RARE DISEASE
Inherited isolated arrhythmogenic cardiomyopathy
Inherited isolated arrhythmogenic cardiomyopathy
Inherited isolated arrhythmogenic cardiomyopathy
Synonyms: ACM, Familial isolated arrhythmogenic right ventricular dysplasia
Synonyms: ACM, Familial isolated arrhythmogenic right ventricular dysplasia
Synonyms: ACM, Familial isolated arrhythmogenic right ventricular dysplasia
Drug discovery
3
drugs
With orphan designations
Overview
Inherited isolated arrhythmogenic cardiomyopathy is a genetic disorder characterized by fibro-fatty replacement of right ventricular myocardium, predisposing to life-threatening ventricular arrhythmias. Associated with autosomal dominant desmosomal gene mutations, it manifests with palpitations, syncope, and sudden cardiac death (SCD), particularly in young individuals and athletes. Diagnosis relies on clinical criteria, imaging, and genetic testing [2][6][12].
Therapies
ICD implantation for primary/secondary SCD prevention (48–78% efficacy in terminating arrhythmias) [3][6].
Antiarrhythmics (sotalol, amiodarone) and β-blockers to reduce ventricular arrhythmias [2][8].
Catheter ablation for recurrent VT; heart transplantation in refractory heart failure/arrhythmias [3][4][12].
Lifestyle restrictions (avoidance of competitive sports) [2][6].
Categories: rare cardiac diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
112 drug discovery papers about Inherited isolated arrhythmogenic cardiomyopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
112 drug discovery papers about Inherited isolated arrhythmogenic cardiomyopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-31 | Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK ‐3β, Resulting in a Loss of Cardiomyocyte Cohesion
ABSTRACT Background Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac desmosome disease, as more than 50% of affected patients carry pathogenic variants in desmosome protein‐coding genes. In this study, we focused on the role and mechanisms of pathogenic and non‐pathogenic autoantibodies against intercalated disc (ICD) proteins such as desmoglein2 (DSG2) in ACM patients, healthy relatives (HR), and murine ACM models. Materials and Methods IgG fractions from ACM patients, HR, healthy controls, and murine ACM models were isolated. Besides ELISA and cleavage assay, dissociation assay, immunostaining, Triton‐X‐100 assay, Western blots, and atomic force microscopy were performed in murine cardiac slices, HL‐1 cells, or induced pluripotent stem cells‐derived cardiomyocytes (hiPSC‐CMs). Results IgG fractions from ACM patients and HR, but not murine ACM model‐derived or grouped healthy controls IgG (G‐HC), revealed positive ICD staining. Three out of six ACM patients derived IgGs that reduced cardiomyocyte cohesion. Pathogenic autoantibodies, bound to DSG2 in healthy and ACM hiPSC‐CMs, cleaved and reduced DSG2 interaction at the molecular level. We investigated GSK‐3β contribution to the cardiomyocyte cohesion loss and observed GSK‐3β reduced baseline cohesion in cultured cardiomyocytes and cardiac slices. Among five ACM‐IgGs, three HR‐IgGs tested, three pathogenic ACM‐IgGs activated GSK‐3β upstream of p38MAPK, leading to phosphorylation and junctional loss of β‐catenin. GSK‐3β inhibition rescued the loss of cell cohesion in ACM hiPSC‐CMs. Conclusion Pathogenic autoantibodies targeting DSG2 are present in ACM patients and impair cardiomyocyte cohesion in a GSK‐3β‐dependent manner. In contrast, autoantibodies are absent in murine ACM models and are non‐pathogenic in some patients and HR.
2025-11-04 | Apremilast improves cardiomyocyte cohesion and arrhythmia in different models for arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is a genetically inherited desmosome heart disease leading to life-threatening arrhythmias and sudden cardiac death. Currently, ACM treatment paradigms are merely symptom targeting. Recently, apremilast was shown to stabilize keratinocyte adhesion in the desmosomal disease pemphigus vulgaris. Therefore, this study investigated whether apremilast can be a therapeutic option for ACM. Human induced pluripotent stem cells from a healthy control (hiPSC) and an ACM index patient (ACM-hiPSC) carrying a heterozygous desmoplakin (DSP) gene mutation (c.2854G > T, p.Glu952Ter), confirmed by whole exome sequencing (WES), were established. Cyclic-AMP ELISA, dissociation assay, immunostaining, and Western blotting analyses were performed in human iPSC-derived cardiomyocytes (hiPSC-CMs), murine HL-1 cardiomyocytes, and cardiac slices derived from wild-type (WT) mice, plakoglobin (PG, Jup) knockout (Jup-/-) (murine ACM model) or PG Serine 665 phosphodeficient (JUP-S665A) mice. Microelectrode array (MEA) analyses in ventricular cardiac slices and Langendorff heart perfusion were performed to analyze heart rate variability and arrhythmia. ACM-hiPSC derived cardiomyocytes (ACM-hiPSC-CMs) revealed a significant loss of cohesion, which was rescued by apremilast. Further, treatment with apremilast strengthened basal cardiomyocyte cohesion in HL-1 cells and WT murine cardiac slices, paralleled by phosphorylation of PG at Serine 665 in human and murine models. In HL-1 cells, apremilast in addition activated ERK1/2, inhibition of which abolished apremilast-enhanced cardiomyocyte cohesion. Further, dissociation assays in slice cultures from JUP-S665A and Jup-/- mice revealed that PG is crucial for apremilast-enhanced cardiomyocyte cohesion. In parallel to enhanced cell adhesion, MEA and Langendorff measurements from WT and Jup-/- mice demonstrated decreased heart rate variability and arrhythmia after apremilast treatment. Apremilast improves loss of cardiomyocyte cohesion, enhances localization of DSG2, and reduces arrhythmia in human and/or murine models of ACM ex vivo and in vitro, providing a novel treatment strategy for ACM by preserving desmosome function.
2025-04-27 | Peritoneal dialysis in congestive heart failure: reflections from a patient with arrhythmogenic right ventricular cardiomyopathy.
After multiple hospitalisations for diuretic-resistant acute decompensated heart failure (ADHF), an early 60s man with isolated right-sided heart failure due to arrhythmogenic right ventricular cardiomyopathy (ARVC) underwent continuous venovenous haemofiltration without lasting success. His blood urea nitrogen/creatinine ratio was high and renal blood flow and filtration fraction were low, indicative of the underlying cardiorenal dysbalance. Peritoneal dialysis (PD) was initiated because this form of renal replacement therapy provides better haemodynamic stability and a flexible schedule. This allowed the patient to maintain his professional activities and spend time with his family for the subsequent 7 months. Following a diabetic foot infection, his condition worsened, leading to his death. Autopsy showed fibrofatty replacement of the right ventricle and chronic ischaemic nephropathy, without signs of hypertensive or diabetic nephropathy.Although ARVC is rare, this case underscores the potential benefits of PD as a palliative option in end-stage heart failure. Early consideration of PD, particularly when other renal replacement therapies are limited or contraindicated, may alleviate symptoms and enhance quality of life, especially after repeated hospitalisations for heart failure and kidney injury. Collaborative care between cardiologists and nephrologists is essential for optimising management in these patients.
2024-09-04 | Hyperactivation of ATF4/TGF-β1 signaling contributes to the progressive cardiac fibrosis in Arrhythmogenic cardiomyopathy caused by DSG2 Variant.
