Ventricular Cardiomyopathy Research Articles

Danon Disease Manifesting as Arrhythmogenic Right Ventricular Cardiomyopathy: A Case Report

Danon disease is a rare X-linked genetic disorder, manifesting as cardiac hypertrophy, myopathy, and intellectual disability. We report a rare case of arrhythmogenic right ventricular cardiomyopathy (ARVC) in a 28-year-old female with Danon disease. An electrocardiogram (ECG) showed sinus bradycardia and first-degree atrioventricular block; echocardiography revealed a right atrial thrombus, and computed tomography (CT) scan displayed an enlarged right ventricular outflow tract and right atrial thrombosis. Genetic testing identified a novel Lysosomal Associated Membrane Protein 2 (LAMP2) gene variant, confirming the diagnosis of Danon disease. The patient was administered anticoagulants and heart failure medications. This case underscores the importance of considering family history and genetic testing in diagnosing Danon disease with ARVC. This expands the disease's phenotypic spectrum beyond its conventional cardiac manifestations.

Fenotypic expressions and clinical manifestations of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a cardiac disorder characterized by structural alterations of the myocardium, which predisposes individuals to ventricular arrhythmias and increases the risk of sudden cardiac death. Initially described as arrhythmogenic right ventricular cardiomyopathy, the involvement of the left ventricle (LV) has been subsequently recognized, leading to the classification of various phenotypes under LV non-dilated cardiomyopathy. The clinical spectrum of ACM ranges from life-threatening ventricular arrhythmias to overt heart failure, sometimes presenting with acute myocarditis-like episodes and extracardiac symptoms, further contributing to the disease's heterogeneity. Diagnosis relies on imaging modalities, such as echocardiogram and cardiac magnetic resonance imaging, to detect areas of fibro-fatty replacement and/or non-ischemic ventricular scarring, integrated with genetic analysis. The 2023 European Society of Cardiology guidelines on Cardiomyopathies underscore the importance of a comprehensive diagnostic approach, combining imaging and genetics for arrhythmic risk stratification and comprehensive patient management. Growing evidence on genotype-phenotype correlation, along with the validation of specific predictive scores, is improving ACM clinical management and promoting personalized treatment tailored to individual and familial characteristics.

Prediction and prognostic role of left ventricular systolic dysfunction in family screening for dilated cardiomyopathy and non-dilated left ventricular cardiomyopathy.

The prognostic significance of detecting left ventricular (LV) systolic dysfunction during family screening programmes (FSPs) in relatives of probands affected by dilated (DCM) and non-dilated left ventricular (NDLVC) cardiomyopathies remain unclear. This study sought to evaluate the prognostic role of LV systolic dysfunction detection in relatives of DCM/NDLVC probands and to define the most accurate FSP. Baseline and follow-up data of first-degree relatives of probands affected by DCM/NDLVC were collected. The primary outcome was all-cause death and heart transplantation. Secondary heart failure (HF) and arrhythmic outcomes were also included. A total of 492 first degree relatives were enrolled. During a median follow-up of 110 months (interquartile range 57-188 months), only subjects that previously developed LV systolic dysfunction had primary outcomes (19 vs. 0, p < 0.001) and secondary outcomes (HF: 12 vs. 0, p = 0.005; arrhythmic: 30 vs. 0, p < 0.001). Subjects with LV systolic dysfunction detected by FSP showed lower rate of primary outcomes (FSP: n = 19 [14%]; no-FSP: n = 40 [37%]; p < 0.001) and secondary arrhythmic outcomes (FSP: n = 18 [13%]; no-FSP: n = 41 [38%]; p < 0.001). In this setting, family history of arrhythmia and being carrier of a pathogenic/likely pathogenic variant are the main risk factors for LV systolic dysfunction, while LV global longitudinal strain (LV-GLS) and Holter electrocardiogram (ECG) showed a relevant role in terms of prediction of LV systolic dysfunction and outcomes. Relatives of DCM/NDLVC probands who developed LV systolic dysfunction during a long follow-up had a significant increased risk of major adverse cardiovascular outcomes. However, LV systolic dysfunction detected by FSP showed a better prognosis. In this context, genetics, Holter ECG and LV-GLS demonstrated their functional role for disease and event prediction.

Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2-Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by irregular rhythms and right ventricular dysplasia. Sequence variations in desmosomal protein-encoding genes are linked to ARVC development. Effective treatments for ARVC are lacking. Whereas mRNA-based therapies have shown efficacy in humans, their therapeutic potential for inherited cardiomyopathies remains unclear. Whole-exome sequencing identified a novel DSC2 sequence variation causing autosomal recessive ARVC in a Chinese family with consanguineous marriage. Mouse models with Dsc2 sequence variation knock-in and constitutive knock-out were generated and analyzed using echocardiography and histology. Transcriptomic and biochemical analyses were conducted to explore ARVC mechanisms. Dsc2 mRNA delivered by intracardiac or transcoronary injection was assessed as a treatment for ARVC in Dsc2 knock-out mice. In addition, effects of Dsc2 mRNA were examined in a transverse aortic constriction mouse model with noninherited right ventricular systolic dysfunction. Dsc2-deficient mice exhibited right ventricular dilation and dysfunction, mimicking human disease. Transcriptomic analysis identified Myl7 as the most downregulated gene in the right ventricles of Dsc2-deficient mice, and its restoration by adeno-associated virus 9 rescued heart function. Dsc2 mRNA delivery, with or without lipid nanoparticle encapsulation, normalized heart size and function in Dsc2-deficient mice. Reduced DSC2 and MLC2a expression was also noted in patients with noninherited dilated cardiomyopathy and in mice with transverse aortic constriction. A single dose of mRNA provided therapeutic effects lasting 2 to 3 months before declining. Our study reveals novel mechanisms of ARVC caused by DSC2 loss of function, supported by human and mouse data. Loss of Myl7 contributes to reduced cardiac contractility in ARVC and dilated cardiomyopathy with right ventricular systolic dysfunction. Dsc2 mRNA treatment demonstrated significant therapeutic potential in ARVC and transverse aortic constriction models, providing a basis for future clinical applications.

The contribution of cardiopulmonary exercise testing in the familial screening for dilated and non-dilated left ventricular cardiomyopathies: case series

Abstract Background The importance of family screening in relatives of patients affected by cardiomyopathies is highlighted in the international guidelines. Although electrocardiogram (ECG) and echocardiogram represent cornerstones of family screening, they may not always be sufficient to detect subtle abnormalities, especially in genotype-positive/phenotype-negative relatives. The role of cardiopulmonary exercise testing (CPET) in providing additional clinical information during family screening, remains to be fully elucidated. Case summary Ten asymptomatic genotype-positive/phenotype-negative first-degree relatives of probands affected by dilated cardiomyopathy (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC) were evaluated in the context of family screening. CPET was integrated into the initial diagnostic evaluation. Two out of ten relatives showed an abnormal CPET, with alteration in O2 kinetic. Conclusion Family screening in relatives of DCM and NDLVC patients, particularly in genotype-positive/phenotype-negative subjects, remains challenging due to difficulties in assessing the subtle abnormalities that may represent an initial clinical manifestation of the disease and support early treatment initiation. A more accurate and comprehensive familial screening may be achieved by integrating ECG and echocardiogram - the current first-line assessments - with data from additional tools, such as global longitudinal strain on echocardiogram, cardiac magnetic resonance, Holter-ECG and CPET.

Coexistence of Large Atrial Septal Defect with Arrhythmogenic Right Ventricular Cardiomyopathy.

Coexistence of Large Atrial Septal Defect with Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmic risk prediction in non-dilated left ventricular cardiomyopathy: The role of overlap with arrhythmogenic cardiomyopathy.

Arrhythmic risk prediction in non-dilated left ventricular cardiomyopathy: The role of overlap with arrhythmogenic cardiomyopathy.

Diagnostic and Prognostic Significance of miRNA-15a-5p, 16-5p, and 92a-3p in Arrhythmogenic Right Ventricular Cardiomyopathy.

Diagnostic and Prognostic Significance of miRNA-15a-5p, 16-5p, and 92a-3p in Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic Right Ventricular Cardiomyopathy: The Importance of Biventricular Strain in Risk-Stratification.

