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BACKGROUND: Type 2 long-QT syndrome results from KCNH2 -encoded Kv11.1 loss-of-function, but whether secondary inward-current dysfunction amplifies dysfunction remains unclear. METHODS: We characterized sodium ( SCN5A , I Na ) and L-type calcium channel ( CACNA1C , I Ca ) function in KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch-clamp measured action potential duration at 90% repolarization (APD90), and potassium (I Kr ), sodium (I Na ), and calcium (I Ca, L ) currents. Fluo-4 imaging quantified calcium transients. A modified Kernik-Clancy iPSC-CM model incorporated experimentally measured persistent I Na,L and I Ca,L fractions and simulated isolated and combined current defects. RESULTS: KCNH2-G604S caused severe I Kr loss-of-function (72.5% reduction). APD90 was prolonged in G604S-iPSC-CMs (765±58 ms) compared with isogenic controls (368±37 ms; P <0.005), with early afterdepolarizations in 50% of G604S cells. Nifedipine, verapamil, and mexiletine successfully shortened APD90 and abolished early afterdepolarizations. Compared with isogenic control, I Na,L (0.60±0.1% versus 0.26±0.06%; P <0.01), persistent I Ca,L (2.88±0.55% versus 1.26±0.35%; P <0.05), and calcium transient decay times ( P <0.0001) were greater in G604S iPSC-CMs. Increased persistent I Ca,L was phenocopied by E-4031 in isogenic controls and reduced by nifedipine in G604S iPSC-CMs. In silico modeling revealed that the I Kr defect alone prolonged APD90 to only 620 ms. The addition of the observed I Na,L defect had a small additive effect (+20 ms); however, incorporating persistent I Ca,L synergistically extended APD90 to 758 ms, replicating the experimental phenotype. Flux dynamics analysis indicated that this persistent Ca 2+ entry suppresses the forward-mode sodium-calcium exchanger, forcing a compensatory reliance on sarcoplasmic-endoplasmic reticulum Ca-ATPase that primes for calcium instability. CONCLUSIONS: The KCNH2-G604S variant drives a severe multihit phenotype via primary I Kr loss-of-function and secondary state-dependent gain-of-function in persistent I Ca,L . These comprehensive validations demonstrate that the remodeled persistent I Ca,L acts as the essential amplifier driving extreme action potential duration prolongation and Ca 2+ mishandling.

Abstract Background Loss-of-function variants in TTN-encoded titin are the most common genetic cause of dilated cardiomyopathy (DCM). In addition, titin truncating variants (TTNtvs) are over-represented in early-onset atrial fibrillation (AF) and unexplained sudden cardiac arrest/death (SCA/SCD) suggesting that in rare circumstances TTNtvs may cause arrhythmias in a pre-cardiomyopathic electrical phase. Purpose To compare the prevalence of AF, sustained ventricular arrhythmias (VAs) and SCA/SCD between TTNtv-positive patients with genotype-positive but phenotype-negative (G+/P-) disease, non-dilated left ventricular cardiomyopathy (NDLVC) and DCM. Methods Retrospective review of 1,229 patients in our Arrhythmogenic/Dilated Cardiomyopathy Registry was used to identify those with TTNtvs in high proportion spliced-in (&gt;90%) exons classified as pathogenic or likely pathogenic according to current American College of Medical Genetics and Genomics variant classification guidelines. Demographic, electrocardiographic, imaging and outcome data were extracted from the electronic record. After exclusion of those without satisfactory imaging data, each TTNtv-positive patient was classified as having G+/P- disease, NDLVC, or DCM according to the 2023 European Society of Cardiology Guidelines for the management of cardiomyopathies. The prevalence of AF, non-SCA major VA events (sustained VT and appropriate VT/VF-terminating ICD therapies), and SCA/SCD was then compared between the three left ventricular morphofunctional subgroups. Results Overall, 232 TTNtv-positive patients (mean age of 44 ± 17 years; 57% male) were included (average LVEF of 39 ± 17%; 32% with a history of AF; 23% with a history of non-SCA VA event and 6% with a history of SCA). Forty-nine (21%) were G+/P-, 45 (19%) had NDLVC, and 138 (59%) had DCM at the time of their most recent clinical evaluation. As expected, the prevalence of AF was higher in TTNtv-DCM patients when compared to both TTNtv-NDLVC [56/138 (41%) vs. 11/45 (24%); p=0.04] and G+/P- disease [56/138 (41%) vs. 5/49 (10%); p&lt;0.001]. Similarly, the number of patients who experienced a non-SCA major VA event was higher in TTNtv-DCM than either TTNtv-NDLVC [44/138 (32%) vs. 6/45 (9%); p=0.01] or G+/P- disease [44/138 (31%) vs. 4/49 (8%); p&lt;0.001]. Interestingly, no difference in the number of TTNtv-positive patients who experienced a SCA/SCD was observed across subgroups [2/49 (4%) for G+/P-; 2/45 (4%) for NDLVC; and 8/138 (6%) for DCM; p=ns for all comparisons]. Conclusion In patients with TTNtv substrates who were evaluated at a quaternary medical center, the prevalence of AF and major VA events correlates with left ventricular morphology/function with the greatest risk observed in those with DCM. However, the prevalence of AF and major VA events, including SCA, in TTNtv-positive patients with G+/P- and NDLVC disease is not trivial and highlights the ability of TTNtvs to present in a pre-cardiomyopathic electrical phase.