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized with progressive cardiac fibrosis and heart failure. However, the exact mechanism driving the progression of cardiac fibrosis and heart failure in ACM remains elusive. This study aims to investigate the underlying mechanisms of progressive cardiac fibrosis in ACM caused by newly identified Desmoglein-2 (DSG2) variation. We identified homozygous DSG2F531C variant in a family with 8 ACM patients using whole-exome sequencing and generated Dsg2F536C knock-in mice. Neonatal and adult mouse ventricular myocytes isolated from Dsg2F536C knock-in mice were used. We performed functional, transcriptomic and mass spectrometry analyses to evaluate the mechanisms of ACM caused by DSG2F531C variant. All eight patients with ACM were homozygous for DSG2F531C variant. Dsg2F536C/F536C mice displayed cardiac enlargement, dysfunction, and progressive cardiac fibrosis in both ventricles. Mechanistic investigations revealed that the variant DSG2-F536C protein underwent misfolding, leading to its recognition by BiP within the endoplasmic reticulum, which triggered endoplasmic reticulum stress, activated the PERK-ATF4 signaling pathway and increased ATF4 levels in cardiomyocytes. Increased ATF4 facilitated the expression of TGF-β1 in cardiomyocytes, thereby activating cardiac fibroblasts through paracrine signaling and ultimately promoting cardiac fibrosis in Dsg2F536C/F536C mice. Notably, inhibition of the PERK-ATF4 signaling attenuated progressive cardiac fibrosis and cardiac systolic dysfunction in Dsg2F536C/F536C mice. Hyperactivation of the ATF4/TGF-β1 signaling in cardiomyocytes emerges as a novel mechanism underlying progressive cardiac fibrosis in ACM. Targeting the ATF4/TGF-β1 signaling may be a novel therapeutic target for managing ACM.
2024-02-08 | GSK3 inhibition ameliorates the abnormal contractility of Newfoundland ACM patient iPSC-cardiomyocytes
Abstract Arrhythmogenic Cardiomyopathy (ACM) is clinically characterized by ventricular arrhythmias causing sudden cardiac death and fibrofatty replacement of the myocardium leading to heart failure. One form of ACM is highly prevalent in the Canadian Province of Newfoundland and Labrador (NL) and has earned the moniker, The “Newfoundland Curse”. This ACM in NL patients is often caused by a fully penetrant heterozygous missense mutation in the TMEM43 gene ( TMEM43 c.1073C>T; TMEM43 p.S358L). Although the causative mutation has been identified, little is known about the function of the TMEM43 protein in cardiomyocytes, how the TMEM43 p.S358L mutation contributes to the development of arrhythmias, or why the disease is more severe in males than females. To explore the role of TMEM43 in cardiomyocyte function, we generated induced pluripotent stem cells (iPSCs) from 2 severely affected male Newfoundland ACM (TMEM43 p.S358L) patients. CRISPR-Cas9 was used to genetically “repair” the heterozygous TMEM43 mutation in ACM patient iPSCs or for TMEM43 gene knockout. ACM patient iPSC-cardiomyocytes with the TMEM43 p.S358L mutation display pro-arrhythmogenic phenotypes in vitro with significantly elevated contraction rates and altered calcium handling, although no obvious gross abnormalities were observed across several major intracellular organelles. TMEM43 protein abundance and half-life appears unchanged in ACM iPSC-CMs where 50% of the TMEM43 protein is WT and 50% is mutant. Gene expression analysis of ACM iPSC-CMs shows an increase in genes related to signaling and metabolism. Importantly, the pro-arrhythmic tendencies of ACM patient iPSC-CMs can be ameliorated with transient GSK3 inhibition.
cell therapies
2023-06-22 | Biological Modification of Arrhythmogenic Substrates by Cell-Free Therapeutics
Ventricular arrhythmias (VAs) represent a major cause of sudden cardiac death and afflict patients with heart failure from both ischaemic and non-ischaemic origins, and inherited cardiomyopathies. Current VA management, including anti-arrhythmic medications, autonomic modulation, implantable cardioverter–defibrillator implantation, and catheter ablation, remains suboptimal. Catheter ablation may even cause significant cardiomyocyte loss. Cell-based therapies and exosome treatment have been proposed as promising strategies to lessen cardiomyocyte death, modulate immune reaction, and reduce myocardial scarring, and, therefore, are potentially beneficial in treating VAs. In this review, we summarise the current cornerstones of VA management. We also discuss recent advances and ongoing evidence regarding cell-based and exosome therapy, with special attention to VA treatment.
2015-03-24 | Isolation and Characterization of Embryonic Stem Cell-Derived Cardiac Purkinje Cells
Abstract The cardiac Purkinje fiber network is composed of highly specialized cardiomyocytes responsible for the synchronous excitation and contraction of the ventricles. Computational modeling, experimental animal studies, and intracardiac electrical recordings from patients with heritable and acquired forms of heart disease suggest that Purkinje cells (PCs) may also serve as critical triggers of life-threatening arrhythmias. Nonetheless, owing to the difficulty in isolating and studying this rare population of cells, the precise role of PC in arrhythmogenesis and the underlying molecular mechanisms responsible for their proarrhythmic behavior are not fully characterized. Conceptually, a stem cell-based model system might facilitate studies of PC-dependent arrhythmia mechanisms and serve as a platform to test novel therapeutics. Here, we describe the generation of murine embryonic stem cells (ESC) harboring pan-cardiomyocyte and PC-specific reporter genes. We demonstrate that the dual reporter gene strategy may be used to identify and isolate the rare ESC-derived PC (ESC-PC) from a mixed population of cardiogenic cells. ESC-PC display transcriptional signatures and functional properties, including action potentials, intracellular calcium cycling, and chronotropic behavior comparable to endogenous PC. Our results suggest that stem-cell derived PC are a feasible new platform for studies of developmental biology, disease pathogenesis, and screening for novel antiarrhythmic therapies. Stem Cells 2015;33:1102–1112
2013-12-03 | Induced pluripotent stem cells as cardiac arrhythmic in vitro models and the impact for drug discovery.
Introduction: The development of new antiarrhythmic agents is challenging and is hampered by high attrition rate of novel drug candidates. One of the reasons for this is limited predictability of existing preclinical models for drug assessment. Cardiomyocytes (CMs) derived from disease-specific induced pluripotent stem cells (iPSC) represent a novel in vitro cellular model of cardiac arrhythmias with an unprecedented potential for generating new mechanistic insight into disease pathophysiology and improving the process of drug development. Areas covered: This review outlines recent studies demonstrating the suitability and limitations of iPSC-derived CMs (iPS-CMs) for in vitro modeling inherited arrhythmias and drug testing. The authors focus on channelopathies and outline the properties of iPS-CMs, highlighting their utility and limitations for investigating the mechanism of cardiac arrhythmias and drug discovery. Expert opinion: The iPS-CMs represent a valuable addition to the already existing armamentarium of cardiac arrhythmic models. However, the superiority of iPS-CMs over other arrhythmia models has not yet been rigorously established and the limitations of the model must be overcome before its full potential for antiarrhythmic drug discovery can be realized. Nevertheless, iPS cell-based platforms hold a great potential for increasing our knowledge about cellular arrhythmia mechanisms and improving the drug discovery process.
2011-02-01 | Use of Mouse Models to Evaluate Novel Therapeutic Approaches to Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy
Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy that is characterized by ventricular arrhythmias, an increased risk of sudden death, and abnormalities of right ventricular (RV) structure and function. The pathological hallmark of ARVD is myocyte loss with fibro-fatty
oligonucleotides
2023-05-01 | PO-01-123 THE BIOPHYSICAL ACTION OF MICRORNA IS ESSENTIAL TO MAINTAIN THE NORMAL FUNCTION AND ELECTROPHYSIOLOGY OF THE HEART
MicroRNAs (miRs) regulate most (if not all) biological events via a broadly-recoginized RNA interference (RNAi) mechnism. miR1, encoded by miR1-1 and miR1-2 genes, is the predominant miRs of the heart and plays critical roles in heart development and cardiac diseases. Previous studies of miRs have focused on the canonical RNAi mechanism. Recently, we discovered a novel biophysical action of miR and found that miR1 directly binds to ion channels physically modulates the electrophysiology of cardiomyocytes.