Despite arrhythmogenic right ventricular cardiomyopathy (ARVC) being predominantly a right ventricular (RV) disease, concomitant left ventricular (LV) involvement has been recognized. ARVC is diagnosed by the RV-centric 2010 Task Force Criteria(TFC) using routine echocardiography, but previous studies have suggested that strain imaging may be more sensitive to detect RV and LV dysfunction. No data however are available regarding the additional value of combining biventricular strain for risk stratification. This study aims to assess the prognostic value of both LV global longitudinal strain (GLS) and RV free wall strain (FWLS) in patients with ARVC. To accomplish this, 204 patients who met the TFC for the ARVC spectrum were included. Patients (age 41 ± 17 years,55% men) were divided into impaired(n = 33), discordant (RV or LV impaired, n = 70), and normal (n = 101) strain groups based on a value of ≥18% for both ventricles. During a follow-up of 87 [24-136] months, 57 (28%) experienced the composite outcome of all-cause mortality, arrhythmic events, implantable cardioverter defibrillator therapy and heart failure events, and a significant difference in event-free survival was observed (p <0.001) between the 3 groups. In the multivariable analysis, the strain groups remained associated with outcomes (p = 0.014) after adjusting for age, sex, history of syncope and definite ARVC diagnosis. A subanalysis including only definite and borderline diagnosed ARVC confirmed that the strain groups were independently predictive of the endpoint (p = 0.023). In conclusion, biventricular involvement by strain analysis may help risk stratification in ARVC patients, with the worst outcomes of patients with both RV and LV impaired strain.

Reduced myocardial CARF and the underlying implications in left ventricular noncompaction cardiomyopathy

Reduced myocardial CARF and the underlying implications in left ventricular noncompaction cardiomyopathy

Risk Factors and Predictors of Ventricular Tachycardia in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy: Insights from a Pakistani Cohort

Objectives: This study aimed to identify risk factors and predictors of ventricular tachycardia (VT) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) treated at Hayatabad Medical Complex, Peshawar. Methodology: A retrospective cohort analysis was performed on 150 ARVC patients diagnosed between January 2019 and June 2024. Key variables included electrocardiographic findings (e.g., T-wave inversions), NT-proBNP levels, genetic mutations (PKP2, DSP), and echocardiographic parameters. Predictors were assessed using univariate and multivariate Cox proportional hazards models. Results: The mean age of the cohort was 45 years, with 60% male. Significant predictors of VT included older age (HR 1.05, p&lt;0.001), male gender (HR 1.75, p=0.002), T-wave inversions on ECG (HR 2.15, p&lt;0.001), and elevated NT-proBNP levels (HR 1.01 per 100 pg/ml increase, p=0.005). During follow-up, 30% of patients experienced VT, 20% developed sustained ventricular arrhythmias, and 10% mortality was observed. Conclusion: Age, male gender, T-wave inversions, and elevated NT-proBNP levels were identified as significant predictors of VT in ARVC patients. These findings highlight the critical role of biomarker testing and electrocardiographic monitoring in improving risk stratification and management for ARVC, particularly in resource-constrained settings.

Long-Term Follow-Up Data on FlecainideUseas an Antiarrhythmic inArrhythmogenic RightVentricularCardiomyopathy: A Multicenter Study.

Long-Term Follow-Up Data on FlecainideUseas an Antiarrhythmic inArrhythmogenic RightVentricularCardiomyopathy: A Multicenter Study.

Physiological Versus Pathological Cardiac Adaptations in Athletes: Unravelling the Complexities of the Athlete’s Heart through Advanced Echocardiographic Imaging

Introduction: The “athlete’s heart” refers to cardiac adaptations from intense training, which can mimic conditions like hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to differentiate physiological and pathological cardiac hypertrophy in athletes using advanced echocardiographic techniques. Methodology: A literature review of studies from 2000–2024 was conducted using PubMed, Scopus, and Google Scholar, focusing on cardiac remodeling, echocardiographic evaluation, and sudden cardiac death (SCD) risk in athletes. Discussion: Endurance athletes develop eccentric hypertrophy, while strength athletes exhibit concentric hypertrophy. Physiological adaptations maintain normal function, whereas HCM and ARVC present with structural abnormalities and increased SCD risk. Advanced imaging, including strain and tissue Doppler, is crucial for accurate diagnosis. Conclusion: Echocardiographic screening is essential for distinguishing normal adaptations from dangerous pathologies in athletes. This study highlights the role of advanced imaging in preventing misdiagnosis and ensuring cardiovascular safety in sports.

