What are the other drivers of atherosclerotic cardiovascular disease besides primary (essential) hypertension?

Major Drivers of Atherosclerotic Cardiovascular Disease Beyond Primary Hypertension

Beyond hypertension, the primary drivers of ASCVD include dyslipidemia (particularly elevated LDL cholesterol), diabetes mellitus, cigarette smoking, obesity, physical inactivity, and unhealthy diet—all of which independently accelerate atherosclerotic plaque formation and cardiovascular events. 1

Modifiable Risk Factors

Lipid Abnormalities

• Dyslipidemia is present in approximately 63% of adults with hypertension and represents a critical independent driver of ASCVD through endothelial dysfunction and direct atherogenesis 1
• Elevated LDL cholesterol is considered the prime driver of atherogenesis, with other risk factors primarily accelerating atherosclerosis or precipitating its complications 1
• Low HDL cholesterol independently predicts CVD incidence and is classified as a major risk factor 1
• Elevated triglycerides contribute to the atherogenic lipid profile 1

Diabetes Mellitus

• Diabetes coexists in 15-27% of hypertensive patients, with approximately 71% of U.S. adults with diagnosed diabetes having concurrent hypertension 1
• Type 2 diabetes confers risk equivalent to established ASCVD in many patients, warranting intensive cholesterol-lowering therapy even without prior cardiovascular events 1
• Elevated glucose directly damages the endothelium and accelerates atherosclerotic plaque formation 2, 3

Tobacco Exposure

• Cigarette smoking and secondhand smoke exposure cause endothelial dysfunction, accelerate atherosclerosis, and increase platelet aggregation 1
• Smoking was the second leading preventable cause of death in the United States (after hypertension itself) 1
• Population studies demonstrate that without LDL elevation, smoking causes minimal coronary disease—highlighting the synergistic nature of risk factors 1

Obesity and Physical Inactivity

• Obesity affects 40-50% of individuals with hypertension, with approximately 36% of obese adults developing hypertension 1, 4
• Physical inactivity and low cardiorespiratory fitness markedly increase ASCVD risk through sympathetic nervous system activation and metabolic derangements 1, 4
• Body mass index and obesity independently correlate with atherosclerotic lesion progression in autopsy studies of young individuals 1

Dietary Factors

• Unhealthy diet patterns—particularly high sodium intake and fewer than 5 servings of fruits/vegetables daily—raise blood pressure and promote endothelial dysfunction 1, 4
• Atherogenic diet contributes to oxidative stress and lipid oxidation, key initiators of atherosclerotic plaque formation 5

Metabolic Syndrome

• Metabolic syndrome is present in approximately 40% of hypertensive patients, representing a cluster of obesity, insulin resistance, dyslipidemia, and elevated blood pressure 4, 6
• This syndrome substantially raises ASCVD risk when combined with diabetes 1

Non-Modifiable Risk Factors

Age and Sex

• Age >65 years is the strongest independent risk factor, with cardiovascular risk rising sharply after this threshold due to cumulative atherosclerotic burden 1, 4
• Male sex confers higher cardiovascular risk compared with premenopausal women of the same age 4
• Early-onset menopause in women increases cardiovascular risk 4

Genetic and Family History

• Family history of premature CVD markedly increases risk, with sibling history carrying stronger predictive value than parental history 1, 4
• Genetic factors influence lipid metabolism and atherosclerotic susceptibility 1

Chronic Kidney Disease

• CKD (eGFR <60 mL/min/1.73 m²) is present in approximately 16% of hypertensive adults, and 86% of CKD patients have hypertension 1, 4
• CKD independently accelerates atherosclerosis and increases cardiovascular mortality 1

Pathophysiological Mechanisms

Oxidative Stress and Inflammation

• Vascular production of reactive oxygen species (ROS) and lipid oxidation are the two major initiators of atherosclerotic CVD 5
• ROS causes rapid loss of endothelium-derived nitric oxide, resulting in endothelial dysfunction and activation of pro-inflammatory pathways 5, 7
• Chronic inflammatory diseases (COPD, rheumatoid arthritis, systemic lupus erythematosus, psoriasis) raise cardiovascular risk through sustained inflammatory activation 4

Plaque Formation and Burden

• Atherosclerotic plaque burden—not stenosis severity—is the main driver of ASCVD risk 8
• Oxidation of LDL in the vessel wall triggers an inflammatory cascade leading to foam cell formation and fatty streak development 5, 7
• Plaque rupture results in acute thrombotic events (myocardial infarction, stroke) 2, 7

Clinical Risk Stratification

Absolute Risk Assessment

• Among U.S. adults with hypertension, 41.7% have a 10-year CHD risk >20%, while only 18.4% have risk <10% 1
• The presence of multiple CVD risk factors results in multiplicative rather than additive increases in absolute risk 6
• In the ARIC study, 25% of cardiovascular events were attributable to hypertension alone, indicating that 75% involved other drivers 1

Population-Specific Considerations

• Hypertension-attributable events are higher in women (32%) than men (19%) and higher in Blacks (36%) than Whites (21%) 1
• Low socioeconomic or educational status is associated with higher ASCVD prevalence 4

Critical Clinical Pitfalls

• Never evaluate hypertension in isolation—simultaneously assess for coexisting diabetes, dyslipidemia, obesity, and kidney disease, as more than half of hypertensive patients have at least one additional cardiovascular risk factor 1, 4
• Population studies demonstrate that without some elevation of LDL cholesterol, other risk factors (smoking, hypertension, diabetes) cause minimal coronary disease, emphasizing the primacy of lipid management 1
• Psychosocial stress and psychiatric disorders elevate cardiovascular risk through neuroendocrine pathways and contribute to resistant hypertension via sympathetic activation 4
• Obstructive sleep apnea contributes to resistant hypertension and should be screened for in appropriate patients 4