Per- and polyfluoroalkyl substances and cardiovascular disease: A mechanistic and epidemiological synthesis

Per- and polyfluoroalkyl substances (PFAS) are globally persistent pollutants increasingly implicated in adverse cardiovascular outcomes. Although research on PFAS toxicity has expanded rapidly, existing literature remains fragmented, with limited integration across exposure science, epidemiological evidence, molecular mechanisms, and mitigation strategies. Current reviews typically provide broad summaries of PFAS toxicity but seldom focus specifically on cardiovascular disease (CVD) or the mechanistic pathways underlying PFAS-induced cardiovascular injury. Moreover, the rapid emergence of short-chain and replacement PFAS introduces additional uncertainty regarding their cardiovascular relevance. To address these gaps, this review provides a comprehensive and mechanistically focused synthesis of PFAS exposure and CVD. A literature search through November 2025 identified eligible epidemiological, clinical, and experimental studies evaluating PFAS, including legacy compounds (Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA)) and emerging PFAS, and their associations with hypertension, blood pressure variation, vascular dysfunction, atherosclerosis, arrhythmias, cardiac injury, and cardiovascular mortality. Studies using serum or plasma biomarkers, drinking-water contamination records, cord blood measurements, and advanced mixture-modeling approaches were included. Extracted evidence encompassed exposure assessment, cardiovascular endpoints, mechanistic pathways, and potential therapeutic or risk-mitigating strategies. Across studies, PFAS exposure was consistently associated with modest but meaningful increases in systolic and diastolic blood pressure, higher risks of hypertension and gestational hypertensive disorders, impaired endothelial function, greater carotid intima-media thickness, and increased CVD incidence and mortality. Mechanistic evidence converges on several key pathways, including endothelial dysfunction, oxidative stress, inflammation, renin–angiotensin system activation, epithelial sodium channel upregulation, dyslipidemia, and placental vascular impairment linked to developmental programming. Vulnerable populations, including women, individuals with metabolic disorders, and those with impaired kidney function, exhibit heightened susceptibility. By integrating evidence across exposure science, epidemiology, mechanistic toxicology, and emerging intervention research, this review advances current understanding of PFAS-related cardiovascular toxicity and supports informed public health policy, clinical risk assessment, and regulatory decision-making. • PFAS exposure increases blood pressure, hypertension risk, and CVD incidence. • Key mechanisms include endothelial dysfunction, oxidative stress, and inflammation. • RAAS activation, ENaC upregulation, and dyslipidemia mediate cardiovascular effects. • Prenatal PFAS exposure impairs placental perfusion and fetal heart programming. • Evidence integration guides cardiovascular risk assessment, mitigation, and policy.