choice of agents must be tailored to the needs of the individual patient, and the physician also has to determine the role of specific agents in the natural history of hypertensive heart disease. A wide variety of drugs are available for the treatment of hypertension and angina pectoris. Essential hypertension increases cardiac oxygen requirements by increasing the workload of the heart and, over time and
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CALCIUM CHANNEL BLOCKERS SYMPOSIUM-BUSH and BULKLEY
Figure 1. Shown is a heart with hypertrophic hypertensive cardiomyopathy with coexisting coronary artery disease. On the left is a postmortem angiogram showing the thick walls, small ventricle, and coronary artery lesions. Also on the left is a transverse section through both ventricles. Such hypertrophied ventricles typically have diastolic filling abnormalities, and congestive heart failure develops on that basis rather than in response to poor systolic function.
with the development of hypertrophy, by increasing the amount of myocardium to be perfused. When coronary artery disease is present, th~ capacity of the heart to respond to an increased workload is diminished. In addition, hypertension is reGqgnizect as a major risk factor for coronary heart disease and may accelerate its development. Selection of a drug regimen that will offer the highe~t therapeutic efficacy when these two common conditions coexist requires attention to the underlying pathophysiology of these disorders. HYPERTENSION AND ITS EFFECTS ON THE HEART
Blood pressure is determined by the product of two factors: cardiac output and peripheral resistance. Hypertension can result from an increase in either or both. In the most common form of hypertension-essential or primary hypertension-an increase in peripheral resistance is the predominant factor. As blood pressure increases, so does wall tension in the heart and in the cardiovascular arteries. The exact sequence of events coupling increases in wall tension to the biochemical process that leads to the development of hypertrophy has yet to be identified. A chronic increase in systolic wall tension appears to be a major factor responsible for cardiac hypertrophy in essential hypertension (1-3]. Other influences such as neurohumoral factors, metabolic status, and genetics may modulate the level of hypertrophy resulting from increases in cardiac load [4]. Thus, in response to chronic elevations in wall tension, the heart is remodeled [5]. Two different types of cardiac remodeling are observed in response to increased load and depend on whether the load is primarily due to increased pressure or increased volume [3]. In response to pressure overload, the ventricle remodels by increasing wall thickness while maintaining a normal or smaller than normal cavity size. This results in an increased ratio of myocardial mass to cavity volume and serves to normalize wall stress. When faced with a chronic volume overload, the heart increases both the ventricular wall thickness and the cavity volume. In most cases, this serves to maintain a relation of myocardial
mass to cavity volume that is similar to the ratio in a normal heart. In response to chronic hypertension, the heart generally remodels as for a pressure overload with an appropriate increase in the myocardial mass to cavity volume so that wall stress remains near normal. Some intriguing recent data suggest that obesity may play a role in the hypertrophic response of the heart to hypertension [6]. It has been postulated that in some patients with hypertension, a degree of hypertrophy adequate to normalize wall stress either cannot be maintained or does not occur; as a result, a dilated cardiomyopathy ensues [7,8] (Figures 1 and 2). The major determinants of myocardial oxygen demand are wall tension, heart rate, and contractility. In a ventricle working under an increased load, hypertrophy that increases the thickness of the ventricular wall relative to the cavity volume should reduce wall stress by the law of Laplace. Provided the other determinants of myocardial oxygen demand were not adversely affected, cardiac hypertrophy could represent a useful adaptation to chronic demands for increased function [3]. However, in association with coronary artery disease, hypertrophic cardiomyopathy may adversely affect the disease process by altering the myocardial supply-demand relationship. This association is supported by the finding that som~ patients with either primary or secondary left ventricular hypertrophy experience angina peetoris and electrocardiographic changes of myocardial ischemia in the presence of normal coronary arteries [9, 10]. Studies have demonstrated a marked reduction in coronary reserve in patients with left ventricular hypertrophy secondary to hypertension and angiographically normal coronary arteries [11 ]. It has been postulated that the reason for this reduced reserve is an inability of the myocardial capillaries to adequately supply hypertrophic myocytes [12,13]. Also, elevated left ventricular and diastolic pressure impairs the transmural perfusion gradient from epicardium to endocardium. Abnormalities in cardiac diastolic function are also observed in the presence of hypertensive hypertrophic cardiomyopathy. These alterations are characterized by a
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CALCIUM CHANNEL BLOCKERS SYMPOSIUM-BUSH and BULKLEY
Figure 2. Shown here is a heart from a patient who died with a dilated cardiomyopathy. Although the mass of the heart is enlarged as is the heart in Figure 1, its major impairment was hypodynamic systolic function.
