ANGIOLOGY Published twelve times a year under the auspices of

THE ANGIOLOGY RESEARCH

FOUNDATION, INC.

Physiopathology and Pharmacotherapy of Occlusive Arterial Disorders Christian De

Mey, M.D., Donald Wellens, Dr.Sc., F.I.C.A., and Paul M. Vanhoutte, M.D.

WILRIJK,

BELGIUM

When the metabolic demands of the tissues exceed the ability of the cardiovascular system to provide them with enough blood, the resulting tissue ischemia may endanger its function. In cardiac and skeletal muscle, the accumulation of anaerobic metabolites causes stimulation of pain receptors, which then cause the symptoms of angina pectoris and intermittent claudication, respectively. These symptoms are nonpathognomonic, and they may have a nonvascular origin, such as severe anemia, prolonged isometric exercise, or hypoxemia. Vasospasm may cause temporary occlusion of the arterial inflow: if prolonged or repeated, tissue function may also be endangered. However, impaired tissue function is seen most frequently in patients with mechanical limitation of the blood flow. Such limitation can be due to compression, to thromboembolism, or, in most cases, to occlusive arterial disease, which will be briefly discussed. Atherosclerosis has been defined by a WHO study group as &dquo;a variable combination of changes in the intima of arteries consisting of the focal accumulation of lipids, complex carbohydrates, blood and blood products, fibrous tissue and calcium deposits, with associated changes in the media.&dquo;’ It affects the aorta and the larger distributing vessels and impairs the arterial circulation to the heart, the brain, and the lower limbs. Symptoms occur when the oxygen demand is no longer balanced by an adequate oxygen supply. Lesions

It is convenient to distinguish three types of change in the arterial intima: 1. Fatty Streaks. The intima is infiltrated by fatty streaks which may be From the

Department of Medicine, University

of

Antwerp, Wilrijk, Belgium.

433

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434 observed within the first decade of life. The extent of aortic fatty streaking in youth does not necessarily. determine the extent of aortic raised lesions later in life.2 2. Fibrous Plaque. The &dquo;plaques&dquo; are localized lesions of the arterial wall composed of fatty or fibrous materials and an accumulation of smooth muscle cells. In males of affluent societies the development of these lesions begins in the second decade and increases slowly but inexorably as age advances. Autopsies of men in their twenties killed in the Korean War indicated a very high incidence of these lesions.’ More recent studies in similar subjects however, failed to confirm this observation.44 3. Additional Changes. Additional changes in the plaques or on their inner surface cause thrombosis, calcification, ulceration, or hemorrhage. .

Risk Factors studies in many countries stressed the existence of associations between atherosclerotic (coronary) disease and a number of different environmental and genetic factors. 5,6 These &dquo;risk factors&dquo; are defined as an attribute which appears to occur more frequently among persons with coronary heart disease than among control subjects, although causality is not necessarily implied.’ Therefore the importance of a single risk factor can only be appreciated if this multicausal aspect is considered. Dietary and pharmacologic measures to manipulate the risk factors will only be successful at the stage where the latter measures still influence the natural progression of the disease. The description of the risk factors of atherosclerotic disease has been confined mainly to the problem of coronary ischemic heart disease. It remains to be proven whether the same factors are important in the genesis and progression of the disease in other vessels. Hypertension is associated with intracranial atherosclerosis, even in the absence of a high fat intake and high cholesterol level.’ Postmortem studies reveal a strong relationship between blood pressure and cerebral atherosclerosis in populations without extensive coronary athero-

Epidemiologic

scierosis.9

Pathogenesis Different mechanisms have been proposed to explain the genesis of the fibrous plaque: (1) Degeneration due to hypoxia in the inner and middle parts of the tunica media leads to diminished energy production by the smooth muscle cells, and to accumulation of cholesterol.10 This hypothesis explains why the structural integrity of the arterial wall is lost, and why areas of patchy necrosis replace the structure seen in early life. (2) Infiltration or insudation of fatty substances from the bloodstream into the arterial wall is the major cause.

