Hypertension and Atherosclerosis EDWARD D. FREIS, M.D. Washington, D.C. I T APPEARS increasingly likely that no single agent will be identified as the sole cause of atherosclerosis. However, of the various known contributing factors which may influence the course of the disease, hypertension appears to be the most important. Despite the present emphasis on disorders of lipid metabolism the fact remains that neither hypercholesterolemia nor hypertriglyceridemia is essential for the development of atherosclerosis. In the presence of hypertension and "normal" concentrations of lipids in the blood, however, such lesions will develop over an appropriate length of time. The failure to place sufficient emphasis on hypertension in research on atherosclerosis is especially surprising in view of our present ability to control the level of blood pressure with antihypertensive agents. The intriguing possibility that the acceleration of athero- sclerosis associated with hypertension can be reduced by antihypertensive treatment at the appropriate time has been little explored either experimentally or clinically. The purpose of this review is to re-empha- size the relationship between hypertension and atherosclerosis and to indicate the possi- bilities of therapeutic modification. For pur- poses of clar'ity it will first be necessary to de- fine the relationship between the two dis- orders. Although hypertension and atherosclerosis usually are interrelated it should b,e clearly understood that they are distinct diseases [I]. Atherosclerosis affects large- and medium- sized arteries. Its pathologic hallmark is the subintimal lipid-containing plaque develop- ing over a medial lesion of unknown cause. The anatomic consequences of hypertension involve the arterioles primarily. The known mechanisms for production of experimental hypertension in animals (renal arterial con- striction, section of the baroreceptor nerves) are quite different from the dietary methods used for producing experimental "athero- sclerosis." Typically these methods are specific for each kind of le,sion. In man hypertension can exist independently of atherosclerosis and vice versa. This deviation is most often seen in the economically underdeveloped countries in which atherosclerosis, especially of the coro- nary arteries, is minimal despite a high prev- alence and mortality from hypertensive dis- ease [2,3]. Hypertensive persons in these coun- tries are more likely to have hypertensive com- plications such as cerebrovascular hemorrhage, malignant hypertension, uremia and dissecting aneurysm as opposed to coronary artery disease which is the most common cause of death in the hypertensive population in this country. Population studies do show however that atherosclerosis is universal in man, groups differing mainly in the extent of lipid infiltra- tion of these lesions. Despite their pathogenetic distinctness there is a close relationship between the two dis- eases [4]. Whatever the ultimate cause of atherosclerosis may be, there is no question that hypertension makes it worse. This con- clusion is supported by an impressive collec- tion of clinical and experimental data. In the rabbit Heptinstall, Barkley and Porter [5] showed that high blood pressure increased the amount of cholesterol-induced atheroma. The correlation between the level of blood pressure and the degree of atheroma forma- tion was much greater than that between the level of serum cholesterol and extent of athero- genesis. In rabbits with bilateral lumbar sym- pathectomy fed cholesterol more severe atherosclerosis of the lumbar aorta and iliac arteries developed. When Snyder and Camp bell [q produced an experimental constriction * From the Veterans Administration Hospital and the Department of Medicine, Georgetown University School of Medicine, Washington, DC. VOL: 46, MAY 1969 735 736 Hypertension and Atherosclerosis-F&J of the abdominal aorta sufficient to cause a sharp pressure drop distal to the narrow seg- ment in sympathectomized rabbits, severe atherosclerosis developed in the aorta above but not below the constriction. In thyroidec- tomized dogs fed cholesterol Sako [7] found that experimental coarctation of the aorta re- sulted in a limitation of atherosclerotic lesions to the proximal vascular tree, includ- ing the coronary arteries. This occurred only when the degree of constriction was such as to produce a pulse pressure above the coarctation that was 30 mm, Hg or higher than that be- low. These are crucial experiments because they demonstrate in the same animal a pre- disposition for atheroma to develop selectively in the areas of elevated blood pressure. Similar effects of coarctation on atherogenesis have been observed repeatedly in man. For example, I have seen the aorta of a thirty-two year old man with severe hypertension in the brachial but not the femoral arteries in whom autopsy disclosed extensive early plaque formation above the coarctation whereas the abdominal aorta was completely free of such lesions. A similar effect has been noted after correc- tion of occlusive lesions at the aortic bifurca- tion [B]. Following surgical intervention atherosclerosis progresses in the arteries of the lower extremities which were previously much less involved. This progression occurs in older patients at a much faster pace than in younger patients with similar blood pressures and con- centrations of lipids. These findings suggest the presence of an additional "tissue factor" associated with aging in the pathogenesis of the lesions. The importance of the level of blood pres- sure in localization of the atherosclerosis is in- dicated by still other observations. In man in the erect position the arterial pressure is higher in the dependent parts of the body. Atherosclerosis tends to be more severe in these areas of higher pressure, in the abdominal aorta as opposed to the thoracic aorta, and in the lower extremities as opposed to the upper extremities. The veins are usually free of sclerotic lesions even though after fatty meals the mesenteric veins contain the highest levels of lipids including cholesterol. However, when venous pressure is chronically elevated, as in varicosities, arteriovenous fistulas of long dura- tion, in the portal vein of patients with portal hypertension and in the hepatic veins of pa- ti,ents with prolonged periods of high venous pressure, phlebosclerosis is common [9]. Whether these lesions are pathogenetically similar to atherosclerosis is debatable but the analogy is obvious. Burch and Phillips [9] have stressed that atherosclerosis is not a generalized process but tends to be localized. Blood which has the same concentration of lipids flows through all the vessels of the body and yet atherosclerosis is regionally different in extent, tending to be most severe in regions of highest pressure, such as in the lower aorta, at sites of bifurcation, at the outer circumference of the aortic arch and in areas proximal to the points of sudden narrowing such as coarctation. This does not imply that for any given level of blood pres- sure alterations in lipid metabolism are not important, but rather that the localizing fac- tors appear to have the