scholarly journals Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β

Circulation ◽  
2019 ◽  
Vol 140 (14) ◽  
pp. 1188-1204 ◽  
Author(s):  
Laura Padrón-Barthe ◽  
María Villalba-Orero ◽  
Jesús M. Gómez-Salinero ◽  
Fernando Domínguez ◽  
Marta Román ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Right Ventricular ◽  
Glycogen Synthase ◽  
Transmembrane Protein ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Mutant Mice ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy

Background: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. Methods: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. Results: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition. Conclusions: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.

scholarly journals Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice

ChemMedChem ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. 1593-1602 ◽  
Author(s):  
Alan P. Kozikowski ◽  
Hendra Gunosewoyo ◽  
Songpo Guo ◽  
Irina N. Gaisina ◽  
Richard L. Walter ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Mutant Mice ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Clock Mutant

Left Side Right Ventricular Cardiomyopathy

2002 ◽  
Vol 42 (4) ◽  
pp. 313-317 ◽  
Author(s):  
M Michalodimitrakis ◽  
A Papadomanolakis ◽  
J Stiakakis ◽  
K Kanaki
Keyword(s):  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Pathologic Examination ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy ◽  
First Case ◽  
Fibrofatty Tissue ◽  
Myocardial Muscle

Arrhythmogenic right ventricular cardiomyopathy or dysplasia, a heart muscle disease of unknown cause, is anatomically characterized by variable replacement of myocardial muscle with adipose or fibroadipose tissue. It is usually considered a selective disorder whereas concomitant left ventricular involvement has been noted in a few cases. Two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination are described. Hearts from two patients who died suddenly showed extensive biventricular infiltration by fibrofatty tissue in the first case and exclusively in the wall of the left ventricle the localization of the fatty and fibrotic lesions. These findings might suggest that the various localizations of the fibroadipose tissue are rather different expressions of the same disease and it is preferable to be termed ‘arrhythmogenic cardiomyopathy’ as other studies also indicate.

scholarly journals The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

2010 ◽  
Vol 107 (6) ◽  
pp. 700-714 ◽  
Author(s):  
Mario Delmar ◽  
William J. McKenna
Keyword(s):  
Right Ventricular ◽  
Current Knowledge ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy ◽  
Intercalated Disc ◽  
Disease Phenotypes ◽  
Molecular Pathophysiology ◽  
Pumping Function ◽  
Desmosomal Protein

Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes transforms into the pumping function of the organ. Mechanical continuity is provided by desmosomes and adherens junctions, while gap junctions provide a pathway for passage of ions and small molecules between cells. These complexes preferentially reside at the site of end-end contact between myocytes, within the intercalated disc. Recognition that some forms of arrhythmogenic cardiomyopathy are caused by mutations in desmosomal protein genes has galvanized interest in the biology of the desmosome and its interactions with other junctional molecules. This review presents the cellular and molecular biology of the desmosome, current knowledge on the relation of desmosomal mutations and disease phenotypes, and an overview of the molecular pathophysiology of arrhythmogenic right ventricular cardiomyopathy. Clinical experience and results from cellular and animal models provide insights into the intercalated disc as a functional unit and into the basic substrates that underlie pathogenesis and arrhythmogenesis of arrhythmogenic right ventricular cardiomyopathy.

scholarly journals Clinical Findings and Diagnostic Yield of Arrhythmogenic Cardiomyopathy Through Genomic Screening of Pathogenic or Likely Pathogenic Desmosome Gene Variants

2021 ◽  
Vol 14 (2) ◽  
Author(s):  
Eric D. Carruth ◽  
Dominik Beer ◽  
Amro Alsaid ◽  
Marci L.B. Schwartz ◽  
Megan McMinn ◽  
...  
Keyword(s):  
Family History ◽  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Diagnostic Testing ◽  
Great Promise ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy ◽  
Patient Reported ◽  
Genomic Screening