2021-02-04 | Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy
Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combinations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from "bench to bedside" can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel "personalized" therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby represents another example for the complex genetic and phenotypic continuum of these diseases.
2020-05-08 | Gene Therapy for the Heart Lessons Learned and Future Perspectives
While clinical gene therapy celebrates its first successes, with several products already approved for clinical use and several hundreds in the final stages of the clinical approval pipeline, there is not a single gene therapy approach that has worked for the heart. Here, we review the past experience gained in the several cardiac gene therapy clinical trials that had the goal of inducing therapeutic angiogenesis in the ischemic heart and in the attempts at modulating cardiac function in heart failure. Critical assessment of the results so far achieved indicates that the efficiency of cardiac gene delivery remains a major hurdle preventing success but also that improvements need to be sought in establishing more reliable large animal models, choosing more effective therapeutic genes, better designing clinical trials, and more deeply understanding cardiac biology. We also emphasize a few areas of cardiac gene therapy development that hold great promise for the future. In particular, the transition from gene addition studies using protein-coding cDNAs to the modulation of gene expression using small RNA therapeutics and the improvement of precise gene editing now pave the way to applications such as cardiac regeneration after myocardial infarction and gene correction for inherited cardiomyopathies that were unapproachable until a decade ago.
2018-10-09 | A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation
Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern. We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/β-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease. Down-regulation of the canonical Wnt/β-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
2012-11-07 | Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy
AimsArrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle.Mutations in several genes encoding desmosomal proteins have been identified in ARVC.We speculated that aT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients.Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes. Methods and resultsWe used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC.Mutations c.281T .A (p.V94D) and c.2293_2295delTTG (p.del765L) were identified in two probands.They are located in important domains of aT-catenin.Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and b-catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells. ConclusionThese findings might point to a causal relationship between CTNNA3 mutations and ARVC.This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes.Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.
gene therapies
2023-10-18 | Genetic testing in the management of inherited cardiac disorders: two cases of Filamin-C arrhythmogenic left ventricular cardiomyopathy
Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a left ventricle-dominant arrhythmogenic cardiomyopathy (ACM) subtype often associated with malignant ventricular arrhythmias, left ventricular (LV) scar and sudden cardiac death. Awareness about LV involvement is now on the rise. The diagnosis relies on structural abnormalities on cardiac magnetic resonance (CMR) imaging and known ACM-causing genetic mutations.A 28-year-old lady (Case 1) was referred for cardiac screening after her father passed away suddenly. Her paternal uncle (Case 2) had been diagnosed with supposed dilated cardiomyopathy prior to referral. Both cases were worked up extensively with an electrocardiogram (ECG), 24-h ambulatory ECG monitor, exercise testing, and CMR imaging. Investigations of Case 1 showed T-wave inversion in the infero-lateral leads and a ventricular ectopic burden of 3% on ambulatory monitoring. Cardiac magnetic resonance imaging revealed moderately reduced LV systolic function (ejection fraction of 40%) with circumferential macroscopic fibrosis. Her uncle (Case 2) also had an impaired and dilated ventricle with extensive scar on CMR. Following the recent introduction of a cardiogenetic service in our unit, both were heterozygous for a pathogenic Filamin-C variant (c.7384+1G>A). Based on CMR findings and genetic results, the diagnosis of both patients was deemed to be ALVC. After years of surveillance, Patient 1 now has an implantable cardioverter defibrillator (ICD) indication.The importance of diagnosing patients with ACM lies in the predisposition to sudden cardiac death. Gene-specific treatment algorithms in ACM may alter management strategies, including ICD implantation as primary prevention. An in-depth multidisciplinary discussion and respecting patient autonomy are key factors in any decision pertaining to ICD implantation.
2023-05-11 | Genome Editing and Cardiac Arrhythmias
This article reviews progress in the field of cardiac genome editing, in particular, its potential utility in treating cardiac arrhythmias. First, we discuss genome editing methods by which DNA can be disrupted, inserted, deleted, or corrected in cardiomyocytes. Second, we provide an overview of in vivo genome editing in preclinical models of heritable and acquired arrhythmias. Third, we discuss recent advancements in cardiac gene transfer, including delivery methods, gene expression optimization, and potential adverse effects associated with therapeutic somatic genome editing. While genome editing for cardiac arrhythmias is still in its infancy, this approach holds great promise, especially for inherited arrhythmia syndromes with a defined genetic defect.
2020-05-05 | Generation of human induced pluripotent stem cell line LUMCi027-A and its isogenic gene-corrected line from a patient affected by arrhythmogenic cardiomyopathy and carrying the c.2013delC PKP2 mutation
Arrhythmogenic Cardiomyopathy (ACM) is a rare inherited heart muscle disease characterised by progressive fibro-fatty replacement of the ventricular myocardium leading to life-threatening arrhythmias. We generated human induced pluripotent stem cells (hiPSCs) from a patient affected by ACM and carrying the heterozygous c.2013delC (p.K672Rfs) PKP2 mutation and then corrected the mutation using CRISPR/Cas9 technology. Both hiPSC lines expressed pluripotency markers, maintained a normal karyotype, and differentiated into derivatives of the three germ layers. This isogenic hiPSC pair represents a genetically controlled system to study the role of the c.2013delC PKP2 mutation in vitro.
2019-05-06 | Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia.
Desmin (DES) mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently, DES mutations were described in patients with inherited arrhythmogenic right ventricular cardiomyopathy/dysplasia, although their cellular and molecular pathomechanisms are not precisely known. Our aim is to describe clinically and functionally the novel DES-p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia. We identified the novel DES mutation p.Glu401Asp in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia and a high incidence of adverse cardiac events. A full clinical evaluation was performed on all mutation carriers and noncarriers to establish clinical and genetic cosegregation. In addition, desmin, and intercalar disc-related proteins expression were histologically analyzed in explanted cardiac tissue affected by the DES mutation. Furthermore, mesenchymal stem cells were isolated and cultured from 2 family members with the DES mutation (1 with mild and 1 with severe symptomatology) and a member without the mutation (control) and differentiated ex vivo to cardiomyocytes. Then, important genes related to cardiac differentiation and function were analyzed by real-time quantitative polymerase chain reaction. Finally, the p.Glu401Asp mutated DES gene was transfected into cell lines and analyzed by confocal microscopy. Of the 66 family members screened for the DES-p.Glu401Asp mutation, 23 of them were positive, 6 were obligate carriers, and 2 were likely carriers. One hundred percent of genotype-positive patients presented data consistent with inherited arrhythmogenic cardiomyopathy/dysplasia phenotype with variable disease severity expression, high-incidence of sudden cardiac death, and absence of skeletal myopathy or conduction system disorders. Immunohistochemistry was compatible with inherited arrhythmogenic cardiomyopathy/dysplasia, and the functional study showed an abnormal growth pattern and cellular adhesion, reduced desmin RNA expression, and some other membrane proteins, as well, and desmin aggregates in transfected cells expressing the mutant desmin. The DES-p.Glu401Asp mutation causes predominant inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia with a high incidence of adverse clinical events in the absence of skeletal myopathy or conduction system disorders. The pathogenic mechanism probably corresponds to an alteration in desmin dimer and oligomer assembly and its connection with membrane proteins within the intercalated disc.
