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atherosclerosis

Nodular thickening or hardening of the layers in the wall of an artery; characterized by irregularly distributed lipid deposits in the intima of large & medium-sized arteries. Etiology: 1) Risk factors: (also see coronary artery disease) a) male age > 45 years b) female age > 55 years c) estrogen deficiency d) elevated LDL cholesterol (> 160 mg/dL) e) low HDL cholesterol (< 35 mg/dL) f) smoking g) hypertension h) elevated homocysteine i) elevated insulin j) diabetes mellitus - much greater risk factor than hypertension or dyslipidemia [1] 2) Postulated risk factors: a) immune complexes (i.e. lupus erythematosus) b) stress (increased sympthetic nervous system activity) c) depression d) low plasma antioxidants e) physical inactivity f) elevated triglycerides g) dietary saturated fat h) small, dense LDL particles i) increased Lp j) increased VLDL remnants k) increased IDL l) leukocytosis m) thrombocytosis & increased platelet activity n) increased fibrinogen o) increased factor VIIa p) increased C-reactive protein Epidemiology: - subclinical atherosclerosis may be detected in 1/2 of patients without major cardiovascular risk factors [5] - male sex & age shows strongest association with subclinical atherosclerosis, followed by LDL cholesterol, then HgbA1c [5] - risk for subclinical atherosclerosis may increase linearly with LDL cholesterol [5] Pathology: 1) endothelial injury a) hemodynamic injury - hypertension - wall shear stress b) chemical injury - low-density lipoprotein - oxidized low-density lipoprotein* - homocysteine - urea - glucose - carbon monoxide - circulating trimethylamine-N-oxide (TMAO) levels correlate with atherosclerosis burden in humans c) infection/immune mediated injury - virus - endotoxin - immune complexes - bacterial proteins ?: HPBP 2) atheromatous plaque formation a) lipid infiltration through injured endothelium b) invasion of monocytes that mature into resident macrophages c) coalescence into fatty streaks d) macrophage rupture forming lipid core of maturing atheromatous plaque e) fibrous tissue produced by migrating smooth muscle cells f) participation of: - cytokines & growth factors secreted by macrophages - T-cells - platelets - smooth muscle cells g) hydroxyapatite crystals are present in early lesions 3) atheromatous plaque growth a) growth is slow, averaging 3% reduction in luminal diameter yearly of 0.03-0.05 mm/year b) atheromatous plaques generally do not narrow the coronary lumen until after 3-4 decades c) rapid growth can occur from intraplaque hemorrhage & intimal injury with incorporation of thrombotic material d) mature plaque is eccentric - 2 dominant forms, may be present in same patient - gradually occlusive fibrous plaque - plaque with soft lipid core & thin fibrous cap - prone to rupture - responsible for most acute ischemic events e) increased activity of the sympathetic nerve fibers within the adventitia of arteries increases growth or atheromas [6] 4) rupture or fissure of atheromatous plaque a) weakening of the fibrous cap a) matrix mellatoproteinases b) shear stress b) rupture of fissure of a relatively soft, lipid-rich atherosclerotic plaque exposes subendothelial structures c) platelet activation d) thrombosis - procoagulant state 6 AM-11 AM - peak incidence of stroke, MI, sudden cardiac death in this time interval - relative resistance to thrombolytic therapy in this time interval e) thrombolysis f) dynamic vasoconstriction g) unstable angina, myocardial infarction, stroke * oxidized choline glycerophospholipids activate platelet CD36, promote platelet activation, impair endothelial function & increase foam cell concentration within atherosclerotic plaques [3] Genetics: - implicated genes - SAMD1, SCUBE1, VASH1, CTHRC1, RSAD2, DDIT4L, P4HA3, FEM1A, CD204, ABCG1, HYOU1 Laboratory: - regression of atherosclerosis associated with reduction in LDL cholesterol & increase in HDL cholesterol Management: - see cardiovascular risk factor for management of cardiovascular disease & cardiovascular risk factors - reducing sympathetic nervous system activity may result in regression of sympathetic nerve fibers in arterial walls & reduce the size of atheromas [6]

Interactions

disease interactions

Related

endothelin-1; preproendothelin-1; PPET1; contains: endothelin-1; ET-1; big endothelin-1 (EDN1)

Specific

aortic atheroma atheroembolism; cholesterol embolism; aortic atheroembolism coronary artery disease; coronary atherosclerosis (CAD) renal artery atherosclerosis

General

arteriosclerosis

Database Correlations

OMIM 108725

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 18. American College of Physicians, Philadelphia 1998, 2018
  2. Nicholls SJ et al, Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007, 297:499
  3. Podrez EA, Byzova TV, Febbraio M, Salomon RG, Ma Y, Valiyaveettil M, Poliakov E, Sun M, Finton PJ, Curtis BR, Chen J, Zhang R, Silverstein RL, Hazen SL. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med. 2007 Sep;13(9):1086-95. Epub 2007 Aug 26. PMID: 17721545 - Jackson SP, Calkin AC. The clot thickens-oxidized lipids and thrombosis. Nat Med. 2007 Sep;13(9):1015-6. PMID: 17828215 http://jama.ama-assn.org/cgi/content/full/297/5/499
  4. Wang Z, Roberts AB, Buffa JA et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 2015 Dec 17; 163:1585 PMID: 26687352
  5. Fernandez-Friera L, Fuster V, Lopez-Melgar B et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol 2017 Dec 19; 70:2979. PMID: 29241485 Free full text http://www.sciencedirect.com/science/article/pii/S0735109717412320
  6. Mohanta SK et al. Neuroimmune cardiovascular interfaces control atherosclerosis. Nature 2022 May 5; 605:152. PMID: 35477759 https://www.nature.com/articles/s41586-022-04673-6 - Clyburn C, Birren SJ. Crosstalk between nerves, immune cells and plaques drives atherosclerosis. Nature 2022 May 5; 605:32 PMID: 35478020 https://www.nature.com/articles/d41586-022-00508-6
  7. What is Atherosclerosis? http://www.nhlbi.nih.gov/health/dci/Diseases/Atherosclerosis/Atherosclerosis_WhatIs.html