What Causes Atherosclerosis
Atherosclerosis is directly caused by elevated LDL cholesterol, with every 30 mg/dL increase in non-HDL cholesterol producing visible incremental increases in atherosclerotic lesion extent and severity. 1
Primary Causative Factors
The development of atherosclerotic lesions requires the following established risk factors, all of which have been demonstrated through pathological autopsy studies to correlate positively and significantly with both presence and extent of atherosclerotic lesions:
Direct Causes
Elevated LDL cholesterol is the fundamental requirement for atherosclerosis development, with genetic disorders providing the biological model—homozygous hypercholesterolemia (LDL >800 mg/dL) causes coronary events in the first decade of life, while heterozygous hypercholesterolemia (LDL typically 200 mg/dL) causes clinical coronary events in 50% of men and 25% of women by age 50. 2
Tobacco smoking directly causes atherosclerosis, with pathological studies demonstrating positive correlation between smoking and both severity and extent of atherosclerotic lesions in young adults. 1
Hypertension 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 The American Heart Association identifies hypertension as the leading modifiable CVD risk factor, second only to cigarette smoking as a preventable cause of death. 3
Diabetes mellitus significantly increases risk and is considered a coronary heart disease risk equivalent, with strong relationships found between diabetes and atherosclerotic severity in pathological studies. 1
Contributing Factors
Low HDL cholesterol independently predicts cardiovascular disease incidence and is considered a major risk factor, though it functions as a marker rather than a direct cause. 1
Obesity tracks more strongly than any other risk factor from childhood to adulthood, with 84% of children at 95th-99th BMI percentile becoming obese adults. 1 Obesity is strongly associated with hypertension, dyslipidemia, and type 2 diabetes beginning in childhood. 2
Physical inactivity is highly prevalent and associates with elevated cholesterol, blood pressure, and reduced HDL. 1
Atherogenic diet high in saturated fats and low in fruits/vegetables increases risk through effects on lipid metabolism and glucose tolerance. 1
Pathophysiological Mechanisms
The atherosclerotic process begins when foam cells (lipid-laden macrophages) break down and release lipids into the extracellular space, creating a primarily acellular lipid pool. 4 Simultaneously, activated smooth muscle cells migrate into the intimal layer, multiply, and dramatically increase collagen production to maintain the fibrous cap. 4
High cholesterol levels, particularly elevated LDL cholesterol, lead to endothelial dysfunction and arterial stiffness. 5 Uncontrolled cholesterol and lipid accumulation in macrophages and smooth muscle cells leads to foam cell formation and progression of the atherosclerotic plaque. 6
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 from the Bogalusa Heart Study demonstrate striking increases in both severity and extent of atherosclerosis as the number of risk factors increases, even in young individuals. 1
The most prevalent multiple-risk combinations include:
- Tobacco use with one other risk factor 2
- Obesity associated with insulin resistance, elevated triglycerides, reduced HDL cholesterol, and elevated blood pressure (metabolic syndrome) 2
- Low cardiorespiratory fitness (identified in 33.6% of adolescents) with overweight/obesity, elevated total cholesterol, systolic blood pressure, and reduced HDL 2
Among adults with hypertension, 49.5% are obese, resulting in high absolute risks for cardiovascular events, with 41.7% having a 10-year CHD risk >20%. 3 Approximately 63.2% of adults with hypertension also have hypercholesterolemia. 5
Evidence from Pathological Studies
The PDAY (Pathobiological Determinants of Atherosclerosis in Youth) study 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 in living children strongly correlated with atherosclerosis extent at autopsy after accidental death. 1
Pathological studies have shown that both presence and extent of atherosclerotic lesions at autopsy after unexpected death of children and young adults correlate positively and significantly with established risk factors: LDL cholesterol, triglycerides, systolic and diastolic blood pressure, body mass index, and presence of cigarette smoking. 2
Critical Pitfalls to Avoid
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
Recognize that peripheral atherosclerotic disease places patients in high-risk category for coronary events regardless of other factors. 1