Atherosclerosis—Relationship to coronary blood flow

Atherosclerosis-Relationship

to Coronary Blood Flow

ROBERT W. WISSLER, MD, PhD, and DRAGOSLAVA

VESSELINOVITCH, DVM, MS

Human atherosclerotic plaques in coronary arteries consist of a variable mixture of lipids, ceils and fiber proteins synthesized by the cells. The 2 major space-occupying components of the advanced lesions, which together obstruct the lumen, are the fibrous cap and the necrotic core from which the lesions derive their name. The smooth muscle cells, which make up most cells of the plaque, including the fibrous caps, are produced by migration from the media as well as by prollferation of these cells in the intima. The lipids, mostly supplied by circulating lipoproteins, are present not only in the atheromatous acellular core, but also in the cytoplasm of the cells of the lesion and extracellularly, often attached to 1 or more constituents of the fibrous matrix of the plaque (collagen, elastin and proteoglycans). In both human and rhesus monkey coronary arteries, the lumen becomes more stenotic as the plaque becomes larger and enlarges as the plaque

becomes smaller in response to lipid-lowering therapy. Recent studies in other nonhuman primate models of advanced atherosclerosis have questioned the influence of the plaque lesion on coronary blood flow. For example, in the cynomolgus species of macaque (M. fascicularis), depending on how the plaques are Induced, the artery lumens may dilate as the plaques become larger because the outside diameters of the arteries increase. Furthermore, some diseased arteries are found to stenose further when the animals with advanced coronary plaques are treated by measures that substantially reduce the lipids in the plaques. Questions now being studied in several animal models and in human arteries include the relative influence of the degree of medial involvement, of lesion cell types, and of lesion circumferential localization (concentric versus eccentric) on these paradoxical phenomena.

Coronary artery atherosclerosis in humans is mostly a disease of the proximal 6 to 8 cm of the major coronary arteries. The lesions, which usually present as intimal plaques, consist of a variable mixture of lipids (including cholesterol and cholesteryl esters), cells and fiber proteins synthesized by the cells. The 2 major space-occupying components of the fully developed plaque, which together can lead to severe stenosis of the lumens of these arteries, are the fibrous cap and the necrotic atheromatous core from which the lesions derive their name (Fig. 1). The smooth muscle cells, which make up most cells of the human plaque including the fibrous cap, are presumably the product of immigration of cells from the media, accompanied or followed by excessive prolifer-

ation (mitosis) of these cells in the intima (Fig. 2). The lipid-cholesterol mixture appears to be mostly supplied by circulating lipoproteins that traverse the endothelial “barrier” and are deposited. This cholesteryl ester-rich lipid is found not only in the atheromatous acellular core, but also in the cytoplasm of the smooth muscle cells, and to a variable extent in macrophages and extracellularly, often attached to 1 or more constituents of the fibrous cap (collagen, elastin or proteoglycans). The fiber proteins of the plaque are largely the products of these proliferated smooth muscle cells. The space-occupying features of the growing plaque, which result in stenosis, are responsible for much of the decrease in coronary blood flow that leads to ischemic heart disease. Nevertheless, many of the acute catastrophic episodes that we call “heart attacks” are triggered by the severe coronary plaques that are often ulcerated or that present a ruptured or torn fibrous cap (Fig. 3). This, in turn, promotes mural or obturating thrombosis or promotes spasm of the major coronary artery superimposed upon or alongside a major plaque that is ulcerated. The forces that favor occlusion or promote fatal arrhythmias or classic myocardial infarction are opposed,

From the Department of Pathology and tfte Specialized Center of Research on Atherosclerosis, University of Chicago, Prltzker School of Medicine, Chicago, Illinois. This study was supported in part by Grants HL 15062 and HL 17648 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda. Maryland and by the University of Chicago’s Cardiovascular Research Foundation. Address for reprints: Robert W. Wissler. PhD. MD. University of Chicago, Department of Pathology, Box 414, 950 E. 59th Street, Chicago, Illinois 60637.

July 20.1983

THE AMERICAN JOURNAL OF CARDIOLOGY Volume52

DJAGRAMOF AN ATHEROSCLEROTIC PLAQUE

3A

NECROTIC CENTER (CELL Dcllnlq CmLLmxoL CWSTALS, CHOLESTERQ ESTERS, CALCIUY~

(Afhr P Cma~ntlr&n~

@ROLIFERAlED SMCOTH YUSCLL CELLS, COLLAQEN, EXTRMELLULAR AND INTRACELLULAR LIPID, INCLUDINB FOAM CELLS)

FIGURE 1. The major components of an advanced atherosclerotic plaque, including the grumous necrotic center from which the lesion derives its name and the fibrous cap made up largely of lipid-filled smooth muscle cells and fiber proteins produced by these cells, mainly collagenand elastin. The evidence of injured endothelium is a common feature of the advanced plaque.

