Citations

Abstract Background and Aims Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. Methods The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter–defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. Results A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62–0.72] and 0.59 (95% CI 0.48–0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68–0.80) and 0.60 (95% CI 0.47–0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59–1.41) for AE and 1.00 (95% CI 0.69–1.32) for nf/fAE. Conclusions These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Abstract Background and Aims Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. Methods This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%–25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. Results One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. Conclusions North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Abstract Background/Introduction Arrhythmogenic mitral valve prolapse syndrome (AMVPS) is a female-predominant sudden cardiac death (SCD)-predisposing disorder characterized clinically by myxomatous mitral valve prolapse (MVP), inferolateral T-wave inversions and complex ventricular ectopy. However, insights into the pathogenesis and potential genetic basis of AMVPS are currently lacking. Purpose Considering recent case reports that suggest a potential role for genetic cardiomyopathies in the pathogenesis of AMVPS, we sought to determine the yield of pathogenic/likely pathogenic (P/LP) genetic variants in strong evidence cardiomyopathy-susceptibility genes amongst AMVPS patients who underwent clinical genetic testing. Methods In this retrospective study, the medical records of 4,907 patients referred to our cardiovascular genetics clinic was used to identify those patients with a clinical phenotype consistent with AMVPS. After exclusion of individuals with severe mitral valve regurgitation, pertinent clinical, electrocardiographic, imaging and genetic testing data was extracted from the electronic record. For those AMVPS that underwent a form of genetic testing that encompassed 23 Clinical Genome Resource-defined strong/definitive evidence cardiomyopathy-susceptibility genes, ultra-rare (minor allele frequency ≤ 0.00005 in the Genome Aggregation Database [n=141,456 individuals]) non-synonymous variants identified within these genes were adjudicated independently as P, LP or variant of uncertain significance with the assistance of Varsome. The frequency of P/LP variants was then compared to a previously published cohort of 973 ostensibly healthy control exomes. Results Overall, 56 unrelated patients with suspected AMVPS were identified (82% female; average age at presentation of 31 ± 13 years; 32% with a family history of MVP and/or SCD). Of these, 24/56 (43%) underwent a form of clinical genetic testing that encompassed the pre-defined panel of cardiomyopathy-susceptibility genes. In comparison to control exomes (n=973), P/LP variants in strong/definitive evidence cardiomyopathy-susceptibility genes were over-represented in AMVPS patients [4/24 (16.7%) vs 20/973 (2.1%); p=0.002]. Interestingly, this enrichment was driven in large part by an excess number of A-band-localizing P/LP truncating variants in TTN-encoded titin in AMVPS cases [3/24 (12.5%) versus 4/973 (0.4%); p=0.0004]. Conclusion This study provides further evidence that a subset of AMVPS may arise secondary to a "two-hit" model whereby an underlying cardiomyopathic genetic substrate is exacerbated by the mechanical force generated by genetically unrelated myxomatous MVP resulting in maladaptive and ventricular arrhythmia-predisposing fibrosis within the inferobasal left ventricle and posteromedial papillary muscles. Larger studies are needed to better understand the potential role of genetic testing in the diagnosis, risk-stratification and management of patients with suspected AMVPS.

