What are the risk factors for atherosclerosis?

Risk Factors for Atherosclerosis

Atherosclerosis develops through the interaction of major modifiable risk factors—tobacco smoking, elevated LDL cholesterol, hypertension, diabetes mellitus, and low HDL cholesterol—with underlying factors including obesity, physical inactivity, and atherogenic diet, all of which should be aggressively targeted for prevention. 1

Major Risk Factors (Direct Causes)

These factors directly cause atherosclerotic disease and independently predict cardiovascular events:

Modifiable Major Risk Factors

• Tobacco smoking is a direct cause of atherosclerosis, with pathological studies demonstrating positive correlation between smoking (measured by thiocyanate concentration) and both severity and extent of atherosclerotic lesions in young adults 1
• Elevated LDL cholesterol directly causes atherosclerosis—every 30 mg/dL increase in non-HDL cholesterol associates with visible incremental increases in atherosclerosis extent and severity 1
• Hypertension (high blood pressure) is both a direct cause and the most widespread modifiable risk factor, with systolic and diastolic blood pressure correlating positively with atherosclerotic lesions at autopsy 1, 2
• Diabetes mellitus significantly increases risk and is considered a coronary heart disease risk equivalent, with strong relationships found between diabetes and atherosclerotic severity 1, 3
• Low HDL cholesterol independently predicts cardiovascular disease incidence and is considered a major risk factor despite being a marker rather than a direct cause 1, 3

Non-Modifiable Major Risk Factors

• Advancing age independently predicts cardiovascular disease by reflecting accumulated atherosclerosis over decades 1, 3
• Male gender confers higher risk, with 81% of high-risk patients in major trials being male 4
• Genetic factors and family history of premature cardiovascular disease increase risk, with children and young adults with family history showing increased carotid intima-media thickness and coronary calcium 1
• Race/ethnicity influences risk, with Asians showing 72% increased hemorrhagic stroke risk per 10 mmHg systolic blood pressure increase compared to 49% in Australians 5

Underlying Risk Factors

These factors affect risk both through major risk factors and through independent mechanisms:

• Obesity and overweight track more strongly than any other risk factor from childhood to adulthood, with 84% of children at 95th-99th BMI percentile becoming obese adults 1, 3
• Physical inactivity is highly prevalent (33.6% of adolescents have low cardiorespiratory fitness) and associates with elevated cholesterol, blood pressure, and reduced HDL 1, 3
• Atherogenic diet high in saturated fats and low in fruits/vegetables increases risk through effects on lipid metabolism and glucose tolerance 1, 3
• Socioeconomic and psychosocial stress independently contribute to atherosclerosis risk 1, 3

Risk Factor Clustering and Multiplicative Effects

The presence of multiple risk factors exponentially increases atherosclerosis risk more than any single severe risk factor alone. 1

• Pathological studies demonstrate striking increases in both severity and extent of atherosclerosis as the number of risk factors increases, even in young individuals 1
• The metabolic syndrome (obesity with insulin resistance, elevated triglycerides, reduced HDL, and elevated blood pressure) represents the most prevalent high-risk combination in contemporary populations 1
• Tobacco use combined with one other risk factor creates particularly high risk 1
• Conversely, absence of risk factors associates with virtual absence of advanced atherosclerotic lesions even in older subjects 1

Evidence from Pathological Studies

The relationship between risk factors and atherosclerosis is definitively established through autopsy studies:

• The PDAY study of 15- to 34-year-olds who died accidentally found strong relationships between atherosclerotic severity/extent and age, HDL cholesterol, hypertension, tobacco use, diabetes, and obesity in men 1
• The Bogalusa Heart Study demonstrated that measured cardiovascular risk factors (lipids, blood pressure, BMI, tobacco) in living children strongly correlated with atherosclerosis extent at autopsy after accidental death 1
• Between 70-90% of atherosclerotic disease risk can be explained by conventional risk factors: smoking, abnormal lipids, hypertension, diabetes, obesity, psychosocial factors, unhealthy diet, and physical inactivity 6

Risk Factor Tracking from Childhood

Risk factors measured in childhood predict adult atherosclerosis better than risk factors measured in adulthood:

• Obesity tracking correlation from childhood to adulthood is strongest among all risk factors, with all children at 99th BMI percentile becoming obese adults 1
• Cholesterol and blood pressure show tracking correlation coefficients of 0.4 from ages 5-10 years to 20-30 years later 1
• Risk factors measured in youth (LDL cholesterol, obesity, hypertension, tobacco, diabetes) correlate with subclinical atherosclerosis measures in adulthood 1

Common Pitfalls in Risk Assessment

• Do not ignore single risk factors if severe and sustained—they can lead to premature cardiovascular disease despite lower short-term risk calculations 1
• Do not underestimate total risk in asymptomatic patients with multiple risk factors—they may carry risk equivalent to patients with established cardiovascular disease, particularly those with type 2 diabetes 1
• Do not apply risk prediction equations uniformly across populations—underlying risk factors cause variability in absolute risk between populations despite similar relative predictive power of major risk factors 1
• Recognize that peripheral atherosclerotic disease places patients in high-risk category for coronary events regardless of other factors 1, 3