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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 17370

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Special Issue Editor

Dr. Stephen P. Chelko

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Guest Editor

Dept. of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306-4300, USA
Interests: arrhythmogenic cardiomyopathy (ACM); sudden cardiac death (SCD); heart disease; cardiomyopathy

Special Issue Information

Dear Colleagues,

Arrhythmogenic cardiomyopathy (ACM) is a leading cause of sudden cardiac death (SCD) and a familial, non-ischemic heart disease that can affect both the left and right ventricles. ACM is often considered a “disease of the cardiac desmosome”, as over 60% of cases are associated with pathogenic desmosomal variants. Clinical characteristics involve cardiac dysfunction and increased arrhythmia, whereas pathological traits include myocardial inflammation and fibrofatty replacement of the myocardium. Exercise is a known contributor to disease progression, and patients with ACM are advised against high-intensity exercise or complete exercise cessation. Antiarrhythmics are the mainstay in ACM therapeutics, with treatment strategies directed at preventing fatal ventricular arrhythmias (FVAs) and aborting SCD. The most effective intervention is an implantable cardiac defibrillator, yet this does not prevent pathological disease progression. Recent advancements in therapeutics, albeit often in animal models of ACM, suggest that alternative therapeutics such as gene therapy may prevent these pathological hallmarks and thus avert cardiac dysfunction.

Dr. Stephen P. Chelko
Guest Editor

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Keywords

arrhythmogenic cardiomyopathy
myocardial inflammation
desmosome
sudden cardiac death
fibrofatty infiltration
exercise

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 199 KiB

Open AccessEditorial

Prognostic Value of Circulating Biomarkers of Fibrotic Remodeling in Arrhythmogenic Cardiomyopathy

by Stephen P. Chelko

Biomedicines 2024, 12(11), 2623; https://doi.org/10.3390/biomedicines12112623 - 16 Nov 2024

Viewed by 298

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a nonischemic, familial heart disease with a high risk of sudden cardiac death (SCD) in the pediatric population and accounts for >20% of SCDs worldwide [...] Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

Research

Jump to: Editorial, Review

22 pages, 5579 KiB

Open AccessArticle

Adipocyte-Mediated Electrophysiological Remodeling of PKP-2 Mutant Human Pluripotent Stem Cell-Derived Cardiomyocytes

by Justin Morrissette-McAlmon, Christianne J. Chua, Alexander Arking, Stanley Chun Ming Wu, Roald Teuben, Elaine Zhelan Chen, Leslie Tung and Kenneth R. Boheler

Biomedicines 2024, 12(11), 2601; https://doi.org/10.3390/biomedicines12112601 - 14 Nov 2024

Viewed by 382

Abstract

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder responsible for nearly a quarter of sports-related sudden cardiac deaths. ACM cases caused by mutations in desmosome proteins lead to right ventricular enlargement, the loss of cardiomyocytes, and fibrofatty tissue replacement, disrupting electrical and mechanical stability. It is currently unknown how paracrine factors secreted by infiltrating fatty tissues affect ACM cardiomyocyte electrophysiology. Methods: A normal and a PKP2 mutant (c.971_972InsT) ACM hiPSC line were cultivated and differentiated into cardiomyocytes (CMs). Adipocytes were differentiated from human adipose stem cells, and adipocyte conditioned medium (AdCM) was collected. Optical mapping and phenotypic analyses were conducted on human iPSC-cardiomyocytes (hiPSC-CMs) cultured in cardiac maintenance medium (CMM) and either with AdCM or specific cytokines. Results: Significant differences were observed in voltage parameters such as the action potential duration (APD₈₀, APD₃₀), conduction velocity (CV), and CV heterogeneity. When cultured in AdCM relative to CMM, the APD₈₀ increased and the CV decreased significantly in both groups; however, the magnitudes of changes often differed significantly between 1 and 7 days of cultivation. Cytokine exposure (IL-6, IL-8, MCP-1, CFD) affected the APD and CV in both the normal and PKP2 mutant hiPSC-CMs, with opposite effects. NF-kB signaling was also found to differ between the normal and PKP2 mutant hiPSC-CMs in response to AdCM and IL-6. Conclusions: Our study shows that hiPSC-CMs from normal and mPKP2 ACM lines exhibit distinct molecular and functional responses to paracrine factors, with differences in RNA expression and electrophysiology. These different responses to paracrine factors may contribute to arrhythmogenic propensity. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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24 pages, 12805 KiB