ABSTRACT Background Ventricular tachycardia (VT) is a life‐threatening arrhythmia frequently observed in structural heart diseases, including LMNA‐related cardiomyopathy, a genetic disorder associated with high risk of sudden cardiac death and progressive systolic dysfunction. While catheter ablation is an established therapeutic option for VT, its efficacy in cardiac laminopathy remains poorly defined. Objectives To synthesize available evidence on the role and outcomes of VT ablation in patients with cardiac laminopathy. Methods A systematic review and single‐arm meta‐analysis was performed in accordance with PRISMA guidelines. PubMed, Embase, and Cochrane databases were searched for studies reporting VT ablation outcomes in LMNA‐related cardiomyopathy. An inverse variance random‐effects model was applied for meta‐analysis of proportions. Results Seven studies (six cohorts, one abstract) comprising 62 patients (mean age 53.2 ± 9.7 years; 85% male; 88% with implantable cardioverter‐defibrillator) were included. An endocardial/endo‐epicardial approach was used in 93% of cases. Acute procedural success was achieved in 37% (95% CI: 14%–63%; I² = 27.4%), and 28% required multiple procedures. Over a median follow‐up of 26 (9–35) months, VT recurrence occurred in 91% (95% CI: 76%–100%; I² = 37.2%). All‐cause mortality was 54% (95% CI: 39%–70%; I² = 28%), predominantly from cardiac causes (51%, 95% CI: 25%–76%; I² = 53%), and 14% (95% CI: 1%–34%; I² = 42%) underwent heart transplantation. Conclusions In LMNA‐related cardiomyopathy, catheter ablation is associated with high VT recurrence, limited long‐term success, and substantial cardiovascular mortality and transplantation rates, underscoring the importance of ICD implantation and the need for alternative strategies, including variant‐specific and molecularly targeted therapies.

Introduction: Titin truncating variants (TTNtv) are a common cause of dilated (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC). Mitral valve prolapse (MVP) occurs commonly in the general population and is characterized by myxomatous structural changes of the mitral valve apparatus. Both TTNtv-mediated DCMs and MVP have been associated independently with an increased risk of ventricular arrhythmias (VA) and sudden cardiac arrest/death (SCA/SCD). However, it remains unclear whether TTNtv-positive patients with co-existing MVP are at increased risk for major VA (MVA) events. Therefore, we sought to compare the prevalence of MVA events between TTNtv-positive patients with or without MVP in a large single-center cohort of genetic cardiomyopathy patients. Methods: Retrospective review of 1,230 ACM/DCM patients was used to identify those with a pathogenic/likely pathogenic (P/LP) TTNtv. Independent review of available imaging data was subsequently used to identify TTNtv-positive patients with co-existing MVP. The prevalence of non-SCA MVA and SCA/SCD was then compared between TTNtv-positive patients with and without MVP. Results: Overall, 253/1,230 (21%) of ACM/DCM patients were P/LP TTNtv-positive (43% female; mean age 44±17 years, mean LVEF 39±17%). Amongst these 253 TTNtv-positive patients, 15 (5.9%) had co-existing MVP (33% female, mean age 49±12 years, mean LVEF 48±12%). Collectively, TTNtv-positive patients with MVP were more likely to experience a MVA event than those without MVP [6/15 (40%) vs 41/238 (17%); p=0.03]. This included a higher risk of appropriate VT/VF-terminating ICD shocks [4/15 (27%) vs. 17/238 (7.1%); p=0.03] and SCA [3/15 (20%) vs 12/238 (5%); p=0.05]. However, despite the increased arrhythmic risk observed in TTNtv-positive patients with MVP, no deaths occurred in this subgroup and the overall cardiac mortality rate across the entire TTNtv-positive cohort was low [6/253 (2.4%)]. Conclusion: TTNtv-positive patients with concomitant MVP are at increased risk for MVA events, including SCA. Future studies are needed to i) better define the prognostic utility of MVP in the risk-stratification of TTN-NDLVC/DCM and other genetic cardiomyopathies and ii) determine whether some patients diagnosed with arrhythmogenic MVP syndrome may have TTNtv-mediated NDLVC exacerbated in a focal manner by the increased mechanical strain generated by the presence of the common and likely genetically unrelated myxomatous MVP.