2015-08-03 | Evolving targeted therapies for right ventricular failure
Although right and left ventricular embryological origins, morphology and cardiodynamics differ, the notion of selectively targeted right ventricular therapies remains controversial.This review focuses on both the currently evolving pharmacologic agents targeting right ventricular failure (metabolic modulators, phosphodiesterase type V inhibitors) and future therapeutic approaches including epigenetic modulation by miRNAs, chromatin binding complexes, long non-coding RNAs, genomic editing, adoptive gene transfer and gene therapy, cell regeneration via cell transplantation and cell reprogramming and cardiac tissue engineering.Strategies for adult right ventricular regeneration will require a more holistic approach than strategies for adult left ventricular failure. Instances of right ventricular failure requiring global reconstitution of right ventricular myocardium, attractive approaches include: i) myocardial patches seeded with cardiac fibroblasts reprogrammed into cardiomyocytes in vivo by small molecules, miRNAs or other epigenetic modifiers; and ii) administration of miRNAs, lncRNAs or small molecules by non-viral vector delivery systems targeted to fibroblasts (e.g., episomes) to stimulate in vivo reprogramming of fibroblasts into cardiomyocytes. For selected heritable genetic myocardial diseases, genomic editing affords exciting opportunities for allele-specific silencing by site-specific directed silencing, mutagenesis or gene excision. Genomic editing by adoptive gene transfer affords similarly exciting opportunities for restoration of myocardial gene expression.
other
2025-10-09 | Epicardial contributions to fibro-inflammatory signaling in a Pkp2-deficient arrhythmogenic cardiomyopathy model
Background: Arrhythmogenic Cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosis and inflammation with right ventricle predominance. Most cases of gene positive ACM are caused by a desmosome protein mutation, with plakophilin-2 (Pkp2) mutations being most common. We hypothesized Pkp2-deficiency in epicardium-derived cells (EPDCs) contributes to fibro-inflammatory signaling and ACM pathogenesis. Methods: We developed transgenic mice that lack Pkp2 in cardiomyocytes (PKP2-cKO) or in both cardiomyocyte and EPDC (PKP2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Non-myocyte populations were isolated 21 days post-tamoxifen injection for single cell RNA-sequencing (scRNA-seq). Immunohistochemistry, flow cytometry, qRT-PCR, and echocardiography were used to interrogate cardiac physiology and cellular composition. Results: We identified a population of epicardium-derived fibroblasts characterized by the expression of Ccl2, Ccl7, Thbs1, and Ptx3 that accumulated upon Pkp2 deletion. While pro-inflammatory EPDCs are found in PKP2-cKO mice, they become significantly enriched in PKP2-ceKO mice. Pro-inflammatory fibroblasts acquired the senescence-associated secretory phenotype (SASP), correlating with elevated Senescence Associated (SA)-βgal staining in the right ventricle. Gene expression, flow cytometry, and histological data also revealed an exaggerated inflammatory response in PKP2-ceKO mice, that progresses from right to bi-ventricular predominance. Importantly, macrophages and B cells accumulate in both PKP2-cKO and PKP2-ceKO mice compared to controls. Antibody-mediated B cell depletion delays the early inflammatory and fibrosis response but did not significantly alter end-stage cardiac physiology. Conclusion: Pkp2 deletion in EPDC facilitates the emergence of a fibro-inflammatory phenotype that may contribute to ACM pathogenesis.
2025-02-12 | Analysis of effector/memory regulatory T cells from arrhythmogenic cardiomyopathy patients identified IL-32 as a novel player in ACM pathogenesis.
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes sudden cardiac death and progressive heart failure. Besides fibro-fatty replacement and myocyte degenerative changes, inflammatory patchy infiltrates are found in myocardial histological analysis of ACM patients. Inflammatory cells could actively participate in ACM pathogenesis, contributing to the alteration of cardiac microenvironment homeostasis, thus triggering disease evolution. In order to characterize the immune-derived mediators involved in ACM pathogenesis, peripheral blood mononuclear cells from ACM patients were characterized and compared to healthy controls' ones. Flow cytometry analysis revealed a lower frequency of CD4+ T helper type 1 cells, NK cells, and terminally differentiated CD8+ EMRA+ T cells in ACM patients compared to age-matched controls. In contrast, a higher proportion of effector/memory FOXP3+ CCR4+ CD45RO+ regulatory CD4+ T cells (Treg) were found in ACM patients. Single-cell RNA-seq performed on isolated memory Treg cells (mTreg) from ACM patients and healthy controls identified 6 clusters characterized by specific gene signatures related to tissue repair and immunosuppressive pathways. Notably, interleukin 32 (IL-32) was the most differentially expressed gene in ACM patients mTreg with respect to healthy controls. Treatment of human cardiac mesenchymal stromal cells with recombinant IL-32 in vitro promoted lipid droplet accumulation and collagen deposition, thus identifying IL-32 as a new potential player in the immune-mediated trigger of cardiac fibro-fatty replacement in ACM. Overall, we here provide the first complete characterization of circulating ACM immune cells, revealing an abundance of Treg. The high expression of IL-32 in ACM Treg may contribute to accelerated cardiac remodeling in ACM patients' hearts.
2022-03-10 | Remodeled Connexin 43 hemichannels alter cardiac excitability and promote arrhythmias
ABSTRACT Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of a dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the β-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pre-treatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability and greater plasma membrane depolarization, which subsequently leads to triggered activity. These cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac stress-induced arrhythmogenicity.
2019-12-12 | RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes
Connexin-based gap junctions are crucial for electrical communication in the heart; they are each composed of two docked hemichannels (HCs), supplied as unpaired channels via the sarcolemma. When open, an unpaired HC forms a large pore, high-conductance and Ca2+-permeable membrane shunt pathway that may disturb cardiomyocyte function. HCs composed of connexin 43 (Cx43), a major cardiac connexin, can be opened by electrical stimulation but only by very positive membrane potentials. Here, we investigated the activation of Cx43 HCs in murine ventricular cardiomyocytes voltage-clamped at -70 mV.Using whole-cell patch-clamp, co-immunoprecipitation, western blot analysis, immunocytochemistry, proximity ligation assays, and protein docking studies, we found that stimulation of ryanodine receptors (RyRs) triggered unitary currents with a single-channel conductance of ∼220 pS, which were strongly reduced by Cx43 knockdown. Recordings under Ca2+-clamp conditions showed that both RyR activation and intracellular Ca2+ elevation were necessary for HC opening. Proximity ligation studies indicated close Cx43-RyR2 apposition (<40 nm), and both proteins co-immunoprecipitated indicating physical interaction. Molecular modelling suggested a strongly conserved RyR-mimicking peptide sequence (RyRHCIp), which inhibited RyR/Ca2+ HC activation but not voltage-triggered activation. The peptide also slowed down action potential repolarization. Interestingly, alterations in the concerned RyR sequence are known to be associated with primary familial hypertrophic cardiomyopathy.Our results demonstrate that Cx43 HCs are intimately linked to RyRs, allowing them to open at negative diastolic membrane potential in response to RyR activation.
