Year three, Pathology: Blood vessel diseases:
Lecture 2: Atherosclerosis:
February 2018 by Dr. Ehsan.
By definition: It is an arterial disease that is characterized by intimal lesions, called atheromas or atheromatous plaques that protrude into lumen and cause narrowing or obstruction of arteries. It affects mainly large elastic arteries and medium sized muscular arteries. Its basic lesion (atheroma) is a fibro-fatty plaque, which is a raised patch within the intima having a core of lipid (mainly cholesterol and its esters) and a cap of fibrous tissue.
Examples of large elastic arteries are aorta, carotid and the iliac arteries.
Examples of medium-sized muscular arteries are coronary and popliteal a.
Epidemiology and risk factors:
The etiology of AT is ill defined, so the study of the causes will depends on the relation of the risk factors to the epidemiological results. It is well known that better recognition and avoidance of the risk factors is associated with better management.
In addition, there is marked geographical variations in the incidence of atherosclerosis-related IHD. It is high in Europe and the USA but remarkably low in Asia (e.g. Mortality rate from IHD is six times higher in USA than in Japan).
Risk factors have a multiplicative effect; two risk factors increase the risk approximately fourfold. When three risk factors are present (e.g., hyperlipidemia, hypertension, and smoking), the rate of myocardial infarction is increased seven times.
Risk factors of atherosclerosis are summarized as follows:
A- Nonmodifiable) constitutional):
Increasing age
Male gender
Family history
Genetic abnormalities
B- Modifiable (Potentially controllable):
Hyperlipidemia
Hypertension
Cigarette smoking
Diabetes mellitus.
Constitutional risk factors:
Age: Increasing age as death rates from IHD rise with each decade of life, and myocardial infarction increases five folds between age 40 and 60.
Male gender: Since myocardial infarction is uncommon in premenopausal women.
Genetic defects: Certain families suffer increased frequency of heart attacks at an early age. This familial predisposition appears to be related to an increased incidence of some diseases in these families that has a minor genetic defect as genetic defects in lipoprotein metabolism.
Modifiable risk factors:
1- Hyperlipidemia:
The evidences linking hypercholestrolemia to atherosclerosis include:
Atherosclerotic plaques are rich in cholesterol and its esters, derived from lipoproteins of the blood.
Atherosclerotic lesions can be induced in experimental animals by feeding them diets that raise their plasma cholesterol levels.
Genetic disorders cause severe hypercholesterolemia lead to premature atherosclerosis, often fatal in childhood.
Acquired diseases associated with hypercholesterolemia for e.g. nephrotic syndrome and hypothyroidism, are associated with increasing risk of atherosclerosis.
Populations having relatively high levels of serum cholesterol show higher mortality from IHD.
The higher the level of serum cholesterol, the higher the risk particularly with levels exceeding 200 mg/dl.
2- Hypertension:
Elevated blood pressure accelerates the process of atherosclerosis and increases the incidence of IHD and CVA.
It is known that both systolic and diastolic levels are important in the development of Ath.
Also HT increase risk of IHD by 60%.
One of the major effects of HT is left ventricular hypertrophy and hence IHD.
But antihypertensive therapy reduces the incidence of atherosclerosis-related diseases, particularly IHD and CVA.
3- Cigarette smoking:
Cigarette smoking is the main cause responsible for the relatively recent increase in the incidence and severity of atherosclerosis in women.
It increases the incidence of sudden death among those with IHD.
Cessation of smoking in high risk individuals is followed within a few years by a reduction in the risk of dying from IHD.
4- Diabetes mellitus
Diabetics are more susceptible to atherosclerosis related diseases as IHD, CVA and gangrene of lower extremities (100 fold). This is related to:
DM induces Hyperlipidemia, in up to 50% of diabetics.
Increased platelets adhesiveness is found in diabetics and so predisposing to thrombotic episodes.
Some diabetics tend to be obese and hypertensive, thus have increased tendency to develop severe atherosclerosis.
All diabetics who have the disease for at least ten years are likely to develop clinically significant atherosclerosis.
Additional risk factors:
Inflammation: is linked to plaque formation and rupture and can be assessed systemically by C-Reactive Protein.
(CRP: Is an acute phase reactant synthesized primarily in the liver. It is a downstream of a number of inflammatory triggers and plays a role in the innate immune response by opsonizing bacteria and activating complement).
