Fixed
Age
Male
Positive family history
Deletion polymorphism in the ACE gene (DD)
Potentially Changeable with Treatment
Hyperlipidaemia
Cigarette smoking (tobacco)
Hypertension
Diabetes Mellitus
Lack of exercise
Blood coagulation factors — high fibrinogen, factor VII
C-reactive protein
Homocysteinaemia
Personality
Obesity
Gout
Soft water
Contraceptive pill
Heavy alcohol consumption
Risk Factors
1)Dyslipidemia
Age
Male
Positive family history
Deletion polymorphism in the ACE gene (DD)
Potentially Changeable with Treatment
Hyperlipidaemia
Cigarette smoking (tobacco)
Hypertension
Diabetes Mellitus
Lack of exercise
Blood coagulation factors — high fibrinogen, factor VII
C-reactive protein
Homocysteinaemia
Personality
Obesity
Gout
Soft water
Contraceptive pill
Heavy alcohol consumption
Risk Factors
1)Dyslipidemia
(See section on lipids and lipoproteins)
2)Hypertension
Hypertension continues to be a major, independent risk factor for CAD. It contributes to MI,cerebrovacsular accidents, congestive heart failure (CHF), peripheral vascular disease(PVD), and increased mortality among men and women of all ages and ethnic groups with
or without signs or symptoms of CAD.
Baseline blood pressure was shown to be strongly and independently related to increased risk of CAD. The relationship was shown to be stronger for systolic than diastolic blood pressure or pulse pressure, with the risk for CAD progressively increasing with an increase in systolic blood pressure.
Risk for cardiovascular disease among patients with hypertension is determined by the level of blood pressure and by the presence or absence of end-organ damage or other risk factors such as smoking, dyslipidemia, and diabetes.Antihypertensive treatment has proved beneficial in the prevention and reduction of the progression of hypertension, cerebrovascular accidents, CHF, renal insufficiency, and renal failure. (See section on hypertension)
3)Diabetes Mellitus
Insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are powerful, independent predictors of CAD. CAD is the leading cause of premature death among patients with IDDM or NIDDM, and accounts for almost 80 per cent of all deaths and hospital admission among persons with diabetes.At autopsy, most persons with diabetes are found to have a greater number of affected coronary vessels, more diffuse distribution of atherosclerosis and greater narrowing of the left main coronary artery than persons without diabetes.
Younger persons with IDDM are not spared. Severe and extensive luminal narrowing of large coronary arteries has been found in persons who had an onset of IDDM before 15 years of age and died before the age of 40 years. Persons with diabetes in the Framingham study were nearly four times more likely to have additional cardiovascular risk factors than persons without diabetes.
Diabetes is associated with metabolic abnormalities in the transport, composition, and metabolism of lipoproteins. These abnormalities are associated with the type of diabetes,4glycemia control, obesity, insulin, resistance, presence of diabetic nephropathy, and genetic factors. The dyslipidemia associated with the diabetes includes hypertriglyceridemia, low levels of high density lipoprotein (HDL), alterations in the composition of LDL, and increase in apo B and apo E. Lipid lowering therapy is considered critical in the management of NIDDM.
An elevated fasting plasma TG level is a hallmark of insulin resistance syndrome, a metabolic disorder characterized by hyperinsulinemia, glucose intolerance, decreased HDL-C level, and possibly central obesity and increased production of atherogenic, small, dense LDL particles Clinicians must consider hypertriglyceridemia a severe metabolic derangement that affects lipoprotein metabolism and coagulation. The defective lipoprotein metabolism involved in hypertriglyceridemia may produce a vascular environment predisposed to atherogenesis. In diabetics, hypertension should be aggressively treated to maintain a goal blood pressure of less than 130/80 mmHg.
Hyperinsulininemia is a clinically under recognized risk factor. There is growing evidence that patients who do not frank diabetes but have marked hyperinsulinemia or insulin resistance are at increased risk for CAD. Persons with a prediabetic condition may have an atherogenic pattern of risk factors before the onset of clinical diabetes.
4)Tobacco
Smoking, the single most preventable cause of death is a leading risk factor for CAD,cerebrovascular accident and PVD. Second hand smoke has been shown to increase risk of CAD. Exposure to second hand smoke increases by 30 per cent the risk of death by CAD.
