Bos, J. Martijn

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disorder characterized by increased left ventricular (LV) wall thickness, often leading to heart failure (HF). The role of cardiovascular magnetic resonance (CMR) imaging in predicting new onset of HF symptoms in patients with HCM remains unknown. This study aimed to identify CMR predictors of new-onset HF symptoms in individuals with HCM. Methods This study was a single-centre retrospective cohort study of HCM patients treated at a tertiary referral centre in the USA who underwent CMR examination between 1998 and 2018, had no HF symptoms at baseline CMR, and at least 1 year of follow-up. Clinical data were collected by review of electronic medical records, and CMR images were analyzed by a blinded expert cardiac radiologis. The primary outcome was new onset of HF symptoms, defined as New York Heart Association (NYHA) class ≥ II at follow-up. Kaplan–Meier analyses and Cox proportional hazard analyses were performed. Results Of 1462 patients diagnosed with HCM who had at least 1 CMR, 276 HCM patients without HF symptoms (average age 52.7 years, 33.3% female),median maximum left ventricular (LV) wall thickness was 19 mm ([IQR] 17–22) with a and median LV ejection fraction of 71% (IQR 66–77). Late gadolinium enhancement was detected in 56.2%) patients (60.7% had mild; 30.7% moderate; 8.6% severe). During a median follow-up period of 6.3 years, 93 patients developed HF symptoms (NYHA class II in 56 (60.2%); class III in 31 (33.3%); and class IV in 6 (6.5%). Multivariable analysis adjusted for age showed that LA enlargement (HR 1.626; 95% CI 1.01–2.62; P = .045) and LV mass index (HR 1.014; 95% CI 1.007–1.022; P≤ .001) and sex (HR 1.7; 95% CI 1.074–2.691; P = .023) were independent predictors of new onset of HF symptoms in patients with HCM. Conclusions Nearly half of the patients with HCM developed HF symptoms within 6.3 years. Left atrial enlargement, LV mass index, and sex were independent predictors of new onset of HF symptoms in HCM patients. These findings emphasize the value of CMR in HF risk stratification.

Abstract Aims SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Abstract Aims Calcium release channel deficiency syndrome (CRCDS) results from loss-of-function (LOF) variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) without abnormalities on a stress electrocardiogram (ECG). Undetected CRCDS may underlie idiopathic ventricular fibrillation (IVF) and sudden unexplained death in the young (SUDY). We aimed to determine the prevalence of potential CRCDS-causative RYR2 variants in IVF and SUDY. Methods and results We reviewed clinical evaluation and RYR2 genetic analysis of 169 IVF patients and 279 SUDY victims. Only ultra-rare (<0.005% in gnomAD) nonsynonymous RYR2 variants were considered potentially pathogenic. Among IVF patients, 6/169 (3%) overall—and 6/67 (9%) with exertion-related SCA—harboured an RYR2 variant and represent potential CRCDS cases. All exhibited normal resting and stress ECGs. Genetic analysis revealed six distinct RYR2 variants, two previously characterized as LOF. In SUDY, 31/279 victims (11%) had a RYR2 variant (30 unique variants), predominantly observed in exertion-related SCD 20/83 (24%) vs. rest-related 11/196 (6%). Of the 14 SUDY victims with functionally characterized RYR2 variants, five (2% of total cohort) had a LOF variant; among the 56 exertion-related SUDY cases, four (7%) had a LOF variant. Conclusion CRCDS may account for 3% of IVF overall and 9% of exertion-related SCA in IVF. Ultra-rare RYR2 variants may underlie up to 11% of SUDY, with 65% of RYR2-positive cases occurring during exertion. LOF-RYR2 variants may contribute to ≥7% of exercise-associated SUDY. Accurate identification of the underlying ryanodinopathy is essential for clinical management of affected patients.

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: 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

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.

Background: Current guidelines discourage athletes with a positive genetic test for arrhythmogenic cardiomyopathy (ACM) from participating in sports. The evidence that exercise may act as a disease-accelerator is most compelling for PKP2-mediated ACM. As such, shared decision making (SDM) and return-to-play (RTP) for athletes with ACM may be possible for some genotypes. Objective: To examine the management, RTP, outcomes, and evolution of phenotype among athletes with genotype positive ACM. Methods: A retrospective review of the electronic medical records was performed on all self-identified athletes with genotype positive ACM. They were evaluated, risk stratified, and treated in Mayo Clinic’s (MC) Windland Smith Rice Genetic Heart Rhythm Clinic. Results: Among the 621 patients with genotype-positive ACM, there were 38 athletes [16 females (42%); mean age at either clinical diagnosis or positive genetic test 28 ± 19 years; mean follow-up 4 ± 4 years] participating in sports at all levels. The majority, 21 (55%), had PKP2-ACM and 7 (18%) had DSP-ACM. Prior to their first MC evaluation, 15 athletes (39%) were engaged in long distance running, swimming, cycling, or triathlons. Seven athletes (18%) had a non-lethal breakthrough cardiac event (BCE) after diagnosis, but prior to MC evaluation. During 150+ athlete-years of follow-up, there have been no ACM-associated deaths, but 5 athletes (13%) experienced a non-lethal BCE. Twenty-two athletes (58%) were phenotype negative at time of first MC evaluation including 10 endurance athletes (45%). Of these, 3 (14%) converted to phenotype positive (average age at conversion 25 ± 15 years), while 7/16 (44%) phenotype positive athletes exhibited further disease progression (average age at progression 32 ± 18 years). For these 10 athletes who either converted or progressed, treatment intensification included an ablation in 4, ICD in 2, and a heart transplant in 2. Seven resumed athletic activity in some capacity after conversion/progression and a non-lethal BCE occurred in 3. Conclusions: This is the first single center cohort of patients with ACM being empowered to remain an athlete. In contrast to athletes with other genetic heart diseases (GHDs), these athletes have exhibited more cardiac events, although nonfatal, and higher rates of disease conversion/progression than our other GHDs. Further studies are needed to determine how to effectively and safely enable appropriate sports participation in genetically-mediated ACM