Search Results (126)

Introduction: Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by fibrofatty replacement of the myocardium and is associated with heart failure and sudden cardiac death. It can involve either ventricle, including left-dominant forms defined partly by genetic findings. Methods: We investigated a consanguineous family with four affected daughters presenting with ACM, epidermolytic palmoplantar keratoderma, and woolly hair. The two eldest siblings died suddenly during childhood. The remaining two affected siblings underwent genetic analysis using autozygosity mapping and whole-exome sequencing, followed by segregation analysis. Results: Autozygosity mapping identified a shared identity-by-descent (IBD) interval at the DSP locus on chromosome 6. Exome sequencing revealed a novel homozygous nonsense variant (c.4297C>T; p.Gln1433*; rs1554108283) in exon 23 of DSP. This variant introduces a premature termination codon within the region specific to transcript variant 1, sparing transcript variant 2. Both parents were heterozygous carriers. Cardiac imaging in the affected siblings demonstrated biventricular involvement, including left ventricular systolic dysfunction and right ventricular dilatation. Skin biopsy in one patient confirmed epidermolytic palmoplantar keratoderma. Conclusions: We describe a novel homozygous nonsense variant in the transcript 1-specific region of DSP causing Carvajal syndrome, characterized by severe biventricular ACM, epidermolytic palmoplantar keratoderma, and woolly hair, in a consanguineous Arabian family with four affected sisters. Full article

Background: Flecainide has remained largely excluded from use in structural heart disease for more than three decades, mainly because of the Cardiac Arrhythmia Suppression Trial, which showed excess mortality in post-myocardial infarction patients treated for ventricular ectopy. However, the influence of this trial has extended well beyond the population actually studied, fostering a broad safety paradigm that may not fully reflect contemporary clinical practice. Aim: This review aims to re-examine the role of flecainide in structural heart disease by examining the historical basis for its restriction and contrasting it with emerging contemporary evidence across specific structural substrates. Discussion: Flecainide remains one of the most effective antiarrhythmic drugs for rhythm control in atrial fibrillation and for the suppression of selected ventricular arrhythmias in patients without overt structural abnormalities. Emerging observational and early prospective data suggest that, in carefully selected patients with stable coronary artery disease without active ischemia, preserved left ventricular function, arrhythmogenic right ventricular cardiomyopathy, and premature ventricular complex-induced cardiomyopathy, flecainide may provide meaningful antiarrhythmic benefit without a clear signal of excess proarrhythmia or mortality. Advances in cardiac imaging, ischemia assessment, and phenotypic risk stratification further support a more individualized approach to candidate selection. Conclusions: Flecainide should not be considered uniformly contraindicated across all forms of structural heart disease. Rather than supporting indiscriminate use, the available evidence supports a mechanistically informed and phenotype-specific reassessment of its role in selected patients. Prospective studies are needed to determine whether current guideline restrictions remain justified in the modern era. Full article

Background/Objectives: To establish a foundation for conserving and utilizing local frog germplasm resources in Zhejiang Province, for Quasipaa spinose, which has high commercial and nutritional value, a pan-genome analysis was performed. Methods: Herein, we characterized 405,263 SNPs for the giant spiny frog, Q. spinose, using the Illumina NovaSeq platform. Results: These loci were highly polymorphic in 59 individuals sampled from three different subpopulations, with 0.05 to 0.30 minor alleles per locus. The observed and expected heterozygosities were 0.2379 and 0.2683 (IBD), respectively. These polymorphic loci would be useful for assessing genetic diversity, population structure, gene flow, population assignment, and paternity in giant spiny frogs. Conclusions: Our investigation demonstrated that there are distinct genetic and evolutionary histories between Zhejiang and Jiangxi frogs. Phylogenetic inference effectively differentiated these three subpopulations based on their geographical origins, and the phylogenetic inference level of domesticated Zhejiang frogs was comparatively higher than that of the Jiangxi-derived population. Furthermore, by utilizing three selective signature methods, namely, Obs/Exp het, nucleotide diversity (Pi), and identical by state (IBS), across subpopulations, we concluded that these three breeds were from an identical population, and no genetic bottleneck occurred among these three lineages, in accordance with LD decay analysis. Finally, 2700 potential candidate genes were identified, including MAPK, calcium signaling pathway, Ras signaling pathway and regulation of actin cytoskeleton; we noted that the key genes associated with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy in humans beings and GnRH signaling pathway-related genes (i.e., CD80, IFNA, and KCNK1) were highly enriched, which could impact cardiac function through immune-associated genes. Full article