5)Pathophysiology
Cigarette use activates platelets, increases circulating fibrinogen, increases heart rate, and elevates blood pressure. It appears to promote plaque disruption. A strong dose response relationship exists between smoke and CAD. Duration of smoking and the daily amount markedly influence risk of CAD. The adverse effect of smoking is present among men and women (but may be stronger in women) of all ages and ethnic groups with or without CAD.
Data suggest that risk for cardiac death is two to four times greater among current smokers than non smokers.Risk for cardiovascular disease begins to decline soon after smoking cessation, irrespective of age and sex. There is 50 per cent reduction in cardiovascular events within the first 2 to 4 years. It is thought to take as long as 20 years to regain baseline risk.
6)Obesity
Obesity is established as a leading predictor of CAD and is associated with several cardiovascular risk factors like cholesterol, hypertension and glucose intolerance which may increase all cause mortality and cardiovascular mortality. A positive association between BMI, TC and TG levels and a reduction in HDL-C levels has been documented in various age groups. Distribution of fat appears to be a more important predictor than total amount of fat because android fat patterns are more metabolically active and highly associated with dyslipidemia. Although waist to hip ratio have indicated a linear association between obesity and CAD, the waist to hip predictor of CAD, among obese persons, those with central adiposity are at particularly high risk.
BMI is recognized as a measurement of obesity and is defined as weight (kg)/height (m2).Guidelines define obesity as a BMI of 27.8 or more for men and 27.3 or more for women.Morbid obesity has been defined as a BMI of 31.1 for men and 32.3 for women. The Nurses health study showed that women with a BMI of 25 to 29 had an age adjusted relative risk of CAD of 1.8 compared with the leanest women. Women with morbid obesity (BMI>29) had a relative risk of CAD of 3.3.
Caloric restriction, behavior modification and exercise are the main treatment modalities for weight loss. The greatest weight losses have occurred with a combined regimen of diet and exercise rather than diet or exercise alone.
7)Sedantary Lifestyle
A sedantary life style is associated with increased risk for CAD. Sedentary persons have almost double the risk for CAD death of active persons.A sedentary lifestyle is associated with obesity, hypertension, NIDDM, and hypercholesterolemia, which point to the need for changes in exercise patterns.The American Heart Association recommends that every US adult accumulate 30 minutes or more moderate–intensity physical activity on most days of the week.Reviews on the effects of CAD rehabilitation on morbidity and mortality demonstrated reductions in all cause mortality of 20 per cent to 24 per cent and in CAD mortality 23 to 25 per cent.
Among patients with premature atherosclerosis the predictive value of these traditional cardiovascular risk factors is limited. Many patients with few traditional risk factors experience life threatening acute coronoary syndromes without prior symptoms of disease.Several potential risk factors have been identified that may enhance risk of CAD. These are levels of C-reactive proteins (CRP), lipoprotein LP (a), High Homocysteine, fibrinigen and possibly polymorphism of genes in the thrombospondin family.
C-reactive Protein (CRP)
CRP is a marker of systemic inflammation. As the role of inflammation in the initiation and progression of atherosclerosis becomes better understood, CRP has gained prominence as and important player in the assessment of cardiovascular risk. CRP has been shown to be an independent risk factor for the development of cardiovascular events in both apparently healthy individuals and in patients with established coronary heart disease.
Risk reduction and therapy
Weight loss by caloric restriction diets has been shown to decrease plasma CRP levels.Additional data indicate that women who exercise regularly have lower CRP levels compared with sedentary women. In primary prevention trials, pravastatin has been shown to reduce CRP levels by about 17 per cent in a manner independent of LDL lowering.
LP(a)
There is a striking amino acid sequence homology between apo A and plasminogen, suggesting that Lp (a) may have an important role in the connection between atherosclerosis and thrombosis.Lp (a) may be more predictive of CAD among younger men, women and persons with hyperlipidemia.The atherogenicity of Lp (a) may be modified through substantial reduction in LDL-C levels.Evidence seems to suggest that niacin and postmenopausal estrogen replacement therapy may lower Lp (a) level.
Homocysteinemia
Possible mechanisms of increased risk are that hyperhomocystinemia may impair release of nitric oxide form endothelial cells, stimulate proferation of atherogenic smooth muscle cells, and contribute to thrombogenesis through activation of proteinC. Homocysteine is derived from the sulfur-containing amino acid methionine and is metabolized through pathways associated with folic acid, vitamin B6, and vitamin B12 as cofactors.
