Atherosclerosis Flashcards
what are the key components of the atheromatous plaque?
VESSEL: LUMEN–> ENDOTHELIUM–> INTIMA–> MEDIA–>
Outside to inside:
Fibrous cap- smooth muscle and collagen in dynamic equilibrium and sit on top of the plaque
Cellular layer- smooth muscle (cells), macrophages, lymphocytes, less connective tissue
Necrotic core- lipid, cholesterol clefts, fibrin, foam cells, cell debris
(basis of the plaque)
•Macrophages, other immune cells and smooth muscle cells that have migrated from the media and proliferated into the intima.
- necrotic core sits underneath the endothelium and builds up in the intima
•Neovascularisation (new vessel formation) can occur- stimulated by cytokines and other growth factors.
angiogenesis helps with the stability of the plaque and affects how it can break off (and possibly damage the endothelium and cause subsequent thrombosis)
give a step by step explanation on how atheromatous plaques develop
(the 6 types of atherosclerotic lesion)
- Initial lesion
- Fatty streaks
- Intermediate lesions
- Atheroma
- Fibroatheroma
- Complicated lesion
• <20y ~ 20% already have significant coronary atherosclerosis
• 20- 29 y ~ 50%
• 30-39 y it’s up to 65%
(Berenson et al. NEJM,1996; Tuzcu et al., Circulation, 2001)
- These lesions also occur in very young people (from 1st to 2nd decade)
- Highlights that this is a disease that takes a long time to progress–> other factors contribute other than traditional factors like smoking, to initiate these lesions
describe each of the 6 types of atherosclerotic lesion
Type 1: initial lesion- isolated macrophage foam cells and adaptive thickening of the smooth muscle. The coronary artery is at a lesion-prone location.
Type 2: fatty streak lesion- mainly intracellular lipid accumulation.
Type 3: intermediate lesion- small pools of extracellular lipids.
type 4: atheroma lesion- core of extracellular lipid
type 5: fibroatheroma lesion- lipid core and fibrotic layer, or multiple lipid cores and fibrotic layers, or mainly calcific, or mainly fibrotic
type 6: complicated lesion- surface defect, hematoma-hemorrhage, thrombus
Resolution of thrombosis means it can switch from classification 5 to 6.
- Calcification contributes to hardening of core
- Fissure – linked to complication of lesion
what are the most common sites of plaque build up?
- Can occur at areas of bifurcations e.g. circle of Willis (where vessel splits into 2)
- vasculature of lower limbs – atherosclerosis –>ischemia/necrosis of lower limbs. Ulcers and ultimately amputations –> diabetic patients can have lower limbs or toes amputated.
- Large descending aorta- atherosclerosis–> aneurysm
Obstruction in heart: MI
Obstruction in brain: typically, ischaemic stroke
what are the clinical presentations of atherosclerosis?
- Myocardial infarction
- Stroke
- Aneurysm
- Peripheral vascular disease
- Kidney injury
name the risk factors contributing to atherosclerosis
- Age
- Male sex (premenopausal women protected)
- Genetics
- Hyperlipidaemia
- Smoking
- Hypertension
- Diabetes mellitus
- Obesity
- Metabolic syndrome
- Alcohol
- Drugs
describe the cardiovascular differences between someone of young age compared to someone to an older individual
Young age – thin vessels, good vascular tissue etc.
Aged – increased apoptosis and necrosis of cardiomyocytes, fibrosis (stiffening of heart), hypertrophy (enlarged heart cells that impact ventricular wall), enlarged heart cells thickening the ventricles, senescent cells (inactive cells that can pump out cytokines and inflammatory mediators)= impacts the size of the heart’s wall and (+vessel’s) function.
what is one gene involved in hypertrophy?
mTOR: encodes a kinase that is responsible for protein synthesis + regulates cell size + energy homeostasis.
