Atherosclerosis

Atherosclerosis is the cause of

more than half of all deaths in the western industrialized nations.

Major complications resulting from ischemia due to atherosclerosis include

myocardial infarction leading to heart attacks and cerebral infarction leading to strokes.

Atherosclerotic lesions produce their effects through:

narrowing of the vessel and production of ischemia; sudden vessel obstruction caused by plaque hemorrhage or rupture; thrombosis and formation of emboli resulting from damage to the vessel endothelium

There is controversy about whether fatty streaks, in and of themselves, are .

precursors of atherosclerotic lesions

Men are at grater risk than are

premenopausal women, because of the protective effects of natural estrogens.

Risk factors contributing to PAD are the

same as those for atherosclerosis.

The LDL is removed from the circulation by

scavenger cells such as monocytes or macrophages.

It is caused by

slowing and turbulence of blood flow in the region of the plaque and ulceration of the plaque.

In larger vessels

such as the aorta, the important complications are those of thrombus formation and weakening of the vessel wall.

Increased risk is due to reduced level of

HDL and accumulation of carbon monoxide in the blood that produces carboxy-haemoglobin and eventually hypoxia in the arterial wall favouring atherosclerosis.

Less well-established risk factors for atherosclerosis

High serum homocysteine levels Elevated serum C-reactive protein Infectious agents

Diseases of the coronary arteries can cause:

Angina Myocardial infarction or heart attack Cardiac dysrhythmias Conduction defects Heart failure Sudden death

The lesions associated with atherosclerosis are of three types:

The fatty streak The fibrous atheromatous plaque Complicated lesion The latter two are responsible for the clinically significant manifestations of the disease.

Infectious agents

The presence of some organisms (Chlamydia pneumoniae, herpesvirus, cytomegalovirus) in atheromatous lesions has been demonstrated by immunocytochemistry, but no cause-and-effect relationship has been established. The organisms may play a role in atherosclerotic development by initiating and enhancing the inflammatory response.

~20% of all cardiovascular events occur in the absence of the

above mentioned risk factors

It causes either

acute or chronic ischemia (lack of blood supply).

As a part of the response to plaque disruption, platelets?

aggregate and release substances that further propagate platelet aggregation, vasoconstriction, and thrombus formation.

Most commonly affected arteries include large and medium sized arteries:

aorta, coronary arteries popliteal arteries cerebral arteries

It can result from

atherosclerosis, inflammatory processes leading to stenosis, an embolism, or thrombus formation.

Often PAD is a term used to refer to

atherosclerotic blockages found in the lower extremity.

The fibrous atheromatous plaque is the

basic lesion of clinical atherosclerosis.

High sensitivity C-reactive protein (hs-CRP) has emerged as one of the

cheapest and most sensitive of the various markers of inflammation (1-3 mg/L= moderate risk)

Diets high in

cholesterol, saturated and "trans" fats raise cholesterol levels

Although atherosclerosis can affect any organ or tissue, the arteries supplying the

heart, brain, kidneys, lower extremities, and small intestine are most frequently involved.

Smoking also promotes Athr. by

increased platelet adhesiveness, raised endothelial permeability, sympathetic nervous system stimulation by nicotene.

The uptake of LDL by macrophages in the arterial wall can result in the accumulation of

insoluble cholesterol esters, the formation of foam cells, and the development of atherosclerosis.

PAD refers to the obstruction of

large arteries not within the coronary, aortic arch vasculature, or brain. About 20% of patients with mild PAD may be asymptomatic;

The major component of serum cholesterol involved in risk is

low-density lipoprotein (LDL), the "BAD" cholesterol Its physiological role is to deliver cholesterol to the peripheral tissues

They consist of

macrophages and smooth muscle cells that have become distended with lipid to form foam cells.

HDL, the "GOOD" cholesterol,

mobilizes cholesterol from developing and existing atheromas and transports it to the liver for excretion in the bile Higher levels of HDL correlate with reduced risk Levels >60 mg/dL confer a negative risk

Thrombosis is the

most important complication of atherosclerosis.

Atherosclerosis is by far the most common cause

of CHD, and atherosclerotic plaque disruption the most frequent cause of myocardial infarction and sudden death.

Risk of PAD also increases in individuals who are

over the age of 50, male, obese, or with a family history of vascular disease, heart attack, or stroke.

Claudication -

pain, weakness, numbness, or cramping in muscles due to decreased blood flow;

Because of the role that platelets play in the

pathogenesis of CHD, antiplatelet drugs (e.g., low-dose aspirin) are frequently used for preventing heart attack.

Hyperlipidemia, particularly LDL with its high cholesterol content, is also believed to play an active role in the

pathogenesis of the atherosclerotic lesion.

In medium-size arteries

such as the coronary and cerebral arteries, ischemia and infarction caused by vessel occlusion are more common.

The scavenger cells,

such as the monocytes and macrophages, have receptors that bind LDL

There are two types of atherosclerotic lesions:

the fixed or stable plaque, the unstable or vulnerable plaque,

The amount of LDL that is removed by the "scavenger pathway" is directly related to

the plasma cholesterol level.

The clinical manifestations of atherosclerosis depend on

the vessels involved and the extent of vessel obstruction.

Fatty streaks are

thin, flat yellow intimal discolorations that progressively enlarge by becoming thicker and slightly elevated as they grow in length.

