BACKGROUND AND AIMS:Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. METHODS:KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). RESULTS:In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%-60% suppression of the mutant KCNH2 transcript. CONCLUSIONS:This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

BACKGROUND:This study investigated the relationship between genetic profiles and clinical, pathologic, and surgical outcomes in patients undergoing septal myectomy for obstructive hypertrophic cardiomyopathy (oHCM). METHODS:Clinical, echocardiographic, and histopathologic data were compared across 3 groups: variant-positive (VP), variant of undetermined significance (VUS), and variant-negative (VN). RESULTS:Genetic testing was conducted in 533 patients undergoing transaortic septal myectomy for oHCM between 2000 and 2022; 153 patients were classified as VP, 73 as VUS, and 307 as VN. Patients in VP and VUS groups were generally younger (mean age 46 [VP] vs 46 [VUS] vs 56 [VN], P < .001) and had fewer comorbidities but had greater prevalences of ICDs at baseline (29 vs 21 vs 9%, P < .001), compared with those in the VN group. The VP and VUS groups more frequently exhibited asymmetrical septal hypertrophy (70 vs 63 vs 53%, P < .001) with slightly more prominent hypertrophy (22 vs 22 vs 20 mm, P < .001) compared to the VN group. Histologically, severe myocardial hypertrophy and interstitial fibrosis were most common in the VP group, followed by VUS, whereas endocardial thickening was more prominent in the VN group. The predischarge median maximal gradient and the long-term survival were similar among all groups. No individual gene mutation significantly affected survival. CONCLUSIONS:In this study of patients with oHCM who underwent septal myectomy and genetic testing, septal myectomy provided effective relief of obstruction and comparable long-term survival across genetic groups.

Very rare and ultra-rare primary inherited arrhythmia syndromes (IAS) represent a heterogeneous group of disorders associated with a significant risk of sudden cardiac death, often manifesting from foetal life to early adulthood. Current guidelines primarily address more common IAS and provide limited, non-specific recommendations for these rare entities, particularly in paediatric populations. This European Heart Rhythm Association Clinical Consensus Statement, developed in collaboration with the Association of Cardiovascular Nursing and Allied Professions and endorsed by the Association for European Paediatric and Congenital Cardiology, integrates available evidence with expert opinion. Recommendations were formulated through structured discussion and voting, following ESC consensus methodology, with a focus on clinically actionable gene-disease associations. The document provides a comprehensive framework for the diagnosis and management of very rare IAS, including calmodulinopathies, Andersen-Tawil syndrome, Timothy syndrome, TRDN-related disease, calcium release deficiency syndrome, and other atypical channelopathies. It highlights age-specific clinical presentations, the importance of genetic testing, and tailored therapeutic strategies, including pharmacological treatments, left cardiac sympathetic denervation, and selective use of implantable cardioverter-defibrillators. Special attention is given to paediatric considerations, foetal diagnosis, and the role of multidisciplinary care. The document also addresses arrhythmic risk in metabolic and cardiomyopathic conditions, as well as the importance of molecular autopsy and family screening in sudden unexplained death. This consensus document fills a critical gap by providing expert-driven, pragmatic guidance for the management of very rare IAS across the lifespan. It underscores the need for specialized care, international collaboration, and prospective registries to improve evidence generation, risk stratification, and patient outcomes in this vulnerable population.