An unusual thrombus in a patient with arrhythmogenic cardiomyopathy

Herein we present a case of a right ventricular (RV) thrombus in a patient with arrhythmogenic cardiomyopathy (ACM). The 24-year old female patient was diagnosed with ACM after echocardiography, genetic test and cardiac magnetic resonance imaging. Interestingly, at echocardiography, an unusal thrombus formation was detected at RV lateral wall. Also, CMR confirmed the thrombus and oral anticoagulant therapy was started. During the patient’s follow-ups, it was observed that the imaging consistent with the reported thrombus disappeared after effective anticoagulant treatment. After the diagnosis was confirmed with genetic tests, an implantable cardioverter-defibrillator (ICD) was implanted in the patient with a high sudden cardiac death (SCD) risk score. Even in arrhythmogenic right ventricular cardiomyopathy patients thrombi are rarely reported. However, the development of imaging techniques may enable more frequent detection and effective treatment of thrombi in these patients.

Overexpression of Wild-Type TMEM43 Improves Cardiac Function in Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.

Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is the most aggressive type of ARVC, caused by a fully penetrant missense mutation (p.S358L) in TMEM43 (transmembrane protein 43). Pathologically, the disease is characterized by dilation of the cardiac chambers and fibrofatty replacement of the myocardium, which results in heart failure and sudden cardiac death. Current therapeutic options are limited, and no specific therapies targeting the primary cause of the disease have been proposed. We investigated whether overexpression of wild-type (WT) TMEM43 could overcome the detrimental effects of the mutant form. We used transgenic mouse models overexpressing either WT or mutant (S358L) TMEM43 to generate a double transgenic mouse line overexpressing both forms of the protein. In addition, we explored if systemic delivery of a codon-optimized self-complementary adeno-associated virus bearing WT-TMEM43 could improve disease progression assessed by ECG and echocardiography. Double transgenic mice overexpressing both WT and mutant TMEM43 forms showed delayed ARVC5 onset, improved cardiac contraction, and reduced ECG abnormalities compared with mice expressing S358L-TMEM43. In addition, cardiomyocyte death and myocardial fibrosis were reduced, with an overall increase in survival. Finally, we demonstrated that a single systemic administration of an adeno-associated virus carrying codon-optimized WT-TMEM43 prevents ventricular dysfunction and ECG abnormalities induced by S358L-TMEM43. Overexpression of WT-TMEM43 improves the pathological phenotype in a mouse model of ARVC5. Adeno-associated virus-mediated delivery of WT-TMEM43 offers a promising and specific therapy for patients suffering from this highly lethal disease. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05885412, NCT06109181, and NCT06228924.

Prevalence and Correlates of Dilated and Non-Dilated Left Ventricular Cardiomyopathy in Transfusion-Dependent Thalassemia: Data from a National, Multicenter, Observational Registry.

We investigated the prevalence, clinical characteristics, and prognostic role of dilated cardiomyopathy (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC) in patients with transfusion-dependent β-thalassemia (β-TDT). We retrospectively included 415 β-TDT patients who underwent cardiovascular magnetic resonance to quantify myocardial iron overload (MIO) and biventricular function parameters and to detect replacement myocardial fibrosis. Demographic and laboratory parameters were comparable among patients with no overt cardiomyopathy (NOCM; n = 294), DCM (n = 12), and NDLVC (n = 109), while cardiac size and systolic function were significantly different. Compared to NOCM patients, DCM and NDLVC patients had a higher prevalence of MIO and replacement myocardial fibrosis. During a mean follow-up of 57.03 ± 18.01 months, cardiac complications occurred in 32 (7.7%) patients: 15 heart failures, 15 supraventricular arrhythmias, and 2 pulmonary hypertensions. Compared to the NOCM group, both the NDLVC and the DCM groups were associated with a significantly increased risk of cardiac complications (hazard ratio = 4.26 and 8.81, respectively). In the multivariate analysis, the independent predictive factors were age, MIO, and the presence of DCM and NDLVC versus the NOCM phenotype. In β-TDT, the detection of NDLVC and DCM phenotypes may hold value in predicting cardiac outcomes.