Deficiencies in the cofactors lead to elevated serum concentrations of homocysteine, although profound deficiencies are rare among persons with high homocysteine CAD.Defects in the genes for 5,10-methylene tetrahydrofolate reductase (rare), cystathione B-synthase (0.5 per cent prevalence), methylene tetrahydrofolate homocysteine methyltransferase (rare), and methioine synthases (rare) can lead to increases in homocysteine.
Elevated plasma homocysteine levels (>15U/L) confer an independent risk for vascular disease,according to cross sectional and prospective case control studies.The relative risk for stroke and MI is approxiametly 2.0 for homocysteine levels greater than 15 Umol/L compared with those less than 10 umol/L.Secondary cause of increased homocysteine levels include age, male, sex, menopause, renal function and some medications (e.g., niacin, oral contraceptives with estrogen, phenytoin,methotrexate, theophyline). Thyroid function also is relevant.No data are available to establish the vascular benefits homocysteine values. Treatment suggestions include 400μg (i.e., typical amount in multivitamins) to 2 mg of folate daily. Second line therapy includes 10 to 25 mg of pyridoxine (vitamin B6) daily with or without 400 μg vitamin B12 for patients with vitamin B12 deficiency. Use of folate in the setting of vitamin B12
deficiency can lead to megaloblastic anemia crisis. This suggests that vitamin B12 levels, albeit of low yield, should be measured for persons with high homocysteine values before initation of folate therapy.
Fibrinogen
Fibrinogen, a large glycoprotein made mostly in the liver, is a clotting factor that activates thrombin, aggregates platelets (through the glycoprotein IIb/IIIa receptor), and stimulates smooth muscle proliferation. There is increasing evidence that fibrinogen is important in the development of premature atherosclerosis.
Several prospective studies, including the Framingham study, have shown an impressive relationship between plasma fibrinogen level and the occurrence of CAD and stroke. Plasma fibrinogen levels higher than 350 mg/dL are powerful independent risk factors for stroke and MI.
Factors associated with a decrease in fibrinogen level include smoking cessation, physical activity, moderate alcohol intake, normalization of body weight, and postmenopausal hormone replacement.Although no clinical trial has identified a drug that reduces fibrinogen level safely and selectively, the following medications have been shown to decrease fibrinogen level in various clinical settings: fibrates, pentoxifylline, ticlopidine, n-3 polyunsaturated fatty acids, and anabolic steroids.
Thrombospondin Polymorphisms
Thrombospondin polymorphisms may present an initial insight into our understanding of the genetic contribution to coronary atherosclerosis. Although a familial linkage for CAD is well documented, little is known about the causative factors leading to premature events in such families.Thrombospondins are a family of glycoproteins that play a pivotal role in cell adhesion, vascular
integrity, and thrombosis. Variations in thrombospondin genes have been linked to premature atherosclerosis and MI and may provide an example of how genetic polymorphisms can lead to the development of coronary disease.
The etiology of Coronary Artery Disease (CAD) is multifactorial. Coronary atherosclerosis is a complex process with inflammation characterized by the accumulation of lipid, macrophages and smooth muscle cells in intimal plaques in the large and medium-sized epicardial coronary arteries. The vascular endothelium plays a critical role in maintaining vascular integrity and homeostasis. Mechanical shear stresses (e.g. from hypertension), biochemical abnormalities (e.g. elevated and modified Low density lipoprotein (LDL), diabetes mellitus, elevated plasma homocysteine, immunological factors (e.g. infection such as Chlamydia pneumoniae and Helicobactor pylori) and genetic alteration may contribute to the initial endothelial ‘injury’ or dysfunction, which is believed to trigger atherogenesis. The development of atherosclerosis follows the endothelial dysfunction, with increased permeability to and accumulation of oxidized lipoproteins, which are taken up by macrophages at focal sites within the endothelium to produce lipid-laden foam cells. Macroscopically, these lesions are seen as flat yellow dots or lines on the endothelium of the artery and are known as ‘fatty streaks’. The ‘fatty streak’ progresses with the appearance of extracellular lipid within the endothelium (‘transitional plaque’). Release of cytokines such as platelet-derived growth factor and transforming growth factor-β (TGF-β) by monocytes, macrophages or the damaged endothelium promotes further accumulation of macrophages as well as smooth muscle cell migration and proliferation. The proliferation of smooth muscle with the formation of a layer of cells covering the extracellular lipid, separates it from the adaptive smooth muscle thickening the endothelium. Collagen is produced in larger and larger quantities by the smooth muscle thickening in the endothelium and the whole sequence of events cumulates as an ‘advanced or raised fibrolipid plaque’. The ‘advanced plaque’ may grow slowly and encroach on the lumen or become unstable, undergo thrombosis and produce obstruction (‘complicated plaque’).
