Pomb Atherosclerosis

Atherosclerosis

• Atherosclerosis: disease that cause focal thickenings of the tunica intima of the large and medium size arteries. These plaque developments are areas of chronic inflammation with deposits of fibrous tissue and lipid.
- Atherosclerosis is a general term for hardening of the arteries
• Structure of muscular arterial wall:
- Tunica intima: endothelial cells (flat thin cells) lying on a basement membrane. Its function include containment of body, selective transport materials in to tissues, control of clotting and blood pressure
- Tunica media: two layers of elastic laminae with smooth muscles cells called pericytes in between for muscular arteries. In arterioles, it exists as a single layer of muscle cells.
- Tunica adventitia: made up of connective tissue (collagen and elastins) with vaso vasora to supply the blood vessel
• Features of vessel walls:
- cell components continually communicate to regulate each other’s function and fate, e.g. smooth muscle secrete substance that stabilized the endothelial cells.
- Structure of arteries depends on their size and function. Large arteries (e.g. aorta) are exposed to high pulsatile pressures, so have prominent elastic lamina. Medium size arteries (e.g. coronary) regulate blood flow so their media is composed largely of smooth muscle.
• Aetiology of atherosclerosis:
- Major positive risk factors: the four are hyperlipidaemia (increase lipid and cholesterol), cigarette smoking, hypertension, diabetes mellitus
- Other positive risk factors: age, family history, obesity, excess alcoholism, LBW, low SES, high saturated fat diet, male gender (female protected by oestrogen)
- Negative risk factors: high levels of HDL, moderate alcohol consumption, cardiovascular fitness
• Lipoprotein: protein units consisting of a lipid core surrounded by a polypeptide coat with apolipoprotein inserted into the coat.
- Abnormal amount or constitution of lipoproteins will affect atherosclerosis, e.g. 10% reduction in serum cholesterol reduce death rate by 15%. HDL decrease risk while LDL increase risk.
• Pathogenesis:
- Endothelial cell injury: caused by haemodynamic force (turbulence) of the blood with hypertension and at branch points or chemical damage from cigarette and cytokines. Consequently vessel increase permeability, allowing lipid infiltration. Adhesion of leucocytes to vessel walls occurs with expression of integrin and chemokines, while thrombosis is also activated.
- Monocyte migration: injury produces a centre of chronic inflammation. Circulating monocytes adhere and enter atherosclerotic lesion and mature into macrophages. They ingest large amount of oxidised lipoproteins forming foam cells.
- Smooth muscle cell activation and migration: macrophages, platelets and endothelial cells produce GF that activate vascular smooth muscles cells. These proliferate and migrate into tunica intima through broken elastic lamina from the tunica media and form an essential part of the plaque
- Lipoprotein infiltration: lipoprotein is oxidised in plaques and these attract monocytes and stimulate release of cytokines and growth factors in the plaque. Smooth muscle cells, macrophages and endothelial becomes dysfunctional as they uptake lipoprotein and lipids and undergo apoptosis and necrosis. Content released from cellular death further stimulate inflammation and necrosis of cells
• Fibrous cap: tough outer covering of the atheroma plaque made up of smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans and neurovasculisation
• Consequences of atherosclerosis: atheroma are silent until they causes symptoms (clinical phase)
- Preclinical phase: Fatty streaks cause damage to internal elastic lamina. Infiltration of lipids forms a fibrofatty plaque (containing foam cells with elastic fibers). The plaque advance into an advanced vulnerable state with continuous events of cell death, inflammation, remodelling, re-organisation and calcification.
- Anerysm and rupture: degeneration of tunica media cause wall weakening leading to rupture of plaque/vessel and dissection of vessel walls
- Occlusion by thrombus: plaque rupture exposes underlying clotting factors to the lumen causing clotting. Thrombus can block of the vessel wall completely
- Critical stenosis: arise from progressive plaque growth
- Complications: myocardial infarction, peripheral vascular disease, cerebrovascular disease

