Genetic Factors Altering Immune Responses in Atrial Fibrillation JACC Review Topic of the Week

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with a range of adverse clinical outcomes. Accumulating evidence points to in flammatory processes resulting from innate immune responses as a cornerstone in AF pathogenesis. Genetic and epigenetic factors affecting leukocytes have been identi fied as key modulators of the in flammatory response. Inherited variants in genes encoding proteins involved in the innate immune response have been associated with increased risk for AF recurrence and stroke in AF patients. Furthermore, acquired somatic mutations associated with clonal hematopoiesis of indeterminate potential, leukocyte telomere shortening, and epigenetic age acceleration contribute to increased AF risk. In individuals carrying clonal hematopoiesis of indeterminate potential, myocardial monocyte-derived macrophage shift toward a proin flammatory phenotype may precipitate AF. Further studies are needed to better understand the role of genetic regulation of the native immune response in atrial arrhythmogenesis and its therapeutic potential as a target for personalized medicine.