Pathophysiology of CAD

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The most widely accepted theory of the process of atherosclerosis is that it is a low-grade inflammatory response due to injury of the vascular endothelium induced by lipoprotein retention in the arterial wall.6 The process begins when lipoproteins migrate between the endothelial cells into the arterial wall and bind to proteoglycans (Fig. 12-5). The initial lesion, known as a fatty streak, appears to form after accumulation of lipoproteins within the intima. After entering the intima, lipoproteins are then structurally modified by oxidation. Oxidized lipoproteins as well as other cyto-toxic agents promote endothelial dysfunction by disturbing the production of vaso-active molecules such as nitric oxide that maintain vasomotor tone. Small, denser

LDL particles migrate into the arterial wall more readily and are particularly susceptible to oxidation. The oxidized particles cause an increased expression of cell-adhesion molecules on vascular endothelial cells leading to recruitment of monocytes into the intima. The monocytes differentiate into macrophages and express scavenger receptors allowing enhanced uptake of Apo B-containing lipoproteins. The macrophages continue to accumulate lipoproteins and ultimately develop into lipid-laden foam cells. Accumulation of foam cells leads to formation of a lipid-rich core, which marks the transition to a more complicated atherosclerotic plaque. Vascular wall remodeling leading to outward growth of the wall occurs to accommodate this lipid-rich core. Thus, the vascular lumen is relatively well preserved and generally the lesion would not be detected using traditional coronary angiographic techniques. Initially, smooth muscle cells migrate and proliferate from the media to the intima forming a protective fibrous cap which separates the potentially thrombogenic lipid core from circulating blood. As the plaque matures, inflammatory cells secrete matrix metal-loproteinases that degrade collagen and fibrin produced by smooth muscle cells that lead to a weakened fibrous cap. Ischemic events result when the fibrous cap of these unstable plaques rupture and produce an occlusive thrombus. In contrast, repeated wound healing secondary to less significant plaque disruption that causes no symptoms might produce a more stable plaque as a consequence of smooth muscle cell, collagen, and fibrin accumulation and a resolution of the lipid core.6 These more stable plaques usually cause luminal encroachment (detected by traditional coronary angiographic techniques) and may produce angina pectoris. Unstable lesions usually outnumber the more stable plaques, thus accounting for a majority of acute coronary syndromes. Evidence demonstrates that aggressive lipid-lowering does stabilize these vulnerable lesions and restores endothelial function.3,6,7

FIGURE 12-4. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. (Acetyl CoA, acetyl coenzyme A; Apo, apolipoprotein; CE, cholesterol ester; FA, fatty acid; HL, hepatic lipase; HMG-CoA, 3-hydroxy-3-methyglutaryl coenzyme A; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein.)

FIGURE 12-4. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. (Acetyl CoA, acetyl coenzyme A; Apo, apolipoprotein; CE, cholesterol ester; FA, fatty acid; HL, hepatic lipase; HMG-CoA, 3-hydroxy-3-methyglutaryl coenzyme A; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein.)

Table 12-2 Selected Characteristics of Primary (Genetic) Dyslipidemias

£i1iiridifrd

Dissrde*

frequency

Miisbolic Delect

Mi in Lipid Parameter

1 --in iili-il !vyptnhulL,!>lr.™l|.,'"J homozygous

1/1 mil On

UDL-H.'iK.'iflJf rK-^alivC

LCK.< rhj» 500 rrxvtfl. tliSSmmol/H

HeeiOiyyOuS

1/500

flfldLKiiijn In ifiL iioipwri

LDL< 255-SX? m9*jU64S-12.95 mmoVLJ

Farnllaf defective Apo B-IQO

1 /M*»

Single nucleotide muidlion

LDLC IEO-SOO mg/L mmolvl}

hamlllal combined rtysftpKlmnli

Gomircn l/Jffl-300

Mtf jlwlk Hind eiwiOnmeHlil Cwrproduc tlan of MIX dncitn IDL

LDL-C 160-3» rpgAIU4.M <. 46 mnwl/l) LOL-t 2SQ-3E0 mg/ii M&-40? nvnol/LJ TG 200-800 mg.'dL mrmMJ

ramiliat hyperapobeiahpopraleinermia

Increase Am 11 productiori

Apo fl gieatef than 1J£ mg/dL (0.55 g/L)

familial a^itjiHlipoptpiUfiemiia

Afnj E 212 f>hH.-i-ioryOt

LDL C 300—SCO fflft'dL (7.77-15£4 iWKifrTJ

i.'irniii.ii hjpefWjIyetHidetflft

It mg/dl. tO-fWM mmofLJ

Type IV

1/300

Untivwvn

It 200-500 nigAJL iiJ6-5£i mmol/U

TypeV

1/305.SW

TO grwwt Hijn 1.000 rp^/dL (11,3 >«r«ttVU

Defect InHDLiaiflbaliwi

H(X< feathtfl 55 irqML «1.91 mmoWJ

Apaapdipapiol)ein,CcfHtet1eiatHDL, high-density hpopiotelrv 1.15)., low-demity tpoprobein. lit rrpgtycefidei VLDL. v«y law-density Ipojwotei.

Apaapdipapiol)ein,CcfHtet1eiatHDL, high-density hpopiotelrv 1.15)., low-demity tpoprobein. lit rrpgtycefidei VLDL. v«y law-density Ipojwotei.

FIGURE 12-5. The process of atherogenesis. Atherosclerosis is initiated by the migration and retention of LDL and remnant lipoprotein particles into the vessel wall. These particles undergo oxidation and are taken up by macrophages in an unregulated fashion. The oxidized particles participate to in-

duce endothelial cell dysfunction leading to a reduced ability of the endothelium to dilate the artery and cause a prothrombotic state. The unregulated uptake of cholesterol by macrophages leads to foam cell formation and the development of a blood clot-favoring fatty lipid core. The enlarging lipid core eventually causes an encroachment of the vessel lumen. Early in the process, smooth muscle cells are activated and recruited from the media to the intima, helping to produce a collagen matrix that covers the growing clot protecting it from circulating blood. Later, macrophages produce and secrete matrix metalloproteinases which degrade the collagen matrix, leading to unstable plaque which may cause a myocardial infarction. (IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; MMP, matrix metalloproteinases; NO, nitric oxide.)

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