Thrombosis and embolism

• Haemostasis: physiological response of blood vessels to injury to prevent blood loss by clotting injured vessels
- In normal vessels, this is inactivated to main blood in clot-free state.
- When activated, the events are co-ordinated by endothelial cells, platelets and clotting cascade
• Inhibition of haemostasis: in health vessels, endothelial cells physically insulate the tissue from the blood and also produce enzymatic and chemical inhibitors.
- Nitric oxide and prostacyclin: two potent inhibitors of platelet activation that is synthesized by endothelial cells. They express antithrombin on their surface that binds and inactivates thrombin.
• Activation of haemostasis: damaged endothelial cells have their barriers breached during injury which exposes the underlying tissue activating both platelets and coagulation cascade.
- Injured cells produce won Villebrand factors that promote platelet adhesion to the extra-cellular matrix proteins and tissue factor thromboplastin that activate the coagulation cascade.
• Platelets: these are activated by exposed extra-cellular matrix proteins (collagen especially). Platelets secrete chemical signal such as thromoxane A2, vasoactive amines and ADP.
- The signals promote vasoconstriction to slow blood flow, and platelet aggregation.
- Loss of platelets significantly impact haemostasis function producing a range of diseases from purpura (bleeding from skin capillaries) to major haemorrhage
• Coagulation: cascade of proteolytic reactions through which inert precursors zymogens are activated.
- Cascade is activated by tissue factors (derived from damaged tissue and active endothelium) which ultimately activate thrombin
- Thrombin: catalyst for the conversion from fibrinogen into fibrin monomers which polymerize into fibrin strands. Thrombin can also activate platelets and earlier steps of the cascade.
- Fibrin form a meshwork with fused platelets to form a haemostatic plug
- Once fibrin deposition occurs, the fibrinolytic system is activated to diassemble the haemostatic plug and prevents further clotting.
• Events of Haemostasis:
- Injury is followed by arteriolar vasoconstriction from reflex and local factors
- Endothelial injury exposes highly thombogenic extra-cellular matrix causing platelets to adhere and activate
- Primary haemostasis: the plates release secretory granules and aggregate to form platelet plug
- Tissue factors secreted by endothelium activate the coagulation cascade to initiate thrombin and local fibrin deposition.
- Secondary haemostasis: further platelet aggregation and granule release induced by thrombin
- Fibrin and platelets aggregate to form solid permanent plug and counter-regulatory mechanism is activated to limit plug size.
• Thrombosis: pathological abnormalities and inappropriate activation of haemostasis.
- Thrombus: mass formed from blood continents within the circulation during life. These are composed of fibrin and platelets and entrapped red/white blood cells.
- Thrombus may form in blood vessel or the heart and cause damage by obstructing the lumen of the vessels or break off into circulation and obstruct blood flow elsewhere
• Blood clot: clotting object formed in static blood and involves primarily the coagulation (not thrombus)
• Predisposing factors: Virchow’s Triad
- Changes in vessel all: endothelial injury from atherosclerotic plaque or myocardial infarction
- Changes in blood flow: turbulence in artery/chamber due to narrowing, aneurysm or infracted myocardium, abnormal cardiac rhythms and heart valve. In vein, stasis due to right side heart failure, immobilization, and economy class syndrome. Pelvic and leg veins are the most affected vessels.
- Changes in constituent of blood: hypercoagulability from increases coagulation factors. Causes are tissue damage, post-operative, malignancy, smoking, increase blood lipids or oral contraceptives.
• Fate of thrombi:
- Dissolution: breakdown by fibrinolytic system
- Propagation: in stagnant blood beyond an occluded vein, travel toward the heart
- Stenosis or occlusion
- Organisation and recanalization
- embolisation
• Emboli: intravascular mass carried by blood flow from its point of origin to a distant site, e.g. thrombus, fat, air, atheromatous debris, bone marrow and amniotic fluid
- Causes stenosis and occlusion, i.e. emboli from pelvis veins will lodge in pulmonary artery and produce pulmonary infarction, reduced cardiac output and heart failure.
- Emboli from left side of heart or aorta will enter systemic system and pass into brain, spleen, kidney etc.

