Human papillomavirus infection and atherosclerotic cardiovascular disease: a comprehensive review of epidemiological evidence, molecular mechanisms, and vaccination-mediated protection.

Emerging epidemiological evidence indicates that persistent infection with high-risk human papillomavirus (HPV) genotypes is independently associated with elevated atherosclerotic cardiovascular disease (CVD) risk, challenging traditional paradigms of cardiovascular risk assessment. This review synthesises current observational data on this association, explores the potential inflammatory, immune, and metabolic mechanisms that may connect HPV to atherogenesis, and evaluates the emerging evidence for cardiovascular protection conferred by HPV vaccination. Large cohort studies report significantly elevated risks of myocardial infarction, stroke, and cardiovascular mortality among women with high-risk HPV infection, independent of conventional risk factors. Mechanistically, HPV oncoproteins E6 and E7 activate nuclear factor-κB (NF-κB)-mediated inflammatory cascades, induce endothelial dysfunction through p53 degradation, and establish a pro-atherogenic systemic inflammatory milieu characterized by elevated interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Preliminary retrospective analyses further indicate that HPV vaccination is linked to a reduced incidence of new-onset cardiovascular and cerebrovascular events, although healthy-user bias and residual confounding limit causal interpretation. Despite these intriguing signals, the bulk of evidence is derived from cross-sectional and retrospective designs, and the direct demonstration of a causal link remains absent. We discuss critical methodological challenges-including confounding by sexual behaviour, socioeconomic status, and co-infections-and outline a roadmap for prospective cohort studies, mechanistic investigations, and rigorous risk-stratification research. Clarifying the nature of the HPV-CVD relationship could open novel avenues for the primary prevention of atherosclerotic disease through vaccination programmes.