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Ann. Rev. Med. 1979. 30:289-300 Copyright @ 1979 by Annual Reviews Inc. All rights reserved

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REGRESSION OF

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ATHEROSCLEROSIS Donald W. Crawford, MD. and David H. Blankenhorn, MD. Department of Medicine, Cardiology Division, University of Southern California School of Medicine, Los Angeles, California 90033

INTRODUCTION

In the past, physicians generally felt that atherosclerosis and its complica­ tions were an inevitable part of the aging process. However, an alternative concept discussed here, arrest or reversion of the process, is not really new. According to Wilens (I), both Krylov (1916) and Anitschkow (1928) noted that persistence of experimental atherosclerosis in rabbits was dependent upon continued feeding of a cholesterol-rich diet. In 1924, Aschoff (2) suggested that human atherosclerosis might be a reversible disease, noting that the reduced incidence toward the end of the first World War seemed attributable to reduced dietary fat. Following the second World War, Malmros (3) reviewed the history of calorie and fat intake in Scandinavia. In Finland, Norway, and Sweden a reduction in mortality paralleled a reduction of dietary calories in the form of eggs and butter. Strom & Jensen (4) also reported similar findings for Norway. In Denmark, total fat con­ sumption declined but butter and egg consumption increased, and no fall was noted. The concept that dietary lipid, particularly as it effects blood cholesterol level, is a central factor in the production of atherosclerosis, gained further support from population studies of Keys et al (5, 6) and risk factor analyses in Framingham (7). Unfortunately, trials of diet for primary or secondary prevention of atherosclerotic events have led to conflicting or equivocal reports. Many factors appear reasonable, but we discuss only two: the multiple events contributing to lesion formation and the inherent limitations of human studies where the usual endpoint is clinical perception of a change in the rate of appearance of complications of atherosclerosis. These studies cannot 289

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distinguish between arrest of the disease, regression of the disease, and progression short of that which causes a new complication. It appears increasingly likely that a common origin of atherosclerosis is endothelial injury, followed by platelet deposition and subintimal cellular proliferation, in addition to incorporation of lipid into the wall. Interactions between hydrodynamics, platelet deposition and release, hormonal effects, mural hypoxia, and metabolic state are not yet fully understood, but all can be involved in the development of early lesions. This suggests many possible avenues of therapeutic approach in addition to diet, blood lipid, or "risk factor" control. Blockade of a single aspect of the complex process might prove effective in some patients. Approaches of this sort cannot be tested adequately in population studies where death or end organ damage serve as end points. We review briefly here the existing evidence for regression of athero­ sclerosis in animal models and in humans, in light of present knowledge of factors responsible for the atherosclerotic lesion. Other recent reviews per­ taining to the reversibility of the atherosclerotic lesion have been published by Gresham (8) and Wissler & Vesselinovitch (9, 10). A REVIEW OF PATHOGENESIS

The classic concept of the progression of the early atherosclerotic lesion is reviewed by Duff & McMillan (11). It is generally accepted that so-called fatty flecks or streaks, which contain foam cells and appear in the intima of the aorta in childhood or adolescence, are the sites of later fully developed atheroma. These areas are flat or only slightly raised, and consist of in­ creased glycosaminoglycan in the intima under the endothelium in which fine droplets of fat are scattered. as well as lipid-laden cells or foam cells. Some lesions may regress, but progression is described as an increase in fibrous proliferation, concentration of foam cells in the deeper regions, and formation of a fibrous cap over the main lipid accumulation. Further devel­ opment consists of foam cell disintegration, which leads to a lipid mass containing necrotic debris and cholesterol crystals. Coalescence occurs, and calcification, hemorrhage, or ulceration produces a complicated lesion, leading to the end organ damage recognized clinically as atherosclerotic vascular disease. Subintimal Thickening

In 1951, Wilens (12) reviewed an alternative, perhaps complementary con­ cept-that diffuse subintimal thickening, which occurs early in life, predis­ poses to the accumulation of lipid and, later, the atherosclerotic plaque. This was based on the finding that early intimal thickening is found in its most advanced state in those areas known to be usual later sites of early

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atheroma formation. An increased severity of the process was noted in hypertension. The "preatheroma" was characterized as an area of subendo­ thelial smooth muscle cell proliferation by Haust et al (13) and Geer et al (14). Such areas were not found or were less marked in populations in which atherosclerosis was uncommon.

