Atherosclerosis: The Birth of a Plaque

Atherosclerosis: The Birth of a Plaque

Dr. Stephen White's presentation on atherosclerosis, focusing on plaque formation, cellular processes, and risk factors.

Part 1: Cellular Processes

Overview of atherosclerosis focusing on the atherosclerotic plaque, the cells involved, and reasons for loss of control.

The Culprit: Atherosclerotic Plaque

The development timeline and components:

  • 1-10 years: Foam cells.
  • 10-20 years: Cholesterol accumulation and oxidation, smooth muscle cell (SMC) migration and proliferation, macrophage accumulation.
  • 20-40 years: Foam cells, cell death leading to a necrotic core, which constitutes the atherosclerotic plaque.
  • 40 years +: Plaque disruption (rupture or erosion), myocardial infarction, and loss of endothelial cell-derived nitric oxide (NO).

Fibrous Cap Rupture

Leads to myocardial infarction and blood clot formation.

Plaque Development

Key processes:

  • Endothelial dysfunction.
  • Smooth muscle cell proliferation and intimal hyperplasia.
  • LDL trapping and oxidation.
  • Inflammatory cell recruitment.
  • Foam cell formation, accumulation, and death.
  • Formation of a necrotic core.

Location of Plaques

Plaques typically occur at areas of disturbed blood flow, commonly at bifurcations (branch points) and curved sections of arteries.

Player 1: Endothelial Cells

  • Master controllers of the artery: Regulate artery size (dilation and constriction) and molecule transport, including immune cells.
  • Exist on a spectrum between activated and quiescent states. Turbulent flow activates endothelial cells, making them more leaky and attractive to immune cells.
  • Endothelial cells respond to flow by reactive oxygen species production, changes in permeability, apoptosis and senescence and Nitric Oxide bioavailability.

Endothelial Dysfunction

  • Disturbed flow primes the endothelium for dysfunction and inflammation.
  • Lifestyle factors like smoking, diabetes, and hypertension contribute to endothelial dysfunction.
  • Poor diet limits essential nutrients and antioxidants, reducing endothelial health and protection.
  • The combination of disturbed flow and other risk factors accelerates plaque formation.

Player 2: Smooth Muscle Cells

  • Produce collagen for artery strength and control artery size.
  • Endothelial dysfunction removes the suppression of SMC proliferation and migration.
  • SMCs respond to plaque damage, triggering further proliferation and de-differentiation.
  • Responsible for forming and maintaining the fibrous cap; cell death (apoptosis) weakens the cap.
  • Contribute to hyperplasia and extracellular matrix formation (fibrosis).

LDL Fat Particles

Cholesterol Metabolism

  • LDL transports cholesterol to tissues.
  • Excess cholesterol is processed into bile by the liver.
  • HDL transports cholesterol from tissues back to the liver.
  • Dietary fiber helps eliminate excess cholesterol.
  • Increased oxidative stress increases the oxidation of trapped LDL.

Player 3: Macrophages

  • Immune cells that phagocytose foreign material, aged/dying cells, and bacteria.
  • Phagocytose oxidized LDL (fat particles).
  • Export excess cholesterol from the artery wall via HDL or leave the artery wall with oxidized LDL.
  • Problems arise when LDL entry overtakes removal.
  • Oxidized LDL(oxLDL) induces cell surface adhesion molecule increase and proinflammatory cytokines increase.

Foam Cell Formation

Macrophage transformation into foam cells due to excessive lipid uptake. Macrophages can't downregulate their scavenger receptors and keep taking up lipid.

Player 4: T Cells

  • 10% of T cells in human plaques recognize oxidized LDL.
  • Activated T cells release proinflammatory cytokines.
  • T cells regulate macrophage function.
  • Antibody response to ox-LDL and HSP65 is common.
  • Treg activation may reduce atherosclerosis.

Part 2: Risk Factors for Plaque Development

  • Plaque development is an inevitable feature of aging, but its rate is controlled by modifiable and non-modifiable risk factors.

Risk Factors

  • AGE (Aging):
    • Senescence, autophagy, inflammation, oxidant stress, fibrosis, oedema, hypertrophy.
    • Diet influences many of these processes via nutritional effects and the gut microbiome.
  • Smoking:
    • Cigarette smoke contains 5000-8000 different chemicals and large amounts of free radicals.
    • Damages the lungs and increases systemic levels of inflammatory cytokines.
    • Soluble chemicals cause endothelial dysfunction; free radicals cause oxidative damage, leading to a chronic stress response.
    • Smoking bans have shown to reduce heart attack rates by up to 14%.
    • Just one cigarette may stiffen arteries, significantly increasing heart attack risk in healthy young people.
  • Poor Diet:
    • Excessive intake of saturated and hydrogenated fats increases circulating cholesterol and triglyceride levels.
    • High salt diet increases hypertension risk.
    • High sugar diet increases diabetes risk.
    • Low fruit and vegetable intake limits antioxidant and vitamin intake, increasing disease susceptibility and inflammation.
    • Low fiber diet limits the body’s ability to excrete excess cholesterol.
    • Five or more portions of fruit and vegetables per day are not consumed enough specially by children.
  • Inactivity:
    • Low activity promotes endothelial dysfunction.
    • Activity increases blood flow, triggering protective mechanisms.
    • Regular activity increases glucose storage as glycogen, reducing diabetes risk.
    • Reduces blood pressure and increases HDL production.
    • Recommendation of 150 minutes of moderate or 75 minutes of vigorous aerobic activity per week.
  • Being Overweight:
    • Increased weight linked to poor diet and little exercise.
    • Central adiposity is an independent risk factor for heart attack, stroke, and diabetes.
    • Increases risk of metabolic syndrome.
    • Metabolic syndrome is a low-grade systemic inflammatory condition.
  • Being Diabetic:
    • Increases circulating glucose levels, increasing oxygen free radical production.
    • Increases production of advanced glycation end products (AGEs), damaging cells and artery walls.
    • Diabetics are 2-4 times more likely to have a heart attack.
  • High Blood Pressure (Hypertension):
    • Increases/linked to endothelial dysfunction.
    • Increases thickness and stiffness of the artery wall.
    • Potentially increases LDL trapping and atherosclerosis.
    • Increases reactive oxygen species production.
  • Other Factors:
    • Genes (e.g., in LDL production or regulation).
    • Sex. Largely all factors are under your control.