2016-09-09 | The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes
The cardiac ryanodine receptor (RyR2) is an intracellular ion channel that regulates Ca2+ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling in the heart. The glutathione transferases (GSTs) are a family of phase II detoxification enzymes with additional functions including the selective inhibition of RyR2, with therapeutic implications. The C-terminal half of GSTM2 (GSTM2C) is essential for RyR2 inhibition, and mutations F157A and Y160A within GSTM2C prevent the inhibitory action. Our objective in this investigation was to determine whether GSTM2C can enter cultured rat neonatal ventricular cardiomyocytes and influence contractility. We show that oregon green-tagged GSTM2C (at 1 μM) is internalized into the myocytes and it reduces spontaneous contraction frequency and myocyte shortening. Field stimulation of myocytes evoked contraction in the same percentage of myocytes treated either with media alone or media plus 15 μM GSTM2C. Myocyte shortening during contraction was significantly reduced by exposure to 15 μM GSTM2C, but not 5 and 10 μM GSTM2C and was unaffected by exposure to 15 μM of the mutants Y160A or F157A. The amplitude of the Ca2+ transient in the 15 μM GSTM2C - treated myocytes was significantly decreased, the rise time was significantly longer and the decay time was significantly shorter than in control myocytes. The Ca2+ transient was not altered by exposure to Y160A or F157A. The results are consistent with GSTM2C entering the myocytes and inhibiting RyR2, in a manner that indicates a possible therapeutic potential for treatment of arrhythmia in the neonatal heart.
small molecules
2026-05-31 | Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK ‐3β, Resulting in a Loss of Cardiomyocyte Cohesion
ABSTRACT Background Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac desmosome disease, as more than 50% of affected patients carry pathogenic variants in desmosome protein‐coding genes. In this study, we focused on the role and mechanisms of pathogenic and non‐pathogenic autoantibodies against intercalated disc (ICD) proteins such as desmoglein2 (DSG2) in ACM patients, healthy relatives (HR), and murine ACM models. Materials and Methods IgG fractions from ACM patients, HR, healthy controls, and murine ACM models were isolated. Besides ELISA and cleavage assay, dissociation assay, immunostaining, Triton‐X‐100 assay, Western blots, and atomic force microscopy were performed in murine cardiac slices, HL‐1 cells, or induced pluripotent stem cells‐derived cardiomyocytes (hiPSC‐CMs). Results IgG fractions from ACM patients and HR, but not murine ACM model‐derived or grouped healthy controls IgG (G‐HC), revealed positive ICD staining. Three out of six ACM patients derived IgGs that reduced cardiomyocyte cohesion. Pathogenic autoantibodies, bound to DSG2 in healthy and ACM hiPSC‐CMs, cleaved and reduced DSG2 interaction at the molecular level. We investigated GSK‐3β contribution to the cardiomyocyte cohesion loss and observed GSK‐3β reduced baseline cohesion in cultured cardiomyocytes and cardiac slices. Among five ACM‐IgGs, three HR‐IgGs tested, three pathogenic ACM‐IgGs activated GSK‐3β upstream of p38MAPK, leading to phosphorylation and junctional loss of β‐catenin. GSK‐3β inhibition rescued the loss of cell cohesion in ACM hiPSC‐CMs. Conclusion Pathogenic autoantibodies targeting DSG2 are present in ACM patients and impair cardiomyocyte cohesion in a GSK‐3β‐dependent manner. In contrast, autoantibodies are absent in murine ACM models and are non‐pathogenic in some patients and HR.
2025-11-04 | Apremilast improves cardiomyocyte cohesion and arrhythmia in different models for arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is a genetically inherited desmosome heart disease leading to life-threatening arrhythmias and sudden cardiac death. Currently, ACM treatment paradigms are merely symptom targeting. Recently, apremilast was shown to stabilize keratinocyte adhesion in the desmosomal disease pemphigus vulgaris. Therefore, this study investigated whether apremilast can be a therapeutic option for ACM. Human induced pluripotent stem cells from a healthy control (hiPSC) and an ACM index patient (ACM-hiPSC) carrying a heterozygous desmoplakin (DSP) gene mutation (c.2854G > T, p.Glu952Ter), confirmed by whole exome sequencing (WES), were established. Cyclic-AMP ELISA, dissociation assay, immunostaining, and Western blotting analyses were performed in human iPSC-derived cardiomyocytes (hiPSC-CMs), murine HL-1 cardiomyocytes, and cardiac slices derived from wild-type (WT) mice, plakoglobin (PG, Jup) knockout (Jup-/-) (murine ACM model) or PG Serine 665 phosphodeficient (JUP-S665A) mice. Microelectrode array (MEA) analyses in ventricular cardiac slices and Langendorff heart perfusion were performed to analyze heart rate variability and arrhythmia. ACM-hiPSC derived cardiomyocytes (ACM-hiPSC-CMs) revealed a significant loss of cohesion, which was rescued by apremilast. Further, treatment with apremilast strengthened basal cardiomyocyte cohesion in HL-1 cells and WT murine cardiac slices, paralleled by phosphorylation of PG at Serine 665 in human and murine models. In HL-1 cells, apremilast in addition activated ERK1/2, inhibition of which abolished apremilast-enhanced cardiomyocyte cohesion. Further, dissociation assays in slice cultures from JUP-S665A and Jup-/- mice revealed that PG is crucial for apremilast-enhanced cardiomyocyte cohesion. In parallel to enhanced cell adhesion, MEA and Langendorff measurements from WT and Jup-/- mice demonstrated decreased heart rate variability and arrhythmia after apremilast treatment. Apremilast improves loss of cardiomyocyte cohesion, enhances localization of DSG2, and reduces arrhythmia in human and/or murine models of ACM ex vivo and in vitro, providing a novel treatment strategy for ACM by preserving desmosome function.
2025-04-27 | Peritoneal dialysis in congestive heart failure: reflections from a patient with arrhythmogenic right ventricular cardiomyopathy.
After multiple hospitalisations for diuretic-resistant acute decompensated heart failure (ADHF), an early 60s man with isolated right-sided heart failure due to arrhythmogenic right ventricular cardiomyopathy (ARVC) underwent continuous venovenous haemofiltration without lasting success. His blood urea nitrogen/creatinine ratio was high and renal blood flow and filtration fraction were low, indicative of the underlying cardiorenal dysbalance. Peritoneal dialysis (PD) was initiated because this form of renal replacement therapy provides better haemodynamic stability and a flexible schedule. This allowed the patient to maintain his professional activities and spend time with his family for the subsequent 7 months. Following a diabetic foot infection, his condition worsened, leading to his death. Autopsy showed fibrofatty replacement of the right ventricle and chronic ischaemic nephropathy, without signs of hypertensive or diabetic nephropathy.Although ARVC is rare, this case underscores the potential benefits of PD as a palliative option in end-stage heart failure. Early consideration of PD, particularly when other renal replacement therapies are limited or contraindicated, may alleviate symptoms and enhance quality of life, especially after repeated hospitalisations for heart failure and kidney injury. Collaborative care between cardiologists and nephrologists is essential for optimising management in these patients.
2024-09-04 | Hyperactivation of ATF4/TGF-β1 signaling contributes to the progressive cardiac fibrosis in Arrhythmogenic cardiomyopathy caused by DSG2 Variant.
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized with progressive cardiac fibrosis and heart failure. However, the exact mechanism driving the progression of cardiac fibrosis and heart failure in ACM remains elusive. This study aims to investigate the underlying mechanisms of progressive cardiac fibrosis in ACM caused by newly identified Desmoglein-2 (DSG2) variation. We identified homozygous DSG2F531C variant in a family with 8 ACM patients using whole-exome sequencing and generated Dsg2F536C knock-in mice. Neonatal and adult mouse ventricular myocytes isolated from Dsg2F536C knock-in mice were used. We performed functional, transcriptomic and mass spectrometry analyses to evaluate the mechanisms of ACM caused by DSG2F531C variant. All eight patients with ACM were homozygous for DSG2F531C variant. Dsg2F536C/F536C mice displayed cardiac enlargement, dysfunction, and progressive cardiac fibrosis in both ventricles. Mechanistic investigations revealed that the variant DSG2-F536C protein underwent misfolding, leading to its recognition by BiP within the endoplasmic reticulum, which triggered endoplasmic reticulum stress, activated the PERK-ATF4 signaling pathway and increased ATF4 levels in cardiomyocytes. Increased ATF4 facilitated the expression of TGF-β1 in cardiomyocytes, thereby activating cardiac fibroblasts through paracrine signaling and ultimately promoting cardiac fibrosis in Dsg2F536C/F536C mice. Notably, inhibition of the PERK-ATF4 signaling attenuated progressive cardiac fibrosis and cardiac systolic dysfunction in Dsg2F536C/F536C mice. Hyperactivation of the ATF4/TGF-β1 signaling in cardiomyocytes emerges as a novel mechanism underlying progressive cardiac fibrosis in ACM. Targeting the ATF4/TGF-β1 signaling may be a novel therapeutic target for managing ACM.