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Intimal Injury

French (15) reviewed the possible importance of intimal injury in athero­ genesis. In experimental animals the intima is easily injured by many physi­ cal and chemical factors, including radiation and carbon monoxide. When injury occurs, muscle cells penetrate into the subendothelial space and new ground substance, collagen and elastin, forms, probably a repair process. Lipid accumulation does not occur in nonlipemic animals. When hyper­ cholesterolemia is present, however, lipid accumulation occurs selectively at injured sites and leads to an exaggerated tissue response (16). A focal distribution of lesions produced by hypercholesterolemia alone may suggest the occurrence of spontaneous, perhaps hemodynamically generated, inti­ mal injury. Platelet Aggregation

Downie, Mustard & Rowsell (17) found that pigs develop atherosclerosis with increased dietary fat in the absence of significant hypercholesterolemia. They also noted the focal nature of the disease in patterns suggesting hemodynamic injury, and the tendency for deposition of microthrombi. They suggested that incorporation of platelet elements into the wall led to atherogenesis, and that this would be accelerated in areas of endothelial injury. Additional support for the role of endothelial cell injury and platelet response was presented recently by Harker et al (18) and by Fuster et al (19). Homocystinemia is known to be associated with an increased inci­ dence of atherosclerosis. In baboons, homocystinemia causes patchy deen­ dothelization and increased platelet consumption followed by the lesions of arteriosclerosis (18). Abnormal platelet consumption and plaque formation were prevented by dipyridamole. Fuster et al found that the platelet defect associated with von Willebrand's disease in pigs prevented atherosclerotic plaque development from a high cholesterol diet, although endothelial dam­ age was present (19). Endothelial Permeability

Physical injury of the endothelium is not necessarily the only mode of increasing intimal permeability and exposing collagen for platelet interac­ tions (see below). For instance, Robertson & Khairallah (20) noted in­ creased endothelial permeability for low density lipoproteins and other

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substances in areas exposed to physiologic concentrations of angiotensin II. The process is further accelerated by an associated contraction and de­ granulation of circulating platelets after attachment to exposed collagen (21). Whether the lesion progresses or regresses may then be determined by the rate of smooth muscle cell migration and proliferation in the subintimal layers as stimulated by low density lipoprotein (22) or platelet factor (23), in addition to the rates of ingress versus removal of lipid due to the increased endothelial permeability. The production of experimental atherosclerosis by hyperlipidemia without apparent physical injury was tentatively explained in this respect by Ross & Harker (24). Chronic hypercholesterolemia led to endothelial cell desquamation and decreased platelet survival as well as lipid accumulation within the wall. Lipid and Metabolite Exchange

Geer et al (25) suggested that unesterified cholesterol enters the wall by exchange with plasma lipoprotein and that esterification of free cholesterol within the arterial wall is a detoxification mechanism. With this in mind, the physical role of the avascular subintimal thickening due to myocyte proliferation must be considered. Relatively immense diffusional distances are produced, leading to the very real possibility that small molecules such as oxygen are in short supply in the inner avascular layers of the thickened wall (26, 27). Since ample amounts of oxygen are needed for many cellular processes, and possibly esterification of cholesterol, a vicious cycle so generated may progress to the complex lesions associated with clinical vascular disease. Other factors may be associated with the balance between cholesterol ingress and removal. It was recently proposed that high density lipoprotein (HDL) is associated with clearance of cholesterol from the arterial wall (28). Reduced HDL would then increase risk of vascular disease by limiting cholesterol transport from the wall. REGRESSION OF EXPERIMENTAL ATHEROSCLEROSIS Diet

In monkeys, relatively short-term feeding of cholesterol with or without other dietary supplements results in an intimal lesion similar to the human fatty streak (29-32). Some months after discontinuation of the dietary supplements, the lesions appear to regress, i.e. lipid content is reduced as observed by histologic examination and chemical analysis. Regression may not occur for some months after removal from the high cholesterol diet (33) and reendothelization of the intima is apparently necessary to begin repair and to halt myocyte hyperplasia (34).