Background: Ventricular tachycardia (VT) is a potentially life-threatening arrhythmia frequently observed in structural heart diseases, including cardiac laminopathy, a genetic cardiomyopathy associated with a high risk of sudden cardiac death (SCD) and progressive systolic dysfunction caused by pathogenic variants in LMNA -encoded lamin A/C. While catheter ablation is a key therapeutic strategy for VT management, its efficacy in cardiac laminopathy remains poorly defined. Objective: This systematic review and single-arm meta-analysis aims to synthesize the available evidence in the literature on the role of VT ablation for patients with cardiac laminopathy. Methods: A single-arm meta-analysis was conducted following PRISMA guidelines, systematically searching PubMed, Embase, and Cochrane databases for studies investigating VT ablation outcomes in patients with cardiac laminopathy. We applied an inverse variance random-effects model for a meta-analysis of proportions. Results: We included 6 cohort studies and 1 abstract comprising 62 patients with LMNA-related cardiomyopathy (mean age at 53.2 ± 9.7 years, 85% males, and 88% with an ICD). The predominant ablation strategy was endocardial/endo-epicardial in 93% of cases. Acute success rate following VT ablation was 37% (95% CI: 14 to 63%) and 28% of the patients required multiple procedures. Over a median follow-up of 26 (9-35) months, VT recurrence rate after ablation was 91% (95% CI: 76 to 100%; Figure A ). The all-cause mortality rate was 54% (95% CI: 39% to 70%; Figure B ), primarily driven by cardiac causes 51% (95% CI: 25 to 76%; Figure C ). There was an elevated rate of heart transplantation 14% (95% CI: 1 to 34%), highlighting overall poor outcomes in this patient population. Conclusion: Catheter ablation in cardiac laminopathy is associated with limited long-term efficacy, with high rates of VT recurrence, cardiovascular mortality and heart transplantation. These findings underscore the importance of ICD implantation for primary prevention and the pressing need to develop alternative treatment strategies. Further research is necessary to determine whether specific LMNA variants influence ablation outcomes and to explore emerging therapies targeting the underlying molecular mechanisms of cardiac laminopathy.

Background: An increased burden of premature ventricular contractions (PVCs)/non-sustained ventricular tachycardia (NSVT) during the recovery phase of exercise stress testing (EST) appears to be a distinctive feature of PKP2-related arrhythmogenic cardiomyopathy (ACM) associated with an increased risk of major ventricular arrhythmia (VA) events. While flecainide may help manage VA, its impact on post-exercise VA burden and the role of EST in guiding its use remain unclear. Objective: To examine the effect of flecainide on EST-VA burden in PKP2-related ACM. Methods: A retrospective analysis of 1,049 genotype-positive ACM patients identified those with PKP2 variants who underwent ESTs on and off flecainide. Clinical data were collected and the arrhythmic burden—measured as PVCs, couplets, bigeminy, NSVT, sustained VT, ventricular fibrillation, and PVCs per minute—during each EST phase (baseline, peak, active recovery, and passive recovery) was assessed and compared between the EST performed pre- and post-initiation of flecainide. Results: Of 147 PKP2-ACM patients, 11 (35 ESTs) had at least one EST on flecainide. Eight patients (mean age 31 ± 13 years, 50% male) underwent both on and off flecainide for a total of 29 ESTs [on beta-blockers (80%), flecainide (52%), amiodarone (3%), or sotalol (3%)]. When comparing EST performed pre- and post-initiation of flecainide, the frequency of PVCs per minute was significantly lower both during exercise (3 ± 3 vs 1 ± 2, p=0.023) and during the recovery phase (12 ± 13 vs 2 ± 4, p=0.010). Similarly, the presence of PVCs during exercise (85% vs 47%, p=0.026) and recovery (85% vs 47%, p=0.027), couplets during exercise (27% vs 0%, p=0.026) and recovery (85% vs 20%, p<0.001), and bigeminy during exercise (36% vs 7%, p=0.054) and recovery (72% vs 13%, p=0.002) was significantly reduced following the initiation of flecainide. No significant differences were observed in the prevalence of NSVT or sustained VT. Five patients (63%) had prior sustained VT without breakthrough events post-flecainide. One patient without prior VT had an early event but remained event-free after dose up titration. Conclusion: Flecainide significantly reduces the EST arrhythmic burden in patients with PKP2-ACM, particularly in the recovery phase. Future studies are needed to determine if the EST can be used to guide flecainide dosing and efficacy in PKP2-ACM akin to current strategies employed for catecholaminergic polymorphic ventricular tachycardia.

