Chamberlin L2-5 Flashcards
What are the risk factors for atherosclerosis?
- Genetics (NM)
- Dyslipidaemia (M)
- Diabetes (M)
- Hypertension (M)
- Obesity (M)
- Smoking/alcohol (M)
- Stress (M)
- Physical activity (M)
- Inflammation (NM)
- Age (NM)
- Family history (NM)
NM = Non modifiable / M = Modifiable through drugs or lifestyle
What are the characteristics of atherosclerosis?
The principal cause of heart attack (myocardial infarction MI), stroke and gangrene of the extremities. One of the major causes of death in Europe, USA & Japan. Main problem comes when plaque ruptures leading to thrombus formation and ultimately death. Influenced by a multitude of lifestyle choices, medical conditions & haemodynamics of blood flow itself. Can take years/decades to develop. Often remain symptomless for majority of life. Start of symptoms signals advanced disease. Always begins with an initial insult to the artery wall.
Where is atherosclerosis often found?
Found within peripheral and coronary arteries. Focal distribution along the artery length. Distribution may be governed by haemodynamic factors: Changes in flow/turbulence (eg at bifurcations) alter gene expression - areas prone to atherosclerosis.
What is the structure of an atheroscletoric plague?
- Lipid
- Necrotic core
- Connective tissue
- Fibrous “cap”
Eventually the plaque will either occlude the vessel lumen resulting in a restriction of blood flow (angina), or it may “rupture” (thrombus formation – death).
What was the response to injury hypothesis?
Suggested in 1856 by Rudolph Virchow and updated by Russell Ross in 1993 and 1999: Initiated by an injury to the endothelial cells which leads to endothelial dysfunction. Signals such as cytokines are sent to inflammatory cells which then accumulate and migrate into the vessel wall, leading to inflammation.
What causes inflammation in arterial wall during atherosclerosis?
LDL - can pass in and out of the arterial wall in excess, accumulates in arterial wall. ECs and macrophages generate free radicals. LDL is oxidised by free radicals (oxLDL). oxLDL is engulfed by macrophages (via scavenger receptors) to form foam cells. Foam cells (macrophage full of lipids) release more pro-inflammatory cytokines, creating more and more foam cells in intima layer of arterial wall.
Why does LDL accumulate in specific regions of the arterial tree?
- Healthy endothelium produces NO (nitric oxide) and other mediators, protect against atheroma.
a. Damaged endothelium alters NO biosynthesis
b. Affects BP control, regional blood flow. - Alteration in shear stress (frictional force blood exerts on vessel wall).
What is turbulent flow?
Arterial junctions or bifurcations experience lower levels of wall shear stress (WSS) compared to straight vessel segments. These areas of low shear stress experience turbulent flow, as opposed to laminar flow. Turbulent flow is more athero-prone due to a disruption of endothelial integrity and greater LDL-C infiltration.
How is adhesion stimulated in atherosclerosis?
Endothelial cell (EC) activation prevents nitric oxide (NO) production due to increased oxidative stress. Causes the synthesis of adhesion molecules (ICAM-1, VCAM-1), chemokines (MCP-1) and pro-inflammatory cytokines (IL-1, TNF-α, and IL-6). The chemo-attractive gradient generated promote T-lymphocyte infiltration and a monocyte recruitment cascade involving capture, rolling, adhesion and eventual intimal transmigration.
What causes plague rupture?
Plaques constantly growing and receding. Fibrous cap has to be resorbed and redeposited in order to be maintained. If balance shifted eg in favour of resorption, cap becomes weak and plaque ruptures. Results in basement membrane, collagen, and necrotic tissue exposure as well as haemorrhage of vessels within the plaque. End result: thrombus formation and vessel occlusion.
What are the main causes of vulnerable plagues?
- Necrotic core enlargement, a thinning of the fibrous cap and a heightened, uncontrolled inflammatory response.
- Intimal ‘synthetic’ VSMCs express scavenger receptors that facilitate oxLDL uptake to form VSMC-derived foam cells, which secrete pro-inflammatory cytokines.
- Specific cytokines (eg, IFN𝛾) inhibit collagen production in VSMCs, which causes a thinning of the fibrous cap due to impaired strength maintenance.
- IFN𝛾 and other inflammatory mediators trigger increased pro-atherogenic cytokine release, MMP production, collagen degradation and greater plaque vulnerability.
- As unresolved inflammation prevails, maintenance of a rigid fibrous cap is impaired and plaque susceptibility to rupture is increased.
What occurs after plague rupture?
Rupture releases pro-thrombogenic factors that cause thrombosis when exposed to platelets and coagulating factors within the plasma. Cholesterol crystals play a fundamental role in inducing plaque rupture as they have been shown to perforate the fibrous cap. Clinical complications may arise as a result of coronary thrombosis caused by plaque rupture or erosion.
What are fibrous plaques characterised by?
Characterised by less lipid accumulation, greater VSMC and ECM protein composition and fewer inflammatory macrophages are more prone to triggering thrombosis via plaque erosion. A complete absence of local ECs occurs in eroded plaques due to EC apoptosis, caused by innate immune activation and neutrophil extracellular traps (NETs). (Compared to ruptured plaques that possess dysfunctional ECs).
