Abstract Body: Introduction: Heart failure (HF) is fundamentally driven by impaired beta-adrenergic signaling and disrupted calcium Ca²⁺ handling. A-kinase anchoring proteins (AKAPs) maintain the spatial organization of cAMP/PKA signaling, which is essential for excitation-contraction coupling (ECC). We previously identified AKAP12 as significantly upregulated in failing human hearts and in infarcted mouse hearts. Within the AKAP12 signalosome, we identified phosphodiesterase 8A (PDE8A), a high-affinity cAMP-specific phosphodiesterase, as a key regulator of localized cAMP hydrolysis. However, the role of the AKAP12-PDE8A axis in electrical remodeling and HF progression remains unexplored.

Hypothesis: AKAP12 sequesters PDE8A to suppress compartmentalized cAMP signaling, thereby impairing Ca²⁺ handling and driving action potential (AP) remodeling, arrhythmia, and HF.

Methods and Results: Using cardiac-specific AKAP12-overexpressing (AKAP12OX) mice and primary left ventricular cardiomyocytes (LVCMs), we mapped the functional impact of this axis. AKAP12OX hearts exhibited reduced compartmentalized cAMP despite unchanged total cAMP levels, confirming enhanced localized hydrolysis. Physiologically, AKAP12OX LVCMs displayed weakened contractility, aberrant Ca²⁺ transients, and prolonged APD90. These defects were associated with downregulation of SERCA and reduced expression of the inwardly rectifying potassium channel Kir2.1. In vivo, AKAP12OX mice developed spontaneous arrhythmias and reduced ejection fraction (EF). Importantly, treatment with the selective PDE8 inhibitor PF-04957325 (PF) rescued Ca²⁺ homeostasis and contractility in vitro and normalized heart rhythm and systolic function in vivo. Unlike chronic isoproterenol infusion, PF-mediated recovery improved EF without inducing maladaptive remodeling.

Conclusions: The AKAP12-PDE8A axis disrupts the cAMP compartments required for normal ECC, driving electrical remodeling and HF. Pharmacological inhibition of PDE8A restores Ca²⁺ homeostasis and improves cardiac performance, positioning the AKAP12-PDE8A complex as a promising precision therapeutic target for preventing arrhythmia and slowing HF progression.