Background: Disease-causative variants in LMNA -encoded lamin A/C cause the laminopathies, a heterogeneous group of diseases variably resulting in arrhythmogenic/dilated cardiomyopathy (ACM/DCM), lipodystrophy, muscular dystrophy, and progeria. The artificial intelligence (AI)-derived electrocardiographic age gap (AI-EAG), determined by the discrepancy between a patient’s artificial AI-enabled electrocardiogram (ECG) predicted biological age versus their chronological age, is accelerated in laminopathy. Thus, we sought to determine if the AI-EAG serves as a prognostic marker in patients with cardiac laminopathy. Methods: Retrospective analysis of 1,049 genotype-positive patients with genetic ACM/DCM was used to identify those with pathogenic/likely pathogenic (P/LP) variants in LMNA . After the exclusion of those who lacked a 12-lead ECG while in sinus rhythm, a previously trained AI-ECG age algorithm was used to determine the AI-EAG by subtracting the patient’s chronological age from the AI-ECG derived biological age. The AI-EAG was then correlated with a combined outcome of major ventricular arrhythmia [sudden cardiac arrest, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator shocks], heart transplantation, and cardiovascular death. Results: Overall, 147/1,049 (14%) patients with genetically-mediated ACM/DCM had a P/LP variant in LMNA . Of these, 80/147 (54%) LMNA variant-positive patients (52% female, mean chronological age 36 ± 15 years) had ECGs suitable for AI-EAG analysis. Most (52/80; 65%) had an AI-EAG >10 years with a mean AI-EAG of 17 ± 13 years. Of note, the AI-EAG was greater in those with a clinical cardiac phenotype (20 ± 14 vs. 13 ± 10 years; p = 0.011). As a continuous variable, an increased AI-EAG was associated with increased risk of the composite outcome at a median follow-up of 20 months (HR 1.036; 95% CI 1.004–1.068; p = 0.026) and AI-EAG > 10 and > 20 years were both associated with elevated risk (HR 4.272; 95% CI 1.388–13.147; p = 0.011 and HR 3.732; 95% CI 1.505–9.255; p = 0.004, respectively). Conclusion: In cardiac laminopathy, an increased AI-EAG was common and correlated with adverse cardiovascular outcomes. Non-invasive ascertainment of electrocardiographic aging by AI may provide a novel prognostic marker in cardiac laminopathy. Future studies are needed to validate this finding and further define the role of the AI-EAG in the risk-stratification of patients with cardiac laminopathy.