What is the long summary of athersclerosis?
Dysfunctional ECs and retention of LDL in subendothelial space. LDL is oxidised – promotes activation of ECs. Activated ECs increase expression of monocyte interaction/adhesion molecules (selectins, VCAM-1), and chemoattractants (MCP-1). Leads to attachment and migration of monocytes and T-lymphocytes into intima. Monocytes differentiate into macrophages.
Macrophages engulf ox-LDL via scavenger receptors (CD36, LOX-1) to become foam cells. Foam cells secrete IL-1 and other pro-inflammatory cytokines that generate another chemoattractive gradient and create a cycle of increased monocyte recruitment, higher foam cell production and greater inflammation, ultimately resulting in lesion growth. This is the start of formation of the fibrous cap.
Foam cells undergo apoptosis and release their lipid content to create isolated pools of cholesterol crystals within the intima. Pro-inflammatory cytokines, growth factors and matrix metalloproteinases (MMPs), secreted by activated foam cells and vascular ECs promote the migration of vascular smooth muscle cells (VSMCs) from the media to the intima. The macrophage-mediated clearance of apoptotic cells is inhibited.
This results in secondary necrosis of foam cells and the development of a necrotic core. VSMCs ‘phenotypic switching’ from a ‘contractile’ to ‘synthetic’ phenotype mediated by oxLDL and cholesterol crystals. ‘Synthetic’ VSMCs secrete extracellular matrix (ECM) proteins (collagen, proteoglycans and elastins) that contribute to the formation of stable plaque consisting of a fibrous cap overlying the necrotic core. The maintenance of a thick fibrous cap is critical for ensuring plaque stability. Anti-inflammatory cytokines (IL-10 and TGF-𝛽) secreted by T-lymphocytes reduce the size of the necrotic core by promoting effective removal of apoptotic cells. Anti-elastase activity of HDL reduce the size of the necrotic core by preventing fibrous cap ECM degradation. Advanced lesions impede blood flow and are prone to rupture.
What is the process of atherosclerosis?
- Endothelial dysfunction causes adhesion molecules (ICAM-1 and VCAM-1) expression
2-4: Monocytes are recruited, trans-migrate to the intima and differentiate into macrophages.
5: Intimal LDL is oxidised to oxLDL, then engulfed by macrophages to form foam cells. - Due to defective efferocytosis, foam cell necrosis occurs, resulting cholesterol-rich necrotic core formation.
- Growth factors and MMPs released from activated ECs and foam cells promote SMC migration into the intima where they adopt a ‘synthetic’ phenotype and can engulf oxLDL to become foam cells.
- The ‘synthetic VSMCs secrete ECM proteins that contribute to fibrous cap development overlying the necrotic core.
How are lipids transported around the body?
Lipids are transported around the body as lipoproteins due to their hydrophobic nature. General structure is central core of hydrophobic lipid (triglycerides, cholesterol) surrounded by hydrophilic coat (phospholipids, free cholesterol, apolipoproteins.
What are the different kinds of lipoproteins?
Lipoproteins can be HDL (smallest), LDL, VLDL and chylomicrons (largest). Classified due to density and the apolipoproteins that are associated. HDL (contain apoA1 and apoA2), diameter 7–20 nm. LDL (contain apoB-100), diameter 20–30 nm. Very-low-density lipoprotein (VLDL) (contain apoB-100), diameter 30–80 nm. Chylomicrons (contain apoB-48), diameter 100–1000 nm.
What are the three pathways for lipid transport?
- Exogenous (dietary: gut to liver)
- Endogenous (liver to cells)
- Reverse cholesterol (cells to liver)
What is the exogenous pathway of lipid transport?
Dietary lipid digested into cholesterol, free fatty acids and monoacylglycerides (MAG). FFA and MAG absorbed into enterocytes and used to form triglycerides, phospholipid and cholesterol ester. Cholesterol passes into enterocytes via NPC1L1. This transport protein is targeted by drugs affecting this pathway. Triglycerides and cholesterol packaged into chylomicron, containing ApoB48, via several steps in endoplasmic reticulum. Nascent (inactive) chylomicron released into lymphatic system.
What is the metabolism of the exogenous pathway?
Lipids are digested. Chylomicrons are assembled with apolipoprotein B-48. Chylomicrons move into the liver and subsequently into the bloodstream, where HDL donates apolipoprotein C-II and E, forming a mature chylomicron. ApoC can only bind to receptors found on adipose tissue while ApoE can only bind to receptors on hepatocytes. Mature chylomicrons activate lipotein lipase (LPL), an enzyme found on the surface of cells. LPL catalyzes a hydrolysis reaction, releasing glycerol and fatty acids from the chylomicrons. Glycerol and fatty acids can be absorbed by the tissue. Remnants bind ApoE at the liver and are endocytosed and hydrolyzed within lysosomes. This also releases glycerol and fatty acids in the cell. Cholesterol & TG enter endogenous pathway, converted to bile, or excreted.
