Atherosclerosis

Atherosclerosis is the most common type of arteriosclerosis, or thickening and stiffening of the arterial wall. Major risk factors include smoking, diabetes mellitus, arterial hypertension, dyslipidemia, family history of early heart disease, and advanced age. The pathogenesis is a complicated process precipitated by endothelial damage, which leads to an invasion of inflammatory cells into the tunica intima and adhesion of platelets to the disrupted endothelium. Invading smooth muscle cells (SMCs) and macrophages take up cholesterol from oxidized low-density lipoprotein (LDL) in the vessel wall. They then become foam cells, which accumulate in early atherosclerotic lesions (fatty streaks), triggering the production of extracellular matrix (e.g., collagen). This leads to the formation of fibrous plaques (foam cells, extracellular matrix, free cholesterol, and cellular debris), which may rupture and lead to thrombosis. Common sites of atherosclerosis include the abdominal aorta, coronary arteries, popliteal arteries, and carotid arteries. Depending on the location, atherosclerosis may lead to a variety of conditions, such as arterial aneurysms, dissection, coronary heart disease (CHD), peripheral artery disease (PAD), intestinal ischemia, subcortical vascular dementia (Binswanger's disease), thrombosis (e.g., acute coronary syndrome and stroke), and renovascular hypertension.

• Arteriosclerosis: arterial wall thickening (hardening) and elasticity loss with variable pathogenesis
  • Atherosclerosis (most common type of arteriosclerosis)
    • Multifactorial inflammatory disease of the intima, manifesting at points of hemodynamic shear stress
    • Characterized by a build-up of cholesterol plaques in the intima
    • Affects elastic arteries and large/medium-sized muscular arteries
  • Mönckeberg arteriosclerosis (less common)
    • Dystrophic calcification of the media and internal elastic lamina causes stiffening of the arteries (intima is not involved)
    • There is no blood flow obstruction.
    • Mainly affects medium-sized arteries
    • X-ray: pipestem appearance
  • Arteriolosclerosis: hardening of the small arteries and arterioles
    • Hyaline arteriolosclerosis
      • Deposition of proteins below the endothelium due to leakage
      • H&E: pink amorphous deposits (hyaline) within the arteriolar walls
      • Causes: chronic essential hypertension, chronic diabetes, and normal aging
    • Hyperplastic arteriolosclerosis
      • Proliferation of subendothelial smooth muscle cells in response to very high blood pressure
      • H&E: "onion-skin" appearance of the arteriole
      • Cause: malignant hypertension

The terms “arteriosclerosis” and “atherosclerosis” are often used synonymously!

References:^[1][2][3]

• Leading cause of vascular disease worldwide
• Sex: ♂ > ♀

References:^[4]

Epidemiological data refers to the US, unless otherwise specified.

• Modifiable risk factors
  • Smoking
  • Diabetes mellitus
  • Arterial hypertension
  • Dyslipidemia
  • High homocysteine levels (homocystinuria)
  • Obesity
  • High fibrinogen levels
  • Hyperphosphatemia
  • Stress
  • Increased alcohol consumption
• Nonmodifiable risk factors
  • Family history: cardiovascular events in first-degree relatives below the age of 55 (♂)/65 (♀)
  • Age: males ≥ 45 years, females ≥ 55 years (postmenopause)

The term metabolic syndrome refers to the presence of at least 3 of the following risk factors: obesity, elevated triglycerides, low high-density lipoprotein (HDL), diabetes mellitus, and arterial hypertension.
References:^{[4][5][6][7][8][9][10]}

Pathogenesis of atherosclerosis

1. Chronic stress on the endothelium
2. Endothelial dysfunction, which leads to
   • Invasion of inflammatory cells (mainly monocytes and lymphocytes) through the disrupted endothelial barrier
   • Adhesion of platelets to the damaged vessel wall → platelets release inflammatory mediators (e.g., cytokines) and platelet-derived growth factor (PDGF)
   • PDGF stimulates migration and proliferation of smooth muscle cells (SMC) in the tunica intima and mediates differentiation of fibroblasts into myofibroblasts
3. Inflammation of the vessel wall
4. Macrophages and SMCs ingest cholesterol from oxidized LDL and transform into foam cells.
5. Foam cells accumulate to form fatty streaks (early atherosclerotic lesions).
6. Lipid-laden macrophages and SMCs produce extracellular matrix (e.g., collagen) → development of a fibrous plaque (atheroma)
7. Inflammatory cells in the atheroma (e.g., macrophages) secrete matrix metalloproteinases → weakening of the fibrous cap of the plaque due to the breakdown of extracellular matrix → minor stress ruptures the fibrous cap
8. Calcification of the intima (the amount and pattern of calcification affect the risk of complications) ^[11][12]
9. Plaque rupture → exposure of thrombogenic material (e.g., collagen) → thrombus formation with vascular occlusion or spreading of thrombogenic material

Common sites (in order of increasing frequency)

• Circle of Willis
• Carotid arteries
• Popliteal arteries
• Coronary arteries
• Abdominal aorta

To remember the order of vessels affected by atherosclerosis (in increasing order of frequency), think of the “Die hard” plot: Bruce Willis CAtches a Perceptive Criminal named HAns.

Atherosclerotic diseases

• Weakening of vessel wall: arterial aneurysm or dissection
• Demand-supply mismatch: coronary heart disease; (CHD), peripheral artery disease; (PAD), intestinal ischemia, and subcortical vascular dementia (Binswanger disease)
• Thrombosis and thromboembolism: acute coronary syndrome, stroke
• Renovascular hypertension: atherosclerosis of the renal artery → activation of the renin-angiotensin-aldosterone system

References:^{[1][2][13][14][15]}

• Lifestyle modifications
  • Weight reduction
  • Dietary modification
  • Moderate aerobic exercise
  • Smoking cessation
  • Moderate consumption of alcohol (about 1–2 glasses of wine or beer per day) presumably has a protective effect.
• Medical treatment: Treat hypertension, diabetes and hyperlipidemia

The most significant therapeutic step patients with vascular disease can take is stopping smoking!
References:^[16]