Ackerman, Michael J.

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 (>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<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<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 The extravascular implantable cardioverter defibrillator (EV-ICD) was designed to avoid lead-related complications associated with transvenous systems and deliver features such as anti-tachycardia pacing (ATP) and reduced generator size that provide an advantage over a subcutaneous ICD (S-ICD). As such, the EV-ICD is an attractive alternative for younger patients with genetic heart diseases (GHDs) who are not in need of permanent pacing. Objective To examine the indications, complications, and the clinical outcomes of patients with GHDs who received an EV-ICD. Methods A retrospective review of the electronic record was done for all GHD patients evaluated in genetic heart rhythm and/or cardiomyopathy clinics who had an EV-ICD implanted between 1/2021 and 2/2025. Basic demographic, ICD indications, complications, and therapy data were then extracted for all study patients. Results Overall, 23 patients (35% female; mean age 39 ± 16 years; 61% with a disease-causative genetic variant; mean LVEF 57%) with an underlying GHD (hypertrophic cardiomyopathy in 9, arrhythmogenic cardiomyopathy in 8, idiopathic ventricular fibrillation in 3, dilated cardiomyopathy in 2, and long QT syndrome in 1) had an EV-ICD implanted. For the majority, an EV-ICD was implanted for primary prevention (15/23; 65%) and represented their first ICD system (21/23; 91%). The success rate of the procedure was 96% with only one abandoned procedure because of poor R-wave sensing. Inadvertent intraprocedural lead placement in the pericardial space occurred in 1 patient with previous thoracotomy and surgically placed epicardial lead without sequelae or need for revision. Over a mean follow-up of 8±9 months, the rate of complications was low (1/23; 4%) with one electrode displacement and this patient underwent defibrillation threshold testing (DFT), the device properly detected VF and emitted a successful shock 30 J. Thus far, 2 patients have received appropriate VT/VF-terminating therapies (3 ICD shocks, 0 ATP) with successful conversion to sinus rhythm. One patient died following an electrical storm. One patient had 3 inappropriate ICD shock for sinus tachycardia while exercising followed by 1 successful shock for VF. Conclusion In this early experience, EV-ICDs appear to be safe and effective in younger patients with genetic arrhythmogenic and hypertrophic cardiomyopathies. Future studies are needed to better understand the utility of EV-ICDs in patients with cardiac channelopathies and advantages of EV-ICDs over transvenous and S-ICD systems in patients with an array of sudden death-predisposing GHDs.

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.

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: Current guidelines recommend prophylactic beta-blocker therapy for all genotype-positive newborns with long QT syndrome (LQTS), despite the potential for QT normalization in the first few weeks of life and the rarity of cardiac events during infancy. We previously reported our early experience with intentional non-therapy (INT) for low-risk adolescents and adults. Objective: To evaluate our single-center experience regarding INT for infants with genotype-positive LQTS identified following family screening/cascade testing. Methods: We retrospectively reviewed all infants diagnosed with genotype-positive LQTS between 2015 and 2024. Only LQTS patients with clinical and ECG data within the first 2 years of life and follow-up were included. INT was defined as adherence to precautionary QT-preventative measures and structured periodic follow-up rather than treating with prophylactic drugs, devices, or denervation. Candidacy for INT was based on absence of symptoms, down-trending QT during first few weeks of life, family agreement with the strategy, and frequent surveillance (e.g., ECG and Holter every 6 months). Prophylactic drug therapy was initiated if a surveillance QTc exceeded 470ms on 2 consecutive ECGs or at family request. Results: Of 94 infants, 38 [40%; 19 females (50%), mean age at diagnosis 0.3±0.4 years] were managed with INT (14 LQT1 (36%), 15 LQT2 (39%), 8 LQT3 (21%)). Genetic testing and ECG screening were performed because of a family history in all 38 infants including 11 (29%) with a family history of SCA/SCD. None had fetal bradycardia reported or any cardiac symptoms prior to diagnosis. Mean neonatal QTc during the first week of life was 477±41ms and 442±6ms at 3 months of age. No cardiac events were reported during a mean follow-up of 3.9±2.3 years. Management was escalated from INT to prophylactic pharmacologic therapy in 8 infants (21%) with nadolol in 4, propranolol in 3, and LQT3 mutation-specific therapy with flecainide in 1 based on 2 consecutive QTc values>470ms, at a mean age of 4.3±2 years (mean QTc at treatment initiation 485±13ms). Conclusions: In selected LQTS infants with favorable down-trending QT and access to close follow-up, INT rather than universal prophylactic drug therapy can be considered. This approach may offer an alternative strategy in infancy, avoiding unnecessary early exposure to medication-related side effects and reinforcing individualized genotype- and phenotype-directed tailoring of therapeutic options.

