SAN function is altered in a mice model of heart failure

Abstract

Sinoatrial node (SAN) is the primary pacemaker of the heart. While SAN spontaneous activity relies on various ion currents in the plasma membrane activated during the diastolic period, intracellular Ca2+ release via Ryanodine Receptor 2 (RyR2) plays an important, yet not completely elucidated, role. Pathological conditions such as heart failure (HF) modulates intracellular Ca2+ handling in ventricular cells, but information about SAN cells is scarce. The aim of this study was to analyze the Ca2+ handling via RyR2 in SAN using the HF mice model induced by transverse aortic constriction (TAC) surgery. Sham surgery was realized to obtain controls. ECG was recorded by telemetry. Six weeks post-surgery, cardiac function (ejection fraction, EF) was assessed by echocardiography, and lung weight taken upon sacrifice. Some animals showed moderate cardiac dysfunction (reduced EF, CD) and some others signs of congestive HF (reduced EF plus enhanced lung weight/tibia length). Heart rate was significantly lower in the TAC group after autonomic nervous system blockade. Ca2+ handling was viewed with a resonant scanning confocal microscope in dissected intact SAN tissues loaded with the fluorescence Ca2+ dye fluo-4 AM. Spontaneous [Ca2+]i transients rate was slower and prolonged in duration in CD than in sham and HF groups. These differences were overcome by β-adrenergic stimulation (20 nM isoproterenol) in the presence of the CaMKII inhibitor KN93 (3 μM). Sarcoplasmic Reticulum (SR) Ca2+ release through sparks during diastolic periods was smaller in both, CD and HF SAN myocytes compared to Sam cells. This was mainly due to shorter and weaker Ca2+ sparks in the TAC groups. In conclusion, our data show that in HF model, the intrinsic pacemaker rate is slower, and this could be due to an impairment on the Ca2+ clock.