BPS2026 – Sex-specific remodeling of cAMP signaling is associated with arrhythmia susceptibility in heart failure

Ventricular arrhythmias are a leading cause of death in heart failure (HF). Chronically elevated sympathetic tone in HF promotes β-adrenergic receptor (β-AR) desensitization and disrupts cAMP signaling, driving calcium overload and electrical instability. Male HF patients are at greater arrhythmia risk, but mechanisms remain unclear. Mice expressing a cardiac-specific FRET-based cAMP biosensor underwent transverse aortic constriction (TAC) to induce HF (N = 11), sham mice (N = 10) received identical surgery without constriction. Once ejection fraction reached >25%, mice were anesthetized (pentobarbital sodium >150 mg/kg I.P.) and hearts were Langendorff-perfused for simultaneous whole-heart imaging of cAMP, voltage and calcium. Arrhythmia susceptibility was assessed following norepinephrine bolus (500 nM). Data considered significant at p < 0.05, two-way ANOVA. Male and female TAC mice developed comparable systolic dysfunction over similar time (7.7 ± 1.8 vs. 7.1 ± 1.7 weeks), yet male HF hearts had higher arrhythmia scores. Optical mapping revealed triggered activity, beat-to-beat action potential (AP) variability, elevated diastolic calcium and prolonged calcium transient duration, particularly in the apex of male HF hearts. Whole-heart cAMP imaging showed blunted β-AR-mediated cAMP responses in right ventricular (RV) basal regions, and prolonged signals at the apex, highlighting regional heterogeneity. To test whether this was due to altered cAMP breakdown, we applied the broad phosphodiesterase (PDE) inhibitor IBMX (100 μM). In HF hearts, IBMX further amplified the regional differences compared with sham, consistent with enhanced PDE activity. Selective PDE4 inhibition with Rolipram (10 μM) failed to normalize the RV base response, suggesting that other PDE isoforms dominate in this region. These effects were absent in female HF hearts. Our findings reveal sex-specific spatial remodeling of cAMP signaling in HF. In males, regional cAMP heterogeneity may promote to calcium leak, providing a mechanism for heightened arrhythmia risk.