Abstract 15361: Loss of Caveolin-3 Disrupts Mouse Sinoatrial Node Pacemaking and Stimulates Atrial Arrhythmogenesis
Introduction: Caveolae represent a population of caveolin-3 (Cav3)-containing membrane microdomains housing a number of ion channels and transporters that are involved in sinoatrial node (SAN) pacemaking. Cav3 organizes these channels within macromolecular signaling complexes providing highly localized autonomic regulation of the SAN.
Hypothesis: Cav3 is required for functional integrity of the SAN, synchronizing Ca release and Ca-voltage coupling.
Methods: ECG telemetry, simultaneous optical mapping of voltage and Ca in whole hearts and isolated atria, and Ca imaging of isolated atrial myocyte were applied to wild type (WT, n=8) and Cav3 knockout (KO, n=8) mice, at baseline and under isoproterenol (Iso).
Results: Though no difference in average heart rate (HR) was revealed between groups, KO mice showed significant beat-to-beat HR variability, both in vivo and in vitro (9.4 ± 2.4% from HR in KO vs. 2.2 ± 1.1% in WT, P<0.01). Optical mapping linked the increased HR variability to enhanced ectopic foci outside the SAN. Under Iso, KO mice had paroxysms of alternating periods of tachycardia-bradicardia rhythm (cycle length varied from 124 ± 3 ms to 464 ± 131 ms in isolated hearts) which were characterized by different leading pacemaker locations. Some ectopic beats resulted in short paroxysms of atrial flutter associated with macro-reentry. Ectopic foci areas had a prolonged Ca release time (CaRT: 12 ± 3 ms vs. 8 ± 1 ms in the rest of KO atria, P<0.01, and vs. 9 ± 2 in the same area in WT, P<0.05) and Ca transient duration (CaTD: 54 ± 22 ms vs. 47 ± 4 ms in the rest of KO atria, P<0.01, and vs. 39 ± 3 ms in WT, P<0.01). In WT isolated atrial myocytes, disruption of caveolae by methyl-β-cyclodextrin treatment dramatically prolonged CaRT (from 59 ± 15 ms to 123 ± 41 ms, P<0.05) and CaTD (from 299 ± 47 ms to 434 ± 98 ms, P<0.05), by desynchronizing sarcoplasmic reticulum Ca release (subcellular Ca release starting time point variation: 25.7 ± 5.6 in KO vs. 13.4 ± 1.1 in WT, P<0.05).
Conclusions: Our findings demonstrate that Cav3 plays a crucial role in supporting functional integrity of the SAN pacemaker complex by synchronizing subcellular Ca dynamics and Ca-voltage coupling. Loss of Cav3 may disrupt caveolae-associated macro-molecular signaling complexes and result in SAN dysfunction.
Author Disclosures: D. Lang: None. A. Warden: None. R. Balijepalli: None. T.J. Kamp: None. A.V. Glukhov: None.
- © 2016 by American Heart Association, Inc.