Open AccessArticle

Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction

by Larissa Fabritz, Lisa Fortmueller, Katja Gehmlich, Sebastian Kant, Marcel Kemper, Dana Kucerova, Fahima Syeda, Cornelius Faber, Rudolf E. Leube, Paulus Kirchhof and Claudia A. Krusche

Biomedicines 2024, 12(5), 985; https://doi.org/10.3390/biomedicines12050985 - 30 Apr 2024

Cited by 1 | Viewed by 1433

Abstract

Desmoglein-2 mutations are detected in 5–10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous Dsg2 mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant (Dsg2^mt/wt) or haploinsufficient (Dsg2^0/wt) mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old Dsg2^mt/wt and Dsg2^0/wt mice and in young Dsg2^mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg2^0/wt and Dsg2^mt/wt mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in Dsg2^mt/wt mice but not in wild types. Dsg2^mt/wt hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult Dsg2^mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2^mt/wt mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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17 pages, 1780 KiB

Open AccessArticle

Structural Progression in Patients with Definite and Non-Definite Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Major Adverse Cardiac Events

by Areej Aljehani, Shanat Baig, Tania Kew, Manish Kalla, Laura C. Sommerfeld, Vaishnavi Ameya Murukutla, Larissa Fabritz and Richard P. Steeds

Biomedicines 2024, 12(2), 328; https://doi.org/10.3390/biomedicines12020328 - 31 Jan 2024

Viewed by 1611

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disease characterised by early arrhythmias and structural changes. Still, there are limited echocardiography data on its structural progression. We studied structural progression and its impact on the occurrence of major adverse cardiovascular events (MACE). In this single-centre observational cohort study, structural progression was defined as the development of new major or minor imaging 2010 Task Force Criteria during follow-up. Of 101 patients, a definite diagnosis of ARVC was made in 51 patients, while non-definite ‘early’ disease was diagnosed in 50 patients. During 4 years of follow-up (IQR: 2–6), 23 (45%) patients with a definite diagnosis developed structural progression while only 1 patient in the non-definite (early) group gained minor imaging Task Force Criteria. Male gender was strongly associated with structural progression (62% of males progressed structurally, while 88% of females remained stable). Patients with structural progression were at higher risk of MACE (64% of patients with MACE had structural progression). Therefore, the rate of structural progression is an essential factor to be considered in ARVC studies. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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13 pages, 3005 KiB

Open AccessArticle

Circulating Biomarkers of Fibrosis Formation in Patients with Arrhythmogenic Cardiomyopathy

by Stephanie M. van der Voorn, Mimount Bourfiss, Steven A. Muller, Tolga Çimen, Ardan M. Saguner, Firat Duru, Anneline S. J. M. te Riele, Carol Ann Remme and Toon A. B. van Veen

Biomedicines 2023, 11(3), 813; https://doi.org/10.3390/biomedicines11030813 - 7 Mar 2023

Cited by 1 | Viewed by 2224

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a progressive inheritable disease which is characterized by a gradual fibro-(fatty) replacement of the myocardium. Visualization of diffuse and patchy fibrosis patterns is challenging using clinically applied cardiac imaging modalities (e.g., late gadolinium enhancement, LGE). During collagen synthesis and breakdown, carboxy–peptides are released into the bloodstream, specifically procollagen type-I carboxy-terminal propeptides (PICP) and collagen type-I carboxy-terminal telopeptides (ICTP). We collected the serum and EDTA blood samples and clinical data of 45 ACM patients (age 50.11 ± 15.53 years, 44% female), divided into 35 diagnosed ACM patients with a 2010 ARVC Task Force Criteria score (TFC)

