Abstract 12587: Sodium Current Deficit and Arrhythmogenesis in a Murine Model of Plakophilin-2 Haploinsufficiency
Mutations in desmosomal protein Plakophilin 2 (PKP2) associate with arrhythmogenic cardiomyopathy (“ARVC”). Cardiac arrhythmias and sudden death can occur in the “concealed” phase of the disease, prior to overt structural damage. The mechanisms underlying these arrhythmias are not understood. Based on previous in vitro data showing cross-talk between PKP2 and the sodium channel (SC) complex, we propose that a decrease in PKP2 causes sodium current (INa) dysfunction, which predisposes the heart to severe arrhythmias if the SC is further challenged. We studied the morphology, histology and ultrastructural features of PKP2-heterozygous-null (PKP2-Hz) murine hearts, and explored the relation between PKP2 abundance, INa and arrhythmias. PKP2-Hz hearts did not show anatomical or histological differences compared to wild-type (WT). Western blot revealed reduced abundance of PKP2, without changes in abundance of other intercalated disc proteins. Tomographic electron microscopy showed loss of desmosomes and expanded intercellular space coinciding with membrane invaginations in the intercalated disc. Voltage clamp revealed decreased amplitude and shift in gating and kinetics of INa. To unmask INa deficiency, we exposed myocytes, isolated hearts and anesthetized animals to a flecainide challenge. The extent of flecainide-induced INa block was greater in PKP2-Hz than in WT myocytes (p<0.05 for 1, 10, 100 uM tested). Flecainide caused a significant decrease in conduction velocity in the right ventricle of PKP2-Hz compared to WT. In vivo, PKP2-Hz showed longer P, PR, QRS and QTc duration (p<0.01 at 5’ or 10’) than WT mice. Most relevant, 6/12 (50%) PKP2-Hz showed ventricular arrhythmias, with arrhythmic death in 3/6 animals. All WT animals survived the procedure without showing any arrhythmias. Our data show for the first time that decreased PKP2 leads to INa deficit in murine hearts. We propose that INa dysfunction can contribute to generation and/or maintenance of arrhythmias in PKP2-deficient hearts, in the absence of overt structural disease. Our data call for caution on use of sodium channel blockers as therapy in patients with PKP2 mutations. Whether pharmacological challenges can help unveil arrhythmia risk in these patients, remains undefined.
- © 2012 by American Heart Association, Inc.