Novel therapeutic cav1.3-C-terminus normalizes L-type calcium current and ejection fraction in ischemia-induced murine heart failure.

INTRODUCTION

Heart failure (HF) affects approximately 6.7 million Americans and rising. Despite multi-modality therapy, patient outcomes remain suboptimal. It has been recently shown that Cav1.3 L-type calcium channels are re-expressed in ischemic failing human ventricles, and the Cav1.3-C-terminus is cleaved and acts as a transcription factor. Here, we leveraged the Cav1.3-C-terminus's auto-enhancer properties as a novel therapy to restore ejection fraction (EF) in HF.

METHODS

HF was established in wild-type (WT) and Cav1.3-heterozygous-knockout (Cav1.3+/-) mice 15-days post-ligation of the left-anterior-descending coronary artery (LAD). Treatment groups received adeno-associated-virus-serotype-9(AAV9)-Cav1.3-C-terminus or vehicle. Echocardiography, histology, biochemistry, patch-clamp, optical mapping, and RNA-seq were performed.

RESULTS

At day 15 post-LAD-ligation, WT-HF mice displayed fibrosis, impaired wall motion, increased left ventricular diameter in diastole and systole, and decreased left ventricular EF and fractional shortening vs. WT-Sham. Cav1.3 mRNA/protein levels increased in WT-HF mice vs. WT-Sham. At day 30 post-AAV9-Cav1.3-C-terminus-treatment, WT-Sham and Cav1.3+/-HF mice showed increased L-type calcium current vs. vehicle. AAV9-Cav1.3-C-terminus-treated WT-HF mice returned to sinus rhythm after premature stimulation while vehicle-treated WT-HF mice showed arrhythmias such as bigeminy and triplets. Left ventricular EF normalized in both WT-HF and Cav1.3+/-HF mice post-AAV9-Cav1.3-C-terminus-treatment. CACN1D, encoding Cav1.3, was upregulated 1.9-Log2-fold in the AAV9-Cav1.3-C-terminus-treated group vs. vehicle.

CONCLUSIONS

AAV9-Cav1.3-C-terminus-treatment of mice with HF resulted in resistance to inducible arrhythmia and normalization of left ventricular EF, likely via a transcriptional upregulation of Cav1.3 and the resulting optimal increase in L-type calcium current. Therefore, AAV9-Cav1.3-C-terminus may be leveraged as a novel therapeutic approach to improve cardiac function.