Angiographic Burden of Coronary Atherosclerosis Contributes To Adverse ASCVD Outcomes Independent Of Traditional Risk Factors

Coronary artery disease (CAD) is a major contributor to cardiovascular morbidity (including myocardial infarction [MI] and heart failure [HF]), and mortality. Although the burden of CAD (number and degree of coronary artery stenosis) has been observationally linked to these outcomes, the causal contribution and independence from traditional cardiovascular risk factors has been poorly defined. Using publicly available genome wide association study (GWAS) data and individual level outcomes data from the Penn Medicine Biobank, we investigated whether angiographic CAD burden contributes to adverse cardiovascular outcomes independent of traditional risk factors. We developed and validated a polygenic risk score (PRS) for angiographic CAD burden, demonstrating that increasing levels of the PRS were strongly associated with increased prevalence of non-obstructive and obstructive CAD on coronary angiography, and was associated with other forms of cardiometabolic disease including peripheral artery disease and atherosclerotic risk factors including hyperlipidemia, hypercholesterolemia and hypertension. Through Mendelian randomization analyses, we found that lipid measures (ApoB, HDL, LDL, total cholesterol, triglycerides) and type 2 diabetes significantly influenced myocardial infarction risk through their effects on angiographic CAD burden. Furthermore, LDL and total cholesterol demonstrated significant indirect effects on heart failure through angiographic CAD burden, suggesting these lipids primarily influence heart failure through their impact on coronary atherosclerosis. Our findings indicate that angiographic burden of coronary atherosclerosis mediates a substantial proportion of the relationship between traditional cardiovascular risk factors and adverse outcomes. These results support prioritizing primary prevention efforts targeting modifiable risk factors to prevent development and progression of coronary plaques before clinical disease manifestation.