BACKGROUND:Current guidelines discourage sports participation for athletes with arrhythmogenic cardiomyopathy (ACM). However, the evidence that exercise is a disease-accelerator is most compelling for PKP2-mediated ACM. OBJECTIVES:This study aims to examine management, return-to-play (RTP) decisions, outcomes, and phenotype evolution among athletes with genotype-positive ACM. METHODS:A retrospective review of electronic medical record of 1,229 patients in our Arrhythmogenic/Dilated Cardiomyopathy Registry was used to identify self-identified athletes. They were evaluated, risk stratified, and treated at Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic between July 2000 and February 2025. RESULTS:A total of 138 genotype-positive athletes with ACM were identified (58 women [42%], mean age of 31 ± 19 years, plakophilin [PKP2]-ACM [n = 61; 44%], desmoplakin [DSP]-ACM [n = 32; 23%]). After diagnosis of ACM, 34 athletes (25%) experienced at least 1 breakthrough cardiac event (BCE), accounting for a total of 68 events, and 6 patients experienced 14 BCEs following physician-approved RTP. During a median follow-up of 25 months (IQR: 6-71), the overall event rate for the entire cohort was 7.9 BCEs per 100 patient-years (95 % CI: 5.8-10.5), and the event rate after physician-approved RTP was 14.6 per 100 patient-years (95% CI: 7.8-24.9). During RTP period, one-half of these BCEs occurred during sports participation, whereas the remainder occurred at rest or unknown context. CONCLUSIONS:This is the first single-center cohort of patients with ACM being empowered to RTP and remain athletes. These athletes have exhibited higher rates of BCEs and disease conversion/progression than our athletes with a variety of other genetic heart diseases. Further studies are needed to determine how to further guide safe sports participation in genetically mediated ACM.

BACKGROUND:Current risk stratification models for hypertrophic cardiomyopathy (HCM) rely on a combination of clinical and imaging factors. Recent studies have highlighted the potential role of late gadolinium enhancement (LGE) in enhancing sudden cardiac death (SCD) risk stratification. This study evaluates whether LGE can recalibrate risk stratification models and influence decisions regarding implantable cardioverter-defibrillator (ICD) implantation. We aim to assess the prognostic value of LGE in predicting SCD and its interaction with other established risk factors in patients with HCM. METHODS:We conducted a retrospective cohort study of HCM patients from a multi-site referral center who underwent CMR imaging and had ICDs implanted. We analyzed the incidence of appropriate ICD discharges with LGE presence as an effect modifier. RESULTS:Out of 326 participants, 50 experienced at least one appropriate ICD discharge over the study period. LGE >15% by itself was significantly associated with a higher rate of appropriate discharges, and significantly adjusted the risk of appropriate discharges in clinical indications such as a family history of SCD and syncope. The study did not find LGE to enhance appropriate ICD discharge risk in patients with already high risk based on imaging features or nonsustained ventricular tachycardia on ambulatory monitoring. CONCLUSIONS:LGE provides incremental prognostic value in refining risk stratification for SCD in HCM patients, especially when the decision for ICD placement may be clinical history alone. This study supports integrating LGE assessments into routine clinical practice to improve the precision of ICD decision-making.

Background To prepare nurses for increasingly complex and challenging roles, nursing education must include a focus on developing an intrapreneurial mind-set that students take with them to future employment and leadership positions. Method Intrapreneurs take on responsibility for innovating within their organization. The combination of skills and energies encompassing leadership, cognitive flexibility, and a future orientation can facilitate the success of nurses in health care organizations, academic institutions, and diverse employment settings. Case studies provide examples regarding how to best integrate the concepts of intrapreneurship into nursing education. Results Nurse educators play a vital role in developing, encouraging, and building an intrapreneurial mentality. Faculty who lead by example serving as intrapreneurial role models can help students and colleagues prepare to innovate within today's rapidly changing health care system. Conclusion This article discusses the importance of intrapreneurial skills for nurses and posits a framework for supporting intrapreneurialism in nursing academia. [ J Nurs Educ . 2025;64(2):69–73.]