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: Long QT syndrome (LQTS) is a genetic heart disease affecting about 1 in 2000 persons. Around 40% of patients with LQTS can have a nondiagnostic, normal QTc at rest. The treadmill exercise stress test (TEST) can help unmask patients with concealed LQTS with a characteristic maladaptive, paradoxical increase in QTc ( 460 ms) during the recovery phase. In fact, the recovery phase QTc value has been added to the latest diagnostic score for LQTS. Objective: To characterize the TEST-derived QTc profile of untreated patients with LQTS and determine its diagnostic and prognostic utility. Methods: Retrospective analysis was performed on TEST data derived from 249 patients with LQTS (129 LQT1, 64 LQT2 and 56 LQT3) untreated at the time of their TEST compared with 236 controls. The Bazett’s corrected QTc was calculated at rest (sitting, supine, and standing), during exercise at 1 min, 3 mins, and peak exercise, and during recovery phase at 1, 3 and 5 mins. Results: The mean resting QTc was significantly higher in LQTS patients (457 ± 30 ms) compared to controls (420 ± 24 ms; p<0.0001) as well as at every stage during the TEST (p<0.001). For LQT1 patients, highest QTc was observed at peak exercise (mean 496 ± 38 ms) and during the third minute of recovery phase (mean 500 ± 40 ms). In contrast, LQT2 patients showed the lowest QTc (mean 452 ± 48 ms) during peak exercise but the greatest QTc latency (QTc at 5 min - QTc at 1 min recovery; mean QTc latency 33 ± 77 ms; p=0.005) compared to controls. For LQT3, the mean QTc was greatest at rest compared to controls (p<0.001), and there was no difference during exercise and recovery phases. Among 162 LQT1 and LQT2 patients that presented with concealed LQTS, 119 (73%) showed a maladaptive QT response. ROC analysis showed that in patients with LQT1, a maladaptive QTc > 523 ms at 3 min of recovery was highly predictive of breakthrough cardiac events (AUC 0.84; sensitivity 100%, specificity 72%); no such association was identified for LQT2 or 3. Conclusions: This comprehensive characterization of the QTc response before, during, and after a TEST in the largest untreated cohort of patients with LQTS provides important genotype-specific characteristics and can be used as a predictor for potential LQT1-triggered cardiac events after diagnosis and treatment.

Introduction: Pathogenic loss-of-function variants in the RBM20 -encoded RNA-binding motif 20 splicing regulator cause a severe form of arrhythmogenic dilated cardiomyopathy (DCM). Erroneous splicing of TTN -encoded titin contributes to the pathogenesis of RBM20 -mediated disease. However, studies exploring the clinical course of RBM20 -mediated arrhythmogenic DCM alone or in comparison to TTN -mediated DCM, the most common familial cause of DCM, are lacking. Methods: The Mayo Clinic Genetic Arrhythmogenic Cardiomyopathy Registry (n=391) was used to identify all patients with a pathogenic/likely pathogenic (P/LP) variant in either RBM20 or TTN . For the purposes of this study, a ventricular arrhythmia (VA) event was defined as sudden cardiac arrest, sustained ventricular arrhythmia, or an appropriate ICD shock and an advanced heart failure (AHF) event was defined as ventricular assist device implantation or heart transplantation. Results: Overall, 40 patients with a P/LP variant in RBM20 (50% female) and 70 patients with a P/LP variant in TTN (43% female) were identified. The prevalence of a cardiac phenotype in patients with RBM20- and TTN -mediated disease was 88% and 83%, respectively. RBM20 patients were more likely to have a family history of sudden cardiac arrest (78% vs 34%; p < 0.0001) and cardiomyopathy (90% vs 61%; p=0.001). No difference in rate of ICD implantation (35% versus 33%) was observed. Interestingly, the prevalence of AHF events (10% vs 6%; p=0.5) and VA events (28% vs 24%; p=0.7) was similar between RBM20 - and TTN -positive patients. However, RBM20 patients were younger than TTN patients at the time of their event (37 ± 18 years vs 50 ± 17; p=0.0004). Time-to-event analysis showed RBM20 patients had an earlier time to AHF event (p=0.05) and time to VA event (p=0.03) than TTN patients. The mean age for AHF events was 25 years for RBM20 patients (N=4) and 47 years for TTN patients (N=4). The mean age for VA events was 29 years for RBM20 patients (N=10) and 42 years for TTN patients (N=14). Conclusions: RBM20 -mediated arrhythmogenic DCM represents a highly penetrant genetic heart disease with potentially life-threatening VAs and end stage heart failure manifestations occurring at a significantly younger age in comparison to TTN -mediated DCM.