\geq

4, and 10 preclinical variant carriers with a TFC

<

4. PICP levels were measured using an enzyme-linked immune sorbent assay and ICTP levels with a radio immunoassay. Increased PICP/ICTP ratios suggest a higher collagen deposition. We found significantly higher PICP and PICP/ICTP levels in diagnosed patients compared to preclinical variant carriers (p < 0.036 and p < 0.027). A moderate negative correlation existed between right ventricular ejection fractions (RVEF) and the PICP/ICTP ratio (r = −0.46, p = 0.06). In addition, significant correlations with left ventricular function (LVEF r = −0.53, p = 0.03 and end-systolic volume r = 0.63, p = 0.02) were found. These findings indicate impaired contractile performance due to pro-fibrotic remodeling. Follow-up studies including a larger number of patients should be performed to substantiate our findings and the validity of those levels as potential promising biomarkers in ACM. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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Review

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14 pages, 1155 KiB

Open AccessReview

Exploring the Therapeutic Potential of Gene Therapy in Arrhythmogenic Right Ventricular Cardiomyopathy

by Juan Mundisugih, Dhanya Ravindran and Eddy Kizana

Biomedicines 2024, 12(6), 1351; https://doi.org/10.3390/biomedicines12061351 - 18 Jun 2024

Cited by 1 | Viewed by 1544

Abstract

Right dominant arrhythmogenic cardiomyopathy, commonly known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), represents a formidable challenge in cardiovascular medicine, as conventional therapies are commonly ineffective in impeding disease progression and the development of end-stage heart failure. Recombinant adeno-associated virus (AAV)-mediated gene therapy presents a promising avenue for targeted therapeutic interventions, potentially revolutionising treatment approaches for ARVC patients. Encouraging results from preclinical studies have sparked optimism about the possibility of curing specific subtypes of ARVC in the near future. This narrative review delves into the dynamic landscape of genetic therapy for ARVC, elucidating its underlying mechanisms and developmental stages, and providing updates on forthcoming trials. Additionally, it examines the hurdles and complexities impeding the successful translation of ARVC genetic therapies into clinical practice. Despite notable scientific advancements, the journey towards implementing genetic therapies for ARVC patients in real-world clinical settings is still in its early phases. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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14 pages, 1921 KiB

Open AccessReview

Management Strategies in Arrhythmogenic Cardiomyopathy across the Spectrum of Ventricular Involvement

by Yash Maniar, Nisha A. Gilotra and Paul J. Scheel III

Biomedicines 2023, 11(12), 3259; https://doi.org/10.3390/biomedicines11123259 - 9 Dec 2023

Cited by 1 | Viewed by 1301

Abstract

Improved disease recognition through family screening and increased life expectancy with appropriate sudden cardiac death prevention has increased the burden of heart failure in arrhythmogenic cardiomyopathy (ACM). Heart failure management guidelines are well established but primarily focus on left ventricle function. A significant proportion of patients with ACM have predominant or isolated right ventricle (RV) dysfunction. Management of RV dysfunction in ACM lacks evidence but requires special considerations across the spectrum of heart failure regarding the initial diagnosis, subsequent management, monitoring for progression, and end-stage disease management. In this review, we discuss the unique aspects of heart failure management in ACM with a special focus on RV dysfunction. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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27 pages, 13624 KiB

Open AccessReview

Desmosomal Arrhythmogenic Cardiomyopathy: The Story Telling of a Genetically Determined Heart Muscle Disease

by Gaetano Thiene, Cristina Basso, Kalliopi Pilichou and Maria Bueno Marinas

Biomedicines 2023, 11(7), 2018; https://doi.org/10.3390/biomedicines11072018 - 18 Jul 2023

