Cardiac Characteristics of a Mouse Model of Timothy Syndrome

Abstract

Timothy Syndrome (TS) is the only L-type Ca2+ channel (Cav1.2) defect linked to arrhythmias and sudden cardiac death (Splawski I et al. Cell 119: 19-31, 2004). Timothy SyTS results from a de novo gain-of-function mutation on the intracellular side of S6 from the first domain which affects the voltage dependent component of inactivation in Cav1.2 and results in prolongation of the QT interval.In addition to arrhythmogenesis, TS is associated with congenital heart disease, syndactyly and autism spectrum disorders. We created a knock-in mutation of TS in mice. Computer modeling suggested that the cardiac AP should be minimally affected under physiological conditions and in mice the arrhythmic potential should be observable only under pathophysiological conditions. The ECGs of conscious, unrestrained, unanesthetized mice and were performed double blinded. The QTc (38) in TS mice was prolonged, shifting from 44.3 ± 0.5 ms (n=8) for control mice to 47.2 ± 0.5 ms (n = 17) for mice expressing the TS mutation (P<0.01). Viewed qualitatively, many of the electrocardiograms from the TS mice showed a marked change in T-wave morphology. Other significant changes in conscious mice were also noted, the duration of the QRS complex shifted from 9.2 ± 0.4 ms (n=8) to 11.1 ± 0.2 ms (n = 17), heart rate showed a slight but not statistically significant increase and normalized heart rate variability showed a decrease from 5.1% ± 1.1 (n=8) to 2.6% ± 0.6 (n=17 P<0.05) indicating an increase in sympathetic tone in the TS mice. TS patients are particularly susceptible to arrhythmias in response to anesthesia and TS mice showed increased sensitivity to anesthetic (ketamine) with much loner QT prolongation and arrhythmias such as premature beats and apparent AV block.