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When atherogenic diets are fed for a longer period of time, more intense cellular proliferation occurs. During the regression phase on a normal diet, intimal lesions are again depleted of lipid (35, 36). Luminal cross-sectional area may increase (36). Of interest is the finding that atherosclerosis occurs in primates after four to six months on a diet similar in fat content to the North American diet (37). Advanced or complicated atherosclerosis quite similar to symptomatic human disease was produced in swine by Daoud et al (38) and Fritz et al (39) who used a combination of endothelial injury and high cholesterol diet. At the end of a low cholesterol regression phase lasting 14 months, atheromas, thrombosis, and hemorrhage essentially disappeared and cal­ cified areas appeared smaller, as compared to those in animals sacrificed at the termination of the cholesterol regimen (38). These findings were con­ firmed by chemical analysis; arteries containing post regression lesions did not differ greatly in composition from normal arteries (39). Similar results were obtained in rhesus monkeys by Vesselinovitch & Wissler (40). Combined Therapy

Since hypoxia of a portion of the media is possible after sufficient subintimal proliferation has occurred, Kjeldsen et al (41) fed rabbits excess cholesterol while exposing them to ambient or hyperoxic atmospheres for a period of 10 weeks. Hyperoxic animals appeared to develop less marked atherosclero­ sis than untreated animals. In an extension of this concept, Vesselinovitch et al (42) reported a standard regression experiment in rabbits in which therapeutic options included low fat diet, hyperoxia, and cholestyramine or estrogen. Most marked regression was seen in the group of animals treated with the combination of low fat diet plus hyperoxia and either drug. In an attempt to modify other components of atherogenesis, Kwak & Lee (43) utilized two antimetabolites, mercaptopurine and hydroxyurea, and pyridinol carbamate (43). Pyridinol carbamate was thought to act as an endothelial cell relaxant and antiplatelet aggregator. During a low choles­ terol regression test in rabbits with atherosclerosis, the antimetabolites and pyridinol carbamate both significantly reduced the surface area of athero­ sclerotic involvement, as compared to low cholesterol diet alone. Of note in this regard, Kramsch & Chan (44) reported suppression of collagen synthesis in atherosclerotic arteries by ethane hydroxydiphosphate (EHDP). INDIRECT EVIDENCE FOR REGRESSION IN MAN

Several investigators have used indirect methods or semiquantitative angi­ ography in small therapeutic trials. Ost & Stenson (45) gave nicotinic acid to a small group of patients with leg claudication and used oscillometry and

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plethysmography as estimators of changes in blood flow. Approximately one third of the patients showed an improvement in both these tests. The authors felt that development of spontaneous collateral could be excluded in three cases, since serial femoral angiograms appeared to show regression of atherosclerosis. Zelis et al

(46)

also used plethysmography in patients with claudication

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and hyperlipoproteinemia. Diet advice and clofibrate were used as therapy and six patients with Type III hyperlipoproteinemia showed marked im­ provement after three to six months. It was believed that collateral develop­ ment did not account for the improvement. Two untreated patients showed no change in peak reactive hyperemic blood flow. Redisch et al

(47) treated

eight patients with pyridinol carbamate and 15 with placebo. All patients had claudication. Seven patients receiving the medication showed "no progression," as examined by venous occlusion plethysmography and nail bed capillary microscopy and confirmed by observation of serial angio­ grams. All patients on placebo showed progression. Another more recent report pertaining to hyperlipoproteinemic patients with claudication was published by O'Connor et al (48). Eight patients were given a placebo and six received dietary supervision. A significant deteriora­ tion in peak reactive blood flow was seen in the placebo group as compared to the diet group over a 12-month period.