Name some genes involved in atherosclerosis development
Multitude of genes impact this disease not just one
• Cholesterol
• LDL receptor
• apolipoprotein B
• apolipoprotein C
• Variants in angiotensinogen associated with hypertension (RAAS system)
• Predisposition to type 2 diabetes
• Ion channel proteins affecting arrhythmias
name the classic risk factors in the formation and progression of atherosclerotic plaque
risk factors associated with metabolic syndrome and T2D:
- microalbuminuria
- atherogenic dyslipidemia (the gene PCKSK9 affects cholesterol= PCKSK9 inhibitors are being looked at)
- hyperglycaemia
- obesity
- hypertension
- inflammation
- thrombosis
other risk factors:
- age
- gender
- psychology
- sedentarism
- smoking
- lifestyle
Take home message: numerous risk factors and numerous genes that can impact atherosclerosis
describe the mechanisms of atherosclerosis
- injury to the endothelium (dysfunctional endothelium)
- chronic inflammatory response
- Migration of SMC from media to intima
- Proliferation of SMC in intima
- Excess production of extracellular matrix
- Enhanced lipid accumulation
EC function in health and disease
• Endothelial cells regulate homeostasis within vessels
• Vital barrier that separates blood from tissue
• Natural physiology is anti-coagulant – no ongoing thrombosis within vessel
• Stimulus activates endothelium to be pro-coagulant
• Regulates blood flow and vascular tone – balance between nitric oxide and prostacyclin that vasodilate and vasoconstrict, checks the balance of fibrin formation.
• EC function alters when activated or injured e.g. due to inflammation.
• Activation of thrombosis: Injury –> exposes subendothelial collagen–> activation of tissue factor–> activation of pro-coagulation/ clotting cascade pathway–> Ischaemia occurs.
• Balance of pro and anti-coagulant factors affect vessel contraction and relaxation.
Imbalance of these factors= endothelial stress i.e. endothelial dysfunction
describe the initiation of atherosclerosis
It may be considered a complex inflammatory response!
ENDOTHELIAL ACTIVATION:
- LDL penetrates the endothelium and is retained in the intima, where it gets oxidised (smoking increases the risk of oxidised LDL).
- oxLDL then releases proinflammatory lipids that stimulate ECs to express adhesion molecules
- rolling hypothesis – circulating monocytes adhere to ECs expressing VCAM-1 and other adhesion molecules and migrate through the dysfunctional Endothelial layer into the intima in response to chemokines–> monocytes differentiate into macrophages (precursor for the foam cell- important for atherosclerotic lesions).
MACROPHAGE ACTIVATION AND FOAM CELL FORMATION:
• Growth factors and cytokines e.g. M-CSF can cause scavenging receptors and toll-like receptors to be expressed on surface of macrophages which mediate uptake of oxidised LDL = accumulation of lipid= to become foam cells
• Interferons and cytokines also are released that attract more immune cells to increase inflammation cascade
- Other adhesion molecules (e.g. ICAM, VCAM, ELAM) are important in attracting monocytes to migrate through the endothelial cell layer
- Can start to see stiffness of the vessels’ layers
VSMC – phenotypic switch from contractile to synthetic (stiff, migratory)= proliferate and migrate= accumulate in number and cause vessel to stiffen
what are the factors that affect the dynamics of plaque stability (i.e. if it will be stable or instable)
- Matrix metalloproteinases cause further disruption to endothelial cell lining= degrade collagen= decrease structural stability of the plaque
- Impacts whether the plaque breaks off–> fissures–> breaking through the fibrous cap–> breaking into endothelial layer–> activation of thrombosis.
what can decrease the structural stability of the plaque?
Activated macrophages secrete matrix metalloproteinases TIMP-1 and 2, which degrade collagen and decrease the structural stability of the plaque. Also secreted are cytokines and interferon, which may initiate smooth muscle apoptosis and damage endothelial cells.
T lymphocytes secrete IFN-gamma, which inhibits collagen synthesis and damages endothelial cells.
