Deleterious variants in SCN5A lead to a wide clinical spectrum that includes pathologies characterized by life-threatening cardiac events (CEs). In the pediatric population, early identification, management, and risk stratification of these pathologies are the main current challenges. This study analyzed a Spanish pediatric cohort (≤18 years) carrying rare SCN5A variants to explore genotype-phenotype correlations. A retrospective descriptive cohort study, including clinical, demographic, and genetic data of probands and their relatives, was conducted. Out of 100 children studied, 69 had definitively deleterious SCN5A variants (26 females, 38%; median age: 3 years, IQR 1-12). The main diagnoses were isolated Brugada syndrome (BrS) (31; 45%); isolated long QT syndrome type 3 (LQT3) (5; 7%); isolated progressive cardiac conduction disease (PCCD) (1; 2%); isolated familial atrial fibrillation (1; 2%); overlapping phenotypes (7; 10%) including: BrS-PCCD (2; 2.8%); BrS-LQT3 (1; 1.4%); premature ventricular contraction-dilated cardiomyopathy (1; 1.4%); BrS-LQT3-PCCD (1; 1.4%); BrS-PCCD-sick sinus syndrome (SSS) (1; 1.4%) and BrS-PCCD-SSS-familial atrial fibrillation (1; 1.4%). Of them, 13 (19%) patients presented with CEs (cardiogenic syncope, ventricular tachycardia/fibrillation, sudden cardiac arrest/death, and appropriate implantable cardio defibrillator shock). These findings underscore the utility of genetic testing for early diagnosis, risk stratification, and personalized management, enhancing preventive strategies for CE prevention in pediatrics.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder characterized by fibrofatty replacement of the right ventricular myocardium. Anthracycline-induced cardiotoxicity typically manifests as left ventricular dysfunction; however, we present a unique case of an acquired ARVC phenotype secondary to anthracycline chemotherapy exposure. A 74-year-old man developed recurrent exertional syncope 8 months after completing rituximab, cyclophosphamide, hydroxydaunorubicin (an anthracycline that is also known as doxorubicin), oncovin, and prednisone chemotherapy. He met 3 major 2010 Revised Task Force Criteria for definite ARVC, despite negative genetic testing and absence of family history. He underwent dual-chamber implantable cardioverter-defibrillator implantation with complete resolution of syncopal episodes. Recognition of acquired ARVC after anthracycline exposure broadens the spectrum of chemotherapy-related cardiomyopathies and calls for vigilance in patients with unexplained right ventricular dysfunction or arrhythmias after chemotherapy. Anthracyclines may cause isolated right ventricular dysfunction mimicking ARVC. Clinicians should maintain vigilance for right ventricular dysfunction or arrhythmias in patients after anthracycline therapy.

Isolated nonischemic left ventricular scar (NILVS), identified by cardiac magnetic resonance, is an increasing finding in athletes and may be the substrate for life-threatening arrhythmias. Clinical significance in asymptomatic athletes is yet to be investigated. This study sought to describe the clinico-genetic profile and follow-up of asymptomatic athletes diagnosed with NILVS through preparticipation screening. We evaluated 40 athletes (90% males, 44 [range:33-52] years) including 9 elites, with isolated NILVS involving at least 2 segments, no previous major arrhythmic events, with available genetic testing and >1 year of follow-up. Data regarding electrocardiography, echocardiography, 24-hour Holter, exercise testing, and genetic analysis were collected. Follow-up assessed therapy, sport participation, and outcome. Electrocardiogram abnormalities were present in 48%, and all showed premature ventricular beats at exercise testing, mostly with right bundle branch/superior axis morphology. Left ventricular ejection fraction was normal or mildly reduced. Genetic testing or family screening was positive in 9 (23%). Athletes without familial/genetic background were older and declared higher cumulative years of sports activity. Over a median follow-up time of 23 months, 84% continued noncompetitive sport, mostly (73%) on beta-blocker therapy. Two major arrhythmic events occurred (resuscitated cardiac arrest and sustained ventricular tachycardia), both in athletes with a positive family history for NILVS, but negative genetic testing, and both during noncompetitive exercise. NILVS in asymptomatic athletes may carry arrhythmic risk even in the absence of previous symptoms or left ventricular dysfunction. Athletes with NILVS and no gene mutations/family history are older and with a higher past exercise volume.

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.

Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder marked by left ventricular hypertrophy and hypercontractility. This excessive mechanical workload creates an energetic mismatch in which consumption exceeds production, leading to myocardial energy depletion. Although CK (creatine kinase) plays a key role in cardiac energy homeostasis, its involvement in HCM remains unclear. This study investigates how hypercontractility-driven mitochondrial stress and the resulting increase in mitochondrial H2O2 disrupt CK function in HCM. CK function was analyzed using myocardial left ventricular tissue from 92 patients with HCM (with and without pathogenic sarcomere variants) and 30 non-failing human controls. Myofilament and mitochondrial CK isoforms were measured using mRNA analysis, protein immunoblotting, enzyme activity assays, mass spectrometry, and redox-sensitive proteomics. To explore links between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction, we used isolated cardiomyocytes from wild-type, mitochondrial-targeted catalase-overexpressing, CK knockout (myofilament and mitochondrial CK deletion), HCM-associated Mybpc3 knock-in, and mito-roGFP2-Orp1 mouse models. We also tested the effects of the Ca2+ sensitizer EMD-57033, the CK inhibitor 1-fluoro-2,4-dinitrobenzene (DNFB), and the myosin inhibitor MYK-581, a mavacamten derivative. Our analysis revealed significant reductions in myofilament and mitochondrial CK protein levels, as well as CK activity, in myocardium of patients with HCM, primarily because of oxidative modifications of CK. In isolated mouse cardiomyocytes from wild-type and CK knockouts, hypercontractility induced by EMD-57033 elevated mitochondrial H2O2, causing cellular arrhythmias and CK inactivation. Hypercontractility-induced oxidative stress, arrhythmias, and CK dysfunction were also observed in Mybpc3 knock-in cardiomyocytes. Mitochondrial-targeted catalase-overexpressing mice with enhanced H2O2 scavenging were protected against H2O2-induced (EMD-57033-mediated) arrhythmias and CK dysfunction. MYK-581 treatment in Mybpc3 knock-in cardiomyocytes reduced hypercontractility, lowered H2O2 production and arrhythmias, and preserved CK function. CK inhibition using DNFB in wild-type cardiomyocytes elevated mitochondrial H2O2 levels and triggered cellular arrhythmias. This mitochondrial oxidation was independently confirmed in mito-roGFP2-Orp1 cardiomyocytes exposed to DNFB. Mitochondrial-targeted catalase-overexpressing mice were protected from DNFB-induced oxidative stress and arrhythmogenic events. This study reveals a mechanistic link between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction in HCM, perpetuating a cycle of energetic dysfunction. Targeting hypercontractility and oxidative stress through myosin inhibition offers a strategy to restore energy balance and reduce arrhythmic risk in HCM.