prolonged left ventricular isovolumic relaxation period and impaired diastolic filling [14]. These abnormalities may also play a role in the increased coronary resistance commonly observed in this setting. In addition, hypertension is a known risk factor for the development of coronary atherosclerosis, which would serve to further compromise myocardial blood supply. PATHOPHYSIOLOGY OF ANGINA PECTORIS
Angina pectoris results when myocardial oxygen demand exceeds supply. Various combinations of events resulting in either an increase in myocardial oxygen requirements or a decrease in blood supply can cause angina. In many patients, angina is due to a decreased coronary blood supply resulting from atherosclerotic plaques narrowing the lumen of epicardial coronary blood vessels. In many patients, coronary vasospasm may also play a role in the development of angina. Vasospasm appears to be rare in patients with purely exertional angina, but it may be an important factor in patients with rest angina. Vasospasm has been demonstrated in approximately 15 percent of patients with exertional angina and in about 40 percent of patients with predominantly rest angina. Parasympathetic stimulation or alterations in prostaglandins-for example, platelet production of thromboxane A2 or decreased prostacyclin production in the vessel wall-may influence the pathogenesis of coronary spasm. Transient decreases in blood supply due to thrombosis or platelet aggregation could also be factors in the etiology of angina. CLINICAL ASSESSMENT OF THE PATIENT WITH HYPERTENSION AND ANGINA
In managing the patient with hypertension and angina, it is important to determine whether the angina is occurring in response to hypertensive hypertrophic disease alone or with coexisting coronary artery stenoses. Lowering the blood pressure will result in reduced cardiac work and thereby a reduction of myocardial oxygen demands regardless of the presence of coronary artery disease. Anti-
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hypertensive therapy should in general improve the ratio of myocardial demand to supply. In patients with angina and hypertrophic ventricles but without coronary disease, a decrease in angina can be expected by control of blood pressure. Reduction in the anginal symptoms in these patients is probably directly related to the control of blood pressure. It has been observed that, in experimental animals as well as in patients, control of blood pressure can reverse the hypertrophic changes associated with longstanding hypertension [15, 16]. The finding that normalization of blood pressure does not, in all instances, result in complete regression of hypertrophic cardiomyopathy may be an indication of additional factors in the pathogenesis of hypertrophy [17-191. It has been suggested that the degree of ventricular hypertrophy in hypertension may be more closely related to blood pressure [8]. Such findings suggest that regression of hypertrophic cardiomyopathy may be more likely with agents that directly lower peripheral resistance. In the setting of significant epicardial coronary artery stenosis, coronary reserve will not be uniform. Antihypert~nsive agents t~~t ~re also vasodilators, such as the calcium channel blockers, may provide an additional benefit for patier~ts with coronary atherosclerosis because they dilate epicardial coronary blood vessels and improve collateral flow to ischemic regions of the left ventricle. The assessment of ventricular size and performance is also relevant to therapy. It is particularly important to distinguish the hypertrophied ventricle that is of normal size with good or adequate function from the ventricle that is dilated with poor function. In patients with hypertrophic cardiomyopathy with thick ventricular walls and normalsized cavities, systolic performance is usually normal, although diastolic filling is often impaired, In such a case, it becomes important to maintain adequate diastolic filling. Agents that are likely to be most beneficial in this group of patients are those that reduce heart rate and therefore improve the diastolic filling period. Agents that substantially reduce preload-nitrates or diuretics, for example-
CALCIUM CHANNEL BLOCKERS SYMPOSIUM-BUSH and BULKLEY
