Sinus node dysfunction in heart failure is characterized by reduced CaMKII signaling

Abstract

Heart failure (HF) is a complex syndrome in which death rates are over 50%. The main cause of death among HF patients is 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 undiscovered. Here, we used a HF model in mice with transverse aortic constriction (TAC) and using telemetry saw slower heart rhythm under autonomic nervous system blockade. Then, using confocal microscopy we analyzed Ca2+ handling in HF SAN tissue and found that intracellular Ca2+ transient rates were slower in addition to 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 demonstrate a reduction in CaMKII activation in the Ca2+-clock function of the SAN tissue in a mouse model of HF.