Impact of atherogenic lipoproteins and inflammatory markers on silent atherosclerosis

Background Atherogenic lipoproteins are causal drivers of atherosclerotic cardiovascular disease (ASCVD). Emerging data has implicated inflammation as a key contributor to ASCVD. However, in adults without established ASCVD, it remains uncertain whether atherogenic lipid-plaque associations persists after accounting for measures of inflammation. Purpose We examined the magnitude of associations of low-density lipoprotein cholesterol (LDLC), non-high-density lipoprotein cholesterol (non-HDLC), and lipoprotein(a) [LP(a)] with silent atherosclerosis in peripheral arteries and assessed how these estimates changed after adjustment for high-sensitivity C-reactive protein (hsCRP) and neutrophil count. Methods We performed cross-sectional analyses of baseline data from the population-based REACT study including adults without pre-existing ASCVD. Plaque presence was assessed by carotid and femoral 3D ultrasound. Plaque burden was calculated as total plaque volume across carotid and femoral arteries. Logistic regression was used to estimate the association between atherogenic lipoproteins and plaque presence. For individuals with plaque, we used linear regression with log-transformed plaque burden. Models were adjusted for sex, age, body mass index, HbA1c, systolic blood pressure, diabetes, smoking, alcohol intake, self-reported dyslipidemia, self-reported hypertension, and country of inclusion (Denmark/Spain). We subsequently refitted these models with additional adjustment for hsCRP and neutrophil count. LP(a) was log2-transformed. Non-HDL was calculated as total cholesterol minus HDL cholesterol. Results We included 9182 participants (median age 47 years [IQR 19], 4600 [50%] women). Higher LDLC (OR 1.18 [95% CI 1.11-1.26 per change in 1 mmol/L, p<0.001]) and non-HDLC (OR 1.19 [95% CI 1.12-1.27 per change in 1 mmol/L, p<0.001]) were significantly associated with atherosclerosis prevalence (yes/no). No association was found between prevalence and LP(a). Among participants with atherosclerosis, plaque burden increased by 9.9% per 1 mmol/L increase in LDLC (95% CI 5.7-14.3, p<0.001) and by 9.4% per 1 mmol/L increase in non-HDLC (95% CI 5.4-13.5, p<0.001). Plaque burden increased by 4.2% per doubling of LP(a) (95% CI 2.2-6.3, p<0.001). These estimates were largely unchanged after additional adjustment for hsCRP and neutrophil count. Notably, neutrophil count was independently associated with plaque presence (OR 1.06, p=0.01) and plaque burden (8.0% higher per unit increase, p<0.001). hsCRP was not associated with either outcome. Conclusions In adults without established ASCVD, LDLC and non-HDLC were associated with prevalence of silent atherosclerosis and with plaque burden, whereas LP(a) was associated with plaque burden only. These associations were largely unchanged after additional adjustment for hsCRP and neutrophil count. Neutrophil count was independently associated with both atherosclerosis prevalence and plaque burden.