may actually be hazardous in this group of patients, as such a reduction may actually aggravate diastolic filling abnormalities. Digitalis is also probably unnecessary and potentially harmful in this group of patients, since systolic function is usually not significantly impaired. In contrast, patients with hypertension and dilated ventricles with poor function are likely to benefit from agents that reduce after~ load without significant negative inotropic effects. To distinguish the hypertrophic ventricle with good left ventricular function from the dilated hypodynamic ventricle, one- or two-dimensional echocardiography is the single most useful test. With the echocardiogram, precise information on wall thickness and left ventr.icular cavity diameter are readily obtainable, as is an assessment of left ventricular function. When coronary artery disease is suspected, it may be difficult to interpr13t changes in the electrocardiogram at rest or during exercise. Exercise testing should not be performed in patients with angina and hypertension until adequate control of blood pressure has been achieved. In patients with markedly abnormal electrocardiograp~ic findings at rest, an exercise stress test can be performed with thallium 201 imaging, which allows a more precise interpretation of exercise-related electrocardiographic changes. Hypertension is a known risk factortor coronary disease, and the two diseases frequently coexist. -In patients with long-standing hypertension, the only way to establish the presence and severity of coronary disease is to perform coronary angiography. The decision to carry out this procedure, however, is only made when a patient is poorly responsive to antianginal medications or if an unstable coronary syndrome develops. ANTIHYPERTENSIVE MEDICATION IN THE PATIENT WITH ANGINA AND HYPERTENSION
Diuretics. These agents are considered to be the cornerstone of antihypertensive therapy. Thiazide diuretics are generally safe and effective for the treatment of hypertension. All diuretics produce their initial blood pressure response by reducing plasma volume via an increase in urinary sodium excretion. Long-term diuretic therapy sustains reductions in blood pressure by lowering peripheral resistance. ·When diuretics are administered to patients for the .tr~atment of hypertension, particular attention shollld be paid to the level of serum potassium in the presence of coexisting ischemic heart disease. Most diuretics will lower serum potassium to some degree. Many of these patients will also be receiving digitalis for the treatment of congestive heart failure. It is well known that hypokalemia in the presence of digitalis is associated with an increased risk for arrhythmic complications. There is also reason to suspect that diuretic-induced hypokalemia may be arrhythmogenic in. patients with ischemic heart disease who are not receiving digitalis. During an attack of angina, the level of circulating catecholamines is usually
increased. It has recently been reported that physiologic increases in circulating epinephrine levels can induce hypokalemia by stimulation of a beta2 receptor (20]. The ischemic myocardium is more sensitive to th.e arrhythmogenic effects of hypokalemia and elevated levels of catecholamines than is the nonischemic myocardium. Thus, during an attack of angina, the level of circulating catecholamines is elevated, and cellular hypokalemia may be induced. Diuretics; which also may ·chronically deplete potassium, might expose patients with angina to an increased risk for arrhythmic complications. Because of the effect of diuretics on ventricular function, they should also be used with caution in patients with hypertrophic ventricles and small or normal cavity size. In these patients, diastolic filling is often markedly abnormal, although systolic function remains normal. Any agent that will reduce preload may further impair diastolic filling. As with idiopathic hypertrophic cardiomyopathy, impaired filling and increased emptying of the hypertrophic ventricle may lead to increased left atrial pressure, pulmonary congestion, and, possibly, lowered cardiac output. Thus, paradoxically, preload reduction with either a diuretic or anitrate may precipitate or aggravate congestive heart failure. Beta Blockers. Beta-adrenergic blocking agents have been shown to be effective in the separate treatment of both angina and hypertension. Although the mechanism by which beta blockers reduce blood pressure is incompletely defined, the beneficial effects of these agents in angina are apparently related to their ability to reduce myoca~dial oxygen demand by decreasing heart rate, contractility, and blood pressure. Thus, this group of agents would seem to be a logical choice when the two conditions coexist. A wide variety of beta blockers are currently available. These compounds differ chemically, and there are differences in some of their pharmacologic effects as well. Pharmacologic properties of beta blockers that theoretically could be relevant to drug selection in the patient with hypertension and angina include cardioselectivity, partial agonist activity, and membrane stabilizing activity (21-23]. Cardioselectivity: There are two categories of beta receptors: beta1 receptors, which cause cardi~c stimulation and renin release, and beta2 receptors, which cause vasodilatation and bronchodilatation. Cardioselectivity refers to beta blockers that inhibit the beta 1 receptor to a greater degree than the beta2 receptor. In lheory, beta2 blockade of peripheral arterioles ·might allow vasoconstriction via unopposed alpha effects. Partial agonist activity: Another phrase to describe partial agonist activity is intrinsic sympathomimetic activity, which is defined as the mild sympathetic stimulation that occurs in the presence of certain beta blockers. Clinically, beta blockers with partial agonist activity demonstrate less resting bradycardia and less reduction of car-
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CALCIUM CHANNEL BLOCKERS SYMPOSIUM-BUSH and BULKLEY
TABLE I
Approximated Relative Effects of Three Calcium Channel Blockers
Calcium Channel Blocker
Vascular Muscle
Cardiac Muscle
Inhibition of Conduction
Diltiazem Nifedipine Verapamil
+++ ++++ ++
++ + ++
++ + +++
diac output. It is not yet clear whether beta blockers with partial agonist properties are as effective for the treatment of hypertension and angina as those without this activity. They have theoretic benefit for the patient with congestive heart failure and a hypodynamic ventricle in the setting of hypertension. Membrane stabilizing activity: This property is demonstrated by certain beta blockers with the ability to produce local anesthesia and alter Phase 0 of the cardiac action potential. Although it has been suggested that membrane stabilizing activity has beneficial antiarrhythmic and antiplatelet effects, these effects may only be present in dosage ranges that are higher than those used clinically. In addition, agents without membrane stabilizing activity have also been shown to demonstrate antiarrhythmic properties. The significance of this effect has not yet been fully explored by clinical studies. The clinical importance of cardioselectivity, partial agonist activity, and membrane stabilizing activity are not fully understood. It has been shown, however, that some patients may experience an increase in angina while receiving beta blockers [24]. This effect is presumably due to an unopposed alpha-adrenergic vasoconstrictor effect on the coronary arteries, which has been shown to be blocked by nifedipine [25]. Thus, combining a vasodilator with a beta blocker would seem especially appropriate for patients with hypertension and exertional angina. In particular, patients with rest angina may benefit from the addition of a calcium channel blocker, either alone or in combination with a beta blocker [26]. Calcium Channel Blockers. Calcium channel blockers are effective in the medical treatment of variant and typical angina as well as hypertension [27]. These drugs also possess an ability to improve collateral flow to ischemic areas of the"myocardium [28,29]. Improved collateral flow should prove to be a cardioprotective benefit to patients with angina. Calcium channel blockers, as a class, act by inhibiting calcium movement across cell membranes, particularly in myocardium and vascular smooth muscle. These drugs have negative inotropic effects in cardiac and vascular smooth muscle, reduce impulse formation, and slow conduction through the sinoatrial and atrioventricular nodes. Increased peripheral resistance is found in
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most types of hypertension. Using vasodilators that act directly on arterial resistance vessels in the treatment of hypertension has a logical appeal. Calcium channel blockers may be particularly attractive as vasodilators in hypertensive patients due to their negative chronotropic action, which appears to limit reflex tachycardia in comparison with other vasodilators. In patients with secondary hypertrophic cardiomyopathy, calcium channel blockers may confer additional advantages: Improvements in diastolic function characterized by decreases in left ventricular and diastolic pressures, improved left ventricular distensibility, and enhanced left ventricular filling have been shown to occur with calcium blockers. Calcium channel blockers have a variety of chemical structures and exhibit differences in their effects on target tissues. Approximated relative effects of several calcium channel blockers are shown in Table I. These differences in tissue effects may be important in drug selection. For example, in patients with dilated, poorly functioning ventricles, concern has been expressed that the negative inotropic properties of some calcium channel blockers might be detrimental. Studies have shown, however, that calcium channel blockers