Background: Pathogenic/likely pathogenic (P/LP) variants in the RBM20-encoded RNA-binding protein motif 20 splicing factor result in a penetrant form of arrhythmogenic/dilated cardiomyopathy (ACM/DCM) characterized by ventricular arrhythmias (VA) and early-onset heart failure. The role of cardiac magnetic resonance (CMR) imaging in characterizing RBM20 cardiomyopathy and guiding risk stratification remains inadequately defined. Objectives: To characterize CMR phenotypes in patients with RBM20 cardiomyopathy and explore associations between variant type, CMR phenotype, and VA risk. Methods: Retrospective analysis of 1,061 genotype-positive ACM/DCM patients was used to identify individuals with P/LP arginine/serine-rich domain-localizing missense (RBM20msv) or truncating (RBM20tv) variants in RBM20. Clinical outcomes, including major VA (MVA; sudden cardiac arrest, sustained ventricular arrhythmia, or appropriate ICD therapy) events, were compared between RBM20msv and RBM20tv-positive patients. When available, CMR findings were also analyzed by variant type and correlated with MVA events. Results: Overall, 64 of 1,061 (6%) ACM/DCM patients possessed an RBM20msv or RBM20tv. Of those, 35 (mean age 38±16 years, 54% female, 94% Caucasian) underwent CMR. Late gadolinium enhancement (LGE) was present in 9/35 (26%), typically in a mid-myocardial septal or inferolateral pattern. Left ventricular (LV) noncompaction was noted in 9/35 (26%). Within the CMR subgroup, RBM20msv accounted for 29/35 (83%) of cases, while RBM20tv was observed in 6/35 (17%). No significant difference in LV ejection fraction (36±7% vs. 42±13%, p=0.358), LV end-diastolic volume index (100±32 mL/m2 vs. 118±44 mL/m2, p=0.342), or LGE prevalence (1/6 [17%] vs. 8/29 [28%], p=1.000) was observed between RBM20tv- and RBM20msv-positive patients. However, MVA events were more frequent among RBM20tv-positive patients in the CMR subset (3/6 [50%] vs. 2/29 [7%], p=0.026) and the overall cohort (7/15 [47%] vs. 6/49 [12%], p=0.008). Conclusions: RBM20tv-positive patients experienced a higher rate of MVA events despite similar rates of LGE and structural remodeling compared to those with RBM20msv. Future studies are needed to determine whether mechanisms independent of fibrosis/re-entry drive arrhythmogenesis in RBM20tv-positive patients and to establish if RBM20tv represents an independent risk factor for MVA events that merits incorporation into genotype-specific risk stratification strategies.

Background: Arrhythmogenic and dilated cardiomyopathies (ACM/DCM) are associated with adverse cardiovascular outcomes, including sudden death. Artificial intelligence (AI)-enabled electrocardiographic aging algorithms estimate biological age from 12-lead tracings and predict cardiovascular outcomes in the general population. However, their utility in genetic ACM/DCM has not been studied. Methods: Retrospective review of 1,045 genotype-positive ACM/DCM patients was used to identify those with a pathogenic/likely pathogenic variant in ClinGen-classified definitive/strong evidence ACM/DCM-susceptibility genes. Following exclusion of patients without a baseline ECG for analysis (e.g. paced rhythms), the AI-ECG age gap (AI-EAG) was calculated by subtracting chronological from AI-ECG age. Genes were grouped into functional categories: desmosomal ( PKP2, DSP, DSG2, DSC2, JUP ), nuclear envelope ( LMNA ), sarcomeric ( TTN, MYH7, TNNT2 ), cytoskeleton/Z-disc ( FLNC, DES, DMD, BAG3 ), and regulatory/ion channel ( PLN, RBM20, SCN5A ). Cardiac MRI data included left ventricular structure, function, and late gadolinium enhancement (LGE) presence and pattern. Mann-Whitney U was used for group comparisons; results are shown as median (IQR). Results: Overall, 824 patients (52.8% male; median age of 40.7 years, IQR 26.5–53.4; and median AI-EAG of 7.49 years, IQR 0.43–15.26) were included. DES variant-positive patients had the highest (19.98 years, IQR 9.66–23.21) and BAG3 variant-positive patients the lowest (–0.95 years, IQR -6.05–7.61) AI-EAGs. Among gene groups, nuclear envelope had the highest (15.12 years, IQR 6.79–25.17) and sarcomeric the lowest (5.75 years, IQR -0.69-14.01) AI-EAGs. Cardiac MRI was available for 538/824 (65%) of which 233/538 (43.3%) had LGE. No significant difference in AI-EAG was observed between LGE-positive and -negative patients (6.99 vs. 7.94 years; p=0.831). However, several LGE patterns were associated with significantly higher AI-EAGs: subepicardial (9.88 vs. 6.84; p=0.004), transmural (13.83 vs. 7.25; p=0.012), apical (12.89 vs. 7.17; p=0.002), and septal (8.91 vs. 7.19; p=0.016). Conclusion: AI-EAG varies by gene and functional group, possibly reflecting gene-specific myocardial remodeling. While certain LGE patterns were linked to increased biological aging, overall LGE status was not. These findings suggest AI-EAG may capture disease activity that is distinct from LGE and could serve as a complementary, non-invasive biomarker in genetic ACM/DCM.