Abstract 21054: Hematopoietic Factors Are Sufficient to Increase AF in Aged, Atherosclerotic Mice

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Abstract

Rationale: Aging is a strong risk factor for atrial fibrillation (AF), the most common sustained arrhythmia in the clinical practice. Atrial inflammation correlates with increased AF susceptibility but whether chronic age-related inflammation that occurs with atherosclerosis contributes to AF is unknown.

Hypothesis: Hematopoietic factors contribute to AF inducibility in aged atherosclerotic mice.

Methods: We used burst electrical stimulation (tachypacing) of the right atrium to test susceptibility to AF in-vivo in young and aged atherosclerotic, low density lipoprotein receptor knockout (C57BL/6 Ldlr-/-) mice, and young and old wildtype (C57BL/6 WT) mice. We also determined the role of the stroma vs. the hematopoietic system, by creating bone marrow chimeras in which aged or young Ldlr-/- mice were transplanted with age-matched or mismatched bone Ldlr-/- bone marrow. We used whole-cell patch-clamping investigate atrial sodium currents. Confocal microscopy and patch-clamping in current clamp mode was used to simultaneously record action potentials and Ca2+ transients.

Results: Upon atrial tachypacing, aged atherosclerotic mice underwent longer and more frequent AF episodes than young (incidence, 0.47±0.09 vs 0.12±0.02 episodes/attempts; p<0.05) and aged WT mice (0.47±0.09 vs 0.16±0.07 episodes/attempts; p<0.05). Importantly, young-to-old bone marrow chimeric mice exhibited reduced AF incidence (0.23 ± 0.05 episodes/attempts), whereas old-to-young chimeric mice exhibited increased AF incidence (0.45 ± 0.08 episodes/attempts). Atrial myocytes from aged atherosclerotic mice presented a 50% reduction in the cardiac inward sodium current (INa). Moreover, compared to young, aged atherosclerotic mice showed prolonged action potential duration (APD90: 34.0±5.0 ms vs 48.1±7.0ms; p<0.05), post-pacing spontaneous calcium releases (25% vs 81.8%; p<0.05) and triggered activity (0% vs 27.2 %; p<0.05).

Conclusions: Aged atherosclerotic prone mice are susceptible to AF induction. Hematopoietic factors are sufficient to increase AF propensity with aging in the atherosclerotic host possibly by causing electrophysiological remodeling and intracellular Ca2+ handling abnormalities.

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