Increased Risk for Atrial Alternans in Rabbit Heart Failure: The Role of Ca²⁺/Calmodulin-Dependent Kinase II and...

Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca²⁺ signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified mechanisms that contribute to the higher risk of atrial arrhythmias in HF. Ca²⁺ transient (CaT) alternans-beat-to-beat alternations in CaT amplitude-served as indicator of increased arrhythmogenicity. We demonstrate that HF atrial myocytes were more prone to alternans despite no change in action potentials duration and only moderate decrease of L-type Ca²⁺ current. Ca²⁺/calmodulin-dependent kinase II (CaMKII) inhibition suppressed CaT alternans. Activation of IP₃ signaling by endothelin-1 (ET-1) and angiotensin II (Ang II) resulted in acute, but transient reduction of CaT amplitude and sarcoplasmic reticulum (SR) Ca²⁺ load, and lowered the alternans risk. However, prolonged exposure to ET-1 and Ang II enhanced SR Ca²⁺ release and increased the degree of alternans. Inhibition of IP₃ receptors prevented the transient ET-1 and Ang II effects and by itself increased the degree of CaT alternans. Our data suggest that activation of CaMKII and IP₃ signaling contribute to atrial arrhythmogenesis in HF.