Incidence of myocardial infarction is ? in diabetics as in nondiabetics

twice as high

the unstable or vulnerable plaque,

which can rupture and cause platelet adhesion and thrombus formation commonly implicated in unstable angina and myocardial infarction.

the fixed or stable plaque,

which obstructs blood flow commonly implicated in chronic ischemic heart disease: stable angina, variant or vasospastic angina, and silent myocardial ischemia;

Left untreated,

~ ½ of hypertensive patients will die of IHD or congestive heart failure (CHF)

Cardiovascular disease related to atherosclerotic coronary heart disease (CHD) or ischemic heart disease (IHD) is the most common cause of

death in the developed countries of the world.

Incidence progressively increasing in

developing nations to an epidemic proportion over the last few decades due to fast changing lifestyles.

The lesions begin as a

elevated thickening of the vessel intima with a core of extracellular lipid (mainly cholesterol, which usually is complexed to proteins) covered by a fibrous cap of connective tissue and smooth muscle.

As the lesions increase in size, they

encroach on the lumen of the artery and eventually may occlude the vessel or predispose to thrombus formation, causing a reduction of blood flow.

These occurs regardless of

geographic setting, gender, or race.

The term coronary heart disease (CHD) describes

heart disease caused by impaired coronary blood flow. In most cases, it is caused by atherosclerosis.

The risk of ? is high in DM

cerebrovascular disease is high and frequency to develop gangrene of foot is about 100 times increased.

One hypothesis of plaque formation suggests that injury to the endothelial vessel layer is the

initiating factor in the development of atherosclerosis.

More than ? of persons with CHD have coronary atherosclerosis.

90%

Diets low in

cholesterol and high in polyunsaturated and omega-3 fats are beneficial

Epidemiologic studies have identified predisposing risk factors: Unchangeable risk factors:

Age Male gender Family history of premature coronary heart disease: Several genetically determined alterations in lipoprotein and cholesterol metabolism have been identified.

HYPERLIPIDEMIA

Hypercholesterolemia has directly proportionate relationship with atherosclerosis and IHD because atherosclerotic plaques contain cholesterol Dietary regulation and administration of cholesterol-lowering drugs have beneficial effect on reducing the risk of IHD

Elevated serum C-reactive protein

It may increase the likelihood of thrombus formation; Inflammation marker;

Diabetes elevates?

blood lipid levels and otherwise increases the risk of atherosclerosis.

SMOKING

The extent and severity of atherosclerosis are much greater in smokers than in non-smokers. Cigarette smoking is associated with higher risk of atherosclerosis, IHD and sudden cardiac death.

? lower CRP, but No evidence shows that lowering CRP reduces risk

Weight loss, smoking cessation, exercise and statins

There is increasing evidence that atherosclerosis is at least partially the result of:

(1) endothelial injury with leukocyte (lymphocyte and monocyte) adhesion and platelet adherence (2) smooth muscle cell emigration and proliferation (3) lipid engulfment of activated macrophages (4) subsequent development of an atherosclerotic plaque with lipid core

Deaths from myocardial infarction

(20-25 % of all deaths) are mostly related to underlying atherosclerosis.

Most, if not all, have one or more lesions causing at least ?

75% reduction in cross-sectional area, the point at which augmented blood flow provided by compensatory vasodilation no longer is able to assure even moderate increases in metabolic demand. of persons with CHD have coronary atherosclerosis.

DIABETES MELLITUS

Atherosclerosis develops at an early age in people with both insulin-dependent and non-insulin dependent diabetes mellitus.

AGE

Atherosclerosis is an age-related disease. Clinically significant lesions are found with increasing age. Fully-developed atheromatous plaques usually appear in 40s and beyond.

Symptoms include:

Claudication Sores, wounds, or ulcers that heal slowly or not at all ; Noticeable change in color (blueness or paleness) or temperature (coolness) when compared to the other limb ; Diminished hair and nail growth on affected limb and digits.

Hypertension

High blood pressure produces mechanical stress on the vessel endothelium. It is a major risk factor for atherosclerosis in all age groups and may be as important or more important than hypercholesterolemia after the age of 45 years.

major modifiable risks: Hypertension

HTN can increase the risk of IHD independently of other factors

The more advanced complicated lesions are characterized by

Hemorrhage Ulceration Scar tissue deposits

Changeable risk factors - life style risk factors

Hyperlipidemia Cigarette smoking Hypertension Diabetes mellitus Insufficient physical activity A stressful lifestyle Obesity

Major modifiable risk factors for IHD

Hyperlipidemia (more specifically, Hypercholesterolemia): Even in the absence of other risk factors, this risk factor is capable of inducing atherosclerotic lesions

Populations having hypercholesterolemia have higher mortality from

IHD.

Additional risk factors for IHD

Inflammation

Inflammation

Inflammation is present during ALL stages of atherogenesis and is intimately linked with atherosclerotic plaque development and rupture

? in many cases, is a marker of long-standing functional HTN

Left ventricular hypertrophy (LVH),

It strongly and independently predicts the risk of

MI, stroke, peripheral artery dz (PAD) and sudden cardiac death (even among seemingly healthy patients)

Pathogenesis of coronary heart disease (CHD)

Plaque disruption may occur with or without thrombosis. Platelets play a major role in linking plaque disruption to acute CHD.

Possible injurious agents are:

Products associated with smoking; Immune mechanisms; Mechanical stress, such as that associated with hypertension.