ARTERIOSCLEROSIS

Arteriosclerosis(hardening of the arteries) is characterized by arterial wall thickening and may

be caused by:
1. Arteriolosclerosis: It affects small arteries and arterioles.
2. Mnckeberg medial sclerosis: It is characterized by deposition of calcium in muscular
arteries seen in old age (above 50 years).
3. Atherosclerosis: It is the most frequent and important disease of intima.
ATHEROSCLEROSIS
Atherosclerosis is primarily a progressive disease of intima involving large and medium-sized
elastic and muscular arteries. It is characterized by focal lipid-rich intimal lesions called
atheromas (atherosclerotic plaques).
Epidemiology: Atherosclerosis is a worldwide disease seen in both developed and developing
countries.
Risk Factors for Atherosclerosis
Classification of risk factors: The risk factors may be broadly classified as modifiable,
nonmodifiable and additional.
A. Modifiable major risk factors
Hyperlipidemia Hypertension Cigarette smoking Diabetes mellitus
B. Nonmodifiable risk factors
Increasing age Male gender Family history Genetic abnormalities
C. Additional risk factors
Inflammation CRP level Hyperhomocystinemia Metabolic syndrome
Lipoprotein (a) Raised procoagulant levels Inadequate physical activity
Stressful lifestyle Obesity Alcohol
Modifiable Risk Factors In IHD
1) hyperlipidemia, 2) hypertension, 3) cigarette smoking, 4) diabetes.
1. Hyperlipidemia: Increase in the serum lipids mainly cholesterol (hypercholesterolemia) is a
major modifiable risk factor. The major components of lipids in the blood:
Low-density lipoprotein (LDL)known as bad cholesterol is one of the components of serum
lipid and its higher level is associated with increased risk of atherosclerosis.
High-density lipoprotein (HDL) known asgood cholesterol and its higher levels are
associated with decreased risk.
HDL mobilizes cholesterol from atheroma and excretes it through bile in liver.
Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking
lower it.
Serum cholesterol level: Normal range is 140 to 240 mg/dL. Serum cholesterol is strongly
related to the dietary intake of saturated fat(in the absence of genetic disorders of lipid
metabolism). Risk of atherosclerosis increases with increasing serum cholesterol
concentrations and lowering serum cholesterol concentrations reduces the risk. The risk
of atherosclerosis can be reduced by lowering LDL or total plasma cholesterol, and/or
raising serum HDL. This can be achieved either by dietary modification or by treatment
with cholesterol-lowering drugs.
Diet which raises blood cholesterol:
Diet high in cholesterol and saturated fats(e.g. egg yolks, animal fats, and butter).
Transunsaturated fats produced by artificial hydrogenation of polyunsaturated oils .
Diet which lower blood cholesterol: Diets low in cholesterol and/or with higher
ratios of polyunsaturated fats.
Omega-3 fatty acids(high in fish and fish oils).
Cholesterol-lowering drug: e.g. statins.
2. Hypertension:It is one of the major risk factor.
Incidence of atherosclerosis increases as BP rises, and this excess risk is related to both
systolic and diastolic levels of blood pressure.
 Control of hypertension with antihypertensive therapy reduces the risk of myocardial
infarction and stroke.
3. Cigarette smoking: It is the most important avoidable cause of atherosclerosis.
Atherosclerosis is more severe and extensive among smokers than in nonsmokers. This may be
the reason for the increased incidence and severity of atherosclerosis in men compared to
women. There is a strong dose-linked relationship between cigarette smoking and ischemic heart
disease. Cessation of smoking reduces the risk.
4. Diabetes mellitus: It is a potent risk factor for atherosclerosis.
Diabetes is associated with hypercholesterolemia increases the risk of atherosclerosis. The
incidence of myocardial infarction and other atherosclerotic vascular diseases (strokes, gangrene
of the lower extremities) is more in diabetics than in nondiabetics.
Nonmodifiable/Constitutional Risk Factors
1. Increasing age: Age is the most powerful independent risk factor. Clinical manifestation of
atherosclerosis is usually observed after middle age and the lesions progressively rise with each
decade.
2. Sex: Premenopausal women have lower incidence of atherosclerosis-related diseases
compared to males of the same age group. However, after menopause this sex difference
disappears. This may be due to protective role of estrogen. However, hormone replacement
therapy has no role in the prevention of coronary heart disease.
3. Family history: Atherosclerotic disease often runs in families. Familial predisposition is
usually multifactorial, due to genetic, environmental and lifestyle factors.
4. Genetic abnormalities: Most common inherited modifiable risk factors (hypertension,
hyperlipidemia, and diabetes mellitus) are polygenic. Mendelian disorders, such as familial
hypercholesterolemia are associated with atherosclerosis.
Additional Risk Factors
1. Inflammation: It plays a role in atherogenesis and may be a risk factor.
2. C-reactive protein (CRP) level: It is a marker of systemic inflammation and predicts the
riskof atherosclerosis related diseases.
3. Hyperhomocysteinemia:It is a rare autosomal recessive inborn error and results in elevated
circulating homocysteine premature and severe atherosclerosis.
4. Metabolic syndrome: It is associated with central obesity, insulin resistance and is known
risk factors for atherosclerosis.
