What study found atherosclerosis in metabolically healthy people with elevated Low-Density Lipoprotein (LDL)?

The PESA Study Found Atherosclerosis in Metabolically Healthy People with Normal LDL Cholesterol

The 2017 PESA (Progression of Early Subclinical Atherosclerosis) study found that subclinical atherosclerosis was present in nearly 50% of individuals with normal LDL cholesterol levels and no conventional cardiovascular risk factors. 1

Key Findings of the PESA Study

The PESA study examined 1,779 middle-aged individuals (mean age 45 years) who were free from conventional cardiovascular risk factors:

• Subclinical atherosclerosis was detected in 49.7% of participants despite having no traditional risk factors
• LDL cholesterol, even at levels currently considered normal, was independently associated with both presence and extent of atherosclerosis
• For every 10 mg/dL increase in LDL-C, there was a 14-18% higher odds of having atherosclerosis
• This association remained significant even in the subgroup with optimal cardiovascular risk factors

Significance of These Findings

This study challenges the conventional understanding of "safe" LDL-C levels by demonstrating that:

• Atherosclerosis begins early in life, even in metabolically healthy individuals
• Current thresholds for defining "normal" LDL-C may be inadequate for preventing atherosclerosis
• The relationship between LDL-C and atherosclerosis appears to be continuous, without a clear threshold below which there is no risk

Supporting Evidence from Other Studies

The PESA findings align with other research showing that:

• The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) and Bogalusa Heart Studies demonstrated that atherosclerosis begins early in life, with higher LDL-C contributing to early atherogenesis 2
• Every 0.26-0.39 mmol/L (10-15 mg/dL) increase in non-HDL cholesterol is associated with an additional year of vascular aging 2
• Mendelian randomization studies have confirmed the causal relationship between LDL-C and atherosclerotic cardiovascular disease 2

Clinical Implications

These findings have important implications for cardiovascular risk assessment and prevention:

• Traditional risk factor assessment may underestimate atherosclerosis burden in seemingly healthy individuals
• Even "normal" LDL-C levels may warrant more aggressive management in some individuals
• Subclinical atherosclerosis detection (through coronary artery calcium or carotid/femoral ultrasound) may identify high-risk individuals who would otherwise be classified as low risk
• Primary prevention strategies may need to target lower LDL-C levels than currently recommended

Common Pitfalls in Interpreting This Evidence

• Assuming that absence of traditional risk factors guarantees freedom from atherosclerosis
• Relying solely on LDL-C thresholds without considering the continuous nature of risk
• Overlooking the importance of lifetime exposure to LDL-C rather than just current levels
• Failing to consider that atherosclerosis development begins decades before clinical manifestations

The PESA study provides compelling evidence that even individuals with "normal" LDL-C levels and no traditional risk factors may harbor significant subclinical atherosclerosis, suggesting that our current approach to primary prevention may need reconsideration.