Molecular Composition of the Intercalated Disc in a Spontaneous Canine Animal Model of Arrhythmogenic Right Ventricular Dysplasia/cardiomyopathy

Overview

Journal Heart Rhythm

Publisher Elsevier

Specialty Cardiology & Vascular Diseases

Date 2007 Sep 4

PMID 17765621

Citations 27

Authors

Eva M Oxford

Melanie Everitt

Wanda Coombs

Philip R Fox

Marc Kraus

Anna R M Gelzer

Jeffrey Saffitz

Steven M Taffet

N Sydney Moise

Mario Delmar

Affiliations

Soon will be listed here.

Abstract

Background: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by ventricular arrhythmias, sudden death, and fatty or fibrofatty replacement of right ventricular myocytes. Recent studies have noted an association between human ARVD/C and molecular remodeling of intercalated disc structures. However, progress has been constrained by limitations inherent to human studies.

Objective: We studied the molecular composition of the intercalated disc structure in a naturally occurring animal model of ARVD/C (Boxer dogs).

Methods: We studied hearts from 12 Boxers with confirmed ARVD/C and 2 controls. Ventricular sections from 4 animals were examined by immunofluorescent microscopy. Frozen tissue samples were used for Western blot analysis. Proteins investigated were N-cadherin, plakophilin 2, desmoplakin, plakoglobin, desmin, and connexin 43 (Cx43).

Results: In control dogs, all proteins tested by immunofluorescence analysis yielded intense localized signals at sites of end-to-end cell apposition. In contrast, myocardial tissues from ARVD/C-afflicted Boxers showed preservation of N-cadherin staining but loss of detectable signal for Cx43 at the intercalated disc location. Western blots indicated that the Cx43 protein was still present in the samples. Gene sequencing analysis showed no mutations in desmoplakin, plakoglobin, Cx43, or plakophilin 2.

Conclusion: Mutation(s) responsible for ARVD/C in Boxers lead, directly or indirectly, to severe modifications of mechanical and electrical cell-cell interactions. Furthermore, significant reduction in gap junction formation may promote a substrate for malignant ventricular arrhythmias. This model may help to advance our understanding of the molecular basis, pathophysiology, and potential therapeutic approach to patients with ARVD/C.

Citing Articles

Evaluation of autoantibodies to desmoglein-2 in dogs with and without cardiac disease.

Walker A, Li R, Nguyen N, Jauregui C, Meurs K, Gagnon A Sci Rep. 2023; 13(1):5044.

PMID: 36977772 PMC: 10043840. DOI: 10.1038/s41598-023-32081-x.

Immunofluorescent Localization of Plakoglobin Is Altered in Endomyocardial Biopsy Samples from Dogs with Clinically Relevant Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).

Oxford E, Pariaut R, Tursi M, Fox P, Santilli R Vet Sci. 2021; 8(11).

PMID: 34822621 PMC: 8623220. DOI: 10.3390/vetsci8110248.

Translational Models of Arrhythmia Mechanisms and Susceptibility: Success and Challenges of Modeling Human Disease.

Piktel J, Wilson L Front Cardiovasc Med. 2019; 6:135.

PMID: 31552276 PMC: 6748164. DOI: 10.3389/fcvm.2019.00135.

Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome.

Salman O, El-Rayess H, Abi Khalil C, Nemer G, Refaat M Front Cardiovasc Med. 2018; 5:77.

PMID: 29998127 PMC: 6028572. DOI: 10.3389/fcvm.2018.00077.

At the heart of inter- and intracellular signaling: the intercalated disc.

Manring H, Dorn L, Ex-Willey A, Accornero F, Ackermann M Biophys Rev. 2018; 10(4):961-971.

PMID: 29876873 PMC: 6082301. DOI: 10.1007/s12551-018-0430-7.

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