Sudden cardiac death (SCD) is a major global health issue, defined as sudden natural death presumed to be of cardiac cause. While in the elderly SCD is commonly associated with coronary artery disease, in the younger population it is linked to inherited cardiomyopathies or channelopathies, even though SCD can remain unexplained even after a comprehensive autopsy in a substantial proportion of cases. In this context, genetic testing has gained importance, supported by the widespread availability of techniques such as next-generation and whole-exome/genome sequencing and their reduced costs. This state-of-the-art review summarizes the genetic bases of sudden cardiac death among cardiomyopathies, channelopathies and in sudden unexplained death presumed to be of arrhythmic cause. Among the structural causes, inherited cardiomyopathies such as hypertrophic, dilated, non-dilated left ventricular, arrhythmogenic right ventricular and restrictive ones represent major substrates for malignant ventricular arrhythmias mostly arising from variants in sarcomeric or desmosomal genes. Channelopathies (long or short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia) are caused by variants in genes encoding cardiac ion channels and/or regulatory proteins, which equally predispose to high risk of life-threatening ventricular arrhythmias. In sudden arrhythmic death syndrome, with a structurally normal heart, post-mortem genetic testing (molecular autopsy) can uncover an underlying inherited condition. However, variants of uncertain significance are detected in more than half of the cases, underscoring the need for a multidisciplinary approach. Genetic testing also plays a key role in cascade screening of first-degree relatives. While monogenic variants drive risk in inherited cardiac disorders, emerging evidence suggests that polygenic contributions may modulate SCD susceptibility, highlighting future roles for polygenic risk scores in risk stratification. Full article

Background: Catheter ablation is a validated treatment for ventricular arrhythmias (VA), but conventional radiofrequency (RF) energy may cause collateral injury due to non-selective thermal damage. Pulsed Field Ablation (PFA), a non-thermal modality based on irreversible electroporation, offers myocardial tissue selectivity and enhanced safety. While PFA is widely adopted for atrial arrhythmias’ ablation, its application in the ventricles remains an evolving frontier. Methods: We report a single-center experience using the Centauri PFA system integrated with a focal, contact-force sensing irrigated catheter (Tacticath™ SE, Abbott Laboratories, St. Paul, MN, USA) in four consecutive patients with drug-refractory VA. Two patients presented with frequent premature ventricular complexes (PVC) arising from the right and left ventricular outflow tract, respectively, while two had ischemic cardiomyopathy with recurrent scar-related ventricular tachycardia (VT). All procedures were guided by high-density mapping using the EnSite X system (Abbott Laboratories, St. Paul, MN, USA). Procedural safety, acute efficacy, and early follow-up outcomes were assessed. Results: All ablations achieved acute procedural success without complications. In both PVC cases, PFA led to immediate and complete suppression of ectopy, with a ≥95% reduction in arrhythmic burden at 12- and 9-months follow-up, respectively. In the VT cases, the arrhythmogenic substrate was effectively modified, rendering the clinical VT non-inducible. ICD interrogation during a 9-month follow-up showed complete absence of recurrent sustained VT. No coronary spasm, atrioventricular block, pericardial effusion, or other adverse events occurred. Conclusions: In this initial experience, focal PFA using a contact-force sensing catheter appeared feasible and effective for both focal and scar-related VA. This system provides an intuitive workflow similar to RF ablation. While our data suggest a favourable safety profile, larger studies are required to definitively confirm safety margins near critical structures. Full article

