Telomere Shortening Drives Atrial Fibrillation Through VCAM-1 Mediated Atrial Electrical and Structural Remodeling

Telomere shortening is a hallmark of aging and has been implicated in cardiovascular disease, but its mechanistic link to atrial fibrillation (AF) remains elusive. Using a high-throughput, single-gene-calibrated dot blot assay, we developed to quantify leukocyte telomere length (LTL). In age-stratified analyses, shorter LTL was associated with AF predominantly in individuals younger than 70 years. In telomerase-deficient (TERT^−/−) mice with telomere dysfunction, higher AF inducibility, atrial electrical conduction slowing, and atrial fibrosis were observed. Transcriptomic profiling revealed significant alterations in extracellular matrix and cell adhesion pathways in response to telomere dysfunction. Subsequent validation identified vascular cell adhesion molecule-1 (VCAM-1) as a potential mediator linking telomere shortening to AF-related atrial remodeling. Functional inhibition of VCAM-1 reversed electrophysiological abnormalities, attenuated atrial fibrosis, normalized ECM gene expression—including Col1α1, α-SMA, and CD168—and reduced AF susceptibility by 30%. These findings establish a telomere–VCAM-1 axis that drives atrial remodeling and arrhythmogenesis in aging, and position VCAM-1 as a candidate therapeutic target for age-related AF.