Abstract
Atherosclerosis remains a leading cause of cardiovascular morbidity and mortality worldwide, traditionally linked to elevated cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C). However, despite aggressive lipid-lowering strategies, residual cardiovascular risk persists, underscoring the need to explore additional contributing factors. This review examines emerging risk factors beyond cholesterol, including chronic inflammation, gut microbiota composition, oxidative stress, and environmental exposures. Inflammation plays a pivotal role in atherogenesis, with markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) serving as indicators of disease activity. The gut microbiome, particularly metabolites like trimethylamine N-oxide (TMAO), has been implicated in vascular inflammation and plaque development, while beneficial short-chain fatty acids (SCFAs) demonstrate protective effects. Oxidative stress further exacerbates endothelial dysfunction and plaque instability, driven by reactive oxygen species (ROS) and lipid peroxidation. Additionally, environmental factors, including air pollution, heavy metal exposure, endocrine disruptors, and chronic psychological stress, have emerged as significant contributors to cardiovascular disease. Understanding these novel risk factors offers a broader perspective on atherosclerosis pathogenesis and provides new avenues for targeted prevention and therapeutic interventions.