Cardiovascular Health Quiz

Pathology of Atherosclerosis

• Atherosclerosis is a disease causing more morbidity and mortality than any other disease.
• Coronary artery disease is a significant manifestation of atherosclerosis.
• Aortic and carotid atherosclerosis also contribute to significant morbidity and mortality, including stroke.
• The likelihood of atherosclerosis is determined by the combination of acquired risk factors (e.g., cholesterol levels, smoking, hypertension), inherited risk factors (e.g. mutated LDL receptor gene), and gender and age-associated factors.

Types of Arteries

• Elastic arteries have more elastic tissue compared to muscular arteries. They are located close to the heart. Examples include the aorta and pulmonary artery.
• Muscular arteries distribute blood to various parts of the body and contain lots of smooth muscle. Examples include femoral and coronary arteries.
• Arterioles deliver blood to capillaries and are important in determining blood pressure.

Arteriosclerosis

• Arteriosclerosis is the hardening of the arteries, a general term for arterial wall thickening and loss of elasticity.
• Four general patterns of arteriosclerosis exist, with different consequences:
  • Arteriolosclerosis: affects small arteries and arterioles, leading to downstream ischemic injury.
  • Mönckeberg medial sclerosis: characterized by calcifications of the medial walls of muscular arteries, typically starting along the internal elastic membrane. Often clinically insignificant in adults over 50.
  • Fibromuscular intimal hyperplasia: occurs in muscular arteries larger than arterioles and is considered a healing response to inflammation or mechanical injury (such as from stents or angioplasty). It leads to vessel stenosis and can limit organ transplants.
  • Atherosclerosis: characterized by atheromatous plaques, or a raised lesion with a soft core of lipid (mainly cholesterol and cholesterol esters) covered by a fibrous cap.