ANGIOGRAPHIC TECHNIQUES TO STUDY REGRESSION Regression trials place demands on angiography more complex than and quite different from recognition of vascular obstruction or evaluation to plan for its repair. In order to quantitate atherosclerosis in vessels examined at autopsy,pathologists began sometime ago to solve the problems inherent in this process. These problems occur because the disorder can lead to both dilation and constriction of local segments in the same vessel. In addition, a wide variety of lesion types can occur, thus relative degrees of severity must be assigned to each. This is an entirely feasible procedure, but certain conceptual problems need resolution before it can be done. For example, which is more significant, a hemorrhagic or an ulcerated lesion? In the evaluation of lesions at autopsy, semiquantitative methods, such as planimetry of lesion area are clearly more precise than visual estimates

(49).

This is also found in evaluating postmortem angiograms. An addi­

tional difficulty in angiographic planimetry arises because only two edges of a vessel are usually observed; variations in density of contrast not on an edge are seldom perceived and never visually quantitated. The findings of Robbins et al (50,51) may be explained partially on this basis. They found

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that quantitative angiographic evaluation made with a caliper improved on visual estimates but still underestimated severity of disease as compared to vessel lumen casts. The clinical angiographer who would measure lesion change must be aware of other conceptual and practical problems not faced by the patholo­ gist. One of these is vasospasm. Recent attention has been given to the difficulty in differential recognition of transient spasm, misinterpreted as atherosclerotic obstruction (52). Experimental pharmacologic maneuvers may eventually resolve this quandary in part (52). Utilization of the proper­ ties of circular symmetry as measured by quantitative angiographic den­ sitometry may also help to resolve the issue (53). In addition to vasospasm, thrombi present a problem because they cannot always be distinguished from plaques by visual inspection of films. Dissolution of a thrombus would mimic rapid plaque resolution. It is possible, however, that advances in the statistical evaluation of fine angiographic lesion characteristics may assist in resolution of this problem, since some progress has been made in the angiographic recognition of lesion types (54). In order to develop angiographic procedures suitable for regression stud­ ies, we began a quantitative angiographic/pathologic study of human ar­ terial disease in 1971 (55). Human cadavers were injected at arterial pressure with a radiopaque silicone rubber bolus, which produces films indistinguishable from those of clinical studies. After catalysis of the sili­ cone rubber, arterial specimens were available for comparison with the three-dimensional information of the cast and with the angiogram. Lesions were assessed with digital densitometric image dissection of the angiograms coupled with automated computer edge-finding and edge roughness evalu­ ation. Pathologic specimens were ordered by a panel with respect to type and extent of disease and used iteratively to "teach" the computer to recognize small degrees of atherosclerosis. The method has proven statisti­ cally accurate in evaluation of nonobstructive disease within the range of our cadaver experience. Because of the difficulty in quantitative visual or computerized angiographic evaluation of small, rapidly moving arteries such as the coronaries, we chose to do this study in the femoral artery. Evaluation of edge contours plays a central role in the computer proce­ dure we developed and is the mainstay of evaluation by human film readers. This cannot reflect in toto the amount or degree of atherosclerosis present even in biplane angiograms. It does not draw an adequate sample of the process because atherosclerosis is not randomly distributed, as noted by Flaherty et al (56) and shown in our studies of high resolution arterial casts (57). To develop a method capable of lesion evaluation in any position on the vessel we studied the profile of density contours within the boundaries of the angiographic shadow (53). Quantitative densitometric information

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from an angiogram can yield chord length distributions of angiographic vascular cross sections to an accuracy of about 300 microns. In the presence of disease visible at necropsy, arteries deviated from the regular smooth contour typical of normal arteries. This method is now being computerized and should prove useful not only in more exact evaluation of the extent of disease and its sequential change, but also for most practical purposes the exclusion of vasospasm.