2024-02-08 | GSK3 inhibition ameliorates the abnormal contractility of Newfoundland ACM patient iPSC-cardiomyocytes
Abstract Arrhythmogenic Cardiomyopathy (ACM) is clinically characterized by ventricular arrhythmias causing sudden cardiac death and fibrofatty replacement of the myocardium leading to heart failure. One form of ACM is highly prevalent in the Canadian Province of Newfoundland and Labrador (NL) and has earned the moniker, The “Newfoundland Curse”. This ACM in NL patients is often caused by a fully penetrant heterozygous missense mutation in the TMEM43 gene ( TMEM43 c.1073C>T; TMEM43 p.S358L). Although the causative mutation has been identified, little is known about the function of the TMEM43 protein in cardiomyocytes, how the TMEM43 p.S358L mutation contributes to the development of arrhythmias, or why the disease is more severe in males than females. To explore the role of TMEM43 in cardiomyocyte function, we generated induced pluripotent stem cells (iPSCs) from 2 severely affected male Newfoundland ACM (TMEM43 p.S358L) patients. CRISPR-Cas9 was used to genetically “repair” the heterozygous TMEM43 mutation in ACM patient iPSCs or for TMEM43 gene knockout. ACM patient iPSC-cardiomyocytes with the TMEM43 p.S358L mutation display pro-arrhythmogenic phenotypes in vitro with significantly elevated contraction rates and altered calcium handling, although no obvious gross abnormalities were observed across several major intracellular organelles. TMEM43 protein abundance and half-life appears unchanged in ACM iPSC-CMs where 50% of the TMEM43 protein is WT and 50% is mutant. Gene expression analysis of ACM iPSC-CMs shows an increase in genes related to signaling and metabolism. Importantly, the pro-arrhythmic tendencies of ACM patient iPSC-CMs can be ameliorated with transient GSK3 inhibition.
cell therapies
2023-06-22 | Biological Modification of Arrhythmogenic Substrates by Cell-Free Therapeutics
Ventricular arrhythmias (VAs) represent a major cause of sudden cardiac death and afflict patients with heart failure from both ischaemic and non-ischaemic origins, and inherited cardiomyopathies. Current VA management, including anti-arrhythmic medications, autonomic modulation, implantable cardioverter–defibrillator implantation, and catheter ablation, remains suboptimal. Catheter ablation may even cause significant cardiomyocyte loss. Cell-based therapies and exosome treatment have been proposed as promising strategies to lessen cardiomyocyte death, modulate immune reaction, and reduce myocardial scarring, and, therefore, are potentially beneficial in treating VAs. In this review, we summarise the current cornerstones of VA management. We also discuss recent advances and ongoing evidence regarding cell-based and exosome therapy, with special attention to VA treatment.
2015-03-24 | Isolation and Characterization of Embryonic Stem Cell-Derived Cardiac Purkinje Cells
Abstract The cardiac Purkinje fiber network is composed of highly specialized cardiomyocytes responsible for the synchronous excitation and contraction of the ventricles. Computational modeling, experimental animal studies, and intracardiac electrical recordings from patients with heritable and acquired forms of heart disease suggest that Purkinje cells (PCs) may also serve as critical triggers of life-threatening arrhythmias. Nonetheless, owing to the difficulty in isolating and studying this rare population of cells, the precise role of PC in arrhythmogenesis and the underlying molecular mechanisms responsible for their proarrhythmic behavior are not fully characterized. Conceptually, a stem cell-based model system might facilitate studies of PC-dependent arrhythmia mechanisms and serve as a platform to test novel therapeutics. Here, we describe the generation of murine embryonic stem cells (ESC) harboring pan-cardiomyocyte and PC-specific reporter genes. We demonstrate that the dual reporter gene strategy may be used to identify and isolate the rare ESC-derived PC (ESC-PC) from a mixed population of cardiogenic cells. ESC-PC display transcriptional signatures and functional properties, including action potentials, intracellular calcium cycling, and chronotropic behavior comparable to endogenous PC. Our results suggest that stem-cell derived PC are a feasible new platform for studies of developmental biology, disease pathogenesis, and screening for novel antiarrhythmic therapies. Stem Cells 2015;33:1102–1112
2013-12-03 | Induced pluripotent stem cells as cardiac arrhythmic in vitro models and the impact for drug discovery.
Introduction: The development of new antiarrhythmic agents is challenging and is hampered by high attrition rate of novel drug candidates. One of the reasons for this is limited predictability of existing preclinical models for drug assessment. Cardiomyocytes (CMs) derived from disease-specific induced pluripotent stem cells (iPSC) represent a novel in vitro cellular model of cardiac arrhythmias with an unprecedented potential for generating new mechanistic insight into disease pathophysiology and improving the process of drug development. Areas covered: This review outlines recent studies demonstrating the suitability and limitations of iPSC-derived CMs (iPS-CMs) for in vitro modeling inherited arrhythmias and drug testing. The authors focus on channelopathies and outline the properties of iPS-CMs, highlighting their utility and limitations for investigating the mechanism of cardiac arrhythmias and drug discovery. Expert opinion: The iPS-CMs represent a valuable addition to the already existing armamentarium of cardiac arrhythmic models. However, the superiority of iPS-CMs over other arrhythmia models has not yet been rigorously established and the limitations of the model must be overcome before its full potential for antiarrhythmic drug discovery can be realized. Nevertheless, iPS cell-based platforms hold a great potential for increasing our knowledge about cellular arrhythmia mechanisms and improving the drug discovery process.
2011-02-01 | Use of Mouse Models to Evaluate Novel Therapeutic Approaches to Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy
Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy that is characterized by ventricular arrhythmias, an increased risk of sudden death, and abnormalities of right ventricular (RV) structure and function. The pathological hallmark of ARVD is myocyte loss with fibro-fatty
oligonucleotides
2023-05-01 | PO-01-123 THE BIOPHYSICAL ACTION OF MICRORNA IS ESSENTIAL TO MAINTAIN THE NORMAL FUNCTION AND ELECTROPHYSIOLOGY OF THE HEART
MicroRNAs (miRs) regulate most (if not all) biological events via a broadly-recoginized RNA interference (RNAi) mechnism. miR1, encoded by miR1-1 and miR1-2 genes, is the predominant miRs of the heart and plays critical roles in heart development and cardiac diseases. Previous studies of miRs have focused on the canonical RNAi mechanism. Recently, we discovered a novel biophysical action of miR and found that miR1 directly binds to ion channels physically modulates the electrophysiology of cardiomyocytes.
2021-02-04 | Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy
Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combinations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from "bench to bedside" can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel "personalized" therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby represents another example for the complex genetic and phenotypic continuum of these diseases.
2020-05-08 | Gene Therapy for the Heart Lessons Learned and Future Perspectives
While clinical gene therapy celebrates its first successes, with several products already approved for clinical use and several hundreds in the final stages of the clinical approval pipeline, there is not a single gene therapy approach that has worked for the heart. Here, we review the past experience gained in the several cardiac gene therapy clinical trials that had the goal of inducing therapeutic angiogenesis in the ischemic heart and in the attempts at modulating cardiac function in heart failure. Critical assessment of the results so far achieved indicates that the efficiency of cardiac gene delivery remains a major hurdle preventing success but also that improvements need to be sought in establishing more reliable large animal models, choosing more effective therapeutic genes, better designing clinical trials, and more deeply understanding cardiac biology. We also emphasize a few areas of cardiac gene therapy development that hold great promise for the future. In particular, the transition from gene addition studies using protein-coding cDNAs to the modulation of gene expression using small RNA therapeutics and the improvement of precise gene editing now pave the way to applications such as cardiac regeneration after myocardial infarction and gene correction for inherited cardiomyopathies that were unapproachable until a decade ago.
