SDF-1/CXCR4 signaling promotes atrial fibrillation in heart failure with preserved ejection fraction

Abstract Background Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases. Atrial fibrillation (AF) occurs in nearly one-third of HFpEF patients and is associated with adverse outcomes. While both systemic and cardiac inflammation have been linked to AF, the role of tissue-intrinsic inflammatory circuits within the atrium in HFpEF remain poorly understood. Purpose To investigate atrial inflammatory signaling in cardiometabolic HFpEF and identify cytokine-receptor circuits that promote AF. Methods We employed a murine model of HFpEF (male C57Bl6N; 15-week high-fat diet + L-NAME) with increased AF susceptibility. Bulk transcriptomic profiling of murine left atrial (LA) myocardium analyzed co-expressed cytokine-receptor pairs based on curated interactions from the KEGG cytokine-cytokine receptor interaction pathway. Human validation included serum SDF-1 measurements in a HFpEF cohort. Functional studies included Ca2+ imaging in isolated adult murine left atrial cardiomyocytes (aACMs) treated with vehicle control or selective CXCR4 antagonist AMD3100 (10µM, 10min). Mechanism was explored using recombinant SDF-1 (125ng/ml, 30min) with AMD3100 or IP3 receptor inhibitor 2-APB (10µM, 10min preincubation). AF susceptibility was evaluated in vivo using rapid atrial pacing in HFpEF mice before and after intracardiac AMD3100 administration. Results Transcriptomic mapping identified upregulated SDF-1/CXCR4 expression in LA tissue. Circulating SDF-1 levels were elevated in HFpEF mice compared to control. In humans, serum SDF-1 concentrations in HFpEF patients correlated with both impaired LA reservoir strain and history of AF (Fig.1 A-D). Murine HFpEF aACMs displayed increased frequency of spontaneous Ca2+ release events, which was significantly reduced by CXCR4 inhibition. AMD3100 treatment attenuated elevated diastolic Ca2+ levels and modestly improved Ca2+ transient kinetics (Fig.1 E-J). Ca2+ spark frequency was elevated in HFpEF aACMs and restored upon CXCR4 blockade (Fig.2 K). Acute SDF-1 stimulation in control murine aACMs significantly elevated diastolic Ca2+ levels, recapitulating the HFpEF phenotype; this effect was fully abrogated by both AMD3100 and IP3 receptor inhibitor 2-APB (Fig.2 L). In vivo, HFpEF mice exhibited heightened AF inducibility compared to controls. Strikingly, acute CXCR4 inhibition via intracardiac AMD3100 significantly reduced AF inducibility in HFpEF mice (Fig.2 M). Conclusions We identify a novel inflammatory-electrophysiologic axis in HFpEF whereby SDF-1 engages CXCR4, triggering Gβγ subunit-mediated IP3 stimulation, leading to diastolic Ca2+ elevation and arrhythmogenic activity in atrial cardiomyocytes. CXCR4 signaling is both sufficient to drive arrhythmogenic Ca2+ abnormalities ex vivo and required to sustain the pro-arrhythmic state in vivo. This CXCR4/IP3-mediated Ca2+ dysregulation represents a potentially targetable mechanism for AF treatment in HFpEF.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.