ANGIOGRAPHIC EVIDENCE FOR HUMAN REGRESSION The literature now reports several cases of arterial obstruction resolution revealed by angiography. For example, Basta et al (58) described a 49-year­ old woman with angina, hypertension, hyperlipidemia, and renal artery stenosis as perceived by arteriogram. Hyperlipidemia and hypertension were treated. Four years later, hypertension was absent and renal arterio­ grams showed a marked reduction in renal artery stenosis. Starzl et al (59) reported the case of 12-year-old girl with hyperlipo­ proteinemia who suffered a massive myocardial infarction. A portacaval shunt was done in an attempt to lower blood cholesterol level. Prior to operation, coronary arteriography showed severe obstructive disease. After operation, her cholesterol level declined markedly, and 16 months later the coronary arteries appeared far more patent. Angina pectoris had disap­ peared. Case reports, however, have limited applicability to the general popula­ tion subject to atherosclerotic death. Small pilot regression studies utilizing angiography with various degrees of quantitation have also been published. Knight et al (60) reported 120 patients who had undergone partial ileal bypass in an effort to control hyperlipidemia and atherosclerosis. Angio­ graphic evidence of progression of atherosclerotic disease in these patients is usual, but they believed that the rate of progression was reduced. They reported apparent regression in three patients. However, in a secondary trial using clofibrate in patients, many of whom have received coronary bypass operations, Cohn et al (61) reported no significant influence of therapy. The study of Ost, who employed nicotinic acid, was more encouraging. Blankenhorn (62) reviewed the current experience with sequential fem­ oral arteriograms in the evaluation of atherosclerosis. Femoral angiograms provide better resolution than is obtained in coronary cinearteriography, but it is still apparent that the vast majority of papers to date report either no change or progression of disease in most patients, with regression in a few. If experimental data pertaining to mobility of cholesterol pools are valid, perhaps this is not surprising. Most reported studies describe late

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obstructive disease-the only type of atherosclerosis that commonly calls for angiography and that least likely to change favorably in a relatively short time. Recently, however, it has been possible to obtain quantitative data from a younger group of patients. Barndt et al (63) demonstrated that nonob­ structive femoral atherosclerosis can be quantitated in early adulthood in patients with hyperlipoproteinemia. In quantitative angiographic study of 25 such patients under treatment, regression of disease was present in nine and was significantly correlated with reduction in serum triglyceride, cho­ lesterol, and blood pressure (64). SUMMARY

Many interacting etiologic factors are necessary for the genesis of the atherosclerotic process. Control of the disease may not depend only upon regulation of blood lipid, but also upon a carefully selected control of endothelial integrity, platelet function, and the hyperplastic response of the arterial wall. Regression of the disease cannot be proven clinically unless carefully controlled sequential radiographic studies are done. Recent radio­ graphic studies suggest that regression of human atherosclerosis can and does occur. Literature Cited

I. Wilens, S. L. 1947. The resorption of 2. 3.

arterial atheromatous deposits in wast­ ing disease. Am. J. Pathol 23:793-804 Aschoff, L. 1924. Lectures in Pathology. New York: Hoeber. 365 pp. Malmros, H. 1950. The relation of nu­ trition to health. A statistical study of the effect of the war-time on arterio­ sclerosis, cardiosclerosis, tuberculosis and diabetes. Acta Med. Scand. Suppl 246:137-53

4.

Strom, A., Jensen, R. A. 1951. Mortal­ ity from circulatory diseases in Norway

5.

Keys, A., Anderson, J. T., Aresu, M., Biorck, G., Brock, J. F., Bronte­ Stewart, B., Fidanza, F., Keys, M. H., Malmros, H., Poppi, A., Posteli, T., Swahn, B., Del Vecchio, A. 1956. Phys­ ical activity and the diet in populations differing in serum cholesterol. J. Clin.

6.

7.

Kannel, W. B., Dawber, T. R., Fried­ man, G. D., Glennon, W. E., McNamara, P. M. 1964. Risk factors in coronary heart disease. An evaluation of several serum lipids as predictors of coronary heart disease. The Framing­ ham Study. Ann. Intern. Med 61:

8.

