94 Postgrad Med J 2001;77:94–98 Postgrad Med J: first published as 10.1136/pmj.77.904.94 on 1 February 2001. Downloaded from New insights into atherosclerotic plaque rupture

D M Braganza, M R Bennett

Coronary is the major generation of the lesion, and therefore are an cause of mortality and morbidity in the indus- undesirable consequence of the atherosclerotic trialised world. Progressive narrowing of cor- process. In contrast, more recent reviews have onary causes angina. However, it is emphasised the role of VSMCs in maintaining rupture of the plaque that causes the cata- the integrity of the plaque,45 and suggested strophic consequences of atherosclerosis, such that VSMC proliferation may be beneficial to as . Recent work has plaque stability. Indeed, fatal events in athero- identified that the stability of the plaque rather sclerosis are due to rupture of the thinnest part than its absolute size determines the likelihood of the fibrous cap region,6 that is synthesised of rupture, making a change in plaque compo- almost exclusively by VSMCs, and rupture sition rather than plaque regression a worth- sites are characterised by relatively low density while clinical goal. This review summarises of VSMCs.2 The fibrous cap region undergoes recent advances in the understanding of plaque continuous damage followed by subsequent rupture, and identifies areas in which new repair in a complex atherosclerotic plaque. therapies may be directed. Most of these episodes of erosion and repair are silent. However, any process that prevents The vulnerable plaque VSMC repair of the cap is potentially danger- Myocardial infarction and unstable angina are ous, such as failure to undergo cell proliferation caused by rupture or erosion of an atheroscle- or a susceptibility to undergo apoptosis. rotic plaque, with subsequent for- mation and occlusion of the artery. The plaque Evidence for cell senescence in that causes a patient’s heart attack is not nec- atherosclerosis essarily the one that is identified at angio- VSMCs in atherosclerotic plaques have low graphy. Cardiologists conventionally describe levels of cell proliferation.78Extensive charac- coronary artery stenoses as significant when terisation of lesion development has shown they occupy >50% of the arterial , that that cell proliferation is low in early atheroscle- is when they become flow limiting. However, a rosis (, Stary type I lesion stage), series of postmortem and angiographic studies peaks in the intermediate lesions (Stary type has identified that nearly 70% of myocardial II–IV), and declines in advanced fibroprolif- infarctions are caused by rupture of plaques erative, complicated plaques (Stary type V that cause <50% stenosis, and that <20% are lesions).9 Although cell proliferation increases

caused by lesions that are >70% stenotic after plaque rupture, the cells that proliferate http://pmj.bmj.com/ (reviewed by Falk et al1). Thus, the quality of are , not VSMCs.9 This indicates the plaque rather than the quantity determines that VSMC proliferation is reduced as plaques the clinical consequences of atherosclerosis. age, and does not increase after plaque The atherosclerotic plaque consists of a col- rupture. The vigorous response to angioplasty/ lection of cells stenting does not imply that it is the fibrous (VSMCs) and inflammatory cells (macro- cap/intimal cells that have responded. Evi- phages and T lymphocytes), with both intra- dence from animal studies implies that the cellular and extracellular lipid. However, the reparative response in restenosis may be due to on September 25, 2021 by guest. Protected copyright. stability of the plaque depends upon the deep medial injury, with subsequent migration VSMC content of the plaque, as only these of medial or adventitial cells that still possess cells are capable of synthesising the structurally the capacity to proliferate.10 important collagens I and III. In contrast, Cell proliferation in the advanced plaque is inflammatory cells (particularly macrophages) regulated by countervailing influences, such as release matrix metalloproteinases (MMPs) the presence of growth factors that bind to which degrade collagen and extracellular ma- cognate receptors on plaque VSMCs, and the trix, potentially weakening the plaque. In restraining influences of cell matrix (see Newby recent years, the characteristics of plaques that and Zalltsman for review11). Advanced athero- Box 110, are predisposed to rupture have been identi- sclerotic plaques are characterised by high level Addenbrooke’s Centre fied. Vulnerable plaques have high lipid and expression of growth factors for VSMCs such for Clinical inflammatory cell contents, increased MMP as platelet derived growth factor and insulin Investigation, 12 13 Addenbrooke’s activity, and a low content of VSMCs and col- like growth factor-1, and rupture sites show Hospital, Cambridge lagen.2 VSMC apoptosis (cell death) is also evidence of matrix breakdown. Under these CB2 2QQ, UK increased in unstable compared with stable circumstances, the failure of VSMCs to prolif- D M Braganza plaques,3 suggesting that VSMC apoptosis may erate is therefore not due to a lack of mitogenic M R Bennett directly promote plaque instability. stimulation or the restraint of matrix alone. Correspondence to: These observations suggest that plaque intimal Dr Bennett Vascular smooth muscle cells in the VSMCs have an intrinsic defect in their capac- [email protected] atherosclerotic plaque ity to proliferate. Submitted 1 June 2000 VSMCs in the atherosclerotic plaque have In vitro studies on plaque and medial Accepted 4 July 2000 been traditionally viewed as responsible for the VSMCs have confirmed that such a defect

