Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. |
| Authors: |
Noorman, M Hakim, S Kessler, E Groeneweg, JA Cox, MG Asimaki, A Van Rijen, HV Van Stuijvenberg, L Chkourko, H Van der Heyden, MA Vos, MA De Jonge, N Van der Smagt, JJ Dooijes, D Vink, A De Weger, RA Varro, A De Bakker, JM Saffitz, JE Hund, TJ Mohler, PJ Delmar, M Hauer, RN Van Veen, TA
|
| Citation: |
Noorman M, etal., Heart Rhythm. 2013 Mar;10(3):412-9. doi: 10.1016/j.hrthm.2012.11.018. Epub 2012 Nov 23. |
| RGD ID: |
11352402 |
| Pubmed: |
PMID:23178689 (View Abstract at PubMed) |
| PMCID: |
PMC3608196 (View Article at PubMed Central) |
| DOI: |
DOI:10.1016/j.hrthm.2012.11.018 (Journal Full-text) |
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is closely associated with desmosomal mutations in a majority of patients. Arrhythmogenesis in patients with AC is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. OBJECTIVE: To assess the immunoreactive signal levels of the sodium channel protein NaV1.5, as well as connexin43 (Cx43) and plakoglobin (PKG), in myocardial specimens obtained from patients with AC. METHODS: Left and right ventricular free wall postmortem material was obtained from 5 patients with AC and 5 controls matched for age and sex. Right ventricular septal biopsies were taken from another 15 patients with AC. All patients fulfilled the 2010 revised Task Force Criteria for the diagnosis of AC. Immunohistochemical analyses were performed using antibodies against Cx43, PKG, NaV1.5, plakophilin-2, and N-cadherin. RESULTS: N-cadherin and desmoplakin immunoreactive signals and distribution were normal in patients with AC compared to controls. Plakophilin-2 signals were unaffected unless a plakophilin-2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to that in controls. Immunoreactive signal levels of PKG, Cx43, and NaV1.5 were disturbed in 74%, 70%, and 65% of the patients, respectively. CONCLUSIONS: A reduced immunoreactive signal of PKG, Cx43, and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.
|
| Genes (Rattus norvegicus) |
 |
| Gja1 (gap junction protein, alpha 1) | Jup (junction plakoglobin) | Scn5a (sodium voltage-gated channel alpha subunit 5) |
| Genes (Mus musculus) |
|
| Gja1 (gap junction protein, alpha 1) | Jup (junction plakoglobin) | Scn5a (sodium channel, voltage-gated, type V, alpha) |
| Genes (Homo sapiens) |
|
| GJA1 (gap junction protein alpha 1) | JUP (junction plakoglobin) | SCN5A (sodium voltage-gated channel alpha subunit 5) |
|
|
|
