Treatment of hypertension with coronary and cerebral arteriosclerosis∗

Treatment

of Hypertension

and Cerebral

with Coronary

Arteriosclerosis

\\IILLI.W LIKOFF, M.D., F.A.C.C. Philadelphia,

Pennsylvania

T

HE ~.4c’1‘ that a considerable number of hypertensive patients are encountered with manifestations of coronary and cerebral vascular disease may bc accepted as clinical evidence that hypertension accelerates and intensifies the development of arteriosclerosis. The present discussion csatnines the therapeutic approach to the coexisting problem of hypertension and arteriosclerosis, particularly when the latter involves the coronary or cerebral arterial systems or t)otli. It requires an initial, brief orientation to the cardiac and cerebral hcmodynamics which dcv-elop when the systemic pressure rernains consistently elevated. Cardiac Hunocf~namic~s: Prolonged systolic ejection time and stretching of the myocardial fibers serve as the specific compensatory mechanisms which maintain a normal cardiac output in early and uncomplicated hypertension.’ At this stage of the discasc process, the left \;entricular work index, the product of cardiac output and arterial I)lood pressure, obviously- is increased. r2s a result, hypertrophyof the myocardial fibers gradually occurs. Although coronary vascular resistance is significantly elevated for the moment, coronary blood flow and myocardial oxygen consumption per unit Thus it may be weight remain quite normal. concluded that early uncomplicated hypertension does not actually disturb cardiac efficiency since the increased work of the myocardium is accompanied by the usual oxygen consumption and is productive of normal output. In the more advanced stages of hypcrtcnsion when the elevation of arterial pressure is more severe and prolonged, the cardiac compensatory mechanisms fail. Presumably this develops when the increased diffusion distance between the capillaries and the center of the hypertrophied myocardial cells impedes the delivery of * From the Cardiovascular delphia, Pennsylvania.

Section,

Department

oxygen to the increased muscle mass. At this point cardiac efficiency becomes impaired because cardiac output and work fall in spite of unaltered oxygen consumption. Quite obviously the imposition of coronary arteriosclerosis exaggerates the error which first accrues when the coronary circulation functionally fails to satisfy the metabolic demands of the muscle fibers. Theoretically, hypertrophied therefore, there is every indication for the treatmcnt of both hypertension and obstructive coronary vascular disease when these conditions coexist. Cerebral Hemodynamics: Many measurements by different investigators indicate that blood flow through the brain is the same in hypertensive as in normal persons.2 The basic mechanisms responsible for normal blood flow through the fundamentally unresponsive cerebral vessels in the presence of a greatly increased perfusion pressure is unknown. However, in contrast to the cardiac events, the implication remains that not hypertension, but its complication, cerebral vascular arteriosclerosis, is solely responsible for diminished blood flow to the brain. CORONARY ARTERIOSCLEROSIS The therapeutic approach to the hypertensive patient with associated coronary arteriosclerosis must acknowledge the coexistence of two independent disease entities, the pathophysiologic effects of which are mutually detrimental. In the inquiry for the proper basic antihypertensive drug, it appears that any agent which reduces left ventricular work and the impetus for myocardial hypertrophy- by reducing blood pressure without altering output is prefNaturally, if the drug also provides for erable. coronary blood flow, additional improved physiologic gains accrue. Conversely, the use

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of any agent which, although reducing systemic pressure, increases cardiac output to a point where left ventricular work actually is increased, is inadvisable. This is true of drugs which singularly reduce coronary blood flow directly or through unpredictably severe and uncontrolled reduction of output. With these considerations and the additional factors of absorption, tolerance and side effects in mind, it is not difficult to select a proper drug program for the control of elevated systemic pressures in patients with significant coronary arteriosclerosis. Of the available drug;s, the diuretics and two of the autonomic blocking agents are most acceptable. The saluretics, chlorothiazide and hydrochlorothiazide, lower pressure in part by reducing the right heart filling pressure.” No adverse effect on coronary arterial perfusion has been recognized with their use. Veratrum and rauwolJia compounds are classified as autonomic blocking agents and are remarkably similar in their physiologic actions.4 Since both agents reduce blood pressure without significantly altering cardiac output, they satisfy a fundamental requirement of the patient with coronary arteriosclerosis.3 Furthermore, it is conceivable that the bradycardia which accompanies their use and which is vagal in origin permits more effective filling of the coronary system. Two unique drugs, bretylium and guanethidine, classified as peripheral sympatholytic agents are currently employed for the more advanced hypertensive person, who is not responsive to the autonomic blocking compounds and the diuretics alone or in combination.5 These compounds exert action at the nerve-arteriole junction where the)- oppose the release and/or distribution of the pressor substance norepinephrine. Bretylium causes a small but significant rise in oxygen uptake and in the resting cardiac output. Contrariwise, guanethidine reduces the resting cardiac output under the same circumstances. This effect, which is exaggerated in the standing position, may be reflected in decreased coronary filling. However, guanethidine is purported to modify the metabolism and concentration of the catecholamines within the myocardium and thereby may provide compensating benefits. In the main, hydralarine, an autonomic blocking agent, is contraindicated in the presence of coronary arterial disease because it produces an important increase in cardiac rate and output JUNE