www.postgradmedj.com New insights into atherosclerotic plaque rupture 95 Postgrad Med J: first published as 10.1136/pmj.77.904.94 on 1 February 2001. Downloaded from exists. Plaque VSMCs show reduced cell Role of inflammation in plaque rupture proliferation rates, increased population dou- /macrophages are present in athero- bling times, and earlier failure to proliferate sclerotic plaques from the earliest lesions to (senescence) than medial VSMCs.14 15 This complicated, ruptured plaques. Activated mac- defect is not corrected by supplementation of rophages infiltrate the fibrous cap, especially at growth factors14 and clearly matrix restraint is the shoulder region where the cap joins the 28 29 not involved in dispersed cells. Plaque VSMCs more normal vessel wall, a particular site for 30 in vitro and in vivo also demonstrate morpho- plaque rupture. infiltration of logical appearances of senescent cells, such as a the fibrous cap is found in >75% of ruptured stellate or flat appearance.16 17 This phenotype plaques, and occurs more commonly in the culprit lesions of unstable versus stable angina of plaque VSMCs implies that they have patients.31 Macrophage infiltration has a undergone cell senescence, possibly due to an number of deleterious eVects, all of which exhaustion of an intrinsic, defined number of reduce the tensile strength of the cap, directly cumulative cell divisions. Plaques have been promoting plaque rupture.29 shown to arise from expansion of a clone of First, macrophages within the plaque are pre-existent VSMCs, or migration from a clone scavenging cells that accumulate lipid to 18 of underlying medial VSMCs. Proliferation become foam cells. Macrophage and extracel- under these circumstances is selective rather lular lipid accumulation expands the lipid core that multifocal, a situation also seen in of lesions, destroying intimal tissue and fibrous proliferation after arterial injury, when intima caps,32 and also results in progressive tissue is formed by proliferation of small number of destruction of the media and elastic lamina cells many times, rather than a few divisions in below the core,33 34 Second, macrophages can all cells that migrate. Thus, it is highly likely degrade extracellular matrix by secreting a that the intimal VSMCs within the fibrous cap variety of MMPs (collagenases, gelatinases, of plaques are senescent. stromolysins).35 36 Cytokines released by mac- rophages and T lymphocytes can stimulate Evidence for vascular smooth muscle cell MMP expression in both macrophages and 37–41 death in atherosclerosis VSMCs, and increased expression and Increasing evidence indicates that apoptosis of activity of MMPs has been demonstrated in 35 VSMCs promotes plaque instability. Thus, vulnerable regions. Furthermore, macro- phages have been directly demonstrated to higher levels of VSMC apoptosis are seen in 42 plaques compared with normal vessels,19–21 and cause collagen breakdown in plaques. Finally, activated macrophages can directly induce in unstable compared with stable plaques.3 In VSMC apoptosis, thus further reducing the addition, plaque derived VSMCs are intrinsi- ability of the fibrous cap to repair itself and cally sensitive to apoptosis mediated by a vari- synthesise collagen. ety of mechanisms.15 More recent work has found that human monocyte/macrophages are Improving plaque stability—the new potent inducers of apoptosis of human VSMCs therapeutic aim http://pmj.bmj.com/ 22 in coculture. Apoptosis requires direct cell- Until recently, the conventional view of athero- cell contact, and is mediated by a number of sclerosis has been of an indolent lesion, gradu- diVerent pathways, including the death recep- ally accumulating cells and lipid and eventually tors Fas and tumour factor-á (TNF- stenosing the vessel to cause symptoms. In á), and by nitric oxide. Apoptosis also requires contrast, evidence accumulated over the last 15 priming of VSMCs by upregulation of surface years has emphasised that the plaque is a Fas and TNF-R1.23 dynamic structure, undergoing a continual on September 25, 2021 by guest. Protected copyright. Apoptosis of VSMCs and inflammatory cells cycle of erosion and repair. Thus, postmortem in atherosclerosis may also have other impor- studies demonstrate that plaque ruptures and tant sequelae. In contrast to the prevailing erosions are frequent phenomena, most of notion that apoptotic deaths are eVectively which are clinically silent. The cycle of erosion silent (that is, they do not elicit an immune and repair is also responsible for plaque response) a number of deleterious eVects of growth. Ruptures that cause that apoptotic cells within the vasculature have are insuYcient to cause lumenal occlusion heal emerged. First, the exposure of phosphatidyl- by organisation of the thrombus, via migration and division of VSMCs. The reorganised serine on the surface of apoptotic cells provides thrombus is then incorporated into the growing a potent substrate for the generation of plaque, further enlarging the lesions. Thus, thrombin and activation of the coagulation 24 25 plaques demonstrate evidence of repeated epi- cascade. Apoptotic cells also release mem- sodes of erosion and healing,43 and plaque brane bound microparticles into the circula- growth is demonstrated clinically by the tion, which remain procoagulant and are sudden appearance of “new” lesions on coron- increased in patients with unstable versus ary angiograms. The silent nature of plaque 26 27 stable coronary syndromes. Although apop- growth means that by the time most patients totic cells are not the only source of circulating present with coronary artery disease, the microparticles, such microparticles may con- plaques may be very advanced. tribute to the increased procoagulant state in From the above discussion, it can be seen these syndromes, and account for almost all of that interruption of the cycle of erosion and the tissue factor activity present in plaque repair will not only inhibit plaque rupture with extracts. its often fatal sequelae, but also inhibit plaque