Cited by 4 | Viewed by 1901

Abstract

The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation family, published in 1728. Contemporary history at the University of Padua started with Dalla Volta, who haemodynamically investigated patients with “auricularization” of the right ventricle, and with Nava, who confirmed familiarity. The contemporary knowledge advances consisted of (a) AC as a heart muscle disease with peculiar electrical instability of the right ventricle; (b) the finding of pathological substrates, in keeping with a myocardial dystrophy; (c) the inclusion of AC in the cardiomyopathies classification; (d) AC as the main cause of sudden death in athletes; (e) the discovery of the culprit genes coding proteins of the intercalated disc (desmosome); (f) progression in clinical diagnosis with specific ECG abnormalities, angiocardiography, endomyocardial biopsy, 2D echocardiography, electron anatomic mapping and cardiac magnetic resonance; (g) the discovery of left ventricular AC; (h) prevention of SCD with the invention and application of the lifesaving implantable cardioverter defibrillator and external defibrillator scattered in public places and playgrounds as well as the ineligibility for competitive sport activity for AC patients; (i) genetic screening of the proband family to unmask asymptomatic carriers. Nondesmosomal ACs, with a phenotype overlapping desmosomal AC, are also treated, including genetics: Transmembrane protein 43, SCN5A, Desmin, Phospholamban, Lamin A/C, Filamin C, Cadherin 2, Tight junction protein 1. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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12 pages, 447 KiB

Open AccessReview

Antiarrhythmic Drug Therapy in Arrhythmogenic Right Ventricular Cardiomyopathy

by Sean P. Gaine and Hugh Calkins

Biomedicines 2023, 11(4), 1213; https://doi.org/10.3390/biomedicines11041213 - 19 Apr 2023

Cited by 7 | Viewed by 3718

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable progressive myocardial disorder that predisposes patients to ventricular arrhythmias and sudden cardiac death. Antiarrhythmic medications have an important role in reducing the frequency of ventricular arrhythmias and the morbidity associated with recurrent implantable cardioverter-defibrillator (ICD) shocks. Although several studies have examined the use of antiarrhythmic drugs in ARVC, these have been mostly retrospective in nature and inconsistent in their methodology, patient population and endpoints. Thus, current prescribing practices are largely based on expert opinion and extrapolation from other diseases. Herein, we discuss the major studies of the use of antiarrhythmics in ARVC, present the current approach employed at the Johns Hopkins Hospital and identify areas where further research is needed. Most notably, there is a great need for high-quality studies with consistent methodology and randomized controlled trial data into the use of antiarrhythmic drugs in ARVC. This would improve management of the condition and ensure antiarrhythmic prescribing is based on robust evidence. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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11 pages, 3316 KiB

Open AccessReview

Cheek-Pro-Heart: What Can the Buccal Mucosa Do for Arrhythmogenic Cardiomyopathy?

by Carlos Bueno-Beti and Angeliki Asimaki

Biomedicines 2023, 11(4), 1207; https://doi.org/10.3390/biomedicines11041207 - 18 Apr 2023

Viewed by 1847

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease associated with ventricular arrhythmias and a high risk of sudden cardiac death (SCD). Although the disease was described over 40 years ago, its diagnosis is still difficult. Several studies have identified a set of five proteins (plakoglobin, Cx43, Nav1.5, SAP97 and GSK3β), which are consistently re-distributed in myocardial samples from ACM patients. Not all protein shifts are specific to ACM, but their combination has provided us with a molecular signature for the disease, which has greatly aided post-mortem diagnosis of SCD victims. The use of this signature, however, was heretofore restricted in living patients, as the analysis requires a heart sample. Recent studies have shown that buccal cells behave similarly to the heart in terms of protein re-localization. Protein shifts are associated with disease onset, deterioration and favorable response to anti-arrhythmic therapy. Accordingly, buccal cells can be used as a surrogate for the myocardium to aid diagnosis, risk stratification and even monitor response to pharmaceutical interventions. Buccal cells can also be kept in culture, hence providing an ex vivo model from the patient, which can offer insights into the mechanisms of disease pathogenesis, including drug response. This review summarizes how the cheek can aid the heart in the battle against ACM. Full article

(This article belongs to the Special Issue Advanced Research in Arrhythmogenic Cardiomyopathy)

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