Introduction: Myocardial inflammation likely contributes to the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a clinically and genetically heterogenous disorder characterized by ventricular dysfunction and potentially life-threatening ventricular arrhythmias. Due to phenotypic overlap, some patients with genetic ACM may have been evaluated for an underlying inflammatory cardiomyopathy, namely cardiac sarcoidosis. However, the cardiac fludeoxyglucose (FDG) positron emission tomography (PET) findings in ACM patients have not been assessed systematically. Methods: All genotype-positive patients in the Mayo Clinic ACM registry who received a cardiac FDG PET were included in this study. The cardiac FDG PET scan consisted of a resting myocardial perfusion scan with N13-ammonia as well as a F18-FDG scan after a high-fat diet to suppress physiologic FDG uptake. Pertinent demographic, genetic, imaging, and outcome data were extracted from the medical record. Results: Collectively, 12 (75% female) genotype-positive ACM patients received a cardiac PET FDG scan as part of their clinical evaluation (median age at scan 45.3 years [IQR 38.9-62.1]). Amongst these patients, pathogenic/likely pathogenic variants were detected in LMNA (n=7), DSP (n=3), FLNC (n=1), and PLN (n=1). Of note, 6/12 (50%) had abnormal myocardial FDG uptake, including diffuse (entire myocardium) uptake in 2/6 (33%), focal (1-2 segments) uptake in 2/6 (33%) and patchy (3+ segments) in 2/6 (33%). Median myocardial standardized uptake value ratio was 2.1 (IQR 1.5-2.6). Interestingly, LMNA -positive patients accounted for 3 out of 6 (50%) positive studies (diffuse uptake in 2 and focal uptake in 1). Conclusion: Myocardial FDG uptake is common in genetic ACM patients undergoing cardiac FDG PET. This finding further supports the role of myocardial inflammation in genetic ACM and demonstrates the ability of cardiac FDG PET to readily detect this phenomenon. Further investigation is needed to determine (i) the role of cardiac FDG PET in the evaluation of genetic ACM, (ii) if FDG uptake in genetic ACM has prognostic value and (iii) whether the attenuation of myocardial inflammation with immunosuppressive agents can impact the clinical course of inflammatory genetic ACMs.

Background: Highly caffeinated energy drinks (HCEDs) can trigger life-threatening cardiac arrhythmias in individuals with and without an underlying genetic predisposition. Though the mechanism(s) responsible for these events remain unclear, it has been postulated that high caffeine may alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a manner that is pro-arrhythmic. Objective: To describe our experience regarding sudden cardiac arrest (SCA) events occurring in proximity to HCED consumption in patients with underling genetic heart diseases. Methods: All SCA survivors referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for clinical and/or molecular evaluation were reviewed to identify those with a history of HCED consumption prior to their event. Patient demographics, clinical characteristics, documented HCED consumption, and temporal relationship of HCED consumption to SCA were extracted from the electronic medical record. Results: Among 144 SCA survivors with a structurally normal heart, 8 (6 females; mean age at event 28 ± 8 years) experienced an unexplained SCA associated temporally with HCED consumption. Of these, 5 (63%) had either long QT syndrome (n=3) or catecholaminergic polymorphic ventricular tachycardia (n=2). The remaining 3 were diagnosed with unexplained SCA/idiopathic ventricular fibrillation after a comprehensive evaluation. Three patients (37%) were habitual HCED consumers while 5 (63%) imbibed for the first time with consumption ranging from several hours to a few minutes before the SCA. Seven patients (88%) required a rescue shock (average 2 ± 2 shocks/patient) while 1 was manually resuscitated. Upon follow-up, 6 (75%) were dismissed with an implantable cardioverter defibrillator, 1 (13%) on pharmacologic therapy, and 1 (13%) underwent denervation surgery. All SCA survivors have quit drinking HCEDs and have been event-free since. Conclusion: Overall, 8/144 (5.6%) of SCA survivors evaluated in our program experienced a SCA in proximity to consuming a HCED. Although larger cohort studies are needed to elucidate the precise mechanism for HCED-triggered/associated SCA and quantify its precise pro-arrhythmic risk, it seems prudent to sound an early warning.