Sinus node dysfunction in heart failure is characterized by reduced CaMKII signaling: Calcium Signaling and Excitation-Contraction Coupling in Cardiac, Skeletal and Smooth Muscle

Heart failure (HF) is a complex syndrome in which death rates are >50%. The main causes of death among HF patients are pump failure and ventricular arrhythmias, but severe bradycardia is also a common cause of sudden cardiac death, pointing to sinoatrial node (SAN) dysfunction. SAN pacemaker activity is regulated by voltage-clock and Ca²⁺-clock mechanisms and, although voltage-clock dysfunction in SAN has been largely proved in HF, Ca²⁺-clock dysfunction mechanisms in SAN remains unraveled. Here, we used an HF model in mice with transverse aortic constriction (TAC) and, using telemetry, saw slower heart rhythm under autonomic nervous system blockade. Then, by confocal microscopy, we analyzed Ca²⁺ handling in HF SAN tissue and found that intracellular Ca²⁺ transients rate were slower together with less frequency of Ca²⁺ sparks than in SHAM SAN tissue. Next, we studied protein expression of key excitation–contraction coupling proteins and found reduced expression of the Na⁺/Ca²⁺ exchanger and reduced phosphorylated status of ryanodine receptor and phospholamban in the CaMKII sites for the SAN in TAC mice. Finally, the application of the CaMKII inhibitor, KN93, caused less effect in slowing the Ca²⁺ transient rates in HF SAN tissue, confirming the reduced CaMKII activation. In conclusion, our data demonstrates a reduction in CaMKII activation in the Ca²⁺-clock function of the SAN tissue in a mouse model of HF.