atherosclerosis

Introduction

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

• Risk factors: (also see coronary artery disease)
  • male age > 45 years
  • female age > 55 years
  • estrogen deficiency
  • elevated LDL cholesterol (> 160 mg/dL)
  • low HDL cholesterol (< 35 mg/dL)
  • smoking
  • hypertension
  • elevated homocysteine
  • elevated insulin
  • diabetes mellitus
    • much greater risk factor than hypertension or dyslipidemia
• Postulated risk factors:
  • immune complexes (i.e. lupus erythematosus)
  • stress (increased sympthetic nervous system activity)
  • depression
  • low plasma antioxidants
  • physical inactivity
  • elevated triglycerides
  • dietary saturated fat
  • small, dense LDL particles
  • increased Lp<a>
  • increased VLDL remnants
  • increased IDL
  • leukocytosis
  • thrombocytosis & increased platelet activity
  • increased fibrinogen
  • increased factor VIIa
  • increased C-reactive protein

Epidemiology

• subclinical atherosclerosis may be detected in 1/2 of patients without major cardiovascular risk factors
  • male sex & age shows strongest association with subclinical atherosclerosis, followed by LDL cholesterol, then HgbA1c
  • risk for subclinical atherosclerosis may increase linearly with LDL cholesterol

Pathology

• endothelial injury
  • hemodynamic injury
    • hypertension
    • wall shear stress
  • 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
  • infection/immune mediated injury
    • virus
    • endotoxin
    • immune complexes
    • bacterial proteins ?: HPBP
• atheromatous plaque formation
  • lipid infiltration through injured endothelium
  • invasion of monocytes that mature into resident macrophages
  • coalescence into fatty streaks
  • macrophage rupture forming lipid core of maturing atheromatous plaque
  • fibrous tissue produced by migrating smooth muscle cells
  • participation of:
    • cytokines & growth factors secreted by macrophages
    • T-cells
    • platelets
    • smooth muscle cells
  • hydroxyapatite crystals are present in early lesions
• atheromatous plaque growth
  • growth is slow, averaging 3% reduction in luminal diameter yearly of 0.03-0.05 mm/year
  • atheromatous plaques generally do not narrow the coronary lumen until after 3-4 decades
  • rapid growth can occur from intraplaque hemorrhage & intimal injury with incorporation of thrombotic material
  • 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
  • increased activity of the sympathetic nerve fibers within the adventitia of arteries increases growth or atheromas
• rupture or fissure of atheromatous plaque
  • weakening of the fibrous cap
  • matrix mellatoproteinases
  • shear stress
  • rupture of fissure of a relatively soft, lipid-rich atherosclerotic plaque exposes subendothelial structures
  • platelet activation
  • 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
  • thrombolysis
  • dynamic vasoconstriction
  • unstable angina, myocardial infarction, stroke

* oxidized choline glycerophospholipids activate platelet CD36, promote platelet activation, impair endothelial function & increase foam cell concentration within atherosclerotic plaques

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

Complications

• disease interaction(s) of atherosclerosis with steatosis (NAFLD)

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

More general terms

• arteriosclerosis

More specific terms

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

Additional terms

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

Patient information

atherosclerosis patient information

Database

• OMIM: https://mirror.omim.org/entry/108725