Abstract 10496: Sinus Nodal Depression and Decreased Heart Rhythm Response to Autonomic Modulation in a Calsequestrin 2 Knockout Mouse Model
Introduction: Calsequestrin (CASQ) is the most abundant Ca2+ binding protein located in the sarcoplasmic reticulum. It has been suggested that CASQ2 is involved in the regulation of the cardiac pacemaker function. CASQ2 null mutations can lead to sinus bradycardia in both human and mice. However, the exact mechanism behind CASQ2 regulation of the sino-atrial nodal (SAN) function is unclear.
Methods: Using high resolution optical mapping, we characterized SAN function in a whole atria preparation, which included the intact SAN and atrioventricular junction (AVJ), isolated from 12-14 month old wild type (WT, n=4) and CASQ2 null (n=4) mice. Isoproterenol (Iso, 1-100 nM) and acetylcholine (ACh, 0.1-3 uM) were used for autonomic stimulation.
Results: The spontaneous rhythm was slower (302±17 vs. 347±9 BPM, p=0.04) in CASQ2 null vs. WT mice before drug application. In WT, the leading pacemaker was located in the anatomically defined SAN area near the superior vena cava (SVC) and shifted (1) superiorly within the SAN (0.83 ± 0.23 mm) during Iso perfusion; (2) inferiorly within the SAN (0.75 ± 0.17 mm) or to the AVJ (4.59 ± 0.66 mm) during ACh perfusion. In 3 out of 4 CASQ2 null mice, the leading pacemaker was located outside of the classical SAN area: near the pulmonary vein (PVs, n=2) or inferior vena cava (IVC, n=1) before drug application. Iso induced irregular pacemaker shift either superiorly (1.92 ± 0.31 mm) or inferiorly (2.03 ± 0.72 mm), whereas ACh induced mostly lateral shift (1.55 ± 0.79 mm). As such, Iso accelerated heart rate by 89±6% vs. 65±5% (p<0.001) and ACh slowed heart rate by 49±8% vs. 31±5% (p=0.02) in WT vs. CASQ2 mice, respectively.
Conclusion: Loss of CASQ2 may cause the SAN to lose its ability to control heart rhythm during control condition and autonomic stimulation. Thus subsidiary pacemakers take over the role of the leading pacemaker, which could explain slowing of the heart rate and its decreased sensitivity to autonomic stimulation in the CASQ2 null mice.
- © 2011 by American Heart Association, Inc.