Gresham, G. A. 1976. Is atheroma a reversible lesion? Atherosclerosis 23:

9.

Wissler, R. W., Vesselinovitch, D. 1976. Studies of regression of advanced atherosclerosis in experimental animals and man. Ann. NY Acad Sci. 275:

10.

Wissler, R. W., Vesselinovitch, D. 1977. Regression of atherosclerosis in experi­ mental animals and man. Mod. Con­

1940-1945. Lancet 1:126-29

Invest. 35:1173-81

Keys, A., Kimura, N., Kusukawa, A., Bronte-Stewart, B., Larsen, N., Keys, M. H. 1958. Lessons from serum cho­ lesterol studies in Japan, Hawaii and Los Angeles. Ann. Intern. Med. 48: 83-94

888-99

379-91

363-78

cepts Cardiovasc. Dis. 46:27-32

II. Duff, G. L., McMillan, G. C. 1951. Pa­ thology of atherosclerosis. Am. J. Med. 11:92-108

12.

Wilens, S. L. 1951. The nature of diffuse intimal thickening of arteries. Am. J.

13.

Haust, M. D., More, R. H., Movat, H. Z. 1960. The role of smooth muscle cells

Pathol 27:825-39

298

14.

Annu. Rev. Med. 1979.30:289-300. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.

15.

16.

17.

18.

eRAWFORD & BLANKENHORN in the fibrogenesis of arteriosclerosis. Am. J. Pathol 37:377-89 Geer, J. C., McGill, H. C., Strong, J. P. 1961. The fine structure of human atherosclerotic lesions. Am. J. PathoL 38:263-87 French, J. E. 1966. Atherosclerosis in relation to the structure and function of the arterial intima, with special refer­ ence to the endothelium. Int. Rev. /!'xp. Pathol. 5:253-353 Still, W. J. S., Dennison, S. M. 1967. Reaction of the arterial intima of the rabbit to trauma and hyperlipemia. Exp. Mol PathoL 6:245-53 Downie, H. G., Mustard, J. F., Rowsell, H. C. 1963. Swine atherosclerosis: the relationship of lipids and blood coagula­ tion to its development. Ann. NY Acad. Sci. 104:539-61 Harker, L. A., Ross, R., Slichter, S. J., Scott, C. R. 1976. Homocystine­ induced arteriosclerosis. The role of en­ dothelial cell injury and platelet re­ sponse in its genesis. J. Clin. Invest. 58:731-41

19. Fuster, V., Bowie, E. J. W., Lewis, J. C., Fass, D. N., Owen, C. A. Jr., Brown, A. L. 1978. Resistance to arteriosclerosis in pigs with von Willebrand's Disease. Spontaneous and high cholesterol diet­ induced arteriosclerosis. J. Clin. Invest. 61:722-30 20. Robertson, A. L., Khairallah, P. A. 1972. Effects of Angiotensin II and some analogues on vascular permeabil­ ity in the rabbit. Cire. Res. 31 :923-31 21. Robertson, A. L. Jr., Khairallah, P. A. 1973. Arterial endothelial,permeability and vascular disease. The "trap door" effect. Exp. MoL Pathol 18:241-60 22. Ross, R., Glomset, J. A. 1973. Athero­ sclerosis and the arterial smooth muscle cell. Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180:1332-39 23. Ross, R., Glomset, J., Kariya, B., Harker, L. 1974. A platelet-dependent serum factor that stimulates the prolif­ eration of arterial smooth muscle cells in vitro. Proc. Natl Acad. Sci. 71: 1207-10 24. Ross, R., Harker, L. 1976. Hyper­ lipidemia and atherosclerosis. Chronic hyperlipidemia initiates and maintains lesions by endothelial cell desquamation and lipid accumulation. Science 193: 1094-1100 25. Geer, J. C., Sharma, H. M., Pan­ ganamala, R. V., Cornwell, D. G. 1977. Progression and regression of experi-

