Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia among the elderly and a major contributor to morbidity and mortality. Inflammation plays a central role in AF pathogenesis, and aging is a key independent risk factor. Cellular senescence is a hallmark of aging and contributes to age-related disease through the senescence-associated secretory phenotype (SASP), characterized by proinflammatory and profibrotic factors. OBJECTIVE: This study aimed to determine whether senescent atrial cells contribute to age-related AF risk and whether senolytic therapy can mitigate this phenotype. METHODS: Young (≤1 year) and aged (≥4 years) New Zealand White rabbits were evaluated using optical mapping, patch-clamp electrophysiology, and histologic and molecular analyses. Senescence markers were assessed using senescence-associated β-galactosidase staining, immunofluorescence, and RNA sequencing. Human atrial specimens from patients with and without AF were examined to assess translational relevance. Aged rabbits received the senolytic compound fisetin to evaluate its effects on atrial senescence and arrhythmia susceptibility. RESULTS: Aged rabbits displayed electrophysiological heterogeneity, prolonged action potentials, and increased AF inducibility, recapitulating clinical features of elderly human atria. Atrial tissue from aged rabbits and patients with AF showed an increase in senescent myocytes and myofibroblasts with upregulation of inflammatory SASP genes. SASP factor expression correlated with left atrial diameter in human samples, an AF risk factor. Short-term fisetin treatment eliminated most senescent atrial cells, reduced inducible AF, and decreased reentry activity without impairing atrial function. CONCLUSION: Senescent atrial cells promote a proinflammatory, proarrhythmic substrate predisposing to AF. Senolytic therapy with fisetin alleviates this phenotype, suggesting a potential strategy to prevent age-related AF.