Background/Objectives: To explore the predictive value of pericardial fat tissue (PFT) radiomics for left ventricular (LV) involvement and major adverse cardiac events (MACE) in arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods: In this retrospective multicenter study, LV involvement was assessed using cardiac magnetic resonance (CMR). A radiomic score (RS) derived from PFT was developed to predict LV involvement. The predictive accuracy of the RS was evaluated through receiver operating characteristic (ROC) analysis. Additionally, multivariable Cox regression analysis was employed to assess the prognosis across the entire dataset. Kaplan–Meier survival curves were used to evaluate the association between RS and MACE. Results: A total of 122 patients (mean age, 44 years ± 17; 76 male) were included, 90 for a development set and 32 for an external test set. The RS demonstrated good predictive performance for LV involvement in both the development and external test sets, with area under the curve (AUC) values of 0.771 and 0.785, respectively. Moreover, a high RS (≥−0.38) was independently associated with MACE during a median follow-up of 5 years (hazard ratio, 3.452; p < 0.001). Based on the right ventricular ejection fraction (RVEF) and RS, a simplified risk score was developed to categorize patients into three groups: high-risk (RVEF ≤ 40%, RS ≥ −0.38), intermediate-risk (RVEF ≤ 40%, RS < −0.38 or RVEF > 40%, RS ≥ −0.38), and low-risk (RVEF > 40%, RS < −0.38). Conclusions: The PFT radiomics can predict LV involvement and be associated with MACE in ARVC patients. Full article

This study investigates FLNC mutations in Chinese cardiomyopathy patients. Background: Inherited cardiomyopathies, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) are major heart failure causes. FLNC, critical for muscle structure, is implicated in myofibrillar myopathy and isolated DCM (3–4% cases) with ventricular arrhythmias. Missense variants are linked to HCM and protein aggregation. A cohort of 25 patients with pathogenic/likely pathogenic FLNC mutations (2022–2025, Beijing Anzhen Hospital) underwent whole-exome sequencing (WES) using IDT kit 1.0/Hiseq 4000. Variants were classified via the American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical data (echocardiography, CMR, labs) and follow-up data (prognosis, meds, and family history) were collected. The statistics used SPSS (p < 0.05). The mean age was 38 ± 14.6 years (13 males). There were 25 FLNC mutations: 12 single nucleotide polymorphisms (SNPs), 5 deletions, 2 duplications, and 3 deletion-insertions, classified as 6 pathogenic, 16 likely pathogenic, and 3 variants of uncertain significance (VUS). Diagnoses: 24% dilated cardiomyopathy (DCM), 8% hypertrophic cardiomyopathy (HCM), and 4% left ventricular non-compaction. Nonsense mutation carriers exhibited significantly higher tricuspid regurgitation prevalence compared to frameshift mutation carriers (6/9 vs. 2/10; p = 0.04). Echocardiography revealed reduced left ventricular ejection fraction (LVEF) (41.5 ± 14.1%), with statistically significant differences in fractional shortening (p = 0.024) and aortic root diameter (p = 0.028). Pedigree analysis confirmed that a frameshift mutation (LP) co-segregated with familial DCM and was associated with severe phenotypes, including sudden cardiac death. Furthermore, nonsense FLNC mutations correlated with increased tricuspid regurgitation severity, smaller aortic root dimensions, and reduced pulmonary artery flow velocity. Full article