Background: Calcium release channel deficiency syndrome (CRCDS) is caused by biogenic or biophysical loss-of-function (LOF) pathogenic variants in the RYR2 -encoded ryanodine receptor (RyR2), a key intracellular Ca 2+ release channel. Previously, we identified a novel homozygous duplication involving the promoter and exons 1-4 of RYR2 , leading to 80% RyR2 protein loss and exertion-related sudden death in the young. Here, we generated a RYR2 knockout (RYR2-KO) induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model to explore intracellular and electrophysiological compensatory mechanisms that overcome this extreme loss of RyR2 protein. Methods: Using CRISPR/Cas9 gene editing, a homozygous c.163delT variant (p.S55Pfs*46) was inserted into a normal iPSC line (isogenic control) to create a homozygous RYR2-KO iPSC line. After re-engineering the lines into ventricular-like cardiomyocytes (iPSC-CMs), intracellular Ca 2+ handling was assessed by Fluo-4 AM cell imaging (0.5 Hz stimulation). Electrical remodeling in the L-type Ca 2+ current (I CaL ) was assessed using the whole-cell patch clamp technique. Results: Significant differences were observed in Ca 2+ transient parameters between RYR2-KO and isogenic control iPSC-CMs. Biogenic RyR2 loss significantly reduced Ca 2+ transient peak amplitude (CTA: 0.16 ± 0.01 ΔF/F0, p<0.0001) and upstroke velocity (CTV: 0.42 ± 0.06 (ΔF/F0)/t, p<0.0001), and prolonged Ca 2+ transient duration (CTD 90 : 1.59 ± 0.03 s, p=0.01) as compared to isogenic control (CTA: 0.48 ± 0.04 ΔF/F0; CTV: 1.30 ± 0.15 (ΔF/F0)/t; CTD 90 : 1.46 ± 0.05 s). Additionally, RyR2 loss abolished SR Ca 2+ leak (0.9 ± 0.9 % versus 35.1 ± 15.5 %, p=0.03). Lastly, a significant reduction in I CaL density was observed in RYR2-KO iPSC-CMs as compared to isogenic control iPSC-CMs (at 0 mV, RYR2-KO: -8.54 ± 1.60 pA/pF, control: -17.45 ± 3.69 pA/pF, p=0.0004). These data indicate that I CaL reduction may contribute to the reduced Ca 2+ transient peak. Conclusions: Complete loss of RyR2 in iPSC-CMs profoundly disrupts intracellular Ca 2+ handling, abolishes Ca 2+ sparks frequency, and secondarily down-regulates the sarcolemmal L-type Ca 2+ channel.

BACKGROUND:Long QT syndrome (LQTS) is a genetic heart disease that increases the risk of ventricular arrhythmias and sudden cardia arrest. Despite advances in genetic testing, a small subset of patients with LQTS remain genetically elusive. OBJECTIVE:This study aimed to determine the prevalence and clinical characteristics of patients with a phenotype of LQTS but without a genotype. METHODS:This study aimed to identify phenotype-positive, genotype-negative patients with LQTS seen at Mayo Clinic (2000-2024). Retrospective data included demographics, clinical evaluations, electrocardiograms, and genetic results. Diagnosis adhered to established criteria, and genotype-negative LQTS was defined by the absence of pathogenic variants despite clinical presentation. RESULTS:The study included 1829 patients with LQTS. Of these, 1706 (93%) had pathogenic or likely pathogenic variants, and 95 patients (5%) had upgraded clinical variants of uncertain significance, leaving 32 (1.7%) with negative genetic tests. Among the genotype-negative patients, 17 underwent next-generation sequencing, identifying a genetic cause in 6 cases (0.3% of the total). The mean age at diagnosis for the remaining 26 patients was 25 ± 15 years, with 76% being women and an average initial corrected QT of 498 ± 41 ms. Fourteen patients (53%) experienced cardiac events prior to diagnosis, and 11 (44%) received an implantable cardioverter-defibrillator. The mean follow-up period was 8 ± 7 years. CONCLUSION:Genotype-negative LQTS accounted for < 2% of our cohort, highlighting diagnostic and management challenges. Comprehensive clinical evaluation and advanced genetic testing remain essential for accurate diagnosis and care.

