PATHOLOGY OF ARTHROSCLEROSIS

 

ARTHROSCLEROSIS

Atherosclerosis refers to the buildup of fats, cholesterol and other substances in and on your artery walls (plaque), which can restrict blood flow. The plaque can burst, triggering a blood clot. Although atherosclerosis is often considered a heart problem, it can affect arteries anywhere in your body.

Atherosclerosis is a slowly progressive disease of large- to medium sized muscular and elastic arteries. Atherosclerosis is characterized by the presence of intimal lesions called atheroma. It is the most prevalent and important form of arteriosclerosis, is a disease that typically affects the aorta and its major muscular distributing branches.

CHARACTERISTICS

The lesions are characterized by elevated intimal-based plaques composed of lipids, proliferating SMC, inflammatory cells, and increased ECM.

CAUSE

The artherosclerosis symptoms enumerate when;

1. Weakening the underlying vessel wall and leading to aneurysm formation
2. Mechanically obstructing flow, especially in smaller-bore vessels, resulting in catastrophic vessel thrombosis
3. Plaque rupture leading to vessel thrombosis

AREAS AFFECTED BY ARTHEROSCLEROSIS

The major pathologic and clinical effects of atherosclerosis involve the;

• Brain
• kidneys
• aorta
• peripheral and visceral arteries
• heart

Atherosclerosis develops as a response of the vessel wall to multifactorial and repetitive injury

EPIDEMIOLOGY

The major classic risk factors emerging from the Framingham Heart Study are;

• family history
• hypercholesterolemia
• hypertension
• smoking
• diabetes.

SYMPTOMS

Symptoms of moderate to severe atherosclerosis depend on which arteries are affected;

•  atherosclerosis in your heart arteries,  symptoms, such as chest pain or pressure (angina).
• atherosclerosis in the arteries leading to your brain,  signs and symptoms such as sudden numbness or weakness in your arms or legs, difficulty speaking or slurred speech, temporary loss of vision in one eye, or drooping muscles in your face. These signal a transient ischemic attack (TIA), which, if left untreated, may progress to a stroke.
• atherosclerosis in the arteries in your arms and legs,  symptoms of peripheral artery disease, such as leg pain when walking (claudication).
• atherosclerosis in the arteries leading to your kidneys, develop high blood pressure or kidney failure.

ENVIRONMENTAL CAUSES

The damage may be caused by:

• High blood pressure
• High cholesterol
• High triglycerides, a type of fat (lipid) in your blood
• Smoking and other sources of tobacco
• Insulin resistance, obesity or diabetes
• Inflammation from diseases, such as arthritis, lupus or infections, or inflammation of unknown cause

CONSTITUTIONAL RISK FACTORS

Genetic susceptibility, environmental factors, and endogenous metabolic alterations are risk factors that participate in the pathogenesis of atherosclerosis and the formation of atherosclerotic plaques in vessel

Age:

 Atherosclerotic burden progressively increases with age, typically reaching a critical mass with clinical manifestations beginning between ages 40 and 60 years. Death rates from IHD continue to rise with each successive decade.

Gender:

 Relative to age-matched men, premenopausal women are relatively protected against atherosclerosis and its complications. In postmenopausal women, the risk rapidly increases and can exceed that for men. Besides affecting the progression to atherosclerosis, female gender also influences hemostasis, infarct healing, and myocardial remodeling

Genetics:

 Family history is the most significant independent risk factor for atherosclerosis. Monogenic disorders such as familial hyperchosterolemia account for only a minor percentage, and numerous genetic polymorphisms (including predilection for hypertension and diabetes) are contributory.

      MODIFIABLE RISK FACTORS

Hypercholesterolemia/ Hyperlipidemia

Increased risk is associated with increased low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL; clears cholesterol from vessel wall lesions). Levels can be favorably modified by diet, exercise, moderate alcohol intake, and statins (inhibitors of hydroxymethylglutaryl-coA reductase, the rate-limiting enzyme in cholesterol biosynthesis).

Recognition of these relationships has spurred the development of dietary and pharmacologic interventions that lower total serum cholesterol or LDL, and/or raise serum HDL, as follows:

• High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol, and/or containing higher ratios of polyunsaturated fats, lower plasma cholesterol levels.
• Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles.
• Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower them.
• Statins are a widely used class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis.

