Abstract 15376: Heart Rate Increase and Repolarization Lability Precede Onset of Ventricular Arrhythmia in Casq2-/- Mice
Introduction Calsequestrin (CASQ2) mutations cause hereditary propensity to ventricular tachycardia (VT) and cardiac arrest in humans. The phenotype is reproduced in Casq2-/- mice. Heart rate (HR) increase and repolarization lability (RL) precede other forms of VT in humans.
Hypothesis HR and RL increase prior to VT onset in Casq2-/- mice.
Methods 24 hr ECG was recorded in 10 unrestrained male mice (5 Casq2-/-[KO], 5 Casq2+/+[WT]). ECG data were manually edited and analyzed with custom-written software. The signal was low-pass filtered at 100 Hz. Cubic spline subtraction was used to correct low-frequency baseline fluctuations. RL was defined as root-mean-square of ECG amplitude in “repolarization window” (30-35 ms after R wave peak). RL was calculated from 60 consecutive sinus rhythm (SR) or junctional rhythm (JR) beats, corrected for nonspecific noise and normalized by QRS amplitude. HR and RL were evaluated in each hour during stable SR, SR preceding VT, SR preceding JR, and JR preceding VT.
Results KO mice have lower HR (average RR interval 135±14 vs 111±12 msec; p<10-4) and more frequent episodes of JR (p<10-4) than WT. VT is only detected in KO mice. JR episodes often precede VT. In KO, HR in SR preceding VT is higher than during stable SR (RR interval 112±8 vs 128±8 msec; p<10-4). HR in SR preceding JR onset is faster than during stable SR; HR is also higher in JR preceding VT onset than during other JR episodes. RL during stable SR is similar in WT and KO. Compared to stable SR, RL increases before VT (0.0034±0.003 vs 0.012±0.009; p<10-4; Figure) and before JR in KO. In JR, RL increases further before VT onset.
Conclusions Onset of VT and JR in KO mice is preceded by increase in HR and RL. Our data suggest that increased adrenergic tone leads to irregular calcium release from sarcoplasmic reticulum, resulting in both repolarization instability and VT triggering. Sinus bradycardia and JR in KO mice attest to importance of calsequestrin in normal physiology of sinus node and Purkinje fibers.
- © 2011 by American Heart Association, Inc.