mental atherosclerotic lesions. Adv. Exp. Med. BioL 82:434-39 26. Zemplenyi, T. 1974. Vascular enzymes and the relevance of their study to prob­ lems of atherogenesis. Med. Clin. North Am. 58:293-321 27. Back, L. H. 1976. Analysis of oxygen transport in the avascular region of art­ eries. Math. Biosei. 31:285-306 28. Miller, G. J., Miller, N. E. 1975. Plas­ ma-high density-lipoprotein concentra­ tion and development of ischaemic heart-disease. Lancet 1:16-19 29. Maruffo, C. A., Portman, O. W. 1968. Nutritional control of coronary artery atherosclerosis in the squirrel monkey. J. Atheroscler. Res. 8:237-47 30. Tucker, C. F., Catsulis, C., Strong, J. P., Eggen, D. A. 1971. Regression of early cholesterol-induced aortic lesions in Rhesus monkeys. Am. J. Pathol. 65: 493-514 31. Eggen, D. A., Strong, J. P., Newman, W. P. III, Catsulis, C., Malcom, G. T., Kokatnur, M. G. 1974. Regression of diet-induced fatty streaks in Rhesus monkeys. Lab. Invest. 31:294--301 32. Strong, J. P., Stary, H. c., Eggen, D. A. 1977. Evolution and regression of aortic fatty streaks in Rhesus monkeys. Adv. Exp. Med. Bioi. 82:603-13 33. Kokatnur, M. G., Malcom, G. T., Eggen, D. A., Strong, J. P. 1975. Deple­ tion of aortic free and ester cholesterol by dietary means in Rhesus monkeys with fatty streaks. Atherosclerosis 21:195-203 34. Weber, G., Fabbrini, P., Capaccioli, E., Resi, L. 1975. Repair of early choles­ terol-induced aortic lesions in rabbits after withdrawal from short-term atherogenic diet. Scanning electron­ microscopical (SEM) and transmission electron-microscopical (TEM) observa­ tions. Atherosclerosis 22:565-72 35. Armstrong, M. L., Megan, M. B. 1972. Lipid depletion in atheromatous coro­ nary arteries in Rhesus monkeys after regression diets. Cire. Res. 30:675-80 36. Armstrong, M. L., Warner, E. D., Con­ nor, W. E. 1970. Regression of coronary atheromatosis in Rhesus monkeys. Circ. Res. 27:59-67 37. Malinow, M. R., McLaughlin, P., Pap­ worth, L., Naito, H. K., Lewis, L., McNulty, W. P. 1976. A model for ther­ apeutic interventions on established coronary atherosclerosis in a nonhuman primate. Adv. Exp. Med. Biol 67:3-31 38. Daoud, A. S., Jarmolych, J., Augustyn, J. M., Fritz, K. E., Singh, J. K., Lee, K. T. 1976. Regression of advanced

REGRESSION OF ATHEROSCLEROSIS Arch. PathoL

51.

Fritz, K. E., Augustyn, J. M., Jar­ molych, 1., Daoud, A. S., Lee, K. T. 1976. Regression of advanced athero­ sclerosis in swine. Chemical studies.

52.

atherosclerosis in swine.

Annu. Rev. Med. 1979.30:289-300. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.

39.

Lab. Med. 100:372-79

Arch. Pathol. Lab. Med. 100:380-85 40. Vesselinovitch, D., Wissler, R W. 1978. In State of Prevention and Therapy in Human Arteriosclerosis and in Animal Models, ed. W. H. Hauss, R. W. Wissler, R Lehmann, pp. 127-34. Le­

41.