A 50 per cent reduction in lumenal diameter (producing a reduction in lumenal cross-sectional area of approximately 70 per cent) causes a haemodynamically significant stenosis. At this point the smaller distal intramyocardial arteries and arterioles are maximally dilated (coronary flow reserve is near zero), and any increase in myocardial oxygen demand provokes ischaemia.
2)Hypertension
Hypertension continues to be a major, independent risk factor for CAD. It contributes to MI,cerebrovacsular accidents, congestive heart failure (CHF), peripheral vascular disease(PVD), and increased mortality among men and women of all ages and ethnic groups with
or without signs or symptoms of CAD.
Baseline blood pressure was shown to be strongly and independently related to increased risk of CAD. The relationship was shown to be stronger for systolic than diastolic blood pressure or pulse pressure, with the risk for CAD progressively increasing with an increase in systolic blood pressure.
Risk for cardiovascular disease among patients with hypertension is determined by the level of blood pressure and by the presence or absence of end-organ damage or other risk factors such as smoking, dyslipidemia, and diabetes.Antihypertensive treatment has proved beneficial in the prevention and reduction of the progression of hypertension, cerebrovascular accidents, CHF, renal insufficiency, and renal failure. (See section on hypertension)
3)Diabetes Mellitus
Insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are powerful, independent predictors of CAD. CAD is the leading cause of premature death among patients with IDDM or NIDDM, and accounts for almost 80 per cent of all deaths and hospital admission among persons with diabetes.At autopsy, most persons with diabetes are found to have a greater number of affected coronary vessels, more diffuse distribution of atherosclerosis and greater narrowing of the left main coronary artery than persons without diabetes.
Younger persons with IDDM are not spared. Severe and extensive luminal narrowing of large coronary arteries has been found in persons who had an onset of IDDM before 15 years of age and died before the age of 40 years. Persons with diabetes in the Framingham study were nearly four times more likely to have additional cardiovascular risk factors than persons without diabetes.
Diabetes is associated with metabolic abnormalities in the transport, composition, and metabolism of lipoproteins. These abnormalities are associated with the type of diabetes,4glycemia control, obesity, insulin, resistance, presence of diabetic nephropathy, and genetic factors. The dyslipidemia associated with the diabetes includes hypertriglyceridemia, low levels of high density lipoprotein (HDL), alterations in the composition of LDL, and increase in apo B and apo E. Lipid lowering therapy is considered critical in the management of NIDDM.
An elevated fasting plasma TG level is a hallmark of insulin resistance syndrome, a metabolic disorder characterized by hyperinsulinemia, glucose intolerance, decreased HDL-C level, and possibly central obesity and increased production of atherogenic, small, dense LDL particles Clinicians must consider hypertriglyceridemia a severe metabolic derangement that affects lipoprotein metabolism and coagulation. The defective lipoprotein metabolism involved in hypertriglyceridemia may produce a vascular environment predisposed to atherogenesis. In diabetics, hypertension should be aggressively treated to maintain a goal blood pressure of less than 130/80 mmHg.
Hyperinsulininemia is a clinically under recognized risk factor. There is growing evidence that patients who do not frank diabetes but have marked hyperinsulinemia or insulin resistance are at increased risk for CAD. Persons with a prediabetic condition may have an atherogenic pattern of risk factors before the onset of clinical diabetes.
4)Tobacco
Smoking, the single most preventable cause of death is a leading risk factor for CAD,cerebrovascular accident and PVD. Second hand smoke has been shown to increase risk of CAD. Exposure to second hand smoke increases by 30 per cent the risk of death by CAD.
5)Pathophysiology
Cigarette use activates platelets, increases circulating fibrinogen, increases heart rate, and elevates blood pressure. It appears to promote plaque disruption. A strong dose response relationship exists between smoke and CAD. Duration of smoking and the daily amount markedly influence risk of CAD. The adverse effect of smoking is present among men and women (but may be stronger in women) of all ages and ethnic groups with or without CAD.
Data suggest that risk for cardiac death is two to four times greater among current smokers than non smokers.Risk for cardiovascular disease begins to decline soon after smoking cessation, irrespective of age and sex. There is 50 per cent reduction in cardiovascular events within the first 2 to 4 years. It is thought to take as long as 20 years to regain baseline risk.
