Academic Journal
Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart
| العنوان: | Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart |
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| المؤلفون: | Park, David S., Shekhar, Akshay, Santucci, John, Redel-Traub, Gabriel, Solinas, Sergio, Mintz, Shana, Lin, Xianming, Chang, Ernest Whanwook, Narke, Deven, Xia, Yuhe, Goldfarb, Mitchell, Fishman, Glenn I. |
| المساهمون: | HHS | NIH | National Heart, Lung, and Blood Institute, Fondation Leducq |
| المصدر: | Circulation Research ; volume 127, issue 12, page 1536-1548 ; ISSN 0009-7330 1524-4571 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health) |
| سنة النشر: | 2020 |
| الوصف: | Rationale: FHFs (fibroblast growth factor homologous factors) are key regulators of sodium channel (Na V ) inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced Na v availability in Fhf2 knockout ( Fhf2 KO ) mice predisposes to abnormal excitability at the tissue level are not well defined. Objective: Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction. Methods and Results: Fhf2 KO mice were challenged by reducing calcium conductance (gCa V ) using verapamil or by reducing gap junctional conductance (Gj) using carbenoxolone or by backcrossing into a cardiomyocyte-specific Cx43 (connexin 43) heterozygous background. All conditions produced conduction block in Fhf2 KO mice, with Fhf2 wild-type ( Fhf2 WT ) mice showing normal impulse propagation. To explore the ionic mechanisms of block in Fhf2 KO hearts, multicellular linear strand models incorporating FHF2-deficient Na v inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced gCa V or diminished Gj are very different. Enhanced Na v inactivation due to FHF2 deficiency shifts dependence onto calcium current (I Ca ) to sustain electrotonic driving force, axial current flow, and action potential (AP) generation from cell-to-cell. In the setting of diminished Gj, slower charging time from upstream cells conspires with accelerated Na v inactivation in mutant strands to prevent sufficient downstream cell charging for AP propagation. Conclusions: FHF2-dependent effects on Na v inactivation ensure adequate sodium current (I Na ) reserve to safeguard against numerous threats to reliable cardiac impulse propagation. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1161/circresaha.120.317349 |
| DOI: | 10.1161/CIRCRESAHA.120.317349 |
| الاتاحة: | http://dx.doi.org/10.1161/circresaha.120.317349 https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.120.317349 |
| رقم الانضمام: | edsbas.4DFF5659 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1161/circresaha.120.317349 |
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