CRP can activate local endothelial cells and induce prothrombotic state, so it is predictors for MI, CVA, and sudden cardiac death.
CRP is reduced by:
Smoking cessation, weight loss and exercise, and also Statins.
2. Hyperhomocystinemia:
Homocystine is elevated by low folate and vitamin B 12 intakes.
Homocystinuria due to rare inborn error of metabolism, results in elevated circulating homocystine (more than 100 Mmol/l.), and premature vascular disease.
3. Metabolic syndrome: Abnormalities of insulin resistance, glucose intolerance, and dyslipidemia, results in endothelial cell dysfunction.
4. Lipoprotein (a) is an altered form of LDL that linked to apolipoprotein A, its increased levels is associated with increased risk of CVA and MI.
5. Factors affecting hemostasis: as elevated plasminogen activator inhibitor 1 and thrombin.
6. Other factors: lack of exercise, competitive, stressful lifestyle, type A personality, and obesity.
Pathogenesis of atherosclerosis:
Two theories, one of intimal cellular proliferation and other of thrombus formation and organization. Elements of both are used: in the most widely accepted theory which is the response to injury hypothesis.In it atherosclerosis is a chronic inflammatory and healing response of the arterial wall, to endothelial injury. Lesion progression occurs through the interaction of modified lipoproteins, monocyte-derived macrophages, and T lymphocytes with the normal cellular constituents of the arterial wall.
Pathogenic events of this theory: (important) (go to figure 11-9 in book)
Endothelial injury: causes increased vascular permeability, leukocyte adhesion and thrombosis.
Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall.
Monocyte adhesion to the endothelium: followed by migration into the intima and transformation into macrophages and foam cells.
Platelet adhesion.
Factor release from activated platelets, macrophages, and vascular wall cells, inducing smooth muscle recruitment from circulation and media into intima.
Smooth muscle cell proliferation and ECM production with collagen.
Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cells).
Endothelial injury: Causes of chronic endothelial injury:
Hyperlipidemia.
Hypertension.
Smoking.
Homocystine.
Hemodynamic factors.
Toxins.
Viruses.
Immune reaction.
Consequences of endothelial dysfunction:
Most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia, and result in:
Increased vascular permeability.
Leukocytes adhesion.
Monocyte adhesion.
Monocyte emigration.
Hemodynamic disturbances:
The importance of hemodynamic turbulence in atherogenesis is illustrated by the observation that plaques tend to occur at ostia of exiting vessels, branch points, and along the posterior wall of the abdominal aorta, where there are disturbed flow.
Lipids:
Lipids are typically transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes).
Dyslipoproteinemia either genetic in origin or from other disorders affecting circulating levels as nephrotic syndrome, alcoholism, hypothyroidism or diabetes mellitus.
Mechanism of HC:
Chronic Hyperlipidemia can directly impair endothelial cell function by increasing local oxygen free radical production that injure tissues and accelerate nitric oxide decay reducing its vasodilator effect.
Then accumulate in intima, oxidized by free radical locally formed by macrophages and endothelial cells. Oxidized LDL ingested by macrophages, accumulates form foam cells.
Oxidized LDL also stimulates secretion of growth factors, cytokines, and chemokines by these cells that increase monocyte recruitment.
Oxidized LDL also causes endothelial cell dysfunction.
(end of pathogenesis of atherosclerosis)
Morphology (pathology) of atherosclerosis
Fatty streaks: the earliest lesions are composed of lipid laden macrophages. Start as multiple minute flat yellow spots; coalesce into elongated streaks 1 cm or more in length. Seen in children older than 10 years, and of uncertain relation to AT.
Atherosclerotic plaques: intimal thickening and lipid accumulation.
Grossly look white to yellow plaques 0.3-1.5 cm, and impinge on lumen, and can coalesce to form large masses. Superimposed thrombus over ulcerated plaques look red to brown can occur.
The superficial portion of these lesions (i.e., facing the lumen) tends to be firm and white; this is the fibrous cap, whereas the deep portion is yellow and soft (lipid component).
Atherosclerotic Plaque Distribution:
Patchy, not circumferential, so look eccentric on cut section.
The most heavily involved arteries by atherosclerosis and in descending order are:
Abdominal aorta, Coronaries, Popliteal arteries, Descending thoracic aorta, Internal carotid arteries and Arteries forming the circle of Willis at the base of the brain.