Background: Pathogenic variants in LMNA -encoded lamin A/C cause a genetic cardiomyopathy marked by conduction disease, atrial and ventricular arrhythmias, and systolic dysfunction. The mechanisms underlying phenotypic differences between Ig-like and coiled-coil domain missense variants remains unclear. Here, we developed a novel suppression-and-replacement disease modeling (SupRep-DM) platform to screen LMNA missense variant function and prioritize mechanistically informative phenotypes. Methods: LMNA-SupRep-DM is a dual-component lentiviral system that enables simultaneous knockdown of endogenous LMNA via an LMNA -targeted shRNA and replacement with an shRNA-immune mutant lamin A cDNA encoding the pathogenic variant of interest with HA-tag. HEK293T cells and iPSC-derived cardiomyocytes (iPSC-CMs) were transduced with 9 unique SupRep-DM constructs harboring variants in either the coiled-coil (E82K, K97E, R216C, H222P, T224I, R335W) or Ig-like (R471H, R541C, R541H) domains. Cells were stained using HA-specific antibodies, imaged by confocal microscopy, and analyzed for nuclear morphology, aggregate burden, and fluorescence intensity. Statistics: Dunnett’s test and one-way ANOVA. Results: In HEK293T cells, 8/9 LMNA variants significantly reduced nuclear circularity (p< 0.05), most notably in K97E (-11%, n=89), R471H (-12%, n=62), and R541C (-9%, n=104). Additionally, K97E increased nuclear area (+24%) and R541C decreased it (−29%) vs wild-type (WT, p<0.0001). Lamin A intensity was significantly reduced in K97E, R471H, and R541C, but increased in T224I and R335W vs WT. In iPSC-CMs, Ig-fold variants R541C and R541H significantly reduced nuclear circularity (−28%, –34%), increased elongation (+42%, +49%), and elevated lamin A aggregates ~4–5-fold vs WT (p≤0.0005). R471H and the coiled-coil variant E82K also increased aggregate burden, while the remaining variants (K97E, R216C, H222P, T224I, R335W) showed no significant effects in iPSC-CMs. Conclusions: LMNA missense variants cause domain-specific nuclear disruptions, with variants localizing to the Ig-like domain inducing nuclear deformities and consistent aggregation across both cellular models. Coiled-coil variants showed more variable, context-dependent effects. The more pronounced phenotypes in iPSC-CMs may reflect contraction-mediated stress absent in HEK293T cells. The SupRep-DM platform sensitively detects these structural changes, demonstrating its utility for mechanistic prioritization of LMNA variants.

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: 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.

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: Congenital long QT syndrome (LQTS) is characterized by a prolongation of the heart rate-corrected QT interval (QTc) and an increased risk of syncope, seizure and sudden cardiac arrest/death (SCA/SCD). Genome-wide association studies have identified numerous QT interval-influencing loci of small effect sizes. Herein, we sought to investigate whether a polygenic background for the QT interval contributes to the phenotypic heterogeneity in patients with genotype-positive LQTS. Methods: We used summary statistics from a recent genome-wide meta-analysis for QT interval (n = 117,532) to derive 160 different polygenic scores for QT interval (PGS QT ) using LDpred2-grid, each comprising ~1.4 million common variants with varying assumptions of the underlying genetic architecture. Next, we applied these PGS QT to predict the QTc value in a genetically unrelated, European ancestry subset of the ‘All of Us’ cohort with available electrocardiogram and genetic data (n=6,404), where the best performing PGS QT was determined based on explained variance. Next, using 225 patients with genetically confirmed LQTS who were evaluated in the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic, we tested the effect of the best performing PGS QT on QTc duration and LQTS-associated cardiac events (defined as a composite of syncope, seizures, sustained ventricular arrhythmia, appropriate ICD shocks, and SCA/SCD) using Bayesian regression models. Results: Overall, the best performing PGS QT explained 11.8% of the variance in the QTc in the ‘All of Us’ cohort. Among patients with genotype-positive LQTS (n [%]; KCNQ1 125 [55.6], KCHN2 76 [33.8], SCN5A 21 [9.3], Other 3 [1.3]), those with higher PGS QT had a higher QTc (predicted mean QTc [95% uncertainty interval], 95 th percentile vs 50 th percentile for PGS QT , 478 ms [464-491] vs 459 ms [449-468]). In comparison to the median PGS, those LQTS patients with a PGS QT >95 th percentile were more than twice as likely to have experienced a LQTS-associated cardiac event (Odds ratio [95% UI], 95 th percentile vs 50 th percentile for PGS QT ; 2.16 [1.02-5.41]), ( Figure ). Conclusions: Individuals with genotype-positive LQTS who have high polygenic susceptibility for QTc prolongation are more likely to phenotypically exhibit a higher QTc value and experience potentially life-threatening LQTS-associated cardiac events. Accounting for polygenic background may refine risk stratification strategies for patients with genotype-positive LQTS