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which more than offsets the increase in coronary blood flow accompanying its use.6 Similarly, the available ganglionic blocking agents are utilized hesitantly sinrr they ma)- unpredictably reduce cardiac output in the \-ertical position to a point \L-here coronar)- filling is compromised.7 Erratic gastrointestinal at)sorption considerably compounds this hazard in patients who have coronary heart disease. The dose schedule of the acceptal)le antihypertensive agents is a matter of individual adjustment. The ideal achievement is a reduction of systemic pressures to a level of 150 mm. HS systolic and 30 mm. Hg diastolic. Angina Pectoris: The major clinical expressions of coronary arteriosclerosis are angina pectoris, myocardial infarction and congestive heart failure. An antihypertensive drug routine which has been effective in controlling systemic pressure levels requires critical evaluation whenever the frequency or severity of angina pectoris increases without obvious cause. This clinical deterioration obviously may develop as a result of the inexorable progress of the obstructive vascular disease. However, on occasion, exacerbations of coronary insufficiency may arise when the systemic pressures “escape” from drug control or when iatrogenic postural hypotension interferes seriously and repetitive11 with coronary arterial filling. In either instance, alterations in agents and dosage are required. Myocardial Infarction and Congestitle Failure: At the outset of an acute m)-ocardial infarction, antihypertensive drugs are rarely required because of the accompanying fall in systemic arterial pressures. Indeed, normotensive levels may be maintained without medication for a considerable period. The decision to institute former or new therapeutic programs, then, is determined by the speed and extent to which hypertension returns. The advent of congestive heart failure requires modification of a previously effective antihypertensive routine on]>- when the myocardial incompetence is accompanied by a significant change in blood pressure levels. MEASURES DIRECTED TO ARTERIOSCLEROTIC: PROCESS In patients with accompanying coronary vascular disease the drug therapy of hypertension must be accompanied by measures designed to arrest or deter the arteriosclerotic process and to correct or modify its specific manifestations. Many aspects of the treatment to retard arterio-

Likoff sclerosis are based more upon concept than truth. Nevertheless, theoretical considerations have matured to a point where certain measures are warranted. Diet: The proscription against a diet high in saturated fats is based upon the view that an error in lipid metabolism is responsible, at least in part, for the genesis of arteriosclerosis. Presumably the effectiveness of the dietary modification depends upon a reduction of the daily fat intake to less than 40 gm., of which at least 50 per cent must be polyunsaturated. This requirement enforces abstinence from dairy products and a considerable restriction in the ingestion of animal but not fish or fowl protein. When practiced assiduously, the low fat diet is effective in weight control and in the modification of abnormal levels of circulating lipids. However, attention has been amply drawn to the fact that the dietary restriction may not be effective continuously because of endogenous escape mechanisms, particularly that which permits the formation of cholesterol from 2carbon fragments derived from cartjohydrates or proteins. Lipid-Lowering Agents: The natural difficulties associated with the practice of a low fat diet and the doubts concerning its long range qualitative and quantitative effectiveness have led to the use of a variety of substances for the control of the lipid abnormalities which frequently accompany coronary vascular disease. These include plant sterols (sitosterol) to block absorption of cholesterol; lipotropic agents (choline, methionine and inositol) to stabilize the colloidal dispersion of cholesterol; and hormones and enzyme inhibitors (thyroid extract, estrogens, nicotinic acid and triparanol) to alter or block the metabolic cycle of cholesterol. In many instances the theoretical purpose for which these agents have been used has not been realized ciinically. This is true of the lipotropic agents. With substances such as the estrogens, the intolerable side effects render their use impractical. Finally, the atherogenicity of desmosterol, the intermediary metabolic product which accrues with the use of triparanol, has not been resolved. Investigators, at present, have heen unable to determine an effective therapeutic approach, assuming that abnormal lipid development is responsible for athero,genesis. The difficulties experienced in providing a safe, tolerable and effective control of ahnormal lipid metabolism suggest that each patient must be critically evaluated. As a rule, the ohese hypertensive

