Per- and Polyfluoroalkyl Substances Exposure as Emerging Cardiovascular Risk Factors: Implications for Ischemic Heart Disease

Ischemic heart disease (IHD), a chronic and progressive condition marked by restricted blood flow predominantly arising from atherosclerosis, is currently the leading cause of mortality within cardiovascular disease. In recent years, per and polyfluoroalkyl substances (PFAS), ubiquitous, highly persistent environmental contaminants and wellestablished endocrine disruptors, have emerged as potential risk factors for IHD, given their documented associations with hypercholesterolemia, hypertriglyceridemia, and insulin resistance. Despite the still limited number of epidemiological studies and the inconsistent findings from investigations conducted in occupational settings, there is growing evidence that elevated exposure to certain PFAS compounds may increase the risk of IHD and vascular dysfunction, in some cases displaying doseresponse relationships and sexspecific patterns. Mechanistic studies support these epidemiological signals. Dysregulation of peroxisome proliferator-activated receptors alpha promotes vascular inflammation and oxidative stress, thereby contributing to endothelial dysfunction and the establishment of a prothrombotic milieu. Epigenetic modifications, together with telomere shortening, and alterations in mitochondrial DNA copy number, provide additional pathways linking PFAS exposure to atherogenesis. Future opportunities offered by novel approaches and intelligent techniques might revolutionize the research in this field attempting to address the existing knowledge gaps and to clarify the mechanistic relationships linking PFAS exposures with clinical cardiovascular outcomes.