5. Increased Lipoprotein (a) Lp(a) levels: It is an altered form of LDL and is associated
with increased risk. Lp(a) has structural similarity to plasminogen. It competes with
plasminogen in clots and decreases the ability to form and clear clots. Increased Lp(a) levels are
associated with higher risk of atherosclerosis, independent of total cholesterol or
LDL levels.
6. Raised procoagulant levels: These procoagulants include: thrombin (procoagulant and
proinflammatory action), platelet activation and raised fibrinogen increased risk.
7. Inadequate physical activity: Lack of exercise doubles the risk.
8. Stressful lifestyle: Certain personality associated with competitive, stressful life (type A
personality) is associated with an increased risk of coronary disease.
9. Obesity: It is often associated with hypertension, diabetes mellitus, hypertriglyceridemia,
decreased HDL and physical inactivity.
10. Alcohol consumption:It is associated with reduced rates of coronary artery disease.
Pathogenesis of Atherosclerosis
There are several theories proposed for pathogenesis of atherosclerosis and few of them are:
A. Insudation hypothesis: According to this, the focal accumulation of lipid in a vessel wall is
due to insudation (transport) of plasma lipoproteins across an intact endothelium.
B. Encrustation hypothesis: This hypothesis states that small mural thrombi are formed at
the site of endothelial damage. These thrombi become organized and form plaque.
C. Monoclonal hypothesis: The monoclonal concept postulates that single clone (monoclonal)
of smooth muscle migrate from the underlying media into the intima and then proliferate. The
stimulus for monoclonal proliferation may be metabolites of cholesterol.
D. Response-to-injury hypothesis: This is the currently favored hypothesis.
Response-to-Injury Hypothesis
According to this theory, atherosclerosis develops as a chronic(inflammatory and healing)
response of the arterial wall to the endothelial injury.
1. Endothelial injury and dysfunction:
Causes of endothelial injury/dysfunction:
Hemodynamic disturbances: Plaques develop in regions having disturbed blood flow such as
origin or ostia of vessels, branching points of vessel and along the posterior wall of the
abdominal aorta.
Risk factors: Hyperlipidemia, hypertension, toxins from cigarette smoke, and advanced
glycation end products in diabetescan produce endothelial injury/dysfunction.
Others: Homocysteine, immunocomplexes, and infectious agents.
Effect of endothelial injury or dysfunction:
Leukocyte (mainly monocyte) adhesion to endothelium
Increased vascular permeability
Platelet adhesion and thrombosis
Movement of low-density lipoproteins (LDLs) across the endothelium into the intima.
2. Migration of monocytes into the intima:
Theleukocytes, which adhere at the site of endothelial injury/dysfunction, are mainly
monocytes and T lymphocytes. Accumulation of leukocytes initiates the atheroma formation.
Locally produced chemokines allows penetration of the endothelial layer by monocytes and
lymphocytes.The monocytes migrate into the intima where they are transformed into
macrophages.
3. Lipid accumulation in the intima:
Endothelial dysfunction also allows penetration of endothelium by lipoproteins (mainly
LDL)from blood LDLs accumulate within the intimaof the vessel.
LDL is oxidized by the action of oxygen free radicals produced locally by monocytes/
macrophages and dysfunctional endothelial cells.
4. Formation of foam cells and activation of macrophages:
Macrophage engulfs lipoproteins and oxidized LDL from the extracellular space in the
intima. Their cytoplasm becomes foamy and these cells are called as foam cells.
Some foam cells may undergo apoptosis release lipids form lipid-rich center,
often called the necrotic core in atheromatous plaques.
Oxidized LDL is cytotoxic to endothelial cells and smooth musclecells and can cause
endothelial dysfunction.
Oxidized LDL causes activated macrophages which produce:
i. Cytokine (e.g. TNF)increases leukocyte adhesion.
ii. Chemokines (e.g. monocyte chemotactic protein 1)accumulation of monocytes.
iii. Reactive oxygen speciesaggravate oxidation of LDL.
iv. Growth factorsstimulate smooth muscle cell proliferation and ECM synthesis.
5. Migration of smooth muscle cells into the intima:
Growth factor (e.g. platelet-derived growth factor) from activated platelets, macrophages, and
endothelial cells causes migration of smooth muscle cells either from the
arterial media or from circulating precursors.
6. Smooth muscle cell proliferation in the intima and ECM production:
Smooth muscle cells proliferate, and produce ECM (mainly collagen and proteoglycans).
Many growth factorscan cause smooth muscle cell proliferation.These includes:
PDGF, fibroblast growth factor (FGF) and transforming growth factor (TGF-).
Smooth muscle cell may also engulf oxidized LDL and form foam cells.
7. Lipid accumulation
 Occurs both intracellularly (within macrophages and smooth muscle cells) and
extracellularly.
Extracellular lipidis derived from insudationfrom the vessel lumen (mainly in the
presence of hypercholesterolemia) and also fromnecrotic foam cells.
Cholesterol in the plaque is also due to an imbalance between influx and efflux. Highdensity
lipoprotein (HDL) probably transfers cholesterol from these lesions and leads to its excretion by
liver.