Abstract 16041: Abnormal Pauses and Altered Sarcoplasmic Reticulum Calcium Cycling in Sinoatrial Myocytes Cause Bradycardia in a Recessive Model of CPVT
Aims: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) patients exhibit bradycardia and atrial arrhythmias for which the underlying mechanism(s) remain unknown. We hypothesized that alteration in sarcoplasmic reticulum (SR) calcium (Ca2+) cycling within the sinoatrial node (SAN) myocytes leads to the observed SAN dysfunction.
Methods and Results: SAN dysfunction, characterized by bradycardia and increased heart rate variability in Calsequestrin 2-/- (CASQ2-/-) mice, a model of recessive CPVT, is paralleled by depressed SAN activation and a beat-to-beat shifting of activation to atrial ectopic sites, revealed by optical mapping in in vitro SAN preparations. Confocal imaging of intracellular SR Ca2+ cycling in isolated SAN CASQ2-/- myocytes showed a significant decrease in the amplitude but increase in the 80% decay time of Ca2+ transient (CaT) with 10 nM Isoproterenol (Iso) treatment. Notably, most CASQ2-/- SAN pacemaker cells showed a progressive elevation of baseline diastolic Ca2+ level and simultaneous decrease in amplitude of CaT followed by pauses in spontaneous Ca2+ oscillations at baseline [in CASQ2-/-: 4/11 (36%) ; WT: 0/11 cells (P=0.09)] and with Iso [in CASQ2-/-: 9/11 (74%) ; WT: 0/11 cells (P=0.0002)] (Fig1A-C ). Rhythmic oscillations resumed only when the baseline Ca2+ returned back to its original level. Low dose caffeine (0.5-2 mM) applications in WT cells induced similar baseline Ca2+ elevations and pauses comparable to the findings in CASQ2-/- cells confirming Ca2+ leak via ryanodine receptors.
Conclusions: Loss of CASQ2 induces abnormal SR Ca2+ release which leads to periods of elevated diastolic Ca2+ levels and subsequent pauses in SAN myocytes which suppress SAN function both in vivo and vitro. Correcting dysfunctional SR Ca2+ cycling in SAN myocytes to prevent pauses and restoring proper SAN activation could present a novel mechanism to treat bradycardia and pro-arrhythmic beat-to-beat ectopic activation in CPVT hearts.
- © 2013 by American Heart Association, Inc.