Ischaemia and infarction

• Ischaemia: inadequate local blood supply to a tissue. Consequences are:
- Hypoxia: a deficiency of oxygen which causes cell injury by reducing aerobic respiration
- Reduced exchange of metabolic/catabolic substances into and out of issues
- Infarction: necrosis of tissue
• Causes of ischaemia:
- External occlusion of vessels: tumours and compressions
- Internal occlusion of vessels: atherosclerosis, thrombosis, or embolism
- Spasm: frostbite
- Capillary blockage: sickle cell anaemia, cerebral malaria
- Shock: circulatory failure with low arterial blood pressure which causes impaired perfusion of tissues
- Increased demand
• Susceptibilities of cells to ischemia: decreasing sensitivity
- Neurons (irreversible damage with 3 minutes of anoxia)
- Renal proximal tubular epithelium (renal ion absorption is highly ATP dependent)
- Myocardium (functional impairment within 1 minute and irreversible damage after 20).
- Skeletal muscle (capable of anoxic work)
- Fibroblasts and macrophages (stromal cells work in granulation tissues which are ischaemic)
- Neutrophils (their action is enhanced by ischemia which relates to their mode of action)
• Factors affecting severity of outcome:
- Anatomy of blood supply: presence of collateral circulation
- Size of occluded vessel: larger the vessel affected the more severe the ischaemia
- Speed of onset: collateral vessel may develop from angiogenesis stimulated by VEGF to compensate for ischemia if slow progressive
- Duration of occlusion: longer period of occlusion greater injury
- Metabolic demand
- General adequacy of circulatory system: co-morbidities such as hear failure and anaemia may worsen conditions
• Range of effect:
- No effect
- Functional defects (renal insufficiency)
- Reversible damage
- Apoptosis
- Infarction (necrosis of tissue due to overwhelming injury)
• Infarction: occurs as the result of thombotic or embolic events.
- Lack of O2 supply from blood means apoptosis can’t be initiated
- Red: haemorrhagic infarcts that occur in tissue with dual blood supply such as lungs or where blood flow re-established following occlusion.
- White: solid tissue supplied by a single artery and often wedge shaped (apex at point of occlusion and base at organ surface)
• Coagulative necrosis: dominant appearance in solid organs.
• Acute inflammation: occurs around the viable margin of the infarcts with recruitment of neutrophils. Later on, macrophages and lymphocytes also enter the tissue.
- Fibroblasts and endothelial cells are recruited for organisation where they repair the tissue by forming granulation tissues. These are remodelled into non-functional fibrous scar over time.
- Regeneration is also possible.
• Ischaemic heart disease: ischaemia of the heart caused by atherosclerotic narrowing of coronary arteries leading to death of cardiac muscles. Consequences include:
- Angina pectoris: pain due to heart muscle ischaemia with symptoms of recurrent episodes of chest discomfort, constricting, squeezing and chocking. However transient duration meaning cellular necrosis does not occur
- Chronic IHD: heart failure
- Myocardial infarction: occur when atherosclerotic plaque in coronary artery suddenly enlarges from rupture or thrombus formation and area of tissue undergoes full transmural cellular death.
• Follow-up complications:
- Dysrhythmia: scar tissue does not conduct action potential properly
- Cardiac failure and pericardial haemorrhage: rupture of vessels cause blood to leak into the pericardium
• Treatment: aimed to restore blood flow
- Treatment with thrombolytic agents such as streptokinase or tissue –type plasminogen activator
- Mechanical re-expansion of occluded vessel (angioplasty)
- Coronary artery bypass grafting
• Effects of ischaemia on individual cells: mild episodes can cause cellular changes leading to adaptation while severe ones lead to death.
- Attempts at repair: mediated by heat shock proteins and other repair mechanism
- Cell atrophy: cell volume reduced by proteasome-mediated proteolysis and lysosomal digestion (autophagy)
- Cell shut-down: occurs rapidly with onset of ischemia with suppression of protein.RNA/DNA synthesis and other non-essential reactions.
- Apoptosis: suicide of irreversibly damage cells amongst non-affected neighbouring cells. It utilized caspase enzyme to dismantle and package cell segments for phagocytosis, hence does not provoke inflammation
- Necrosis: passive uncontrolled death of cells after overwhelming hypoxic damage. It occurs when energy is not present for apoptosis. The process is disordered with cellular swelling and bursting and spillage of cytoplasmic content which initiates an inflammatory response.
• Reperfusion: restoration of blood after a period of ischemia
- Reperfusion damage: after long ischemic period, introduction of blood flow cause damaging reactive oxygen species to be produced in the cells, e.g. superoxide, H2O2 and hydroxyl radical (OH). These cause lipid peroxidation in membranes and damage enzyme and DNA.
- Such damage occurs in many organs such as heart, liver, brain and especially relevant in situations of myocardial infarction and organ transplantation (hypoxic).
- In skeletal muscle, reperfusion causes tissue swelling within volume enclosed by fascia of the muscle which creates tissue hydrostatic pressure, capillary compression and secondary ischemia/necrosis.
- Vascular endothelial cells are especially vulnerable to reperfusion injury

