Objective: To investigate the functional effects and genotype-phenotype correlation of a coding variant within the Neuregulin-1 gene (NRG1), which we previously identified from a community-based study of sudden cardiac death (SCD). Methods: The Missense variant Met286Thr within NRG1 was characterized by transfecting NRG1 wild type and mutant in HEK293 cells with a tag placed on the extracellular domain for assessment of membrane expression. To study genotype-phenotype correlations, we performed a case-case analysis comparing SCD carrier cases of the risk allele (n=384) vs. non SCD carrier cases (n=888). A total of 1,272 SCD cases of European descent were included in the study. Regression models adjusted for age and sex were tested to evaluate the correlation of the risk allele and clinical variables obtained ECGs and Echocardiograms of SCD cases. Results: We found that, unlike wild type NRG1, the Met286Thr variant did not traffic to the cell membrane (Figure), indicating defects in antegrade protein transport. We also found that in the subset of SCD cases with echocardiograms available (n=253), carriers of the risk allele were more likely to present with low ejection fraction (LVEF ≤35%) compared with the non-carrier cases (P=0.02, OR= 2.26 [1.14-4.5]. Other investigated risk factors such as QT prolongation, QRS duration, heart rate, left ventricular hypertrophy and coronary artery disease were not significantly different (P>0.05). Conclusions: We have identified a novel variant in the transmembrane domain of NRG1, which results in defective antegrade transport and is associated with SCD and low ejection fraction. These findings support a role for Met286Thr in trafficking pathways leading to both functional compromise and ventricular arrhythmogenesis.
Background The Romhilt‐Estes point score system ( RE ) is an established ECG criterion for diagnosing left ventricular hypertrophy ( LVH ). In this study, we assessed for the first time, whether RE and its components are predictive of sudden cardiac arrest ( SCA ) independent of left ventricular ( LV ) mass. Methods Sudden cardiac arrest ( SCA ) cases occurring between 2002 and 2014 in a Northwestern US metro region (catchment area approx. 1 million) were compared to geographic controls. ECG s and echocardiograms performed prior to the SCA and those of controls were acquired from the medical records and evaluated for the ECG criteria established in the RE score and for LV mass. Results Two hundred forty‐seven SCA cases (age 68.3 ± 14.6, male 64.4%) and 330 controls (age 67.4 ± 11.5, male 63.6) were included in the analysis. RE scores were greater in cases than controls (2.5 ± 2.1 vs. 1.9 ± 1.7, p < .001), and SCA cases were more likely to meet definite LVH criteria (18.6% vs. 7.9%, p < .001). In a multivariable model including echocardiographic LVH and LV function, definite LVH remained independently predictive of SCA ( OR 2.04, 95% CI 1.16–3.59, p = .013). The model was replicated with the individual ECG criteria, and only SV 1.2 ≥ 30 mm and delayed intrinsicoid deflection remained significant predictors of SCA . Conclusion Left ventricular hypertrophy ( LVH ) as defined by the RE point score system is associated with SCA independent of echocardiographic LVH and reduced LV ejection fraction. These findings support an independent role for purely electrical LVH , in the genesis of lethal ventricular arrhythmias.
Introduction: Presentation with shockable rhythm markedly improves survival from out-of-hospital sudden cardiac arrest (SCA). Shockable rhythms (ventricular fibrillation/tachycardia; VF/VT) are known to deteriorate to asystole or pulseless electrical activity (PEA) over time, but little population-based data is available regarding this phenomenon. Also, bystander CPR (BCPR) improves survival from SCA but its association with maintenance of shockable rhythms is unclear. Hypothesis: With longer EMS response time, the proportion of EMS-assessed shockable initial rhythms will decrease. BCPR may influence this association. Methods: We analyzed EMS-assessed initial rhythm of SCA cases from the Oregon SUDS study in the Portland, OR metro area (pop ~1 million). For this analysis, we included bystander-witnessed SCA cases (2002-2018) aged ≥18 with resuscitation attempted by EMS. SCA was defined as a sudden, unexpected pulseless condition of likely cardiac origin. We assessed initial rhythm proportions across EMS response times using Cochran-Armitage trend tests. Results: Among 3,309 SCA cases, 1,748 (53%) were bystander-witnessed, and of these, 706 (40%) received BCPR. Response time was 7.3 ± 3.4 minutes for cases with BCPR and 6.8 ± 3.1 minutes without BCPR (p=0.01). In the group receiving BCPR, the proportion with shockable rhythm remained near 60% across response times from <3 to ≥12 minutes (Figure, solid line; p=0.88), and proportions of PEA and asystole remained stable. In the group without BCPR, shockable rhythm declined from 70% at <3 minutes to 44% at ≥12 minutes response time (Figure, dashed line; p<0.001), while non-shockable rhythms increased. Conclusions: Among community-based SCA cases who received bystander CPR, there was no significant decrease in shockable rhythm as response time increased. In contrast, among SCA cases without bystander CPR, longer response times were associated with a lower proportion of shockable rhythms.
Background: Sports-related sudden cardiac arrest (sport SCA) has always attracted attention and the United States and European Union have developed divergent strategies for prevention over the last decade; notably regarding screening of younger athletes but also for SCA prevention in middle-aged and senior individuals. In this context, the extent to which outcomes of sports SCA differ between Europe and the USA have not been characterized. Methods: SCA cases aged 15-75 years were identified in two large prospective, population-based SCA programs, one in the Paris region (Paris-SDEC) and the other in a Northwestern US metro region (Oregon-SUDS) between 2002 and 2012. Cases of SCA, occurring during sports activity were compared between the two regions. Results: Of the 7,357 cases studied, 290 (4%) occurred during sports, with very similar proportions in both regions: 86 out of 1,894 (4.5%) in Oregon and 204 out of 5,463 (3.8%) in Paris. Subjects’ characteristics of cases in both programs were very similar (Paris vs. Oregon, respectively, for all results following), regarding age (50.7±14 vs. 50.4±13 years, P=0.55), male proportion (94%vs. 92%, P=0.53), past medical history of ≥2 cardiovascular risk factors (16% vs. 23%, P=0.16) and/or heart disease (10% vs. 8%, P=0.55). There was a high proportion of witnessed events in both populations (89% vs. 90%, P=0.94). However, we observed significant differences with more bystander cardiopulmonary resuscitation in Paris (63% vs. 48%, P=0.02), faster response time in Oregon (8.3±6 vs. 6.9±4 min, P=0.05), and more initially shockable rhythms in Oregon (52% vs. 70%, P=0.006). Overall, resuscitation outcomes were very similar for return of spontaneous circulation (26% vs. 33%, P=0.21) and survival to hospital discharge (27% vs. 26%, P=0.80). Conclusions: On either side of the Atlantic, burden and characteristics of sports-related SCA are very similar. Survival rates are approximately one in four cases. Optimizing bystander cardiopulmonary resuscitation rates and emergency response times could further improve outcomes. Deployment of uniform, effective strategies for screening and prevention are likely to make the greatest impact on sports SCA.
