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

TL;DR

Telomere shortening contributes to atrial fibrillation by increasing VCAM-1, which causes heart tissue changes and can be reversed with VCAM-1 inhibition.

Contribution

Identifies VCAM-1 as a novel mediator linking telomere shortening to atrial fibrillation and a potential therapeutic target.

Findings

Shorter leukocyte telomere length is associated with atrial fibrillation in individuals under 70 years old.

Telomere dysfunction in mice leads to atrial fibrosis, conduction slowing, and increased AF inducibility.

VCAM-1 inhibition reverses atrial remodeling and reduces AF susceptibility by 30%.

Abstract

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.

This study reveals that telomere shortening promotes atrial fibrillation by upregulating VCAM‐1, leading to fibrosis and electrical remodeling. Inhibiting VCAM‐1 reverses these abnormalities, identifying it as a therapeutic target for age‐related AF.

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