BACKGROUND:Over the past decade, the care of athletes with a genetic heart disease (GHD) has shifted. Guidelines surrounding return-to-play (RTP) for athletes who are genotype positive but phenotype negative (G+/P-) remain variable and their management challenging. Recommendations depend on diagnosis, ranging from RTP with monitoring [hypertrophic cardiomyopathy (HCM), and long QT syndrome (LQTS)] to automatic disqualification [catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic cardiomyopathy (ACM)]. OBJECTIVES:This study sought to examine the prevalence, management, and outcomes of athletes with G+/P- GHD using a retrospective cohort of all self-identified athletes considered G+/P- treated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic between July 2000 and November 2023. METHODS:There were 274 G+/P- athletes [119 females (43%); mean age at diagnosis 15 ± 12 years; median follow up 32 months] participating in sports at all levels. Diagnoses included LQTS (231; 84%), CPVT (19; 7%), ACM (15; 6%), or HCM (9; 3%). Treatments initiated after our first evaluation, but required for RTP approval, included pharmacologic therapy (187; 68%), left cardiac sympathetic denervation (11; 4%), or an implantable cardioverter defibrillator (6; 2%). RESULTS:For 76 athletes (27%), an intentional non-therapy strategy was implemented. One in five athletes (53; 19%) specifically sought RTP approval following disqualification elsewhere. CONCLUSIONS:Despite possessing a GHD-associated variant, a GHD-associated cardiac event or death has not occurred in over 1,300 combined years of follow-up. RTP for most G+/P- athletes is safe. Restricting such athletes based solely on a positive genetic test result should be viewed as genetic discrimination.

BACKGROUND:Brugada syndrome (BrS) is a genetic heart disease that predisposes individuals to ventricular arrhythmias and sudden cardiac death. Although implantable cardioverter-defibrillators (ICDs) and quinidine are primary treatments, recurrent BrS-triggered ventricular arrhythmias can persist. In this setting, epicardial substrate ablation has emerged as a promising alternative for symptomatic patients. OBJECTIVE:Evaluate the effectiveness and safety of epicardial substrate ablation in patients with BrS. METHODS:In this single-arm meta-analysis, we systematically searched PubMed, Embase, and Cochrane databases following PRISMA guidelines for studies including BrS patients with epicardial substrate ablation. Data were extracted, and statistical analysis was performed using random-effects modeling for proportional meta-analysis. RESULTS:Thirteen cohort studies comprising 555 BrS patients were included. The mean age at enrollment was 42.6 ± 12.3 years; 82.7% were male patients, and 50% exhibited spontaneous type 1 Brugada electrocardiographic (ECG) pattern. Pooled analysis demonstrated resolution of the type 1 pattern in 91% of the cases (95% confidence interval [CI] 80-98%; I2 = 86%) and elimination of abnormal electrograms in 91% (95% CI 78-99%; I2 = 74%). Rates of recurrent VT/VF and appropriate ICD therapies during postablation follow-up were 12% (95% CI 4-21%; I2 = 86%) and 8% (95% CI 2-18%; I2 = 87%), respectively. CONCLUSION:Epicardial substrate ablation shows promise for patients with BrS experiencing BrS-triggered ventricular arrhythmias, offering therapeutic efficacy with an acceptable safety profile. High heterogeneity among studies highlights the need for further research and standardized protocols.

Introduction: Sudden cardiac arrest (SCA) and death (SCD) are the most serious sequelae of many genetic heart diseases (GHDs). Increased awareness of this has led to increased detection in employment screenings. For patients in high-risk jobs, premature and potentially unnecessary termination from their profession, rather than “Return-to-Work (RTW),” has become an undesired consequence of this awareness. The objective of this study is to evaluate the outcomes of patients with GHDs in high-risk professions who were allowed to RTW. Methods: We performed a retrospective review of 3,641 working-age patients referred for evaluation of a potential GHD between 6/2000-12/2021 to identify those either in or being recruited into a high-risk profession. A profession was defined as “high-risk” if it is safety-sensitive or required regular medical evaluations. Charts were reviewed for medical history, RTW decision making, and breakthrough cardiac events (BCEs). Results: Overall, 33 patients [(0.9%); 3 females (9%); mean age at diagnosis 25 ± 15 years] had been either put on hold from their high-risk job (n = 15; 45%) or disqualified as a recruit (18; 55%) prior to our evaluation due to their GHD diagnosis. This included 15 military, 10 pilots, 6 law enforcement and first responders, and 2 commercial driver license professionals and recruits. Most patients were diagnosed with Long QT syndrome (n = 23; 70%). After treatment initiation, 14 (93%) professionals and 16 (89%) recruits received physician RTW approval while 3 (9%) patients did not receive RTW approval due to disease severity and/or unwillingness to initiate treatment. Of the remaining 14 professionals that received physician RTW approval, 4 (29%) were not allowed to return to their jobs, while 14/16 recruits (88%) were not permitted to start their career. None of the RTW-approved patients had a BCE after evaluation (160.7 follow-up years). Conclusions: Patients with GHDs in high-risk professions are often terminated due to perceived SCA/SCD risk. However, within our small cohort, the risk of BCEs in optimally treated patients was low. This data suggests that the certification process of individuals in these high-risk and safety-sensitive occupations should be further examined and potentially modified.