Hypertension:

 Both diastolic and systolic hypertension are important and independent of other risk factors; high blood pressure increases the risk of atherosclerotic ischemic heart disease by 60%.

Smoking:

 Smoking of one pack of cigarettes daily over many years doubles the death rate from ischemic heart disease.

Diabetes mellitus:

 Directly and indirectly (by inducing hypercholesterolemia), diabetes accelerates atherosclerosis and doubles the risk of myocardial infarction and markedly increases the risk of stroke or extremity gangrene.

ADDITIONAL RISK FACTORS

Inflammation:

 Present at all stages of atherosclerosis, inflammation plays a significant causal role. A number of circulating markers of inflammation correlate with risk of ischemic heart disease; C-reactive protein (CRP; a liver-synthesized acute phase reactant involved in bacterial recognition and complement activation) has emerged as one of the simplest and most sensitive to measure. It strongly and independently predicts risk of cardiovascular events, even in healthy individuals.

Hyperhomocystinemia:

 Elevated levels of homocysteine are associated with increased atherosclerotic vascular disease. Levels can be increased in the setting of low folate or vitamin B12 or with hereditary homocystinuria

Metabolic syndrome:

 A constellation of findings including central obesity, hypertension, glucose intolerance, dyslipidemia, and a systemic pro-inflammatory state. Adipose tissue cytokines have been implicated

Lipoprotein:

 This is an altered form of the lipoprotein constituent in LDL; elevated levels confer increased risk independent of LDL or total cholesterol levels

Hemostatic factors:

 Systemic markers of hemostasis or fibrinolysis are predictors of risk for atherosclerotic events.

PATHOGENESIS

Atherosclerosis is a chronic inflammatory and healing response of the arterial wall to EC injury.

• EC injury causes increased endothelial permeability, white blood cell (WBC) and platelet adhesion, and coagulation activation.
• These events induce chemical mediator (e.g., growth factors and inflammatory mediators) release and activation, followed by recruitment and subsequent proliferation of SMC in the intima to produce the characteristic intimal lesion

ENDOTHELIAL INJURY

endothelial injury leads to endothelial cell dysfunction with increased adhesivity and procoagulant activity

STIMULUS

injury mechanisms include;

• hypercholesteromia
• hemodynamic disturbances (e.g., disturbed flow)
• smoking
• hypertension
• toxins
• infectious agents.

MECHANISM OF ACTION

Mediators and cellular interactions in atherosclerosis. A host of noxious insults (e.g., hyperlipidemia, hypertension, smoking) cause endothelial injury or dysfunction. This results in monocyte (and platelet) adhesion and growth factor release, leading to smooth muscle cell recruitment, and proliferation in the intima; matrix synthesis is also increased. Foam cells result when macrophages and smooth muscle cells accumulate cholesterol through the uptake of low-density lipoprotein (LDL; e.g., in the form of oxidized LDL). These lipids derive from insudation from the vessel lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Circulating high-density lipoprotein (HDL) can help remove cholesterol from these accumulations.

HEMODYNAMIC DISTURBANCES

Despite presumably uniformly distributed injurious agents (e.g., hypercholesterolemia, cigarette toxins, hyperglycemia), atherosclerotic plaques are not randomly distributed and, in fact, characteristically develop at vascular branch points and other areas of disturbed flow. Indeed, non-turbulent laminar flow activates EC genes whose products are protective against atherosclerosis.

LIPIDS

• Defects in lipid uptake, metabolism, or binding to circulating apoproteins can lead to elevated lipids.
• Increased circulating levels accumulate in the vessel wall and cause EC dysfunction by increasing local oxygen free radical formation.
• Accumulated lipoproteins also become oxidized; oxidized LDL in particular are directly toxic to EC and SMC, causing dysfunction.
• oxidized LDLs are ingested by macrophages through scavenger receptors, causing the formation of foam cells and leading to pro-inflammatory macrophage activation

INFLAMMATION

Dysfunctional EC express increased levels of adhesion molecules (e.g., vascular cell adhesion molecule-1 [VCAM-1]) promoting increased inflammatory cell recruitment. Subsequent T cell and macrophage accumulation and activation leads to local increased cytokine production that drives SMC proliferation and matrix synthesis

INFECTION

Herpesvirus, cytomegalovirus, and Chlamydia pneumonia have all been detected in atherosclerotic plaques. It is not clear whether this is coincidence (these are common organisms) or causal (e.g., by driving inflammatory responses)

CLINICAL CONSEQUENCES OF ARTHEROSCLEROSIS

Most plaques are typically asymptomatic for decades until manifesting via one of the following mechanisms.