6)Obesity
Obesity is established as a leading predictor of CAD and is associated with several cardiovascular risk factors like cholesterol, hypertension and glucose intolerance which may increase all cause mortality and cardiovascular mortality. A positive association between BMI, TC and TG levels and a reduction in HDL-C levels has been documented in various age groups. Distribution of fat appears to be a more important predictor than total amount of fat because android fat patterns are more metabolically active and highly associated with dyslipidemia. Although waist to hip ratio have indicated a linear association between obesity and CAD, the waist to hip predictor of CAD, among obese persons, those with central adiposity are at particularly high risk.
BMI is recognized as a measurement of obesity and is defined as weight (kg)/height (m2).Guidelines define obesity as a BMI of 27.8 or more for men and 27.3 or more for women.Morbid obesity has been defined as a BMI of 31.1 for men and 32.3 for women. The Nurses health study showed that women with a BMI of 25 to 29 had an age adjusted relative risk of CAD of 1.8 compared with the leanest women. Women with morbid obesity (BMI>29) had a relative risk of CAD of 3.3.
Caloric restriction, behavior modification and exercise are the main treatment modalities for weight loss. The greatest weight losses have occurred with a combined regimen of diet and exercise rather than diet or exercise alone.
7)Sedantary Lifestyle
A sedantary life style is associated with increased risk for CAD. Sedentary persons have almost double the risk for CAD death of active persons.A sedentary lifestyle is associated with obesity, hypertension, NIDDM, and hypercholesterolemia, which point to the need for changes in exercise patterns.The American Heart Association recommends that every US adult accumulate 30 minutes or more moderate–intensity physical activity on most days of the week.Reviews on the effects of CAD rehabilitation on morbidity and mortality demonstrated reductions in all cause mortality of 20 per cent to 24 per cent and in CAD mortality 23 to 25 per cent.
Among patients with premature atherosclerosis the predictive value of these traditional cardiovascular risk factors is limited. Many patients with few traditional risk factors experience life threatening acute coronoary syndromes without prior symptoms of disease.Several potential risk factors have been identified that may enhance risk of CAD. These are levels of C-reactive proteins (CRP), lipoprotein LP (a), High Homocysteine, fibrinigen and possibly polymorphism of genes in the thrombospondin family.
C-reactive Protein (CRP)
CRP is a marker of systemic inflammation. As the role of inflammation in the initiation and progression of atherosclerosis becomes better understood, CRP has gained prominence as and important player in the assessment of cardiovascular risk. CRP has been shown to be an independent risk factor for the development of cardiovascular events in both apparently healthy individuals and in patients with established coronary heart disease.
Risk reduction and therapy
Weight loss by caloric restriction diets has been shown to decrease plasma CRP levels.Additional data indicate that women who exercise regularly have lower CRP levels compared with sedentary women. In primary prevention trials, pravastatin has been shown to reduce CRP levels by about 17 per cent in a manner independent of LDL lowering.
LP(a)
There is a striking amino acid sequence homology between apo A and plasminogen, suggesting that Lp (a) may have an important role in the connection between atherosclerosis and thrombosis.Lp (a) may be more predictive of CAD among younger men, women and persons with hyperlipidemia.The atherogenicity of Lp (a) may be modified through substantial reduction in LDL-C levels.Evidence seems to suggest that niacin and postmenopausal estrogen replacement therapy may lower Lp (a) level.
Homocysteinemia
Possible mechanisms of increased risk are that hyperhomocystinemia may impair release of nitric oxide form endothelial cells, stimulate proferation of atherogenic smooth muscle cells, and contribute to thrombogenesis through activation of proteinC. Homocysteine is derived from the sulfur-containing amino acid methionine and is metabolized through pathways associated with folic acid, vitamin B6, and vitamin B12 as cofactors.
Deficiencies in the cofactors lead to elevated serum concentrations of homocysteine, although profound deficiencies are rare among persons with high homocysteine CAD.Defects in the genes for 5,10-methylene tetrahydrofolate reductase (rare), cystathione B-synthase (0.5 per cent prevalence), methylene tetrahydrofolate homocysteine methyltransferase (rare), and methioine synthases (rare) can lead to increases in homocysteine.
