CHAPTER 1 Pathophysiology of acute coronary syndromes

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CHAPTER 1

Pathophysiology of acute coronary syndromes

Alisa B. Rosen and Eli V. Gelfand

Introduction

Acute coronary syndromes (ACS) comprise a spectrum of clinical conditions, initiated by rupture of an atherosclerotic coronary plaque with overlying acute thrombosis. The consequences of thrombosis include direct obstruction of blood flow to the coronary beds, as well as distal embolization of the platelet-rich thrombus. Both of these processes may lead to myocardial ischemia and may progress to myocyte necrosis and myocardial infarction. The coronary thrombus may be completely occlusive, as is frequently seen in ST-segment-elevation myocardial infarction (STEMI), or nonocclusive, as can be observed in unstable angina or non-ST-elevation myocardial infarction (UA/NSTEMI). The latter two entities are also known collectively as non-STelevation acute coronary syndromes (NSTEACS). This chapter discusses the basic pathophysiology underlying ACS.

Braunwald has described five processes contributing to development of ACS, or any atherothrombotic event (Figure 1.1). These processes include: (1) thrombus on preexisting plaque, (2) dynamic obstruction from coronary spasm or Prinzmetal's angina, (3) progressive mechanical obstruction, (4) inflammation and/or infection, and (5) secondary unstable angina due to global myocardial oxygen supply and demand mismatch.

Management of Acute Coronary Syndromes Eli V. Gelfand and Christopher P. Cannon ? 2009 John Wiley & Sons, Ltd

2 Pathophysiology of acute coronary syndromes

Platelet activation, aggregation, and adhesion

Secondary activation of

plasma coagulation

system

Coronary vasoconstriction

Rupture of a vulnerable atherosclerotic

plaque

ACS

Imbalance in myocardial

oxygen and demand

Figure 1.1 Processes contributing to the development of ACS.

Formation of atherosclerotic plaque

Complex plaques of mature atherosclerosis are the endresult of a long pathophysiologic process, which typically begins in early adulthood. Endothelial dysfunction appears to play an initial role in atherosclerosis. Injury to the endothelium results in establishment of the cycle of inflammatory cell migration and proliferation, tissue damage, and repair, and ultimately leads to plaque growth. These mechanisms are outlined in Table 1.1 and are further illustrated in Figure 1.2 (see color plate for a full-color version).

On histological specimens, early precursors of complex plaques include intimal thickening, isolated lipid-containing macrophage foam cells, and pools of extracellular lipids. These are visible on gross specimens as fatty streaks, and

Table 1.1 Primary components of atherosclerotic plaque formation, initiated by endothelial dysfunction (data from Ross1)

? Increased endothelial adhesiveness ? Increased endothelial permeability ? Migration and proliferation of smooth muscle cells and macrophages ? Release of hydrolytic enzymes, cytokines, and growth factors ? Focal vessel wall necrosis ? Tissue repair with fibrosis

Formation of atherosclerotic plaque 3 A

Endothelial permeability

Figure 1.2

Leukocyte migration

Endothelial adhesion

Leukocyte adhesion

B

Adherence and Adherence Smooth-muscle Foam-cell T-cell aggregation of and entry

migration formation activation platelets of leukocytes Figure 1.2 The mechanism of atherosclerotic plaque formation (reproduced from Ross N Engl J Med 1999; 340: 115?26). (A) Early endothelial dysfunction in atherosclerosis; (B) fatty streak formation; (C) formation of advanced complex lesion of atherosclerosis; (D) formation of an unstable fibrous plaque. A full-color version of this figure appears in the plate section.

4 Pathophysiology of acute coronary syndromes C

Macrophage accumulation Figure 1.2

D

Formation of Fibrous-cap formation necrotic core

Plaque rupture Thinning of fibrous cap Hemorrhage form plaque micorovessels

Figure 1.2 Continued.

are present in a substantial proportion of young adults who live in the developed world. Eventually, a reactive fibrotic cap and a large lipid core are formed, the lesion may become neovascularized, and calcium is deposited within the plaque (Figure 1.2).

Plaque instability and the development of ACS 5

Plaque instability and the development of ACS

If given enough time, most atherosclerotic plaques gradually progress, although their architecture generally remains stable. Symptoms occur when luminal stenosis reaches 70?80 %. In contrast, the inciting event in the majority of ACS cases is plaque rupture, and most of such plaques occupy ................
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