-ADVENTITIA

CELL

PROLIFERATION (BUT

AS

NEGLECTED)

PATHOGENESIS

PART

OF

AN

IMPORTANT OF

THE

ATHEROSCLEROSIS

MEN

CELL IN CREA SED MI TOSI S’ MOSTLY MUL TIFUNCMEDIAL :: ONAL CELLS ME SENC HYMAL

-EN DOTH

ELIUM

-IN TERN AL ME MBRA NE

ELASTIC

NE DIA

FIGURE 2. Arterial smooth muscle cell migration (from the underlying media) and active proliferation in both the intima and the media as important components of athemgenesis in humsn and nonhuman primate w esis. LDL = low-density lipoprotein. Modified from Wissler RW. In: Homburger F, ed. Comparative Pathology of the Heart. Basel: S. Karger, 1974.:10-31.

to a variable extent, by coronary artery collaterals1 and by dilation of severely diseased arteries.2 Weakening of the media and enlargement of the entire circumference counteract stenosis, as reflected by morphometric evaluation of the external elastic membrane. The stenosing tendencies of the plaque are also strongly opposed in most humanoid animal models, and probably in humans with advanced disease as well, by an effective set of reactiolns that occur when the lipid levels in the blood are lowered to levels often observed in most adults in populakions where atherosclerosis usually does not progress and ischemic heart disease is rare. This evidence of decrease in lesion size (regression), healing of endothelium and remodeling of the fibrous cap has been well documented in numerous quantitative studies of regression of advanced atherosclerosis in macaques, dogs and swine.This presentation documents and evaluates some recent human clinical-pathologic and experimental pathophysiologic data that, support the concept of these opposing forces involved in progression, healing and regression.

* RAY

RE

STIMULATED

1. FACTORS AND 2, FACTORS 3. OTHER

4Y

FROtl

PLATELETS,

tlACROPHAGES

ENDOTHELIUR FROM CELL

HYPERLIPIDEUIC TRANSFORNING

LDL STIMULI,

E.G. V I R U SE S

FIGURE 3. Photomicrograph frcm an occludedcoronary artery in which thethrombosisappearstobedirectlyrebtedtoaNphredfikouscap over a very severely diseased plaque, which has a large necrotic, cholesterol-rich core. Reproduced from Buja LM, Willerson JT. Am J Cardiol 1981;47:343-356. with permission of the publisher.

4A

ATHEROSCLEROSIS AND CORONARY BLOOD FLOW

FIGURE 4. Coronary artery plaque from a 54-year-old man who was found to have subendocardial myocardial necrosis when he died, about 12 hours after acute onset of chest pain. The lesion, a prototype of many observed at autopsy and probably not detected by angiography, is characterized by a thin, loose, fibrous cap and a proportionately larger necrotic center.g

New Data on Plaque Progression Roberts9 studied severe atherosclerotic plaques from human autopsies and recognized that the mass of the plaque may not be as important as the relative quantities of components in triggering a clinical event. For example, many relatively small, eccentric plaques, each with a very lipid-rich center and a very thick fibrous cap, have been shown that could not be detected with angiography. These soft and “florid” plaques are dangerous because of their propensity to “fibrous” cap rupture and platelet adherence, resulting in thrombosis or coronary spasm (Fig. 4). Robert&’ proposed patterns of stenosis and described eccentric and concentric plaques. Two examples of advanced concentric and eccentric coronary lesions in the human are shown in Figure 5. Our observations in rhesus monkeys and cynomolgus monkeys using identical atherogenic rations in our laboratory have suggested a new interpretation of eccentric versus concentric lesions (Fig. 6).

