Probing the Effects of Calmodulinopathy Mutations on Cav2.1 Channels

Abstract

Cardiotoxicity is a major complication of anthracycline-based cancer therapy, which leads in time to progressive electro-mechanical dysfunction, irreversible myocardial tissue remodeling and heart failure. We are developing novel preclinical large animal models to study early structural and functional cardiotoxic effects induced by doxorubicin (DOX) chemotherapy. In this pilot study, a weekly 1mg/kg dose of DOX was injected intravenously in n=4 pigs, during a four-week treatment. MR imaging was performed pre-DOX and post-DOX therapy (i.e., at: 1, 5 and 9 weeks after ending DOX injections) using a scanning protocol at 3T that included: left ventricle function quantification (i.e., ejection fraction and strain), gadolinium-based contrast-enhanced T1-mapping MR methods at 1.4mm isotropic resolution for diffuse fibrosisdetection, and T2mapping of edema/inflammation. Our results showed that compared to mean baseline values pre-DOX, ejection fraction gradually decreased from 47% to 34% post-DOX while global longitudinal strain decreased by $5%, indicating that the cardiac biomechanical function started to deteriorate within 9 weeks post-DOX. The initially increased T2-derived edema at week 5 appeared to resolve by week 9, as confirmed by H&E histological stains. Furthermore, subtle patches of diffuse fibrosis were detected by contrast-enhanced MRI only at week 9 but not at week 5, and confirmed by collagen-sensitive Masson Trichrome histological stains. Lastly, in two pigs we recorded endocardial bipolar voltage maps 9 weeks post-DOX and revealed the presence of small scattered tissue patches with low voltages (<1.5mV). In these 2 pigs we also induced ventricular fibrillation via rapid pacing, suggesting that gradual deposition of DOX-induced diffuse fibrosis increases vulnerability to arrhythmia. These novel results will help us establish image-based biophysical models to predict early DOX-mediated cardiotoxicity, and will help clinicians conduct studies on cardioprotective strategies to prevent malignant arrhythmia and heart failure progression.