The resulting restricted flow can cause tissue atrophy or infarction, depending on the severity of the narrowing and the rate at which it develops.

ARTHEROSCLEROTIC STENOSIS

Artherosclotic stenosis restricts blood flow to downstream tissues; effects depend on the degree of stenosis and the metabolic demands of the affected tissues.

 • Slow insidious narrowing of vascular lumens occurs by gradual accumulation of plaque matrix

• At early stages of stenosis, outward remodeling of the vessel media (leading to overall vessel dilation) can preserve the luminal diameter

• At approximately 70% stenosis (critical stenosis), the vascular supply typically becomes inadequate to meet demand, and ischemia supervene

ACUTE PLAQUE CHANGE

Acute plaque change means that there is plaque erosion, frank rupture, or hemorrhage into the plaque, which expands the plaque volume and can increase luminal stenosis.

Vulnerable plaques have large deformable atheromatous cores, thin fibrous caps, and/or increased inflammatory cell content (leading to the elaboration of matrix metalloproteinases [MMPs] that degrade ECM)

Stable plaques have minimal atheromatous cores and thicker, wellcollagenized fibrous caps, with relatively less inflammation.

THROMBOSIS

Thrombus that forms over a disrupted plaque or contents of a friable atherosclerotic plaque can embolize and obstruct downstream vessels

VASOCONSTRICTION

Vasoconstriction can occur at sites of plaque formation due to endothelial dysfunction (with loss of nitric oxide production that normally promotes vasorelaxation) or to products elaborated by aggregated platelets or inflammatory cells.

VESSEL WALL FORMATION

Vessel wall weakening can be followed by aneurysm formation and possible rupture

Complications

The complications of atherosclerosis depend on which arteries are blocked. For example:

• Coronary artery disease. When atherosclerosis narrows the arteries close to your heart, you may develop coronary artery disease, which can cause chest pain (angina), a heart attack or heart failure.
• Carotid artery disease. When atherosclerosis narrows the arteries close to your brain, you may develop carotid artery disease, which can cause a transient ischemic attack (TIA) or stroke.
• Peripheral artery disease. When atherosclerosis narrows the arteries in your arms or legs, you may develop circulation problems in your arms and legs called peripheral artery disease. This can make you less sensitive to heat and cold, increasing your risk of burns or frostbite. In rare cases, poor circulation in your arms or legs can cause tissue death (gangrene).
• Aneurysms. Atherosclerosis can also cause aneurysms, a serious complication that can occur anywhere in your body. An aneurysm is a bulge in the wall of your artery.

Most people with aneurysms have no symptoms. Pain and throbbing in the area of an aneurysm may occur and is a medical emergency.

If an aneurysm bursts, you may face life-threatening internal bleeding. Although this is usually a sudden, catastrophic event, a slow leak is possible. If a blood clot within an aneurysm dislodges, it may block an artery at some distant point.

• Chronic kidney disease. Atherosclerosis can cause the arteries leading to your kidneys to narrow, preventing oxygenated blood from reaching them. Over time, this can affect your kidney function, keeping waste from exiting your body.

TREATMENT

Treatment of established disease may include medications to lower cholesterol such as statins, blood pressure medication, or medications that decrease clotting, such as aspirin. A number of procedures may also be carried out such as percutaneous coronary intervention, coronary artery bypass graft, or carotid endarterectomy.

PREVENTION

Medical management of atherosclerosis first involves modification to risk factors–for example, via smoking cessation and diet restrictions. Prevention then is generally by eating a healthy diet, exercising, not smoking, and maintaining a normal weight