TABLE

I

The cynomolgus monkey regularly develops concentric coronary lesions, but the same diet fed to the rhesus monkey (Fig. 6) almost exclusively produces eccentric coronary lesions. These cynomolgus lesions often display a large proportion of mononuclear cells, many of which are converted to foam cells. The foam cells are not only intimal but often become concentrically transmural with extensive destruction of the media. In numerous instances, the adventitia is also extensively involved. These atheromatous lesions resemble the transmural lipid-rich lesions seen in some patients with incompatible human heart transplants or those produced experimentally by Alonso et all1 in homologously transplanted animals and Minick et aPJ3 in rabbits with serum sickness (both groups received an atherogenic ration). These lesions resemble those seen in hypercholesterolemic subjects who also have immune complex panarteritis. When findings in rhesus and cynomolgus monkeys were compared with those from our laboratory, over 80% of cynomolgus monkeys had definite evidence or circulating Ag-Ab complexes, but rhesus monkeys did not. We believe that this widespread concentric and often highly destructive lesion in cynomolgus monkeys is different from most coronary lesions in humans and may explain why regression is uncommon.8J4,15 Other investigators have observed different regression patterns in cynomolgus lesions under conditions that consistently lead to regression of advanced atherosclerosis in the rhesus species of macaques (Mucaca mulatta). These transmural lesions, with their smoldering medial inflammation, form scars that constrict when they lose their lipids. Malinow et all6 reported an exception. Using a less atherogenic ration and a short induction, these worker8 reported substantial regression resulting from incorporation of either alfalfa meal or cholestyramine in the slightly modified atherogenic ration. Bond et al2 reported that this lesion produces more dilatation of the artery, as measured by the increase in diameter or circumference of the internal elastic membranes during induction, than they observed in rhesus monkeys (Table I) and that this may alter coronary flow. Vesselinovitch and Wissler17 showed a

Plasma Lipid and Coronary Artery Size Characteristics* Baseline (19~Month Progression)

Number TPC’ IEL area lntimal area Luminal area Percent stenosis

777 1.08 0.30 0.78

18 f 36 f 0.10 f 0.06 f 0.07 28

24Month Regression

48-Month Regression

High TPC

Low TPC

High TPC

302:88 1.31 f 0.16 0.44 f 0.08 0.87 f 0.10 34

19424 1.35 f 0.16 0.26 f 0.08 1.09 f 0.12 19

316ZO 1.80 f 0.12 0.29 f 0.07 1.51 f 0.09 16

Adapted from Bond et al.2 + Area measurements are expressed as millimeters squared (mean f standard error of the mean). + Total mean plasma cholesterol concentration (mean f standard error of the mean). IEL = internal elastic luminal; TPC = total plasma cholesterol.

Low TPC 202 1.80 0.21 1.60

:84 f 0.09 f 0.05 f 0.07 12

July 20,1983

THE AMERICAN JOURNAL OF CARDIOLOGY

Volume 52

5A

FIGURE 5. Photomicrographs of concentric and eccentric lesions in coronary arteries, which illustrate much more medial involvement and medial degeneration and atrophy in the concentric lesion. Note the intact media opposite the eccentric lesion. Reproduced from Roberts9 with permission of the publisher.

FIGURE 6. Advanced plaques from a recent experiment.” Left, lesion stained with a fat stain, is a typical concentric lesion, with abundant destructive medial involvement and extensive adventitial foam cell infiltration. Right, a typical rhesus lesion with an advanced eccentric plaque showing a necrotic center and very little damage to the arterial medial musculature except in small focal areas.

6A

ATHEROSCLEROSIS

AND CORONARY

1

BLOOD FLOW

sp.&m t-

Plaque Emwn-Rupture

J Plaque Hemorrhage

Platelet Aggregation

Other Pfeded,spos,ng or PrfeClpMng Cardwascular Alterat,ons increasedMywardial OxygenDemand

!4echanisms of lnductioo 01 major syndromes of acute ischemtc heari dfsease

FIGURE 7. The two types of pathogenetic sequences, each of which may account for about half of the heart attacks in the United States. Reproduced from Buja et al’s with permission of the publisher.

definite arterial dilatation in cynomolgus monkeys but no change as the lumen filled in with plaque in the adult male rhesus monkeys. These observations may be clinically important because concentric coronary lesions, with extensive medial destruction or atrophy, are occasionally seen in humans, and may be detected by noninvasive techniques and differentiated from the usual eccentric intimal coronary plaque. Concentric transmural medial lesions should be associated with greater dilation of lumens during ather-

ogenesis2 and less decrease in stenosis during regression.14J5J7 The concentric lesion may be less likely to be associated with vasomotor change.18 The more usual eccentric lesions would not increase the outside diameter of the artery during progression, except that those which accompany growth would be associated both with a more effective regression with less fibrous replacement of the media and with restoration of the original lumen. The intact media away from the plaque may develop spasm due to the greater preservation and availability of smooth muscle cells. A recent reviewls suggests that a disrupted intima over a soft (but not necessarily angiographically visible) plaque may be important in the pathogenesis of coronary spasm. This suggests a dual pathogenesis of clinical event (Fig. 7), both associated with severe atherosclerosis, 1 associated with spasm and 1 with thrombosis. Figure 7 illustrates the probable pathogenetic sequencels and shows agreement with the findings of other investigators.1s,20 Increased levels of catecholamines during stressful episodes or those liberated from platelets spread over ulcerated or partially denuded atherosclerotic plaques may trigger vasomotor changes. Coronary spasm, which could be the missing link of the chain, is such a common cause of acute heart attacks due to sudden onset of arrhythmia.

