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

Shorter leukocyte telomere length (LTL) was associated with atrial fibrillation predominantly in individuals younger than 70 years in age-stratified analyses.

• LTL was quantified using a high-throughput, single-gene-calibrated dot blot assay developed by the authors.
• The association between shorter LTL and AF was identified through age-stratified analyses.
• The relationship was predominantly observed in individuals younger than 70 years rather than in older age groups.

Telomerase-deficient (TERT-/-) mice with telomere dysfunction exhibited higher AF inducibility, atrial electrical conduction slowing, and atrial fibrosis.

• The mouse model used was telomerase-deficient (TERT-/-) mice, which display telomere dysfunction.
• Phenotypes observed included increased AF inducibility, slowed atrial electrical conduction, and atrial fibrosis.
• These findings establish a causal link between telomere dysfunction and AF-related atrial remodeling in a murine model.

Transcriptomic profiling of TERT-/- mice revealed significant alterations in extracellular matrix and cell adhesion pathways in response to telomere dysfunction.

• Transcriptomic profiling was used to identify pathway-level changes associated with telomere dysfunction.
• Significantly altered pathways included extracellular matrix organization and cell adhesion pathways.
• Subsequent validation from these transcriptomic findings identified VCAM-1 as a potential mediator.

VCAM-1 was identified as a potential mediator linking telomere shortening to AF-related atrial remodeling.

• VCAM-1 (vascular cell adhesion molecule-1) was identified through transcriptomic profiling and subsequent validation.
• VCAM-1 was implicated in the pathway connecting telomere shortening to electrophysiological and structural atrial abnormalities.
• The findings establish a 'telomere-VCAM-1 axis' that drives atrial remodeling and arrhythmogenesis in aging.

Functional inhibition of VCAM-1 reversed electrophysiological abnormalities, attenuated atrial fibrosis, normalized ECM gene expression, and reduced AF susceptibility by 30%.

• VCAM-1 inhibition reversed atrial electrophysiological abnormalities and attenuated atrial fibrosis.
• ECM-related gene expression normalized following VCAM-1 inhibition, including Col1α1, α-SMA, and CD168.
• AF susceptibility was reduced by 30% following functional inhibition of VCAM-1.
• These results position VCAM-1 as a candidate therapeutic target for age-related AF.