Evolution of clinical and genetic concepts of cardiomyopathies

The definitions and classifications of cardiomyopathies are presented from a historical perspective based on an analysis of databases on platforms such as PubMed, Web of Science, Scopus, and Google Scholar, using appropriate keywords. It is noted that the implementation of high-tech research methods is accompanied by the creation of concepts of cardiomyopathies, establishing etiological and pathogenetic links that are being transformed into clinical signs, which require stratification, risk factor assessment, and prognosis. The diagnostic value of structural and functional heart anomalies for ranking classical phenotypes of dilated, hypertrophic, restrictive cardiomyopathies, and arrhythmogenic right ventricular cardiomyopathy is аnalyzed. A description is provided of a new phenotype of non-dilated left ventricular cardiomyopathy and syndromes associated with cardiomyopathy phenotypes such as left ventricular hypertrabeculation (non-compaction) and takotsubo syndrome. The possibilities of genetic research in determining the primary etiological factors of myocardial damage, risk groups for-ming are analyzed. It is noted that the prerequisite for the application of laboratory genetic methods in practical work is genetic analysis at the family and individual level with establishing genealogical, sex-age, phenotypic, and other characteristics of patients and their relatives. It is determined that the interpretation of the results of a comprehensive clinical examination and complete genetic testing provides a fundamental base and practical tools for the stratification of symptoms and differentiation of cardiomyopathies, timely implementation of measures to eliminate arrhythmias, prevent sudden cardiac death in patients, and for providing consultation on prognostic and preventive medical recommendations to family members.

A single RBM20 missense variant is a potential contributor to dilated cardiomyopathy and/or isolated left ventricular dilatation in the Emilia Romagna region of Italy.

A single RBM20 missense variant is a potential contributor to dilated cardiomyopathy and/or isolated left ventricular dilatation in the Emilia Romagna region of Italy.

The role of MicroRNAs in arrhythmogenic right ventricular cardiomyopathy: A systematic review.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited heart condition with structural and functional abnormalities of the right ventricle. Microribonucleic acids (miRNAs, miRs) could be a solution in detecting ARVC earlier, more commonly, and in a less invasive way. We aimed to systematically review the current knowledge about the role of miRNAs in ARVC. Primary original research written in English assessing miRNAs in ARVC were included. Systematic reviews, meta-analyses, reviews, case reports, letters to editors, commentaries, conference abstracts, guidelines/statements, expert opinions, pre-prints, and book chapters were excluded at the screening stage. Five databases were searched: Embase, Medline Ultimate, PubMed, Scopus, and Web of Science, last on October 4, 2024. Eventually, 3 13 original studies relevant to the discussed area were included. The quality of research was assessed with the Newcastle-Ottawa Scale. MiR-216a was consistently increased in mice ARVC models and in patients suffering from this disease. Based on the reviewed literature, miR-1, miR-21, and miR-122 are other most important miRNAs in the ARVC. Nevertheless, the research that has already been performed on these miRNAs gives evidence only for their diagnostic potential. Bioinformatic analyses revealed that the following miRNAs are the most important ones involved in ARVC: let-7b, miR-10b-5p, miR-15a-5p, miR-21-5p, miR-29b-3p, miR-122-5p, miR-144-3p, miR-149-5p, miR-182-5p, miR-186-5p, miR-320a, miR-494-3p, and miR-590-3p. Creating a miRNA panel that could identify ARVC patients with high sensitivity and specificity would be helpful. Currently, there are many gaps in the existing knowledge, which makes miRNA in ARVC an attractive field for future investigation.

Arrhythmogenic Cardiomyopathy in Children. Case Series and Review of the Literature

Abstract Arrhythmogenic cardiomyopathies (ACM) are rare inherited cardiac disorders, with an incidence below 1% in adults and an undetermined prevalence in pediatric populations. Formerly recognized primarily as arrhythmogenic right ventricular cardiomyopathy (ARVC), affecting exclusively the right ventricle (RV), recent diagnostic advancements have shed light on the involvement of the myocardium in ACM, revealing fibrous infiltration in both ventricles. In 2023, the European Society of Cardiology introduced updated phenotypic classifications of cardiomyopathy, highlighting the coexistence of multiple types within families and the potential transition from one cardiomyopathy to another. We present a case series comprising four pediatric cases of ARVC with diverse presentations and outcomes. Subsequent evaluations unveiled both left ventricle (LV) and RV dysfunction, culminating in a diagnosis of ARVC based on the 2020 diagnostic criteria. Additionally, genetic testing uncovered mutations in genes associated with cardiomyopathies. Cardiac magnetic resonance imaging (MRI) corroborated the biventricular involvement, aligning with a diagnosis of ACM per the 2020 Padua criteria. In conclusion, recent updates in diagnostic criteria have refined the classification of ACM, underscoring the importance of cardiac MRI and morphological features for precise diagnosis. Genetic testing has identified novel mutations linked to cardiomyopathy, emphasizing the significance of personalized treatment strategies and genetic counselling for affected individuals and their families.