Cardiomyocyte Hypertrophy in Arrhythmogenic Cardiomyopathy.
Arrhythmogenic cardiomyopathy (AC) is a hereditary disease leading to sudden cardiac death or heart failure. AC pathology is characterized by cardiomyocyte loss and replacement fibrosis. Our goal was to determine whether cardiomyocytes respond to AC progression by pathological hypertrophy. To this end, we examined tissue samples from AC patients with end-stage heart failure and tissue samples that were collected at different disease stages from desmoglein 2-mutant mice, a well characterized AC model. We find that cardiomyocyte diameters are significantly increased in right ventricles of AC patients. Increased mRNA expression of the cardiac stress marker natriuretic peptide B is also observed in the right ventricle of AC patients. Elevated myosin heavy chain 7 mRNA expression is detected in left ventricles. In desmoglein 2-mutant mice, cardiomyocyte diameters are normal during the concealed disease phase but increase significantly after acute disease onset on cardiomyocyte death and fibrotic myocardial remodeling. Hypertrophy progresses further during the chronic disease stage. In parallel, mRNA expression of myosin heavy chain 7 and natriuretic peptide B is up-regulated in both ventricles with right ventricular preference. Calcineurin/nuclear factor of activated T cells (Nfat) signaling, which is linked to pathological hypertrophy, is observed during AC progression, as evidenced by Nfatc2 and Nfatc3 mRNA in cardiomyocytes and increased mRNA of the Nfat target regulator of calcineurin 1. Taken together, we demonstrate that pathological hypertrophy occurs in AC and is secondary to cardiomyocyte loss and cardiac remodeling.
Institutes for Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
Mustafa
M
Gerçek
Institutes for Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
Muhammed
M
Gerçek
Institutes for Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
Sebastian
S
Kant
Institute of Pharmacology and Clinical Pharmacology, Heinrich Heine University, Düsseldorf, Germany.
Sakine
S
Simsekyilmaz
Heart and Diabetes Center North Rhine-Westphalia, Erich and Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany.
Astrid
A
Kassner
Heart and Diabetes Center North Rhine-Westphalia, Erich and Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany.
Hendrik
H
Milting
Institute for Molecular Cardiovascular Research and Interdisciplinary Center for Clinical Research Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
Elisa A
EA
Liehn
Institutes for Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
Rudolf E
RE
Leube
Institutes for Molecular and Cellular Anatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany. Electronic address: ckrusche@ukaachen.de.
Claudia A
CA
Krusche
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D020013:Calcium Signaling / Q000235:genetics; D006332:Cardiomegaly / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D009202:Cardiomyopathies / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D048429:Cell Size; D051301:Desmoglein 2 / Q000378:metabolism; D004106:Dilatation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000473:pathology; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009336:Necrosis; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D051301:Desmoglein 2; C495315:Dsg2 protein, mouse; D007074:Immunoglobulin G; C551613:Myh7 protein, mouse; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D018995:Myosin Heavy Chains