Refining the impact of early intermittent hyperlipidemia on atherosclerosis: Unveiling the role of neutrophil reprogramming, sex differences, gut microbiota, and maternal hypercholesterolemia

Atherosclerotic cardiovascular diseases (ASCVDs) remain a leading cause of mortality, with early cholesterol control being pivotal in mitigating long-term risk. Recent findings suggest that intermittent hyperlipidemia, characterized by oscillatory cholesterol exposure, uniquely accelerates atherosclerosis compared to continuous high-fat diets. This review synthesizes emerging evidence on early intermittent hyperlipidemia's impact on atherogenesis, emphasizing macrophage dysfunction, autophagy impairment, and efferocytosis deficits. We also discuss critical gaps, including sex-specific differences, gut-microbiota interactions, and the influence of maternal hypercholesterolemia. Notably, recent insights into IL-1β-dependent neutrophil reprogramming under oscillatory diets reveal novel inflammatory mechanisms driving plaque destabilization. Addressing these gaps will advance our understanding of early atherogenesis and guide the development of innovative prevention strategies and therapeutic interventions.