Background: Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening. Methods: Of 64 548 eligible participants in Geisinger MyCode Genomic Screening and Counseling program (2015–present), 92 individuals (0.14%) identified with pathogenic/likely pathogenic desmosome variants by clinical laboratory testing were referred for evaluation. We reviewed preresult medical history, patient-reported family history, and diagnostic testing results to assess both arrhythmogenic right ventricular cardiomyopathy and left-dominant ACM. Results: One carrier had a prior diagnosis of dilated cardiomyopathy with arrhythmia; no other related diagnoses or diagnostic family history criteria were reported. Fifty-nine carriers (64%) had diagnostic testing in follow-up. Excluding the variant, 21/59 carriers satisfied at least one arrhythmogenic right ventricular cardiomyopathy task force criterion, 11 (52%) of whom harbored DSP variants, but only 5 exhibited multiple criteria. Six (10%) carriers demonstrated evidence of left-dominant ACM, including high rates of atypical late gadolinium enhancement by magnetic resonance imaging and nonsustained ventricular tachycardia. Two individuals received new cardiomyopathy diagnoses and received defibrillators for primary prevention. Conclusions: Genomic screening for pathogenic/likely pathogenic variants in desmosome genes can uncover both left- and right-dominant ACM. Findings of overt cardiomyopathy were limited but were most common in DSP -variant carriers and notably absent in PKP2 -variant carriers. Consideration of the pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate in the setting of genomic screening.

scholarly journals Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy

2021 ◽  
Vol 10 (1) ◽  
pp. 26-32
Author(s):  
Ryan Wallace ◽  
Hugh Calkins
Keyword(s):  
Ventricular Arrhythmia ◽  
Risk Stratification ◽  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Young Population ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy ◽  
Increased Risk ◽  
Fibrofatty Tissue

Arrhythmogenic right ventricular cardiomyopathy (ARVC), also called arrhythmogenic right ventricular dysplasia or arrhythmogenic cardiomyopathy, is a genetic disease characterised by progressive myocyte loss with replacement by fibrofatty tissue. This structural change leads to the prominent features of ARVC of ventricular arrhythmia and increased risk for sudden cardiac death (SCD). Emphasis should be placed on determining and stratifying the patient’s risk of ventricular arrhythmia and SCD. ICDs should be used to treat the former and prevent the latter, but ICDs are not benign interventions. ICDs come with their own complications in this overall young population of patients. This article reviews the literature regarding the factors that contribute to the assessment of risk stratification in ARVC patients.

scholarly journals Left Ventricular Dysfunction in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): Can We Separate ARVC From Other Arrhythmogenic Cardiomyopathies?

2020 ◽  
Vol 9 (23) ◽  
Author(s):  
Stephan Altmayer ◽  
Saman Nazarian ◽  
Yuchi Han
Keyword(s):  
Young Adults ◽  
Right Ventricular ◽  
Cause Of Death ◽  
Ventricular Dysfunction ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Left Ventricular ◽  
The Other ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy ◽  
Advanced Imaging

Abstract Arrhythmogenic right ventricular cardiomyopathy was first described as a right ventricular disease that is an important cause of death in young adults. However, with the advent of advanced imaging, arrhythmogenic right ventricular cardiomyopathy has been found to commonly have biventricular involvement, and a small portion of patients have left ventricular–dominant forms. On the other hand, a number of primarily left ventricular disease such as sarcoid and myocarditis can be arrhythmogenic and have right ventricular involvement. A few recent publications on arrhythmogenic right ventricular cardiomyopathy cohorts have average left ventricular functions that are comparable to sarcoid or myocarditis cohorts. We review the current literature and compare these cohorts of patients, and call for left ventricular functional criteria for arrhythmogenic right ventricular cardiomyopathy as inherited arrhythmogenic cardiomyopathy.

scholarly journals Right ventricular arrhythmogenic cardiomyopathy

2021 ◽  
pp. 38-42
Author(s):  
V. Y. Tseluyko ◽  
O. O. Butko
Keyword(s):  
Sudden Cardiac Death ◽  
Right Ventricular ◽  
Cardiac Death ◽  
Clinical Presentation ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy ◽  
Death Risk ◽  
Basic Approaches ◽  
Sudden Cardiac Death Risk

The article describes the questions of prevalence, etiology and pathogenesis, clinical presentation, instrumental diagnostics of arrhythmogenic right ventricular cardiomyopathy (ARVC). Diagnostic criteria, sudden cardiac death risk stratification in patients with ARVC and basic approaches in the treatment of this disease are proposed.

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