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a congenital cardiac disorder, but its severity has been increasingly linked to inflammatory processes. This study aimed to investigate gene expression profiles in ARVC to identify genes potentially driving inflammation in affected individuals. Methods: Publicly available gene expression datasets comprising 12 ventricular tissue samples from six clinically confirmed ARVC patients (paired left and right ventricular biopsies) and 12 ventricular samples from six non-failing donor hearts were analyzed to identify differentially expressed genes. Immune infiltration was assessed to determine the proportions of immune cells in the ARVC condition. Correlation analysis between immune cell proportions and gene expression profiles was further performed to identify genes linked with inflammation-specific immune cells. Functional enrichment analysis of associated genes was performed to pinpoint the key involvement of genes in different inflammatory-specific pathways. Finally, the key gene associated with inflammation-specific immune cells and its active involvement in inflammatory pathways was further subjected to molecular docking against a curated library of marine-derived phytochemicals, followed by 100 ns molecular dynamics simulations to evaluate ligand stability. Results: A total of 141 significantly upregulated genes were identified in ARVC. Immune infiltration analysis revealed elevated proportions of regulatory T cells, CD8⁺ T cells, plasma cells, M2 macrophages, resting mast cells, and activated NK cells in the ARVC phenotype, indicating an immunologically active microenvironment. Correlation analysis identified four genes—LIFR, SCN2B, RGCC, and PIK3R1—showing significant positive associations with these immune cells. Functional enrichment analysis highlighted PIK3R1 (LogFC > 2.00) as a central regulator in the PI3K/AKT and mTOR pathways, which govern immune activation, cell survival, and fibrosis. Molecular docking identified two marine compounds, CMNPD18967 and CMNPD756, with strong binding affinities (−5.9 and −5.7 kcal/mol, respectively). Molecular dynamics simulations confirmed stable ligand binding within the PIK3R1 active site. Conclusions: PIK3R1 emerges as a key inflammation-associated gene in ARVC, with strong involvement in immune-regulatory pathways. Marine-derived phytochemicals CMNPD18967 and CMNPD756 demonstrate promising inhibitory potential through stable interaction with PIK3R1. While these findings present potential anti-inflammatory leads, validation in larger clinical cohorts and experimental models is essential to confirm translational applicability. Full article

This study examines pediatric cardiomyopathies by analyzing genetic and clinical data from 55 patients (2021–2024) at Beijing Anzhen Hospital. Four subtypes were studied: dilated (DCM, 24), hypertrophic (HCM, 22), arrhythmogenic right ventricular (ARVC, 7), and restrictive (RCM, 2). Clinical data, imaging, labs, and family histories were collected, with whole-exome sequencing (WES) identifying disease-causing variants classified via ACMG guidelines. Statistical analysis revealed a median age of 11 years, a proportion of 58% male participants, and ethnic diversity (21 northern Han, 29 southern Han, 5 minorities). In the cohort, 13 cases had an LVEF below 35%. Pathogenic/likely pathogenic (P/LP) variants were found in 21.8% of the patients, and variants of uncertain significance (VUS) were present in 38.2%, with MYH7 (seven cases) and MYBPC3 (five) being the most common. The WES positivity rates varied, at 58.3% (DCM), 72.7% (HCM), and 33.3% (ARVC/RCM). DCM patients with P/LP/VUS variants showed better contractile function (Fractional Shortening: 29.0% vs. 16.5%, p = 0.008). Females in the DCM group had poorer cardiac function (lower LVEF, higher LVESd, lower cardiac output) compared to males, with more females (nine vs. three) exhibiting an LVEF < 35% (p = 0.041). No significant gender differences were observed in the HCM cases. These findings highlight genotype–phenotype correlations and underscore the need for early intervention in female DCM patients. Full article

