A 44-year-old man is evaluated in the clinic for occasional chest discomfort that is not consistently related to exertion. The patient's past medical history is significant for hypertension and hyperlipidemia. His grandfather experienced a myocardial infarction at age 50. Coronary CT angiography reveals several nonobstructive atherosclerotic plaques in the coronary arteries. One plaque in the proximal left anterior descending artery appears extensive, has a large hypodense core, and occupies 40% of the lumen. No intervention is performed. One year later, the patient comes to the emergency department with acute severe chest pain and is found to have thrombotic occlusion of the proximal left anterior descending artery. High intraplaque activity of which of the following enzymes most likely resulted in this patient's myocardial infarction?

Question

A 44-year-old man is evaluated in the clinic for occasional chest discomfort that is not consistently related to exertion.  The patient's past medical history is significant for hypertension and hyperlipidemia.  His grandfather experienced a myocardial infarction at age 50.  Coronary CT angiography reveals several nonobstructive atherosclerotic plaques in the coronary arteries.  One plaque in the proximal left anterior descending artery appears extensive, has a large hypodense core, and occupies 40% of the lumen.  No intervention is performed.  One year later, the patient comes to the emergency department with acute severe chest pain and is found to have thrombotic occlusion of the proximal left anterior descending artery.  High intraplaque activity of which of the following enzymes most likely resulted in this patient's myocardial infarction?

Quizplus · Accepted Answer

11ec160b_38c0_22db_9249_b379125cf4a5_MD0001_00 This patient with coronary atherosclerosis has likely developed plaque rupture with thrombotic occlusion of the left anterior descending artery, resulting in acute coronary syndrome (unstable angina, myocardial infarction). Patients with coronary atherosclerosis can be asymptomatic but typically develop symptoms of stable angina (exertional chest pain relieved with rest/nitroglycerin) if progressive enlargement of the atherosclerotic plaque causes >70% luminal stenosis. Acute coronary syndrome usually occurs due to plaque rupture, which leads to superimposed thrombosis and vessel occlusion. The likelihood of plaque rupture is typically related to plaque stability rather than plaque size or degree of luminal narrowing. Plaque stability largely depends on the mechanical strength of the fibrous cap: Thin-cap fibroatheromas are generally unstable and more vulnerable to rupture. During the chronic inflammatory progression of an atheroma, the fibrous cap is continually being remodeled. The balance of collagen synthesis and degradation determines the mechanical strength of the cap. Thin-cap fibroatheromas are characterized by a large necrotic core covered by a thin fibrous cap. Activated macrophages infiltrating the atheroma contribute to the breakdown of extracellular matrix proteins (eg, collagen) by secreting metalloproteinases. Ongoing intimal inflammation can destabilize the mechanical integrity of the plaque through release of these metalloproteinases, resulting in plaque rupture and consequent acute coronary syndrome. (Choice A) Hydroxymethylglutaryl (HMG) CoA reductase is the rate-limiting enzyme in cholesterol synthesis and is mostly expressed in the liver, intestine, adrenal cortex, and reproductive tissues. Patients with hyperlipidemia are typically treated with statins (eg, atorvastatin), which competitively inhibit HMG CoA reductase. (Choice B) Lysyl oxidase strengthens extracellular collagen fibers by mediating cross-link formation between lysine and hydroxylysine residues (requires copper). Therefore, a high activity of lysyl oxidase would favor atheroma stabilization by strengthening collagen in the fibrous cap. (Choice D) Procollagen peptidase cleaves the terminal regions of procollagen molecules exocytosed by fibroblasts or smooth muscle cells, transforming procollagen into insoluble tropocollagen. Tropocollagen then aggregates to form collagen fibrils. (Choice E) Prolyl hydroxylase is responsible for the hydroxylation of proline on procollagen chains (requires vitamin C), which is a necessary step in the formation of a stable collagen triple helix. Educational objective: The likelihood of plaque rupture is related to plaque stability rather than plaque size or the degree of luminal narrowing. Plaque stability largely depends on the mechanical strength of the fibrous cap. Inflammatory macrophages in the intima may reduce plaque stability by secreting metalloproteinases, which degrade extracellular matrix proteins (eg, collagen). __________ References: Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. (http://www.ncbi.nlm.nih.gov/pubmed/10330380) Inflammation in atherosclerosis. (http://www.ncbi.nlm.nih.gov/pubmed/12490960)

A 44-Year-Old Man Is Evaluated in the Clinic for Occasional