Rachel Inselmann

Introduction. Arrhythmogenic Cardiomyopathy (ACM) is a leading cause of ventricular arrhythmias in previously healthy, young individuals which can result in Sudden Cardiac Death (SCD).¹  Mutations in the desmosomal protein, Plakophilin-2 (PKP2), is the most common cause of ACM, resulting in dysfunction of cell-to-cell adhesions and intracellular gap junctions, including calcium mishandling.^1,2,3 Some patients continue to experience life-threatening arrhythmias despite medication and catheter ablation.  Methods. Cardiomyocyte-Specific, tamoxifen activated PKP2 knockout mice (PKP2cKO) were used to control the onset of PKP2 expression, limit to adult myocytes, and monitor closely the time line for the development of ACM.^4,5 Right Ventricular (RV) dysfunction was identified as the first manifestation of the disease in PKP2cKO mice at 14 days post tamoxifen injection (dpi), followed by fibrosis of RV, and eventually biventricular dilated cardiomyopathy and end-stage failure.⁵ Electrocardiograms (ECGs) were performed on PKP2cKO mice and controls to detect spontaneous premature ventricular contractions (PVCs) during an Isoproterenol-induced challenge (ISO). Using single molecule localization microscopy, the average RyR2 cluster size, percentage of super clusters (2 small RyR2 within 100nm that have increased probability of propagating Ca2+), and density of RyR2 clusters was reported in the control and PKP2cKO myocytes.⁴  Results. Previous studies have shown that the Class IC antiarrhythmic, Flecainide, blocks the RyR2 receptor. With this knowledge, a small study of 8 patients with ACM who have uncontrolled arrhythmias after unsuccessful single-agent therapy and/or catheter ablation were monitored with device interrogations that detected major ventricular arrhythmias. Frequency of ventricular tachycardia arrhythmias before and after combination therapy of flecainide and sotalol/metoprolol were investigated in a clinical trial.⁸  The ISO challenge did not increase arrhythmia burden at 14 dpi, but showed high arrhythmia susceptibility at 21 dpi and after. The size of PKP2cKO RyR2 clusters were significantly smaller, but there were a higher percentage of super clusters and the density of RyR2 units within a cluster was significantly larger in PKP2cKO cells compared to the control, likely facilitating cross-activation of Ca2+ induced Ca2+ release.⁴ The Flecainide study showed 6 of the 8 patients experienced no significant recurrent arrhythmias in an average of 35.5 month follow-up period.⁶  Conclusions. In the PKP2cKO mice, data showed that there were increased number of PVCs and changes in expression of RyR2 receptor that resulted in super clusters of RyR2, affecting Ca2+ regulation. ⁴ Flecainide likely mechanism of action for ACM patients involves blocking the RyR2 receptor release of Ca2+, thereby preventing life threatening ventricular arrhythmias.

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