Cardiology - Atherosclerosis and haemodynamic disorders Flashcards
What is arteriosclerosis?
The walls of arterial vessels are made of smooth muscle, elastin, and collagen which help maintain vascular tone. Alterations in the relative amounts of these specialised elements leads to hardening, thickening and loss of elasticity of the vessel walls leading to disease. The term arteriosclerosis is often used as a general descriptive term for such diseases.
What is atherosclerosis?
The commonest type of arteriosclerosis is that affecting large and medium sized arteries. The underlying pathological lesion is called an atheroma, so this form of arteriosclerosis is known as atherosclerosis. Other forms of arteriosclerosis do occur, such as thickening of the walls of arterioles in association with hypertension but atherosclerosis is the most important clinical condition.
Name some risk factors associated with atherosclerosis?
These risk factors predispose to severe atherosclerotic lesions and have a high incidence of complications. They are:
1) Constitutional - age, sex, genetic
2) Modifiable - hyperlipidaemia*, hypertension, smoking, diabetes, alcohol
- atherosclerosis is associated with raised total cholesterol and higher LDL:HDL ratio. Hypertriglyceridaemia appears to be more associated with myocardial infarction than coronary artery disease, possibly because it affects coagulation.
What is the structure of a normal artery?
The artery is lined internally by smooth flat endothelium which lies on a thin tunica intima. This is fibroelastic loose connective tissue that contains occasional multifunctional myointimal cells. Underneath the intima is a strong internal elastic lamina underneath which is the tunica media. This is a layer of smooth muscle containing some elastic fibres. On the outer surface is the lose tunica adventitia.
What causes the development of atheroma?
Initial events in plaque formation are likely to be due to:
1) Endothelial cell damage allowing reaction of platelets with the intima
2) Release of platelet mitogen factors causing smooth muscle proliferation
3) The damaged endothelial cells allow lipid from the plasma to pass through to the intima where they accumulate - called insudation
What is a fatty streak?
These are the earliest microscopic evidence of atherosclerosis. Lipid (mainly cholesterol) enters the intima, probably from the blood across a damaged endothelium. Much of the lipid is phagocytosed by foam cells (probably blood derived macrophages and myointimal cells) but some eventually becomes free and more free lipid accumulates when bloated foam cells undergo cell death.
What happens during the fibro-lipid plaque stage?
Lipid in the intima initiates the formation of fibrocollagenous tissue. Cytokines secreted by macrohages stimulate the proliferation of myotintimal cells and switch the function of some of them towards active collagen synthesis to form a thick cartilagenous cap.
As the intimal deposit of atheroma enlarges, the underling muscular media begins to atrophy and thin as smooth muscle cells are lost.
What is a complicated atheroma?
This happens when the atheromatous intimal plaque is extensive, and there is marked atrophy of the associated tunica media, with contractible muscle being replaced by collagen. The lipid deposits in the intima frequently acquire deposits of calcium salts, and the fibro-lipid plaque becomes progressively calcified. Ulceration of the overlying endothelium predisposes to the deposition of thrombus on the exposed atheromatous plaque.
Surface ulceration happens because the enlarging atheromatous plaque becomes very thick relative to the normal thickness of the vessel wall. The blood supply to the intima may become insufficient and the lesion may undergo necrosis and surface ulceration.
What vessels are most commonly affected by atherosclerosis?
Atherosclerosis can affect all arterial vessels, but the aorta, coronary, cerebral, carotid, renal and ilio-femoral arteries tend to be most severely affected.
What are the most important consequences of atheroma?