Atherosclerosis: Additional Information

• Atheroma (atheromatous or atherosclerotic plaques): intimal lesions that protrude into vessel lumens. They consist of a raised lesion with a soft core of lipid (mainly cholesterol and cholesterol esters) covered by a fibrous cap.
• Basic structure of an atherosclerotic plaque: composed of a complex interplay of cells and extracellular materials, including a fibrous cap (smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization) and a necrotic center (cell debris, cholesterol crystals, foam cells, calcium). These plaques can cause damage to underlying smooth muscle cells.
• Atherosclerotic plaques can cause mechanical obstruction of blood flow. Rupture can lead to catastrophic obstructive vascular thrombosis. Increased diffusion distance due to plaque formation leads to ischemic injury and weakening of the vessel wall and aneurysm formation.
• High-yield atherosclerosis progression sequence: involves endothelial injury and dysfunction leading to vascular permeability and leukocyte adhesion, followed by accumulation of oxidized LDL in vessel walls; monocytes transform into macrophages and foam cells; platelets adhere, factors are released, and smooth muscle recruitment occurs, leading to lipid accumulation both extracellularly and within smooth muscle cells (macrophages & SMCs). Calcification of extracellular matrix and necrotic debris occur in later pathogenesis.
• Endothelial injury: the cornerstone of the response-to-injury hypothesis, begins at sites of morphologically intact endothelium with features of endothelial dysfunction, including increased permeability, enhanced leukocyte adhesion, and altered gene expression. Important causes of EC dysfunction include hemodynamic disturbances, hypercholesterolemia, and inflammation.
• Hemodynamic disturbances: plaques are not distributed randomly, but are more prevalent at ostia of exiting vessels, branch points, and along the posterior abdominal aorta, where flow patterns are disturbed and non-laminar. Laminar (non-turbulent) flow associated with production of transcription factor KLF2 that leads to atheroprotection; while turbulent (non-laminar) flow promotes atheroprone genetic transcription.
• Hypercholesterolemia: increased LDL cholesterol levels, decreased HDL cholesterol levels, and increased abnormal Lp(a), caused by mutations in apoproteins and lipoprotein receptors/underlying disorders affecting lipid levels(nephrotic syndrome, alcoholism, hypothyroidism, diabetes mellitus). This causes impaired EC function and modified LDL.
• Impaired EC function results from Hypercholesterolemia leading to local reactive oxygen species, leading to membrane damage, mitochondrial damage, and decreased NO (vasodilator) activity.
• Modified LDL: Accumulation of lipoproteins within the intima, oxidized LDL is accumulated by macrophages via scavenger receptors leading to foam cells, and SMCs can similarly transform into lipid-filled foam cells by ingesting modified lipids.
• Inflammation in atherosclerosis: Inflammation is triggered by cholesterol crystal and fatty acid accumulation in macrophages, and other cells that can detect abnormal materials through cytosolic innate immune receptors that are parts of the inflammasome. Inflammasome activation leads to the production of IL-1, which recruits and activates macrophages and T lymphocytes leading to local cytokine and chemokine production and recruitment of more inflammatory cells. Activated macrophages release reactive oxygen species (ROS), leading to LDL oxidation and elaboration of growth factors that drive SMC proliferation. Activated T lymphocytes, in growing intimal lesions, release Interferon-y,activating macrophages, ECs, and SMCs.
• Smooth muscle proliferation and matrix synthesis: Intimal SMC proliferation and ECM deposition converts early fatty streaks into mature atheromas. Growth factors (e.g., PDGF, FGF, TGF-alpha) drive SMC proliferation and ECM synthesis. These factors also stimulate SMCs to synthesize ECM, which helps stabilize atherosclerotic plaques.
• Overview of Atherosclerosis: A chronic inflammatory response, driven by EC injury, lipid oxidation, lipid accumulation, and inflammation; Atheromas (dynamic lesions) consist of dysfunctional ECs, proliferating SMCs, and various inflammatory cells. All four cell types can release mediators influencing atherogenesis. At early stages, intimal plaques are aggregates of SMCs, macrophages, and foam cells, but death of these cells releases lipids and necrotic debris.
• Overview of Atherosclerosis (continued): With progression, atheromas are modified via ECM synthesized by SMCs, leading to a prominent fibrous cap on the intimal aspect of the plaque, a central core filled with lipids, and fatty debris that can become calcified. The plaques can grow and advance toward the lumen compromising blood flow, compress the media, leading to degeneration, and erosion/rupture exposing thrombogenic factors, leading to thrombus formation and vascular occlusion.
• Atherosclerotic Plaque:
  • Intimal thickening
  • Lipid accumulation
  • Yellow-tan color
  • Thrombus over ulcerated plaque will appear red-brown.
  • Vary in size but can coalesce to form larger lesions
  • Patchy, rarely circumferential; lesions can appear eccentric on cross-section.
  • Focality of lesions is attributable to vascular hemodynamics.
• Consequences of Atherosclerotic Disease:
  • MI
  • Cerebral infarction (stroke)
  • Aortic aneurysms
  • Peripheral vascular disease (gangrene)
  • Major targets of atherosclerosis include large elastic arteries (e.g., aorta, carotid, and iliac), large- and medium-sized muscular arteries (e.g., coronary and popliteal).
  • These effects typically involve major arteries supplying the brain, kidneys, and lower extremities.
• Atherosclerotic stenosis: gradual occlusion of vessel lumen by plaque in small arteries, compromised blood flow leading to ischemia. Critical stenosis occurs when occlusion produces a 70-75% decrease in luminal cross-sectional area, causing tissue ischemia (e.g. stable angina).
• Atherosclerotic stenosis (continued): Chronically diminished arterial perfusion leads to mesenteric occlusion, bowel ischemia, sudden cardiac death, chronic ischemic disease, and ischemic encephalopathy. Intermittent claudication is pain in calf, thigh, and buttock, induced by exercise and relieved by rest, due to muscle ischemia. Slow progression of stenosis may cause enlarging of smaller adjacent blood vessels, creating collateral circulation, to partially compensate and perfuse the organ.
• Acute Plaque Change: involves complete or partial vascular thrombosis related to plaque erosion/rupture leading to acute tissue infarction (myocardial, cerebral). Plaque changes include rupture/fissuring, erosion/ulceration, and hemorrhage into the atheroma, expanding the diseased area.
• Plaque Rupture:
  • Occurs when plaque cannot withstand mechanical stresses (e.g. vascular shear forces).
  • Complex events with both intrinsic (plaque structure/composition) and extrinsic factors (blood pressure, platelet reactivity, vessel spasm) involved.
  • The fibrous cap undergoes continuous remodeling; thus collagen balance (synthesis vs. degradation) is crucial to maintaining cap integrity. Thus, vulnerable plaques (thin fibrous caps, active inflammation) are more likely to rupture.
• Stable vs Vulnerable Plaques
  • Stable: thickened, densely collagenous fibrous caps, minimal inflammation, small/central lipid core
  • Vulnerable: thin fibrous caps, large lipid cores, increased inflammation
• Collagen in atherosclerotic plaque: Collagen is primarily produced by smooth muscle cells (SMCs). Loss of SMCs correlates with a decreased capacity of the cap. Both macrophages and SMCs produce MMPs to regulate collagen turnover. EC, SMC, and macrophages produce TIMPs to regulate MMP activity. Increased plaque inflammation leads to collagen degradation.
• Inflammation & Statins: Cholesterol deposits stimulate inflammation, destabilizing plaques. Statins lower cholesterol leading to a therapeutic effect, reduced inflammation in plaques, and plaque stabilization. Statins have pleiotropic effects on atherosclerosis, including antioxidant, anti-thrombotic, and anti-inflammatory activities, and lipid lowering activities.
• Influences extrinsic to plaques: Adrenergic stimulation leads to increased BP and induce local vasoconstriction, physically stressing plaques even more; intense emotional stress can also contribute to plaque disruption, and increased incidence of sudden death can be associated with natural or man-made disasters.
• Circadian periodicity of MI: Morning awakening/rising activates adrenergic stimulation leading to blood pressure spikes, which trigger potentially acute MI events, peaking between 6 a.m. and 12 noon.
• Thrombosis: Thrombosis is a central factor in acute coronary syndromes. Complete occlusion is the most serious. Incomplete luminal obstruction may even wax/wane with time. Thrombin and factors involved with thrombosis are potent activators of SMCs contributing to lesion growth.
• Vasoconstriction at sites of atheroma: Vasoconstriction from adrenergic agonists can lower lumen size, increase local mechanical forces on plaques, and lead to disruption. Vasoconstriction is also triggered by platelet contents, endothelial dysfunction with impaired NO secretion relative to contracting factors (endothelin), and mediators from perivascular inflammatory cells.
• Atherosclerosis key concepts: An intimal-based lesion consisting of a fibrous cap and atheromatous core (SMCs, ECM, inflammatory cells, calcifications, lipids, and necrotic debris). Atherosclerosis is driven by the interaction of vessel wall injury and inflammation, where multiple risk factors influence inflammatory cell and SMC recruitment and stimulation.
• Atherosclerosis key concepts (continued): Atherosclerotic plaques develop slowly over decades. Stable plaques are associated with narrowing lumens, chronic ischemia, and symptoms related to chronic ischemia. Unstable plaques are associated with potentially fatal ischemic complications (acute rupture, thrombosis, and embolization). Stable plaques have a dense fibrous cap, minimal lipid accumulation, and little inflammation. Vulnerable plaques have thin fibrous caps, large lipid cores, and dense inflammation.