MacIntyre, Ciorsti

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.

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.