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435

Hyperlipemia, lack of high-density lipoproteins, hypertension, and endothelial desquamation promote this infiltration.&dquo; When the enzymes that normally hydrolyse the lipids are saturated, deposits of cholesterol are formed. (3) Proliferation of vascular smooth muscle cells due either to a benign neoplasia after irritation or triggering of a single smooth muscle cell, 12 or to deficient negative feedback from the stem cells in the media on the proliferation of smooth muscle cells in the intima, 13 or to growth factors liberated by platelets.&dquo; The latter hypothesis implies that mechanical (slowing of flow, turbulence occurring at bifurcations, hypertension etc.), chemical (coagulation disorder, hyperviscosity, hyperlipemia), and immunologic aggression will lead to endothelial desquamation, thus exposing the subendothelial connective tissue to plasma compounds and platelets. Adhesion of platelets on the collagen will occur, followed by aggregation and degranulation. Compounds from the platelets, plasma protein, and hormones trigger the focal proliferation of vascular smooth muscle cells in the intima, the migration of smooth muscle cells from the media, the formation of a connective tissue matrix, and deposition of lipid material in the wall. The balance between re-endothelialization, cell proliferation, and destruction will determine the further regression of the lesion, or the progression to complicated atherosclerotic lesions with clinical repercussions. The same mechanisms are involved in the formation of large mural thrombi on atherosclerotic lesions. They contribute to the occlusion of the vessel and can be responsible of embolization of the smaller arteries and arterioles. The recognition of the role of platelets in the early and later stages of atherosclerotic disease inspired the use of antiplatelet agents at various stages of atherosclerotic disease.&dquo;

Functional Aggravating Factors According

to Poiseuille’s

law, the resistance

to

flow

depends mainly

on

the

vessels. In atherosclerotic disease the resistance is

diameter of the perfused increased by intramural and intraluminal changes. This increase can be aggravated by perivascular compression and active constriction of the blood vessels. Such active constriction can be due either to norepinephrine released from sympathetic nerve endings, to circulating vasoconstrictive substances (e.g., catecholamines and angiotensin II), or to vasoconstrictors liberated in the blood vessel wall itself (e.g. prostaglandins). In addition, hyperviscosity of the blood can lead to increased resistance to flow, and may explain episodes of claudication in certain patients.is,&dquo; The main determinants of the blood viscosity are plasma viscosity, hematocrit, and the aggregability and deformability of the red blood cells. Aggregability is important in the areas of slow blood flow, for example, distally from the atherosclerotic obstruction, where sludging may occur. Deformability is impor-

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436 tant for the passage of the cells in

the microcirculation. It depends on an ATPand calcium-mediated reversible sol-gel transformation at the interface between the cell membrane and the soluble interior of the cell.18,19

Physiologic Defense Mechanism Exercise Hyperemia and Reactive Hyperemia. Contraction of a skeletal muscle requires ATP. A limited amount of ATP as such or as creatine phosphate, is available in each muscle cell to initiate the contraction. The muscle cell also contains stored substrate (glycogen) and stored oxygen (myoglobin), and oxydative regeneration of ATP can be started almost immediately after initiation of the contraction. However, in most cases, it is necessary to increase the blood flow to the contracting muscle in order to supply more oxygen and substrate and to eliminate the metabolites. This requirement is met by exercise hyperemia, which results from the depression of myogenic and neurogenic vascular smooth muscle tone caused by local anoxia, a tendency toward acidosis, local hyperosmolarity, and the accumulation of potassium ions, adenine nucleotides, and organic phosphates.2o-22 Exercise hyperemia can be inadequate as a result of peripheral circulatory impairment or mechanical compression of the microvessels during contractions of the skeletal muscle. Anaerobic metabolism then predominates, giving rise to further local acidosis and anoxia, to cramps and fatigue of the skeletal muscles, and presumably to release of factors (e.g. P substance and prostaglandins) causing a sensation of pain. When the exercise is stopped after anaerobic work, a marked and long-lasting reactive hyperemia occurs. This reactive hyperemia provides a measure of circulatory reserve in the limb under study. Collateral Circulation. The obliteration of a main artery results in the development of collateral circulation through anastomotic branches. Thus the poststenotic pressure, which approximates zero at the moment of complete obstruction of the main vessel, gradually increases with time, reflecting the functional significance of the collateral circulation. The mechanism by which this occurs is unknown.