New Data on Plaque Regression Atherosclerosis in humans211z2 and in the rhesus monkey mode123s24can be partially reversed; studies suggest that a small decrease in an advanced obstructive plaque could greatly increase coronary blood flow. In chronic hypercholesterolemic animals, when serum cholesterol level is lowered the damaged endothelium is repaired. The atherosclerotic plaques may not cause platelets to stick and release vasoactive amines.2sJs The changes that occur in experimental studies of regression in the rhesus monkey are shown in Figure 8.27 In humans, Barndt et al28 documented that regression occurs in patients who have lowered their serum cholesterol levels substantially in contrast to those who could not.

FIGURE 8. The major changes observed in quantitative studies of plaque regression in several species of experimental animals. Left, a typical advanced plaque. The main features usually seen in this process (right)are healing of endothelium, a substantial decrease in size and lipid cholesterol content of the necrotic center, a marked reduction in intra- and extracellular lipid in the fibrous cap, and condensation of the fiber proteins in this part of the plaque: as a result of these changes, the plaque size is reduced. Reproduced from Barndt et al*s with permission of the publisher.

July 20,1983

Similarly, Bevans et al3 reported that sequential coronary arteriograms may show regression of atherosclerosis a year or 2 after partial ileal bypass therapy when patients have significantly lowered serum cholesterol and low-density lipoprotein values. Our present knowledge of the mechanisms by which coronary atherosclerosis produces its effect on coronary blood flow suggests that regression of plaque size would occur in those persons who have a sustained lowering of their serum lipid levels. Future Prospects In the animal models such as Macaca mulatta, whose advanced plaques resemble human atherosclerosis most closely, the same type of stenosing lesions as those in humans are found and various therapeutic regimens can be tested. Effects of therapy over time on coronary flow and lesions can be studied. In the experimental model, these results can be validlated in vivo by highly quantitative morphometric observations made in postmortem specimens. The large, cumbersome, often complex mass clinical trials in humans, with their end points of mortality or myocardial infarction, can be replaced by evaluation of intervention using direct noninvasive imaging and Doppler flow techniques. These can be monitored by quantitative morphometric techniques applied to the human autopsy specimens of the same coronary arteries. These approaches are being explored in both experimental animals and human carotid and femoral arteries.2g References 1.

t9~_‘:“o,R. Coronary

Artery Disease. Philadelphia: WB Saunders, 1976:

2. Bond GM, Adams MR, Bullock BC. Complicating factors in evaluating coronary artery atherosclerosis. Artery 1981;9:21-29. 3. Bevans M, Davldson JD, Kendall FE. Regression of lesions in canine atherosclerosis. Arch Pathol 195 1;51:288-292. 4. Armstrong ML, Warner ED, Conner WE. Regression of coronary athercmatosis in rhesus monkeys. Circ Res 1970;27:59-67. 5. Daoud AS, Jarmolych J, Augtrstyn JM, Fritz KE, Slngh JK, Lee KT. Reoression of advanced atherosclerosis in swine. Arch Pathol Lab Med ?976;100:372-379. 6. Fritz KE, Augusiyn JM, Jarmolych J, Daoed AS, Lee KT. Regression of advanced atherosclerosrs of swine (chemical studies). Arch Pathol Lab Med 1976;100:380-385. 7. Wlssler RW. Current status of regression studies. In: Paoletti R. Gotto AM Jr, eds. Atherosclerosis Reviews. Vol 3. New York: Raven Press, 1978: 213-229.