can be given to patients with depressed left ventricular function [30-33]. Nifedipine may be particularly useful in this group of patients since its powerful vasodilating effects may actually work to improve cardiac function. Calcium channel blockers and beta blockers both have useful effects in the treatment of hypertension and angina, and they work by different mechanisms. Their use in combination, therefore, might be desirable in many instances, particularly in patients with coexisting hypertension and angina. There has been concern that the use of beta blockers and calcium channel blockers together might markedly reduce left ventricular contractility and heart rate. T.he combination of nifedipine and propranolol, however, has been shown to be safe in patients with concomitant hypertension and angina. In patients with depressed ventricular function, however, especially in the presence of dilated cardiomyopathy, caution in the combined use of calcium channel blockers and beta blockers seems prudent. In such patients, nifedipine, which has fewer myocardial depressant effects than verapamil, might be advantageous, especially when it is to be used in combination with a beta blocker [34]. Other Antihypertensive Agents and Nitrates. In addition to diuretics, calcium blockers, and beta blockers, several other classes of antihypertensive agents are available for the treatment of hypertension. Such drugs include sympathetic blockers, which may act either by central mechanisms (for example, methyldopa, clonidine) or peripherally (for example, reserpine, guanethidine). Vasodilators such as hydralazine and minoxidil and converting enzyme inhibitors such as captopril are also useful in the treatment of hypertension. Insofar as hypertension aggra-
CALCIUM CHANNEL BLOCKERS SYMPOSIUM-BUSH and BULKLEY
vates angina by increasing the workload of the heart, any therapy that reduces blood pressure should be beneficial. As beta blockers and calcium blockers each have direct therapeutic efficacy in the treatment of hypertension and angina,· their use in patients in whom these conditions coexist is particularly attractive. Nitrates are useful in the treatment of angina of all causes. Nitrates are not, however, particularly effective in the management of chronic hypertension. CARDIOVASCULAR RISK IN ANTIHYPERTENSIVE THERAPY
The question of whether antihypertensive therapy favorably affects all the diseases with which hypertension is an associated risk factor has not been answered. Several large cooperative studies have shown that antihypertensive therapy does reduce the incidence of stroke, renal failure, and heart failure, but they do not show statistically significant decreases in deaths related to coronary events [35,36]. Further concern has been raised by results from the Multiple Risk Factor Intervention Trial in which patients with multiple risk factors for atherosclerosis were assigned to either a special regimen of stepped-care therapy or to standard community health services [37]. In this study, no significant differences were found in overall coronary deaths between the two groups. Even more disturbing was the finding that in the special-care group, coro-
nary deaths were actually higher among hypertensive patients with resting electrocardiographic abnormalities. It has bee.n postulated that in these patients, many of whom presumably had underlying coronary disease, diuretic therapy may have been a factor in the higher mortality in the special-care group. · The recent report of the· Lipid Research Clinic Primary Prevention Trial showed that treatment of primary hypercholesterolemia with cholestyramine reduced the incidence of coronary heart disease [38]. These findings raise questions as to whether drugs that alter lipoprotein profiles by increasing triglyceride and total cholesterol levels (such as occurs with thiazides), reduce high-density lipoprotein cholesterol levels (as with beta blockers), or reduce the ratio of high-density lipoprotein cholesterol to total cholesterol (as is the case with methyldopa, reserpine, furosemide, and spironolactone) may actually increase the risk of coronary artery disease in patients receiving these drugs. Prazosin is an agent that is known not to have those effects. Another question is whether ri!)k factors associated with initiation of atherosclerosis are the same ones responsible for its progression. Results of studies evaluating primary risk factors as factors in the progression of coronary heart disease have yielded mixed results [39-42]. These questions, which may have a significant impact on the management of patients with hypertension and angina, await further clarification.
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