Therapeutic A pproaches



Risk Factors. Measures that diminish the so-called risk factors will succeed in treating the atherosclerotic process only if the lesions are reversible or if the measures are taken at the appropriate stage of the disease. These risk factors include hyperlipemia (diet and hypolipemics), hypertension (diet and antihypertensives), diabetes (diet and insulin), smoking (abstinence), obesity (diet), sedentarism (physical training). Proliferation of the Smooth Muscle Cells. The vascular smooth muscle cell proliferation that characterizes the fibrous plaque has been inhibited by calcium

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437 in animal experiments.23 Whether this finding is relevant to human disease remains to be seen. Platelets. Reduction of the aggregation and degranulation of the platelets may avoid the proliferation process. Thus, for example, aspirin prevents platelet aggregation. This is a long-lasting effect, owing to irreversible inhibition of platelet cyclo-oxygenase, which normally generates cyclic endoperoxides from which the aggregating principle Thromboxane A2 is formed. The platelet cyclooxygenase is more sensitive to aspirin than the vessel wall cyclo-oxygenase, which catalyzes the formation of prostacyclin, a strong inhibitor of platelet aggregation. Hence, low doses of aspirin will not affect the release of pros-

antagonists

tacyclin. The latter activates

platelet adenylcyclase and increases platelet c-AMP, thereby decreasing platelet aggregability, which may explain why the antithrombotic activity of phosphodiesterase inhibitors such as dipyridamole and theophylline is largely dependent on the presence of circulating prostacyclin.24 Other agents that affect the adherence, aggregation, and release reaction of platelets are sulfinpyrazone, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, antiserotonins (Cyproheptadine, Methergoline, Methysergide), vasodilators (Papaverine, Verapamil, Viquidil), tranquilizers (Chlorpromazine), antihistamines, hypoglycemics (Gliclazide), hypolipemics (Clofibrate), nitrofurantoin. 21 Prevention of Thrombosis. Thrombosis may be a complicating phenomenon in the natural evolution of atherosclerotic disease. Thrombolytic therapy is indicated in some cases of acute arterial thrombosis and embolism; its usefulness in chronic disturbances and old occlusions is questionable.26-28 Good results with anticoagulation have been reported in impending myocardial infarction (unstable angina, extensive coronary insufficiency). Its use in patients with acute myocardial infarction, however, is controversial. 21,11 Blood Viscosity. Clofibrate, nicotinic acid derivatives, and Arvin, a purified enzyme derived from the venom of the Malayan pit viper,31 improve the flow properties of blood by lowering excessive plasma fibrinogen, a major determinant of plasma viscosity. A clear-cut inhibition of hyperviscosity has been reported after treatment with cinnarizine.32 Such improvement of the flow properties of blood may mean a promising new therapeutic approach in patients with occlusive arterial disease.33 Vasodilatation. The efficacy of vasodilator drugs will depend largely on their effects on the systemic circulation, blood pressure regulation, cardiac function, and the flow distribution between prestenotic areas and the collateral-dependent areas. Therefore the use of systemic vasodilators is controversial, while they are likely to induce systemic hypotension with reflectory tachycardia and excessive inotropic stimulation. This risk is especially important if the drug almost

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438

exclusively acts on arteries and arterioles without a change in the venous capacity. Since flow distribution is determined by the resistance and pressure gradient from nonimpaired to impaired areas, the use of generalized peripheral vasodilation will sometimes cause a redistribution of the blood supply in favor of the unimpeded areas, &dquo;stealing&dquo; the blood away from the collateral-dependent areas.34 Paul M. Vanhoutte, M.D. Universitaire Instelling Antwerpen Department of Medicine Universiteits Plein 1 B2610 Wilrijk

Belgium

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plaques.

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Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N. Engl. J. Med., 297: 1091, 1977. 30. Ribner, H. S., Frishman, W. H.: Anticoagulation in myocardial infarction: new approaches to an old problem. Cardiovasc. 2: 787, 1977. Med., 31. Dormandy, J. A., Reid, H. L.: Controlled defibrination in the treatment of peripheral vascular disease. Angiology, 29: 80, 1978. 32. Di Perri, T., Forconi, S., Guerrini, M.: Action of cinnarizine on the hyperviscosity of blood in patients with obliterative arterial disease. Proc. R. Soc. Med., 70: 25, 1977 33.

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Physiopathology and pharmacotherapy of occlusive arterial disorders.

ANGIOLOGY Published twelve times a year under the auspices of THE ANGIOLOGY RESEARCH FOUNDATION, INC. Physiopathology and Pharmacotherapy of Occlus...
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