Haemodynamic disorders

• Regulation of blood pressure: determined by cardiac output and peripheral vascular resistance.
- Cardiac output: regulated with heart rate , heart contractility and blood volume (sodium and ANP)
- Peripheral vascular resistance: size of arterioles mediated by a neural (alpha adrenergic constrictors) and humoral factors (angiotensin II constriction and NO dilation)
• Hypertension: abnormally high blood pressure in vascular bed
- Systemic arterial hypertension
- Pulmonary hypertension
- portal hypertension
• Systemic hypertension: varies with posture, exercise and stress. Accurate measurement requires reading taken on at least three occasions over a 1 month period. Arbitrary values for hypertension is >140/90
- Secondary hypertension: occurs as a result of other disease such as renal disease, endocrine disorder and vascular disease etc. Affects 5%.
- Primary/essential hypertension: systemic arterial hypertension which have no obvious single cause. Affects 95%.
- Essential hypertension have a genetic predisposition, since black American have twice the incidence as whites. Candidate genes includes ACE, renin and NO synthase and most importantly angiotensinogen gene in which polymorphisms are linked with increase plasma level of the protein and elevated blood pressure.
- Environmental factors such as stress smoking and inactivity also have important contribution to pathogenesis
• Pathology due to hypertension:
- Atherosclerosis
- Left ventricular hypertrophy
- Cardiac failure
- Cerebral haemorrhage (stroke)
- Aortic dissection (occlusion of major vessels and aortic rupture)
- Small blood vessel disease
- Renal insufficiency and renal failure
• Heart failure: failure of heart to maintain and output of blood that is adequate for demands of the body
- Reduced output with hypoxic effects
- Damming back of blood with congestive effect on organs
• Adaptive mechanism: helps maintain cardiac output
- Hypertrophy of myocardial fibres
- Dilatation of heart chambers (mechanical advantage)
- Increased circulating volume (renin pathway)
- Increased catecholamine released to stimulate sympathetic response (increase HR and contractility)
• Cardiac decompensation: when heart failure is progressive and prolonged and cardiac output changes is beyond the capability of the adaptive mechanism to maintain. In fact adaptive processes become pathological with increased volume causing volume overload and inadequacy of coronary blood supply to cope with metabolic demands of hypertrophied cardiac muscles. Excessive cardiac dilation is also an mechanical disadvantage
• Fluid homeostasis: maintenance of vessel wall integrity, intravascular pressure and osmolarity. Movement of substance is determined by the balance of hydrostatic and osmotic pressures.
- In healthy vessels, a small amount of net fluid moves out of the interstitial spaces and removed by lymphatics.
- With hypertension, large amount of fluid moves into the interstitial spaces and lymphatic drainage is overwhelmed leading to tissue oedema.
• Tissue oedema: increase of fluid within interstitial tissue spaces. In other conditions, oedema can occur in dependant tissues such lungs, brain or fluid can accumulate within body cavities (ascites)
- Local oedema occurs with inflammation due to increased blood flow and local increases in vascular permeability (protein-rich exudates)
- Oedema in non-inflammatory cases involves a protein-poor transudate.
- Causes of non-inflammatory oedema: increased intravascular hydrostatic pressure, reduced plasma osmotic pressure (hypoproteinaemia), lymphatic obstruction (e.g. neoplasia) and sodium retention (e.g. renal hypoperfusion)
• Hyperaemia: active process with increased inflow to capillary bed as a result of arteriolar dilatation.
• Congestion: passive process with decreased outflow from capillary bed as a result of heart failure (systemic process) or venous obstruction (local process)
• Haemorrhage: extravasation of blood due to vessel rupture. It usually follows vessel injury due to trauma, atherosclerosis or erosion.
- Haemorrhagic diatheses: disorders that increase the likelihood of haemorrhage which include low platelet counts (thrombocytopaenia), clotting factors defects and amyloidosis (vessel fragility)
- Haematoma: haemorrhage enclosed within tissues
- Range of haemorrhage: petechiae (1-2mm), purpura (>3mm), ecchymoses (>1cm)
• Shock: potentially lethal systemic hypoperfusion due to reduction in cardiac output and a reduction in effective circulating blood volume. Consequences:
- Hypotension, impaired tissue perfusion and cellular hypoxia
- Long term cause irreversible cell injury
• Disorders resulting in shock:
- Cardiogenic: disorder related to inadequate cardiac output, e.g. MI (myocardial damage), ventricular rupture, pulmonary embolism
- Hypovolaemic: disorders of blood volume such as haemorrhage and fluid loss (vomiting, diarrhea etc)
- Septic: problems related to infection, e.g. endotoxic shock, gram-positive septicaemia, overwhelming microbial infections (vasodilation and pooling of blood, endothelial injury and leukocytes induced damage, disseminated intravascular coagulation and activation of cytokine cascade)
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