Mouse Model of a Novel Molecular Subtype of Atrial Fibrillation: Physiologic Characterization and Therapeutic Drug Targeting

The mechanisms underlying atrial fibrillation (AF), the most common cardiac arrhythmia, are not fully understood, hindering the development of novel drugs. Elucidating the genetic causes of familial forms of AF can provide significant mechanistic insights and reveal novel drug targets. Our research group studied a large family with AF and identified a single rare variant shared exclusively by affected individuals, a heterozygous missense mutation in the CaV3.2 T-type calcium channel (TTCC) gene, CACNA1H (p.R1823H). Electrophysiological studies revealed that this mutation increases CaV3.2 current density, an effect that could be reversed by selective blockade of the affected channel. These data identify CACNA1H as a novel gene associated with the development of AF, but the underlying mechanisms are unknown. Moreover, TTCCs, though known to regulate atrial automaticity, have never been implicated in the pathogenesis of AF. Using a knock-in (KI/+) mouse model expressing the murine ortholog of the human variant, p.R1828H-CaV3.2, this thesis demonstrates direct causation of AF by the mutation and implicates enhanced atrial triggered activity as the major underlying electrophysiological mechanism. KI/+ mice had frequently prolonged episodes of AF and significantly enhanced vulnerability to AF induction compared to wild-type (WT) littermates. Characterization of the novel mouse model in vivo and at the cellular level revealed electrophysiological functional abnormalities known to provoke triggered activity and AF, including an increased frequency of spontaneous atrial beats in ambulatory animals and a significant burden of DADs in isolated atrial myocytes. AF vulnerability in KI/+ mice appears to be the direct result of the primary electrophysiologic abnormality, as KI/+ mice had structurally normal hearts noted by the absence of excess fibrosis, and HRV analysis revealed no evidence of autonomic tone imbalance. Selective blockade of CaV3.2 channels suppressed the increased DADs seen in mutant atrial myocytes and abolished AF inducibility in vulnerable KI/+ mice, suggesting that the CaV3.2-R1828H variant is directly responsible for the AF phenotype of KI/+ mice. The successful suppression of AF vulnerability and DADs by selective CaV3.2 blockade suggests TTCC modulation may be a potential therapeutic strategy in the treatment of AF.

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