Abstract 3498: Targeted Loss of Cardiac L-type Ca2+ Cav1.2 Channels in Adult Mouse Causes Sinus Node Dysfunction, AV block and Supraventricular Tachycardias
Influx of Ca2+ through L-type Ca2+ channels in the heart contributes to excitation-contraction coupling, automaticity in nodal tissues, and maintenance of the plateau phase of the cardiac action potential. In the heart, expression of both Cav1.2 and Cav1.3, encoding the pore forming subunits of L-type Ca2+ channels, has been measured. However, the relative contribution of Cav1.2 and Cav1.3 channels to normal sinus nodal pacemaking and AV conduction are debated. To better understand the impact on cardiac function of Cav1.2 L-type calcium channels, we engineered a cardiac-restricted conditional Cav1.2 knockout mouse in which floxed Cav1.2 mice were crossed with αMHC-MerCreMer mice. Southern blot analysis of tissue samples of tamoxifen treated mice demonstrated cardiac restricted knockout of Cav1.2. Homozygous fCav1.2+/+ αMHC-MerCreMer adult mice from 8 –14 weeks of age were fed tamoxifen-laden chow (0.5 mg/g chow), and mice died on average after 20 days compared to no death in control tamoxifen treated mice. To understand the contribution of arrhythmias to the knockout phenotype ECG telemetry recordings were performed. Knockout mice developed sinoatrial block and episodes of high degree AV block over 20 days, and the mice died with progressive bradycardia. Furthermore, a subset of knockout mice developed paroxysmal supraventricular tachycardias (rates 800 –900 bpm). Electrical mapping of isolated atrial preparations demonstrated that the intrinsic sinus cycle length significantly lengthened from 138±5 ms in the control mice to 177±11 ms in knockout mice (n=6–7, at treatment days 11–16). Electrical maps from knockout mice showed slow and fractionated atrial conduction in contrast to the more uniform conduction in control mice. Mapped atria also exhibited episodes of AVNRT as well as atrial tachycardias consistent with telemetry observations. These data demonstrate that the Cav1.2 Ca2+ channel is essential in the adult mouse heart for normal sinus node automaticity and AV conduction, and reduction of Cav1.2 gene expression also unexpectedly leads to a variety of supraventricular arrhythmias. Thus reductions in Cav1.2 expression in disease states such as CHF and atrial fibrillation may prominently contribute to a variety of arrhythmias.