2018-10-09 | A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation
Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern. We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/β-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease. Down-regulation of the canonical Wnt/β-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
2012-11-07 | Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy
AimsArrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle.Mutations in several genes encoding desmosomal proteins have been identified in ARVC.We speculated that aT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients.Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes. Methods and resultsWe used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC.Mutations c.281T .A (p.V94D) and c.2293_2295delTTG (p.del765L) were identified in two probands.They are located in important domains of aT-catenin.Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and b-catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells. ConclusionThese findings might point to a causal relationship between CTNNA3 mutations and ARVC.This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes.Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.
gene therapies
2023-10-18 | Genetic testing in the management of inherited cardiac disorders: two cases of Filamin-C arrhythmogenic left ventricular cardiomyopathy
Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a left ventricle-dominant arrhythmogenic cardiomyopathy (ACM) subtype often associated with malignant ventricular arrhythmias, left ventricular (LV) scar and sudden cardiac death. Awareness about LV involvement is now on the rise. The diagnosis relies on structural abnormalities on cardiac magnetic resonance (CMR) imaging and known ACM-causing genetic mutations.A 28-year-old lady (Case 1) was referred for cardiac screening after her father passed away suddenly. Her paternal uncle (Case 2) had been diagnosed with supposed dilated cardiomyopathy prior to referral. Both cases were worked up extensively with an electrocardiogram (ECG), 24-h ambulatory ECG monitor, exercise testing, and CMR imaging. Investigations of Case 1 showed T-wave inversion in the infero-lateral leads and a ventricular ectopic burden of 3% on ambulatory monitoring. Cardiac magnetic resonance imaging revealed moderately reduced LV systolic function (ejection fraction of 40%) with circumferential macroscopic fibrosis. Her uncle (Case 2) also had an impaired and dilated ventricle with extensive scar on CMR. Following the recent introduction of a cardiogenetic service in our unit, both were heterozygous for a pathogenic Filamin-C variant (c.7384+1G>A). Based on CMR findings and genetic results, the diagnosis of both patients was deemed to be ALVC. After years of surveillance, Patient 1 now has an implantable cardioverter defibrillator (ICD) indication.The importance of diagnosing patients with ACM lies in the predisposition to sudden cardiac death. Gene-specific treatment algorithms in ACM may alter management strategies, including ICD implantation as primary prevention. An in-depth multidisciplinary discussion and respecting patient autonomy are key factors in any decision pertaining to ICD implantation.
2023-05-11 | Genome Editing and Cardiac Arrhythmias
This article reviews progress in the field of cardiac genome editing, in particular, its potential utility in treating cardiac arrhythmias. First, we discuss genome editing methods by which DNA can be disrupted, inserted, deleted, or corrected in cardiomyocytes. Second, we provide an overview of in vivo genome editing in preclinical models of heritable and acquired arrhythmias. Third, we discuss recent advancements in cardiac gene transfer, including delivery methods, gene expression optimization, and potential adverse effects associated with therapeutic somatic genome editing. While genome editing for cardiac arrhythmias is still in its infancy, this approach holds great promise, especially for inherited arrhythmia syndromes with a defined genetic defect.
2020-05-05 | Generation of human induced pluripotent stem cell line LUMCi027-A and its isogenic gene-corrected line from a patient affected by arrhythmogenic cardiomyopathy and carrying the c.2013delC PKP2 mutation
Arrhythmogenic Cardiomyopathy (ACM) is a rare inherited heart muscle disease characterised by progressive fibro-fatty replacement of the ventricular myocardium leading to life-threatening arrhythmias. We generated human induced pluripotent stem cells (hiPSCs) from a patient affected by ACM and carrying the heterozygous c.2013delC (p.K672Rfs) PKP2 mutation and then corrected the mutation using CRISPR/Cas9 technology. Both hiPSC lines expressed pluripotency markers, maintained a normal karyotype, and differentiated into derivatives of the three germ layers. This isogenic hiPSC pair represents a genetically controlled system to study the role of the c.2013delC PKP2 mutation in vitro.
2019-05-06 | Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia.
Desmin (DES) mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently, DES mutations were described in patients with inherited arrhythmogenic right ventricular cardiomyopathy/dysplasia, although their cellular and molecular pathomechanisms are not precisely known. Our aim is to describe clinically and functionally the novel DES-p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia. We identified the novel DES mutation p.Glu401Asp in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia and a high incidence of adverse cardiac events. A full clinical evaluation was performed on all mutation carriers and noncarriers to establish clinical and genetic cosegregation. In addition, desmin, and intercalar disc-related proteins expression were histologically analyzed in explanted cardiac tissue affected by the DES mutation. Furthermore, mesenchymal stem cells were isolated and cultured from 2 family members with the DES mutation (1 with mild and 1 with severe symptomatology) and a member without the mutation (control) and differentiated ex vivo to cardiomyocytes. Then, important genes related to cardiac differentiation and function were analyzed by real-time quantitative polymerase chain reaction. Finally, the p.Glu401Asp mutated DES gene was transfected into cell lines and analyzed by confocal microscopy. Of the 66 family members screened for the DES-p.Glu401Asp mutation, 23 of them were positive, 6 were obligate carriers, and 2 were likely carriers. One hundred percent of genotype-positive patients presented data consistent with inherited arrhythmogenic cardiomyopathy/dysplasia phenotype with variable disease severity expression, high-incidence of sudden cardiac death, and absence of skeletal myopathy or conduction system disorders. Immunohistochemistry was compatible with inherited arrhythmogenic cardiomyopathy/dysplasia, and the functional study showed an abnormal growth pattern and cellular adhesion, reduced desmin RNA expression, and some other membrane proteins, as well, and desmin aggregates in transfected cells expressing the mutant desmin. The DES-p.Glu401Asp mutation causes predominant inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia with a high incidence of adverse clinical events in the absence of skeletal myopathy or conduction system disorders. The pathogenic mechanism probably corresponds to an alteration in desmin dimer and oligomer assembly and its connection with membrane proteins within the intercalated disc.
2015-08-03 | Evolving targeted therapies for right ventricular failure
Although right and left ventricular embryological origins, morphology and cardiodynamics differ, the notion of selectively targeted right ventricular therapies remains controversial.This review focuses on both the currently evolving pharmacologic agents targeting right ventricular failure (metabolic modulators, phosphodiesterase type V inhibitors) and future therapeutic approaches including epigenetic modulation by miRNAs, chromatin binding complexes, long non-coding RNAs, genomic editing, adoptive gene transfer and gene therapy, cell regeneration via cell transplantation and cell reprogramming and cardiac tissue engineering.Strategies for adult right ventricular regeneration will require a more holistic approach than strategies for adult left ventricular failure. Instances of right ventricular failure requiring global reconstitution of right ventricular myocardium, attractive approaches include: i) myocardial patches seeded with cardiac fibroblasts reprogrammed into cardiomyocytes in vivo by small molecules, miRNAs or other epigenetic modifiers; and ii) administration of miRNAs, lncRNAs or small molecules by non-viral vector delivery systems targeted to fibroblasts (e.g., episomes) to stimulate in vivo reprogramming of fibroblasts into cardiomyocytes. For selected heritable genetic myocardial diseases, genomic editing affords exciting opportunities for allele-specific silencing by site-specific directed silencing, mutagenesis or gene excision. Genomic editing by adoptive gene transfer affords similarly exciting opportunities for restoration of myocardial gene expression.
