Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency
| العنوان: | Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency |
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| المؤلفون: | Walter Birchmeier, Mario Delmar, Feng-Xia Liang, Marina Cerrone, Thomas J. Hund, Halina Chkourko, Harold V.M. van Rijen, Toon A.B. van Veen, Roel van der Nagel, Peter J. Mohler, Maartje Noorman, Xianming Lin |
| المصدر: | Cardiovascular Research. 95:460-468 |
| بيانات النشر: | Oxford University Press (OUP), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | medicine.medical_specialty, Physiology, Action Potentials, Haploinsufficiency, Biology, Sudden death, Sodium Channels, Right ventricular cardiomyopathy, Electrocardiography, Mice, Physiology (medical), Internal medicine, medicine, Animals, Genetic Predisposition to Disease, Myocytes, Cardiac, Flecainide, Arrhythmogenic Right Ventricular Dysplasia, Mice, Knockout, Voltage-Gated Sodium Channel Blockers, Sodium, Original Articles, medicine.disease, Arrhythmogenic right ventricular dysplasia, Perfusion, Disease Models, Animal, Kinetics, Phenotype, Endocrinology, Sodium channel complex, Ventricular fibrillation, Cardiology, Cardiology and Cardiovascular Medicine, Anti-Arrhythmia Agents, Ion Channel Gating, Plakophilins, medicine.drug |
| الوصف: | Aims The shRNA-mediated loss of expression of the desmosomal protein plakophilin-2 leads to sodium current (INa) dysfunction. Whether pkp2 gene haploinsufficiency leads to INa deficit in vivo remains undefined. Mutations in pkp2 are detected in arrhythmogenic right ventricular cardiomyopathy (ARVC). Ventricular fibrillation and sudden death often occur in the ‘concealed phase’ of the disease, prior to overt structural damage. The mechanisms responsible for these arrhythmias remain poorly understood. We sought to characterize the morphology, histology, and ultrastructural features of PKP2-heterozygous-null (PKP2-Hz) murine hearts and explore the relation between PKP2 abundance, INa function, and cardiac electrical synchrony. Methods and results Hearts of PKP2-Hz mice were characterized by multiple methods. We observed ultrastructural but not histological or gross anatomical differences in PKP2-Hz hearts compared with wild-type (WT) littermates. Yet, in myocytes, decreased amplitude and a shift in gating and kinetics of INa were observed. To further unmask INa deficiency, we exposed myocytes, Langendorff-perfused hearts, and anaesthetized animals to a pharmacological challenge (flecainide). In PKP2-Hz hearts, the extent of flecainide-induced INa block, impaired ventricular conduction, and altered electrocardiographic parameters were larger than controls. Flecainide provoked ventricular arrhythmias and death in PKP2-Hz animals, but not in the WT. Conclusions PKP2 haploinsufficiency leads to INa deficit in murine hearts. Our data support the notion of a cross-talk between desmosome and sodium channel complex. They also suggest that INa dysfunction may contribute to generation and/or maintenance of arrhythmias in PKP2-deficient hearts. Whether pharmacological challenges could help unveil arrhythmia risk in patients with mutations or variants in PKP2 remains undefined. |
| تدمد: | 1755-3245 0008-6363 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::06131f54cf59419478731ad6e8bb8a8a https://doi.org/10.1093/cvr/cvs218 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....06131f54cf59419478731ad6e8bb8a8a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17553245 00086363 |
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