1) Occlusions - narrowing of the arterial lumen produces partial or complete obstruction to blood flow and may result in ischaemia and infarction of the tissue supplied
2) Thrombosis - endothelial ulceration stimulates formation of an overlying thrombus. This may occlude the vessel at the site of thrombosis, or fragments of the thrombus may become detached to form emboli which block one or more smaller vessels distally
3) Aneurysm - loss of muscle and elastin from the media causes weakening of the vessel wall, pre disposing to localised areas of dilatation. This dilatation is known as an aneurysm. Rupture of the weakened and dilated artery wall, leading to a fatal haemorrhage. Aneurysm may also lead to thrombus formation because of venous stasis in some areas of the aneurysm cavity
What are non staining angular clefts?
In early atherosclerotic disease, foam cells filled with lipid break down and liberate free lipid into the intima where it is represented by non staining angular clefts. The presence of free lipid appears to induce a fibrous reaction in the surrounding tissues, which appear eosinophilic.
How does haemorrhage into an atherosclerotic plaque occur?
There are 2 mechanisms by which haemorrhage can occur into a plaque:
1) the rigid fibrotic plaque may split under the constant trauma of pulsatile movements and allow blood from the vessel lumen to greatly expand the plaque lesion - this is called plaque fissuring
2) small capillary vessels that develop in established plaques may rupture and lead to haemorrhage
The haemorrhage can reduce the diameter of the arterial lumen (which has already been reduced by the atheromatous plaque) which can lead to an abrupt reduction in arterial flow causing acute ischaemia.
What is the difference between haemostasis and thrombosis?
Haemostasis is the consequence of tightly regulated processes that maintain blood in a fluid, clot free state in NORMAL VESSELS while rapidly forming a localized haemostatic plug at the site of vascular injury.
Thrombosis is a pathological form of haemostasis. It involves blood clot (thrombus) formation in uninjured vessels or thrombotic occlusion of a vessel after relatively minor injury.
Both haemostasis and thrombosis involve 3 components - the vascular wall, platelets and the coagulation cascade.
Outline the process of normal haemostasis
After vascular injury, a period of arteriolar vasoconstriction occurs mostly as a result of reflex neurogenic mechanisms mediated by endothelin (potent vasoconstrictor produced by endothelium). The effect is transient, and bleeding would resume were it not for activation of the platelet and coagulation systems.
Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix, allowing platelets to adhere and be activated. Activation of platelets results in dramatic shape change and release of secretory granules. These recruit additional platelets (aggregation) to form a haemostatic plug; this is the process of primary haemostasis.
Tissue factor is also exposed at the site of injury. Also known as factor III and thromboplastin, tissue factor is a membrane bound procoagulant glycoprotein synthesised by endothelium. It works with factor VII as the major in vivo pathway to activate the coagulation cascade, eventually leading to thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork. Thrombin also induces further platelet recruitment and granule release. This secondary haemostasis sequence lasts longer than the initial platelet plug and helps to stabilise it. At this stage counter regulatory mechanisms (e.g. t-PA) are set into motion to limit the haemostatic plug to the site of injury.
What is the pathogenesis of thrombosis?
Three major factors predispose to thrombosis, they are Virchow’s triad:
1) Endothelial injury
- turbulent blood flow at arterial bifurcations
- homocysteine, oxidised LDL, cigarette smoking, cytokines
- atherosclerosis (arterial), endocardial damage (heart)
2) Stasis of blood flow
- sluggish blood flow due to prolonged bed rest or sitting (e.g. long flight or immobilisation)
- left atrial dilatation due to mitral valve disease (e.g. mitral stenosis)
3) Hypercoagulability
- activation of the coagulation cascade - e.g. DIC
- hereditary or acquired factor deficienes - e.g. hereditary anti-thrombin III deficiency, oral contraceptives
- antiphospholipid syndrome
- thrombocytosis (increased number of platelets)
- polycythaemia
How do arterial thrombi form?
These form in areas of active blood flow, and damage to the intimal layers is the most common predisposing factor. Thrombosis in the arterial system is mostly due to atherosclerosis.
Less commonly, arterial thrombi occur in other disorders such as arteritis, trauma and blood diseases.