Spared vessels are: brachial, mesenteric and renal aa. Except at their ostia.
Microscopy:
Components of plaques:
Cells: smooth muscle cells, macrophages and T lymphocytes.
ECM including collagen, elastic fibers and proteoglycans.
Intracellular and extracellular lipids.
Superficial fibrous caps composed of smooth muscle cells and relatively dense collagen.
Just beneath and to the sides of the cap (shoulders) there is a cellular area which consists of a mixture of macrophages, smooth muscle cells and T-lymphocytes.Deep to the cellular area is a necrotic core: consisting of lipid material, cholesterol clefts, cellular debris and lipid –laden foam cells.
Around the edges of the lesion there are proliferating small, thin-walled blood vessels (neovascularization)
Progress: atherosclerotic plaques tend to be progressively enlarge, due to cell death, and degeneration, with cholesterol clefts look microscopically empty by tissue processing (by effect of ethanol). Also there is synthesis and degradation of ECM and organization of thrombus, and at last there is calcification.
Atherosclerotic plaques are susceptible to the following important changes:
Focal rupture, ulceration, or erosion of the luminal surface, so expose the highly thrombogenic substances and induces thrombosis. Can partially or totally occlude the lumen, result in ischemia. If patient survive it will organize.
Hemorrhage into the plaque by rupture of fibrous cap, or of the thin walled vessels in the neovascularization area, which is especially seen in the coronaries. The atheroma expands by hematoma result in stenosis or rupture.
Atheroembolism: rupture, discharge debris into stream and microthrombi.
Aneurysm formation: pressure or ischemic atrophy of underlying media, weakness and dilation, may rupture.
End of morphology:
Look for the Pictures is the book.
Clinical features:
Large elastic arteries (e.g., the aorta, carotid, and iliac arteries) and large and medium-sized muscular arteries (e.g., coronary and popliteal arteries) are the major targets of atherosclerosis.
Symptomatic atherosclerotic disease most often involves the arteries supplying the heart, brain, kidneys, and lower extremities.
Myocardial infarction (heart attack), cerebral infarction (stroke), aortic aneurysms, and peripheral vascular disease intermittent claudication and (gangrene of the legs) are the major consequences of atherosclerosis.
Consequences of atherosclerotic disease: (مهم)
Atherosclerotic stenosis: clinically evident if there is 70% occlusion by fixed atheroma, so may present as angina, mesenteric occlusion, intermittent claudication, chronic IHD and ischemic encephalopathy.
Acute plaque changes: result in, myocardial infarction.
Thrombosis: leading to MI.
Aneurismal dilatation of the wall due to weakness of the media.
Vasoconstriction. It deases the lumen size, and can potentiate plaque disruption.
Atherosclerotic stenosis:
In cases of slow, progressive narrowing of the arterial lumen, there will be chronic ischemia of tissues. In smaller arteries such as the coronary, cerebral, popliteal, renal and mesenteric arteries, the main effect is narrowing of the lumen leading to chronic ischemia. Critical stenosis affects the function of the supplied organ by the stenosed artery as in the coronary a. and is asymptomatic at early stages but if reaches to 70% fixed occlusion, and so the patients classically develop chest pain (angina) on exertion (so-called stable angina).Acute Plaque Change:
Plaque erosion or rupture is typically followed by partial or complete vascular thrombosis, resulting in acute tissue infarction (e.g., myocardial or cerebral infarction). Plaque changes fall into three general categories:•
Rupture/fissuring, exposing highly thrombogenic plaque constituents•
Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood
•
Hemorrhage into the atheroma, expanding its volume
Sudden occlusion of the lumen by superimposed thrombosis or hemorrhage into the atheroma will lead to severe ischemia and infarction.
Thrombosis:
Partial or total thrombosis associated with a disrupted plaque is critical to the pathogenesis of the acute coronary syndromes. In the most serious form, thrombus superimposed on a disrupted but previously only partially stenotic plaque converts it to a total occlusion.
Mural thrombus in a coronary artery can also embolize andf small fragments of thrombotic material go to the distal intra-myocardial circulation and so microinfarcts can be found at autopsy in patients after sudden death or in rapidly accelerating anginal syndromes.
End of clinical features.