Sinoatrial node dysfunction: molecular mechanisms, arrhythmogenesis, and translational pathways toward precision therapy.

Authors

Nam V Truong, Julianna N Quinn, Mark Returan, Jun Wang

Published in

Pharmacology & therapeutics. Pages 109131. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

Sinoatrial node dysfunction (SND) is a major cause of bradyarrhythmia, chronotropic incompetence, tachy-brady syndrome, and a common indication for permanent pacemaker implantation, particularly in older adults. Although SND has diverse etiologies, this review focuses on aging-associated intrinsic SND, while considering other common causes where they inform differential diagnosis, arrhythmogenic mechanisms, or therapeutic development. Although current medical interventions provide effective rhythm support, they does not correct the molecular and tissue-level processes that drive sinoatrial node (SAN) degeneration. The review integrates current knowledge of SAN biology with mechanisms underlying SND, including fibrosis, ion-channel and calcium-clock remodeling, mitochondrial dysfunction, cellular senescence, impaired β-adrenergic signaling, genetic susceptibility, and epigenetic or epitranscriptomic regulation. We further discuss how these mechanisms contribute to impaired impulse generation, SAN exit block, reduced chronotropic reserve, and increased susceptibility to atrial arrhythmia. We discuss approaches for studying the molecular and cellular mechanisms and evaluating therapeutic strategies using emerging animal models, human pluripotent stem cell-derived SAN-like pacemaker cells, organoids, assembloids, and single-cell and spatial omics platforms . Finally, we highlight translational opportunities, including senescence-directed, metabolic, antifibrotic, autonomic, gene-based, regenerative, and biological pacing strategies. A mechanism-guided classification of SND may support future precision therapies that complement conventional pacing by linking dominant rhythm phenotypes to targetable biological drivers, molecular and functional pharmacodynamic markers, and human-relevant models of pacemaker failure.

PMID:
42869137
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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