They form by successive deposition of a number of layers of platelets and fibrin. This layering results in the lines of Zahn, a lamination of alternate dark and pale areas.
What are the consequences of arterial thrombi?
Arterial thrombosis secondary to atherosclerosis is the most common cause of death in the western world. Because most arterial thrombi occlude vessels, they often lead to ischaemic necrosis of tissue supplied by that artery (i.e. an infarct). Thrombosis in a coronary vessel will cause myocardial infarction, or thrombosis in a cerebral artery will lead to cerebral infarction.
End arteries can be affected by atherosclerosis and also suffer thrombosis. These include the mesenteric arteries, renal arteries and arteries of the leg (gangrene).
What can happen to a thrombus once it has been formed?
1) Lysis - thrombolytic activity of the blood
2) Propagation (i.e. an increase in size) - thrombus serves as a focus for other thrombus formation
3) Organisation - invasion of connective tissue elements involved in repair causes the thrombus to appear firm and greyish white
4) Canalisation - new lumen lined by endothelial cells forms WITHIN an organised thrombus
5) Embolisation - when part or all of the thrombus becomes detached, travels through the circulation and lodges in a blood vessel some distance from the site of formation
What causes thrombosis in the heart?
Endocardial injury and changes in blood flow within the heart may lead to MURAL thrombosis (i.e. a thrombus adhering to the underlying wall of the heart).
Myocardial infarction is often associated with mural thrombi adherent to the left ventricle. Damaged myocardium does not pump effectively and ischaemia disrupts the endocardium. This creates a surface on which blood can clot.
Mural thrombi are also associated with AF, cardiomyopathies, and endocarditis - the last is characterised by small thrombi (vegetations) on cardiac valves.
What is the main complication of mural thrombi?
The major complication of thrombi in the heart is detachment of fragments and lodging in blood vessels at distant sites (e.g. cerebral arteries) - EMBOLISATION.
What causes venous thrombi?
DVT (deep vein thrombosis) is the most common manifestation of thrombosis in the venous system.
Venous thrombosis is multifactorial. DVT are caused by the same factors that favour arterial and cardiac thrombi (i.e. altered blood flow, endothelial damage, hypercoagulability). Certain conditions may predispose to venous thrombosis:
- Stasis: heart failure, chronic venous insufficiency and postoperative immobilization and prolonged bed rest
- Injury: trauma, surgery and childbirth
- Hypercoagulability: oral contraceptives, late pregnancy, cancer and inherited thrombophilic disorders
- Advanced age: venous varicosities and phlebosclerosis
- Sickle cell disease
Where do venous thrombi commonly form?
Most (>90%) of venous thrombi occur in the deep veins of the legs, the rest usually involve the pelvic veins. Most start in the large calf veins, frequently in the sinuses above the venous valves. The fate of thrombi in this location are the same as those in the arterial system. A thrombus may lyse and cause no further problems, or it may propagate to involve the iliofemoral vessels. The thrombus may then dislodge (embolise) and be carried to the lung (most commonly) as a pulmonary embolus.
What are the clinical features of venous thrombi?
Small thrombi in the calf veins or even larger ones in the iliofemoral vessels may cause no symptoms. Occlusive thrombosis of femoral and iliac veins result in severe congestion, oedema and cyanosis of the lower extremity.
Venous valves are always impaired in a vein with thrombosis and oragnisation. As a result, chronic deep vein insufficiency (i.e. impaired venous drainage) occurs. If a lesion is restricted to a small segment of the venous system then the condition may be asymptomatic. More extensive involvement leads to pigmentation, oedema and induration of the skin. Ulceration above the medial malleolus can also occur.
Venous thrombi elsewhere may also be dangerous: thrombosis in the mesenteric veins can cause haemorrhagic small bowel infarction; thrombosis in cerebral veins may be fatal and hepatic vein thrombosis (Budd-Chiari syndrome) may destroy the liver.