Background/Objectives: Atrial fibrillation (AF) is the most common sustained arrhythmia, with catheter ablation outcomes differing significantly between paroxysmal and persistent forms. While pulmo-nary vein isolation (PVI) remains the cornerstone of ablation, persistent AF is often associ-ated with atrial remodeling and non-pulmonary vein triggers, reducing procedural success rates and necessitating repeat interventions. However, in selected patients with minimal atrial substrate, a single PVI may achieve durable rhythm control. This case report illus-trates such a scenario in a young patient with persistent AF and tachyarrhythmia-induced cardiomyopathy (TIC). Methods: A 42-year-old previously healthy male presented with newly diagnosed persistent AF complicated by TIC and heart fail-ure (left ventricular ejection fraction [LVEF] 25%). Despite rate control, anticoagulation, guideline-directed heart failure therapy, amiodarone pretreatment, and two failed electrical cardioversions, the patient remained symptomatic. Elec-troanatomic mapping was performed to assess atrial substrate prior to radiofrequency ablation. Results: Mapping revealed no extensive low-voltage zones, indicating absence of significant atrial fibrosis. During ablation, si-nus rhythm was restored spontaneously with a single application targeting the infero-posterior aspect of the right infe-rior pulmonary vein. No additional arrhythmogenic substrate was identified. The patient maintained sinus rhythm throughout 14 months of follow-up, with marked clinical improvement, normalization of LVEF (55%), regression of atrial and ventricular enlargement, and resolution of heart failure symptoms. Quality of life, assessed by the ASTA question-naire, improved from 24 to 0 points. Conclusions: This case highlights that even in therapy-resistant persistent AF with severe structural and functional cardiac impairment, arrhythmia may be driven by discrete pulmonary vein-dependent mechanisms. Careful patient selection, particu-larly in younger individuals without advanced atrial remodeling, can identify those in whom PVI alone achieves durable rhythm control and reverse cardiac remodeling. Full article

Background: Flecainide, a class Ic antiarrhythmic agent, has long been contraindicated in structural heart disease (SHD) due to findings of the Cardiac Arrhythmia Suppression Trial (CAST). However, its proven efficacy in patients without structural abnormalities and emerging safety data in selected SHD populations have prompted reconsideration of its role. Aim: This mini review evaluates recent evidence on the safety and efficacy of flecainide in atrial fibrillation (AF) and premature ventricular contractions (PVCs), particularly in patients with stable coronary artery disease (CAD), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Results: Modern imaging and improved risk stratification allow for more precise identification of patients who may safely receive flecainide, even in the presence of specific structural abnormalities. Observational studies have reported no mortality or ventricular arrhythmias incidence increase in stable CAD or ARVC when flecainide is administered under stringent criteria. While current guidelines remain cautious, clinical practice is beginning to reflect a more individualized approach. Conclusions: Flecainide use in selected SHD patients appears both feasible and safe when guided by comprehensive imaging and clinical judgment. The need for prospective randomized trials to confirm these findings and potentially inform future guideline updates is urgent and of utmost importance in the field of antiarrhythmic therapies. Full article

Arrhythmogenic cardiomyopathies (ACMs) are a phenotypically and etiologically heterogeneous group of myocardial disorders characterized by fibrotic or fibro-fatty replacement of ventricular myocardium, electrical instability, and an elevated risk of sudden cardiac death. Initially identified as a right ventricular disease, ACMs are now recognized to include biventricular and left-dominant forms. Genetic causes account for a substantial proportion of cases and include desmosomal variants, non-desmosomal variants, and familial gene-elusive forms with no identifiable pathogenic mutation. Nongenetic etiologies, including post-inflammatory, autoimmune, and infiltrative mechanisms, may mimic the phenotype. In many patients, the disease remains idiopathic despite comprehensive evaluation. Cardiac magnetic resonance imaging has emerged as a key tool for identifying non-ischemic scar patterns and for distinguishing arrhythmogenic phenotypes from other cardiomyopathies. Emerging classifications propose the unifying concept of scarring cardiomyopathies based on shared structural substrates, although global consensus is evolving. Risk stratification remains challenging, particularly in patients without overt systolic dysfunction or identifiable genetic markers. Advances in tissue phenotyping, multi-omics, and artificial intelligence hold promise for improved prognostic assessment and individualized therapy. Full article