patient with coronary sclerosis should be submitted to a low fat, low caloric diet to assure a gradual weight loss. Abnormal levels of circulating lipids, independent of obesity, require limitation in the dietary intake of fat. This routine should he followed carefully for not less than six months before the addition of lipidlowering agents is considered. Of the latter, nicotinic acid or triparanol is preferred. However, even when required, these substances do not negate the requirement for a continued regulation of ingested fat. Exercise: Current views hold that moderate, regulated exercise provides a physiologic stimulus for the overdevelopment of coronary collaterals and should be practiced by patients with coronary arteriosclerosis provided fatigue and angina pectoris do not result. Although the essential wisdom of this concept is not questioned, its indiscriminant application to the hypertensive patient cannot be supported. It is unlikely that any work load in addition to the existing elevated systemic pressures initiates a more effective expansion of the coronarv circulation. This is particularly true in those’instances in which the pathophysiology of hypertension already has resulted in discernible myocardial hypertrophy. Hence, patients with hypertension and the clinical manifestations of coronary arteriosclerosis should be clearly instructed regarding the inadvisability of physical burdens, however casual, that do not contribute to basic socioeconomic requirements. It is in this prohibition that the therapeutic routine of the hypertensive patient differs most radically from that of the normotensive with coronary arteriosclerosis. Psychotherapy: Despite the purported relationship between unresolved stress, hypertension and the development of coronary arteriosclerosis, there is no valid support to the view that the coexistence of these issues is a precise indication for psychotherapy. Although psychoneurotic tendencies and serious personality defaults may he alleviated hy psychotherapy, it is unlikely that hope for the modification of blood pressure levels or the retardation of the arteriosclerotic process rests with this approach to the problem. Other Measures: In all other matters pertaining to the treatment of the acute and chronic manifestations of coronary vascular disease, the therapy of the hypertensive person is unchanged from that of the normotensive patient. Particular mention is made of the fact that the coexistence of hypertension is not a contraTHE

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indication for acute and chronic anticoagulation programs unless significant renal insufficiency also is present; it does not modify the need and judicious use of the nitrites for angina pectoris; and it does not alter the standards which determine the institution of digitalis therapy. CEREBRAL ARTERIOSCLEROSIS In the contest to alleviate the combined presence of hypertension and cerebral arteriosclerosis, the program is based on the ability to influence cerebral blood flow with current drug therapy. The predominant view holds that hypertension ,ber se does not alter cerebral flow. Isolated exceptions have been taken toward this If accurate, concepL8 the early phases of elevated arterial blood pressures may cause an increase in blood flow while the more advanced states ma)- reduce it below normal levels. Drug Therapy: An identical difference of opinion exists concerning the response of the Although most cerebral circulation to drugs. of the agents are believed to exert little influence on cerebral blood flow, evidence has been presented that hydralazine and papaverine have perceptible and beneficial effects. Under these circumstances, therapy is guided more by the inadvisability of interfering with blood flow by causing precipitous transient hypotensi\Te episodes than by the precise expectation of improving perfusion through obstructed arterial channels. It is with this objective in mind that ganglionic blocking and peripheral sympatholytic agents are used with caution and under carefully regulated conditions in keeping with the individual clinical problem. However, it remains unlikely that cerebral vascular accidents occurring during antihy-pertensi\-e therapy are commonly attributable to drug action. Il‘lrr mcuszlres to inhibit cerebral arteriosclerosis are identical to those employed when the coronary

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vessels are involved. However, because of the statistical possibility of hemorrhage as an inherent complication of cerebral arteriosclerosis, prophylactic anticoagulation is hazardous in the h>-pertensive individual. SUMMARY Under the circumstances of dynamic coronaryand cerebral arteriosclerosis, the most acceptable and basic antihypertensive routine appears to be a rauwolfia compound in combination with a saluretic. If additional medication is required guanethidine is preferable particularly in view of its effect on the myocardial catecholamincs. REFERENCES 1. ROWE, G. G., COSTILLO, C. A., MAXWELL, A. M. and CRUMPTON, C. W. A hemodynamic study of hypertension including observations on coronary blood flow. Ann. ht. Med., 54: 405, 1961.

2. PICKERING,

G. W. The arterial pressure in the population at large and its relationship to age. In: A Consideration of “Normal” and “High” Blood Pressure, p. 154. New York, 1955. Grune & Stratton.

3. FROHLICH, E. D., SCHNAPER, H. LV., WILSON, I. M. and FREIS, E. D. Hemodynamic alterations in hypertensive patients due to chlorothiazide. .Vrw

England J. Med., 262: 1261, 1960. 4. FREIS,

E. D., STANTON, J., CULBERTSON, J. L., HALPERIN, M. H., BURNETT, C. H. and WILKINS, R. IV. The hemodynamic effects of hypotensive J. C’lin. Znwsf., drugs in man. I. Veratrum viride.

28 : 353,1949. The circulation K. W. tosylate and guancthidine.

5. TAYLOR, S. H. and DONALD, effects

of

bretylium

Lancrt, 2: 389, 1960. 6. FREIS,

E. D. Observations on cardiac output, peripheral blood flow and blood volume in hypertension-before treatment. In and during Hypertension, p. 123. Edited by Moyer, J., Philadelphia, Pa., 1959. W. B. Saunders Co.

7. PLUMMER, A. J. The pharmacology of rauwolfia In compounds (including syrosingopine). ref. 6, p. 319. Cerebral circulation in 8. 14~~~~<~, T. and TOZAKI, Y. cerebrovascular disease. TV&d N~urolqv, 2: 635.

1961.