www.postgradmedj.com 96 Braganza, Bennett Postgrad Med J: first published as 10.1136/pmj.77.904.94 on 1 February 2001. Downloaded from

Key points Vascular smooth muscle cells from x Myocardial infarction is caused mostly atherosclerotic plaques show: by plaques that cause <50% stenosis x Poor proliferation after plaque rupture x Statins cause profound changes in in vivo or in culture plaque composition and reduce clinical x Higher levels of apoptosis in vivo and events, with little change in plaque size spontaneously in culture than cells from x Statins reduce inflammatory cell con- normal vessels tent and lipid content of experimental x Both of these properties contribute to atherosclerotic plaques ineVective plaque repair x Statins increase vascular smooth muscle cell and collagen content of experimen- tal atherosclerotic plaques pendent of LDL lowering. Thus, benefit from statins occurs in low risk patients with relatively “normal” cholesterol levels.46 47 In addition, administration of pravastatin to Vulnerable plaques contain: lipid fed monkeys at doses that did not reduce x High lipid contents cholesterol levels still reduced macrophage x High inflammatory cell contents content of plaques.57 Animal studies with drugs x Low vascular smooth muscle cell and other than statins also show the same changes collagen contents in plaque composition.58 x Higher levels of vascular smooth muscle Statins also have potent eVects on inflamma- cell apoptosis tion, both locally within the plaque and systemically. Statins reduce the macrophage content of atherosclerotic plaques and the growth and progression. The vulnerable plaque activity of the residual macrophage popula- contains large amounts of lipid, a high tions, and some statins also reduce serum C proportion of activated inflammatory cells, reactive protein and interleukin-6 in patients, high levels of expression of MMPs, low VSMC independent of lipid lowering.59–61 In addition, contents and high levels of VSMC apoptosis. statins reduce activity of natural killer cells62 The ideal drug to stabilise plaques would and inhibit antibody production.63 Statins also therefore reduce lipid and inflammatory cell inhibit MMP-9 expression of both mouse and contents, reduce MMP activity, and increase human macrophages,64 and have variable ef- VSMC and collagen contents of plaques. fects on matrix proteins and collagen.65 Oxi- In recent years primary and secondary dised LDL induced growth of macrophages prevention trials have unequivocally proved and foam cell formation is also inhibited by that reduction in cholesterol using 3-hydroxy- statins.66 67 3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (the statins) reduces sub- Conclusions sequent clinical events on average by 30%– In summary, we have entered a new phase in http://pmj.bmj.com/ 40%.44–48 HMGCoA reductase catalyses the the study and treatment of atherosclerosis. rate limiting enzyme in cholesterol biosynthe- Clinically, we aim to improve the stability of sis, and drug treatment reduces serum low established atherosclerotic plaques by reducing density (LDL) cholesterol in pa- both lipid and inflammatory cell contents, tients. However, angiographic trials of lipid indirectly increasing VSMC and collagen con- lowering have indicated that statins produce tents. Interrupting the cycle of subclinical little if any regression of established lesions49–51 plaque rupture/erosion and repair also inhibits on September 25, 2021 by guest. Protected copyright. but do reduce the appearance on angiograms plaque progression, and reduces the appear- of “new” lesions. Thus, the evidence suggests ance of new lesions. Although the beneficial that statins may change the characteristics of eVects of the statins are salutatory, many the plaque to stabilise fragile, moderate sized patients have clinical events despite optimal plaques, with little reduction in plaque volume. treatment of serum cholesterol. There is thus Indeed, preliminary evidence suggests that huge scope and requirement for drugs that fur- statins increase collagen content and decrease ther reduce the inflammation within plaques to lipid content, inflammation, matrix metallo- promote stability. proteinases, and cell death in human carotid plaques.52 MRB is supported by a British Heart Foundation Senior Recent studies in animals have confirmed Fellowship. profound diVerences in plaque characteristics 1 Falk E, Shah PK, Fuster V. Coronary plaque disruption. and components in established atherosclerosis Circulation 1995;92:657–71. 2 Davies MJ, Richardson PD, Woolf N, et al. Risk of after lipid lowering. Cholesterol lowering in thrombosis in human atherosclerotic plaques: role of extra- rabbits or monkeys reduces macrophage con- cellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993;69:377–81. tent of plaques, and increases VSMC content, 3 Bauriedel G, Hutter R, Welsch U, et al. Role of smooth with VSMCs showing markers of a more muscle cell death in advanced coronary primary lesions: 53–55 implications for plaque instability. Cardiovasc Res 1999;41: diVerentiated phenotype. Lipid lowering 480–8. also reduces MMP expression and activity in 4 Weissberg P, Clesham G, Bennett M. Is vascular smooth 56 muscle cell proliferation beneficial? Lancet 1996;347:305–7. plaques and increases collagen content. 5 Libby P. Molecular bases of the acute coronary syndromes. Although many of the beneficial eVects of Circulation 1995;91:2844–50. 6 Davies M, Thomas A. Plaque fissuring—the cause of acute statins may be via reduction in cholesterol, myocardial infarction, sudden ischaemic death and cre- many eVects of these drugs appear to be inde- scendo angina. Br Heart J 1985;53:363.