Transmembrane protein 43 (TMEM43 or LUMA) encodes a highly conserved protein found in the nuclear and endoplasmic reticulum membranes of many cell types and the intercalated discs and adherens junctions of cardiac myocytes. TMEM43 is involved in facilitating intra/extracellular signal transduction to the nucleus via the linker of the nucleoskeleton and cytoskeleton complex. Genetic mutations may result in reduced TMEM43 expression and altered TMEM43 protein cellular localization, resulting in impaired cell polarization, intracellular force transmission, and cell–cell connections. The p.S358L mutation causes arrhythmogenic right ventricular cardiomyopathy type-5 and is associated with increased absorption of lipids, fatty acids, and cholesterol in the mouse small intestine, which may promote fibro-fatty replacement of cardiac myocytes. Mutations (p.E85K and p.I91V) have been identified in patients with Emery–Dreifuss Muscular Dystrophy-related myopathies. Other mutations also lead to auditory neuropathy spectrum disorder-associated hearing loss and have a negative association with cancer progression and tumor cell survival. This review explores the pathogenesis of TMEM43 mutation-associated diseases in humans, highlighting animal and in vitro studies that describe the molecular details of disease processes and clinical, histologic, and molecular manifestations. Additionally, we discuss TMEM43 expression-related conditions and how each disease may progress to severe and life-threatening states. Full article

Brugada syndrome (BrS) has been traditionally considered a pure electrical disorder without an underlying structural substrate. However, early ECG studies showed the presence of depolarization abnormalities in this condition, while many studies based on advanced imaging have suggested the presence of subtle structural alterations. On the other hand, electrophysiological study (EPS) and electroanatomic mapping (EAM) techniques have provided important data regarding right ventricular functional and structural arrhythmic substrate. More recently, histology and immunology shed light on the possible role of fibrotic and inflammatory substrates in BrS. Notably, a significant overlap between electro anatomical and structural features in BrS and arrhythmogenic cardiomyopathy has been proposed. In this review, we summarized the physio pathological pathways and substrate underlying BrS. A deeper knowledge of the structural abnormalities involved in the pathogenesis of this disease could improve our diagnostic and prognostic approach, while novel findings regarding the role of inflammation and immune activation could potentially lead to new therapeutic strategies for BrS. Full article

Acute heart failure (AHF) is a complex clinical syndrome characterized by the rapid or gradual onset of symptoms and/or signs of heart failure (HF), leading to an unplanned hospital admission or an emergency department visit. AHF is the leading cause of hospitalization in patients over 65 years, thus significantly impacting public health care. However, its prognosis remains poor with high rates of mortality and rehospitalization. Many pre-existing cardiac conditions can lead to AHF, but it can also arise de novo due to acute events. Therefore, understanding AHF etiology could improve patient management and outcomes. Cardiomyopathies (CMPs) are a heterogeneous group of heart muscle diseases, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), non-dilated cardiomyopathy (NDLVC), and arrhythmogenic right ventricular cardiomyopathy (ARVC), that frequently present with HF. Patients with CMPs are under-represented in AHF studies compared to other etiologies, and therefore therapeutic responses and prognoses remain unknown. In DCM, AHF represents the most frequent cause of death despite treatment improvements. Additionally, DCM is the first indication for heart transplant (HT) among young and middle-aged adults. In HCM, the progression to AHF is rare and more frequent in patients with concomitant severe left ventricle (LV) obstruction and hypertrophy or severe LV systolic dysfunction. HF is the natural evolution of patients with RCM and HF is associated with poor outcomes irrespective of RCM etiology. Furthermore, while the occurrence of AHF is rare among patients with ARVC, this condition in NDLVC patients is currently unknown. In this manuscript, we assessed the available evidence on AHF in patients with CMPs. Data on clinical presentation, therapeutic management, and clinical outcomes according to specific CMPs are limited. Future HF studies assessing the clinical presentation, treatment, and prognosis of specific CMPs are warranted. Full article