Background: Previously, we discovered that DENND3, a guanine nucleotide exchange factor regulating Rab GTPases, influences cardiac ion channel trafficking. Both electrophysiological dysfunction and arrhythmic events were identified in variant inserted inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) expressing DENND3-p.R534S. This was a novel missense variant identified in a patient with familial idiopathic ventricular fibrillation (IVF). Notably, augmented membrane retention of key cardiac ion channels was observed in both DENND3-p.R534S expressing TSA201 cells and variant inserted iPSC-CMs. To further study the mechanisms underlying arrhythmogenesis associated with IVF, intracellular calcium handling was characterized in these re-engineered heart cells with DENND3-p.R534S. Methods: Here, iPSC-CMs expressing DENND3-p.R534S and isogenic controls (IC) were studied. Optical action potentials were recorded using the FluoVolt voltage-sensitive dye at a constant pacing rate of 1 Hz. Multi-electrode array (MEA) recordings assessed beat period and conduction dynamics. Intracellular calcium dynamics were analyzed using Fluo-4 calcium imaging. Results: DENND3-p.R534S iPSC-CMs exhibited frequent arrhythmic activity, including irregular beating patterns (78%, n=28/36), alternans (25%), early afterdepolarizations (EADs, 8%), and delayed afterdepolarizations (DADs, 8%) versus 0% in IC lines (n=0/36, p<0.05). MEA recordings revealed significantly prolonged and irregular beat periods (2.59±0.26s vs. 1.37±0.10s, p<0.05), indicating electrical instability. Calcium imaging further showed significantly reduced calcium transient amplitude in DENND3-p.R534S iPSC-CMs compared to ICs (0.035±0.039ΔF/F 0 vs. 0.302±0.099ΔF/F 0 , p<0.05), and slowed upstroke velocity (0.170±0.212 ΔF/F 0 ●s -1 vs. 1.340±0.463ΔF/F 0 ●s -1 ) suggesting impaired intracellular calcium release. Conclusion: The DENND3-p.R534S variant not only disrupts ion channel distribution as shown previously but also markedly perturbs intracellular calcium handling, contributing to electrophysiological instability and arrhythmogenic cellular phenotypes. These findings highlight DENND3’s novel and emerging role in maintaining cardiac cellular homeostasis and rhythm stability.

Cardiovascular diseases are the leading cause of death globally, with cardiac arrhythmias contributing substantially to this burden. Gene therapy, which directly targets the underlying disease pathobiology, offers an appealing treatment strategy for cardiac arrhythmias owing to its potential as a one-time, curative solution. Over the past two decades, substantial efforts have been made to develop new gene therapy approaches that overcome the limitations of conventional treatments. In this Review, we describe the rationale for gene therapy to treat cardiac arrhythmias; discuss advantages and disadvantages of gene silencing, gene replacement, gene suppression-and-replacement and gene editing technologies; summarize vector modalities and delivery approaches used in the field; present examples of gene therapy strategies used for atrial and ventricular arrhythmias; and highlight the current challenges and limitations in the gene therapy field. In this Review, Ackerman and colleagues describe the rationale for gene therapy to treat cardiac arrhythmias; discuss advantages and disadvantages of gene silencing, replacement and editing technologies; summarize vector modalities and delivery approaches; present examples of gene therapy strategies used for atrial and ventricular arrhythmias; and highlight the current challenges and limitations in the gene therapy field.