THE AMERICAN JOURNAL OF CARDIOLOGY

Volume 52

7A

6. Vessellnovfich D, Wlssler RW. Reversal of atherosclerosis: Comparison of non-human primate models. In: Gotto AM Jr, Smith LC, Allen B. eds. Atherosclerosis V. New York: Springer Verlag. 1980:389-374. 9. Roberta WC. The coronary arteries in coronary heart disease. Morphologic observations. Pathobiol Arinu 1975:5:249-282. IO. Roberts WC. Coronary heart disease. A review of abnormalities observed in the coronary arteries. Cardiovasc Med 1977;2:29-49. 11. Alenso DR, Starek PK, Mlnlck CR. Studies on the pathogenesis of atheroarteriosclerosis induced in rabbit cardiac allografts by the synergy of grant rejection and hypercholesterolemia. Am J Pathol 1977;87:415442. 12. Mlnlck CR, Murphy GE, Campbell WC. Experimental induction of atherosclerosis by the synergy of allergic injury to arteries and lipid rich diet. I. Effect of repeated injection of horse serum in rabbii fed dietary cholesterol supplement. J Exp Med 1968;124:635-651. Mlnlck CR, Murphy GE. Experimental induction of atheroarteriosclerosis 13. bv the svnerav of alleraic iniutv to arteries and lioidrich diet. Il. Effect of r&ate& ir$cted fcrergn protein in rabbit fed a li‘pid-rich.cholesterol-pwr diet. Am J Pathol 1973;73:265-300. 14. Hollander W. Kirkpatrick B. Paddock B. Colombo J. Naaral M. Frustv S. Studies on the progression and regression of coronary ana peripheral atherosclerosis in the cynomulgus monkey. Exp Mol Pathol 1979;30:55-73. 16. Armstrong ML, Megan MG. Responses of two macaque species to atherogenic diet and its withdrawal. In: Schettler G, Weizel A. eds. Atheroscla rosis Ill. Berlin: Springer-Verlag, 1974:336-338. 16. Mallnow MR, McLaughlin P, Nalto HK, Lewis LA, McNuRy WP. Effect of alfalfa meal on shrinkage (regression) of atherosclerotic plaques during cholesterol feeding in monkeys. Atherosclerosis 1978;30:27-43. 17. Vessellnovltch D, Wfasler RW. Correlation of types of induced lesions with regression of coronary atherosclerosis in two species of monkeys. Lipoproteins and Coronary Atherosclerosis. New York: Elsevier. 1981:107111. 16. Buja LM, Hlllls LD, Petty CS, Willenoa JT. The role of coronary arterial spasm in ischemic heart disease. Arch Pathol Lab Med 1981;105:221228. 19. Wlealer RW. Current concepts of coronary thrombosis as related to atherosclerosis and myocardial infarction. In: Manning GW, Haust MD. eds. Atherosclerosis: Metabolic. Moroholooic and Clinical Asoects. New York: Plenum Press, 1977;86-93. 20. Schwartz CJ, Gerrity RG. Anatomical pathology of sudden unexpected cardiac death. Circulation 1975;51-52: Suppl lll:lll-18-111-28. 21. Malinow MR. Regression of atherosclerosis in non-human primates. An overview. In: Kalter SS, ed. The Use of Nonhuman Primates in Cardiovascular Diseases. Austin, TX: University of Texas Press, 1980;181-220. 22. Wlasler RW. Regression of advanced atherosclerotic lesions. In: Paoletti R, Lewis B, eds. Regressione delle lesioni Aterosclerotiche in stadio avanzato. Milano: Gruppo Lepetit, 1981. 23. Wlssler RW, Vessellnovltch D. Studies of regression of advanced athero sclerosis in experimental animals and man. Ann NY Acad Sci 1976;275: 383-378. 24. Wlesler RW, Vessellnovltch D. Animal models of regression. In: Gotto Y, Hata Y, Klose G, eds. Atherosclerosis IV. Berlin: Springer-Verlag. 1977: 377-385. 25. Weber 0, Fabbrlnl P, Resl L, Jones R. Vessellnovtlch D, Wksler RW. Regression of arteriosclerotic lesions in rhesus monkey aortas after recression diet: scanninc and transmlssicn electron microscooe observations zf the endothelium. A?herosclerosts 1977;26:535-547. ’ 26. Scotf R, Thomas WA, Florentln RA, Reiner JM. Population dynamics of arterial cells duing atherogenesis. XII. Reversal of endothelial cell loss over atherosclerotic aortic lesions in swine changed to normolipidemic-regression diet. Exp Mol Pathol 1981;35:163-189. 27. WLasler RW. Principles of the pathcgenesis of atherosclerosis. In: Braunwatd E. ed. A Textbook of Cardiovascular Medicine. Philadelchia: WB Saunders. 1980:1221-1245. 26. Barndt R Jr, Blankenhorn DH, Crawford DW, Brooks SH. Regression and progessicn of early femoral atherosclerosis in treated hyperlipoproteinemic patients. Ann Intern Med 1977;86:139-146. 29. Blankenhorn DH, Sanmarco ME. Angicgraphy for study of lipid-lowering therapy (editorial). Circulation 1979;59:212-214.