Elevated plasma homocysteine levels (>15U/L) confer an independent risk for vascular disease,according to cross sectional and prospective case control studies.The relative risk for stroke and MI is approxiametly 2.0 for homocysteine levels greater than 15 Umol/L compared with those less than 10 umol/L.Secondary cause of increased homocysteine levels include age, male, sex, menopause, renal function and some medications (e.g., niacin, oral contraceptives with estrogen, phenytoin,methotrexate, theophyline). Thyroid function also is relevant.No data are available to establish the vascular benefits homocysteine values. Treatment suggestions include 400μg (i.e., typical amount in multivitamins) to 2 mg of folate daily. Second line therapy includes 10 to 25 mg of pyridoxine (vitamin B6) daily with or without 400 μg vitamin B12 for patients with vitamin B12 deficiency. Use of folate in the setting of vitamin B12
deficiency can lead to megaloblastic anemia crisis. This suggests that vitamin B12 levels, albeit of low yield, should be measured for persons with high homocysteine values before initation of folate therapy.
Fibrinogen
Fibrinogen, a large glycoprotein made mostly in the liver, is a clotting factor that activates thrombin, aggregates platelets (through the glycoprotein IIb/IIIa receptor), and stimulates smooth muscle proliferation. There is increasing evidence that fibrinogen is important in the development of premature atherosclerosis.
Several prospective studies, including the Framingham study, have shown an impressive relationship between plasma fibrinogen level and the occurrence of CAD and stroke. Plasma fibrinogen levels higher than 350 mg/dL are powerful independent risk factors for stroke and MI.
Factors associated with a decrease in fibrinogen level include smoking cessation, physical activity, moderate alcohol intake, normalization of body weight, and postmenopausal hormone replacement.Although no clinical trial has identified a drug that reduces fibrinogen level safely and selectively, the following medications have been shown to decrease fibrinogen level in various clinical settings: fibrates, pentoxifylline, ticlopidine, n-3 polyunsaturated fatty acids, and anabolic steroids.
Thrombospondin Polymorphisms
Thrombospondin polymorphisms may present an initial insight into our understanding of the genetic contribution to coronary atherosclerosis. Although a familial linkage for CAD is well documented, little is known about the causative factors leading to premature events in such families.Thrombospondins are a family of glycoproteins that play a pivotal role in cell adhesion, vascular
integrity, and thrombosis. Variations in thrombospondin genes have been linked to premature atherosclerosis and MI and may provide an example of how genetic polymorphisms can lead to the development of coronary disease.
The etiology of Coronary Artery Disease (CAD) is multifactorial. Coronary atherosclerosis is a complex process with inflammation characterized by the accumulation of lipid, macrophages and smooth muscle cells in intimal plaques in the large and medium-sized epicardial coronary arteries. The vascular endothelium plays a critical role in maintaining vascular integrity and homeostasis. Mechanical shear stresses (e.g. from hypertension), biochemical abnormalities (e.g. elevated and modified Low density lipoprotein (LDL), diabetes mellitus, elevated plasma homocysteine, immunological factors (e.g. infection such as Chlamydia pneumoniae and Helicobactor pylori) and genetic alteration may contribute to the initial endothelial ‘injury’ or dysfunction, which is believed to trigger atherogenesis. The development of atherosclerosis follows the endothelial dysfunction, with increased permeability to and accumulation of oxidized lipoproteins, which are taken up by macrophages at focal sites within the endothelium to produce lipid-laden foam cells. Macroscopically, these lesions are seen as flat yellow dots or lines on the endothelium of the artery and are known as ‘fatty streaks’. The ‘fatty streak’ progresses with the appearance of extracellular lipid within the endothelium (‘transitional plaque’). Release of cytokines such as platelet-derived growth factor and transforming growth factor-β (TGF-β) by monocytes, macrophages or the damaged endothelium promotes further accumulation of macrophages as well as smooth muscle cell migration and proliferation. The proliferation of smooth muscle with the formation of a layer of cells covering the extracellular lipid, separates it from the adaptive smooth muscle thickening the endothelium. Collagen is produced in larger and larger quantities by the smooth muscle thickening in the endothelium and the whole sequence of events cumulates as an ‘advanced or raised fibrolipid plaque’. The ‘advanced plaque’ may grow slowly and encroach on the lumen or become unstable, undergo thrombosis and produce obstruction (‘complicated plaque’).
A 50 per cent reduction in lumenal diameter (producing a reduction in lumenal cross-sectional area of approximately 70 per cent) causes a haemodynamically significant stenosis. At this point the smaller distal intramyocardial arteries and arterioles are maximally dilated (coronary flow reserve is near zero), and any increase in myocardial oxygen demand provokes ischaemia.
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