other
2025-10-09 | Epicardial contributions to fibro-inflammatory signaling in a Pkp2-deficient arrhythmogenic cardiomyopathy model
Background: Arrhythmogenic Cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosis and inflammation with right ventricle predominance. Most cases of gene positive ACM are caused by a desmosome protein mutation, with plakophilin-2 (Pkp2) mutations being most common. We hypothesized Pkp2-deficiency in epicardium-derived cells (EPDCs) contributes to fibro-inflammatory signaling and ACM pathogenesis. Methods: We developed transgenic mice that lack Pkp2 in cardiomyocytes (PKP2-cKO) or in both cardiomyocyte and EPDC (PKP2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Non-myocyte populations were isolated 21 days post-tamoxifen injection for single cell RNA-sequencing (scRNA-seq). Immunohistochemistry, flow cytometry, qRT-PCR, and echocardiography were used to interrogate cardiac physiology and cellular composition. Results: We identified a population of epicardium-derived fibroblasts characterized by the expression of Ccl2, Ccl7, Thbs1, and Ptx3 that accumulated upon Pkp2 deletion. While pro-inflammatory EPDCs are found in PKP2-cKO mice, they become significantly enriched in PKP2-ceKO mice. Pro-inflammatory fibroblasts acquired the senescence-associated secretory phenotype (SASP), correlating with elevated Senescence Associated (SA)-βgal staining in the right ventricle. Gene expression, flow cytometry, and histological data also revealed an exaggerated inflammatory response in PKP2-ceKO mice, that progresses from right to bi-ventricular predominance. Importantly, macrophages and B cells accumulate in both PKP2-cKO and PKP2-ceKO mice compared to controls. Antibody-mediated B cell depletion delays the early inflammatory and fibrosis response but did not significantly alter end-stage cardiac physiology. Conclusion: Pkp2 deletion in EPDC facilitates the emergence of a fibro-inflammatory phenotype that may contribute to ACM pathogenesis.
2025-02-12 | Analysis of effector/memory regulatory T cells from arrhythmogenic cardiomyopathy patients identified IL-32 as a novel player in ACM pathogenesis.
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes sudden cardiac death and progressive heart failure. Besides fibro-fatty replacement and myocyte degenerative changes, inflammatory patchy infiltrates are found in myocardial histological analysis of ACM patients. Inflammatory cells could actively participate in ACM pathogenesis, contributing to the alteration of cardiac microenvironment homeostasis, thus triggering disease evolution. In order to characterize the immune-derived mediators involved in ACM pathogenesis, peripheral blood mononuclear cells from ACM patients were characterized and compared to healthy controls' ones. Flow cytometry analysis revealed a lower frequency of CD4+ T helper type 1 cells, NK cells, and terminally differentiated CD8+ EMRA+ T cells in ACM patients compared to age-matched controls. In contrast, a higher proportion of effector/memory FOXP3+ CCR4+ CD45RO+ regulatory CD4+ T cells (Treg) were found in ACM patients. Single-cell RNA-seq performed on isolated memory Treg cells (mTreg) from ACM patients and healthy controls identified 6 clusters characterized by specific gene signatures related to tissue repair and immunosuppressive pathways. Notably, interleukin 32 (IL-32) was the most differentially expressed gene in ACM patients mTreg with respect to healthy controls. Treatment of human cardiac mesenchymal stromal cells with recombinant IL-32 in vitro promoted lipid droplet accumulation and collagen deposition, thus identifying IL-32 as a new potential player in the immune-mediated trigger of cardiac fibro-fatty replacement in ACM. Overall, we here provide the first complete characterization of circulating ACM immune cells, revealing an abundance of Treg. The high expression of IL-32 in ACM Treg may contribute to accelerated cardiac remodeling in ACM patients' hearts.
2022-03-10 | Remodeled Connexin 43 hemichannels alter cardiac excitability and promote arrhythmias
ABSTRACT Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of a dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the β-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pre-treatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability and greater plasma membrane depolarization, which subsequently leads to triggered activity. These cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac stress-induced arrhythmogenicity.
2019-12-12 | RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes
Connexin-based gap junctions are crucial for electrical communication in the heart; they are each composed of two docked hemichannels (HCs), supplied as unpaired channels via the sarcolemma. When open, an unpaired HC forms a large pore, high-conductance and Ca2+-permeable membrane shunt pathway that may disturb cardiomyocyte function. HCs composed of connexin 43 (Cx43), a major cardiac connexin, can be opened by electrical stimulation but only by very positive membrane potentials. Here, we investigated the activation of Cx43 HCs in murine ventricular cardiomyocytes voltage-clamped at -70 mV.Using whole-cell patch-clamp, co-immunoprecipitation, western blot analysis, immunocytochemistry, proximity ligation assays, and protein docking studies, we found that stimulation of ryanodine receptors (RyRs) triggered unitary currents with a single-channel conductance of ∼220 pS, which were strongly reduced by Cx43 knockdown. Recordings under Ca2+-clamp conditions showed that both RyR activation and intracellular Ca2+ elevation were necessary for HC opening. Proximity ligation studies indicated close Cx43-RyR2 apposition (<40 nm), and both proteins co-immunoprecipitated indicating physical interaction. Molecular modelling suggested a strongly conserved RyR-mimicking peptide sequence (RyRHCIp), which inhibited RyR/Ca2+ HC activation but not voltage-triggered activation. The peptide also slowed down action potential repolarization. Interestingly, alterations in the concerned RyR sequence are known to be associated with primary familial hypertrophic cardiomyopathy.Our results demonstrate that Cx43 HCs are intimately linked to RyRs, allowing them to open at negative diastolic membrane potential in response to RyR activation.
2016-09-09 | The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes
The cardiac ryanodine receptor (RyR2) is an intracellular ion channel that regulates Ca2+ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling in the heart. The glutathione transferases (GSTs) are a family of phase II detoxification enzymes with additional functions including the selective inhibition of RyR2, with therapeutic implications. The C-terminal half of GSTM2 (GSTM2C) is essential for RyR2 inhibition, and mutations F157A and Y160A within GSTM2C prevent the inhibitory action. Our objective in this investigation was to determine whether GSTM2C can enter cultured rat neonatal ventricular cardiomyocytes and influence contractility. We show that oregon green-tagged GSTM2C (at 1 μM) is internalized into the myocytes and it reduces spontaneous contraction frequency and myocyte shortening. Field stimulation of myocytes evoked contraction in the same percentage of myocytes treated either with media alone or media plus 15 μM GSTM2C. Myocyte shortening during contraction was significantly reduced by exposure to 15 μM GSTM2C, but not 5 and 10 μM GSTM2C and was unaffected by exposure to 15 μM of the mutants Y160A or F157A. The amplitude of the Ca2+ transient in the 15 μM GSTM2C - treated myocytes was significantly decreased, the rise time was significantly longer and the decay time was significantly shorter than in control myocytes. The Ca2+ transient was not altered by exposure to Y160A or F157A. The results are consistent with GSTM2C entering the myocytes and inhibiting RyR2, in a manner that indicates a possible therapeutic potential for treatment of arrhythmia in the neonatal heart.
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Drug Discovery Landscape
3 orphan drug designations for Inherited isolated arrhythmogenic cardiomyopathy.
3 orphan drug designations for Inherited isolated arrhythmogenic cardiomyopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated virus serotype rh.10 containing the human PKP2 gene | gene therapies | EMA | 2025-02-26 | — | Scendea (NL) B.V. |
Adeno-associated virus serotype rh.74 vector containing the human PKP2 gene isoform | gene therapies | EMA | 2024-05-24 | — | Rocket Pharmaceuticals B.V. |
adeno-associated virus serotype rh.10 encoding for the human PKP2 gene (AAVrh.10hPKP2) | gene therapies | FDA | 2023-12-14 | — | LEXEO Therapeutics, Inc. |
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