Background: Previous studies have shown reduced cardiovascular (CV) risk with increasing high-density lipoprotein cholesterol (HDL-C) levels. However, at elevated HDL-C levels (>60mg/dl), its atheroprotective functions, such as cholesterol efflux and anti-oxidant capacity, may be impaired. The association between high levels of HDL-C and adverse outcomes remains unclear.
Purpose: To study the relationship between elevated HDL-C levels (>60mg/dl) and adverse CV outcomes in an at-risk population.
Methods: Participants included 5,965 individuals (mean age 63.3±12.4 years, 35% female, 23% African American) enrolled in the cardiovascular biobank. Restricted cubic spline curves were used to examine the potential non-linear association between HDL-C and adverse outcomes using HDL-C of 50mg/dL as reference. Individuals were also stratified by HDL-C categories (<30, 31–40, 41–50, 51–60 and ≥60 mg/dL) and a Cox proportional hazards model was used to examine the association between HDL-C and adverse outcomes, with HDL-C 51–60 mg/dL as the reference group. All models were adjusted for age, race, sex, body mass index, hypertension, smoking, triglycerides, low density lipoprotein cholesterol, heart failure history, myocardial infarction (MI) history, diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use, beta blocker use, statin use, aspirin use, estimated glomerular filtration rate, obstructive coronary artery disease.
Results: Over a median follow-up of 3.9 years (interquartile range 1.6 to 6.6 years), there were 769 CV death/non-fatal MI events. Restricted cubic spline regression models demonstrated a “U-shaped” association between HDL-C and CV death/non-fatal MI (Figure 1) and all-cause mortality (not pictured). Individuals with HDL-C <30 mg/dL (n=825) and ≥60 mg/dL (n=570) had an increased risk of all-cause mortality and CV death/non-fatal MI (HR 1.62; 95% CI=1.16–2.26, p=0.005 and HR 1.44; 95% CI = 1.01–2.06, p=0.04 respectively) after adjusting for aforementioned variables.
Conclusion: Elevated HDL-C levels are paradoxically associated with an increased risk of adverse CV events in an at-risk population, suggesting dysfunctional HDL and impaired atheroprotection.