www.postgradmedj.com New insights into atherosclerotic plaque rupture 97 Postgrad Med J: first published as 10.1136/pmj.77.904.94 on 1 February 2001. Downloaded from 7 Gordon D, Reidy MA, Benditt EP, et al. Cell proliferation in 37 Galis ZS, Muszynski M, Sukhova GK, et al. Cytokine- human coronary arteries. Proc Natl Acad Sci U S A 1990;87: stimulated human vascular smooth muscle cells synthesize a 4600–4. complement of enzymes required for extracellular matrix 8 O’Brien ER, Alpers CE, Stewart DK, et al. Proliferation in digestion. Circ Res 1994;75:181–9. primary and restenotic coronary atherectomy tissue. Implica- 38 Galis ZS, Sukhova GK, Libby P. Microscopic localization of tions for antiproliferative therapy. Circ Res 1993;73:223–31. active proteases by in-situ zymograph—detection of matrix 9 Lutgens E, de Muinck ED, Kitslaar PJ, et al. Biphasic metalloproteinase activity in vascular tissue. 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IMAGES IN MEDICINE

Auto-TIPS

A 54 year old man with Child’s C liver cirrho- sis resulting from alcohol abuse presented with pleuritic right upper quadrant abdominal pain. He did not have ascites or any history of gastrointestinal bleeding. On examination, his liver was palpable 4 cm below the costal margin and was lobular and non-tender. Abdominal ultrasound revealed a mass in the right lobe of the liver (later proved by biopsy to be a hepatoma) as well as a shunt on Doppler study. Magnetic resonance angiography of the liver (fig 1) revealed a shunt (S) between the portal http://pmj.bmj.com/ (PV) and the hepatic vein (HV) which is seen joining the right atrium (RA) leading to the inferior vena cava (IVC). On further ques- tioning, the patient admitted being stabbed in the right upper quadrant 20 years ago. The majority of the patients with Child’s C cirrhosis have complications like ascites or on September 25, 2021 by guest. Protected copyright. gastrointestinal bleeding caused by portal Figure 1 Magnetic resonance angiogram of the liver. . The trauma experienced by our patient resulted in formation of a transcutane- ous intrahepatic portocaval shunt or “auto- TIPS” (transjugular intrahepatic portosys- temic shunt) which prevented the development of . P SCHWAB A KERMANI S BASARIA Division of Internal Medicine, University of Texas Health Science Center at Houston Correspondence to: Dr Shehzad Basaria, Division of Endocrinlogy and Metabolism, Johns Hopkins University School of Medicine, 1830 E Monument Street, Suite 332, Baltimore, MD 21287, USA

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