42.

verkusen: Westdeutscher Kjeldsen, K., Astrup, P., Wanstrup, J. 1969. Reversal of rabbit atheromatosis by hyperoxia. J. Atheroscler. Res. 10:173-78

Vesselinovitch, D., Wissler, R. W., Fisher-Dzoga, K., Hughes, R., Dubien L. 1974. Regression of atherosclerosis in rabbits. Part I. Treatment with low­ fat diet, hyperoxia and hypolipidemic agents. Atherosclerosis 19:259-75 43. Kwak, Y. S., Lee, K. T. 1976. Drug­ induced regression of experimental atherosclerosis in rabbits. Fed. Proc 35:598 (Abstr.) 44. Kramsch, D. M., Chan, C. T. 1976. In­ creased in vivo synthesis of elastin and collagen in atherosclerotic arteries and its suppression by drugs. Fed. Proc �.5:598 (Abstr.) 45. Ost, C. R., Stenson, S. 1967. Regression of peripheral atherosclerosis during therapy with high doses of nicotinic acid. Scand. J. Clin. Lab. Invest Suppl. 99:241-45

47.

Redisch, W., Clauss, R H., Rouen, L. R., Katz, M. C., Terry, E. N. 1975. Progression of occlusive atherosclero­ sis. Long-term administration of pyridi­ nol carbamate. Arch. Surg. 110:258-61 O'Connor, J., Ballantyne, D., PoJlock, J. G., Cairney, B., Lawrie, T. D. V. 1977. Limb blood flow in treated hyper­ lipoproteinaemic patients with periph­ eral vascular disease. Atherosclerosis

48.

49:1007-15

27:325-31

49.

Cranston, W. I., MitcheJl, J. R A., Rus­ seJl, R. W. R., Schwartz, C. J. 1964. The assessment of aortic disease. J. Atheros­

50.

Robbins, S. L., Rodriguez, F. L., Wragg, A. L., Fish, S. J. 1966. Problems in the quantitation of coronary arterio­ sclerosis. Am J. Cardiol 18:153-59

41:787-89

Crawford, D. W., Brooks, S. H., Barndt, R Jr., Blankenhorn, D. H. 1977. Measurement of atherosclerotic luminal irregularity and obstruction by radiographic densitometry. Invest.

54.

Brooks, S. H., Crawford, D. W., Selzer, R. H., Blankenhorn, D. H., Barndt, R. Jr. 1978. Discrimination of human ar­ terial pathology by computer process­ ing of angiograms for serial assessment of atherosclerosis change. Comput. Biomed. Res. In press Crawford, D. W., Brooks, S. H., Selzer, R H., Barndt, R. Jr., Beckenbach, E. S., Blankenhorn, D. H. 1977. Computer densitometry for angiographic assess­ ment of arterial cholesterol content and gross pathology in human atherosclero­ sis. J. Lab. CUn. Med. 89:378-92 Flaherty, J. T., Ferrans, V. J., Pierce, J. E., Carew, T. E., Fry, D. L. 1972. In

55.

56.

.

Zelis, R, Mason, D. T., Braunwald, E., Levy, R. I. 1970. Effects of hyperlipo­ proteinemias and their treatment on the peripheral circulation. J. Clin. Invest.

McGill, H. C. Jr., Brown, B. W., Gore, I., McMillan, G. C., Pollak, O. J., Rob­ bins, S., Roberts, J. C. Jr., Wissler, R. W. 1968. Grading stenosis in the right coronary artery. Circulation 37:460-68 Helfant, R H. 1978. Coronary arterial spasm and provocative testing in is­ chemic heart disease. Am J. Cardiol

53.

.

46.

299

Radiol 12:307-13

Atherosclerosis and Coronary Heart Dis­ ease, ed. W. Likoff, B. L. Segal, W. In­ suJl, Jr., J. H. Moyer, pp. 40-83. New

57.

58.

59.

York: Grune & Stratton Crawford, D. W., Barndt, R. Jr., Back, L. H. 1976. Surface characteristics of normal and atherosclerotic human art­ eries including observations suggesting interaction between flow and intimal morphology. Lab. Invest. 34:463-70 Basta, L. L., Williams, C., Kioschos, J. M., Spector, A. A. 1976. Regression of atherosclerotic stenosing lesions of the renal arteries and spontaneous cure of systemic hypertension through control of hyperlipidemia. Am J. Med. 61: 420-23

Starzl, T. E., Chase, H. P., Putnam, C. W Nora, J. J. 1974. Follow-up

Regression of atherosclerosis.

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