The Lancet Commission to reduce the global burden of sudden cardiac death: a call for multidisciplinary action.

Despite major advancements in cardiovascular medicine, sudden cardiac death (SCD) continues to be an enormous medical and societal challenge, claiming millions of lives every year. Efforts to prevent SCD are hampered by imperfect risk prediction and inadequate solutions to specifically address arrhythmogenesis. Although resuscitation strategies have witnessed substantial evolution, there is a need to strengthen the organisation of community interventions and emergency medical systems across varied locations and health-care structures. With all the technological and medical advances of the 21st century, the fact that survival from sudden cardiac arrest (SCA) remains lower than 10% in most parts of the world is unacceptable. Recognising this urgent need, the Lancet Commission on SCD was constituted, bringing together 30 international experts in varied disciplines. Consistent progress in tackling SCD will require a completely revamped approach to SCD prevention, with wide-sweeping policy changes that will empower the development of both governmental and community-based programmes to maximise survival from SCA, and to comprehensively attend to survivors and decedents' families after the event. International collaborative efforts that maximally leverage and connect the expertise of various research organisations will need to be prioritised to properly address identified gaps. The Commission places substantial emphasis on the need to develop a multidisciplinary strategy that encompasses all aspects of SCD prevention and treatment. The Commission provides a critical assessment of the current scientific efforts in the field, and puts forth key recommendations to challenge, activate, and intensify efforts by both the scientific and global community with new directions, research, and innovation to reduce the burden of SCD worldwide.

Optimizing Outcomes After Out-of-Hospital Cardiac Arrest With Innovative Approaches to Public-Access Defibrillation: A Scientific Statement From the International Liaison Committee on Resuscitation.

Out-of-hospital cardiac arrest is a global public health issue experienced by ≈3.8 million people annually. Only 8% to 12% survive to hospital discharge. Early defibrillation of shockable rhythms is associated with improved survival, but ensuring timely access to defibrillators has been a significant challenge. To date, the development of public-access defibrillation programs, involving the deployment of automated external defibrillators into the public space, has been the main strategy to address this challenge. Public-access defibrillator programs have been associated with improved outcomes for out-of-hospital cardiac arrest; however, the devices are used in <3% of episodes of out-of-hospital cardiac arrest. This scientific statement was commissioned by the International Liaison Committee on Resuscitation with 3 objectives: (1) identify known barriers to public-access defibrillator use and early defibrillation, (2) discuss established and novel strategies to address those barriers, and (3) identify high-priority knowledge gaps for future research to address. The writing group undertook systematic searches of the literature to inform this statement. Innovative strategies were identified that relate to enhanced public outreach, behavior change approaches, optimization of static public-access defibrillator deployment and housing, evolved automated external defibrillator technology and functionality, improved integration of public-access defibrillation with existing emergency dispatch protocols, and exploration of novel automated external defibrillator delivery vectors. We provide evidence- and consensus-based policy suggestions to enhance public-access defibrillation and guidance for future research in this area.

Alert system-supported lay defibrillation and basic life-support for cardiac arrest at home.

AIMS: Automated external defibrillators (AEDs) are placed in public, but the majority of out-of-hospital cardiac arrests (OHCA) occur at home. METHODS AND RESULTS: In residential areas, 785 AEDs were placed and 5735 volunteer responders were recruited. For suspected OHCA, dispatchers activated nearby volunteer responders with text messages, directing two-thirds to an AED first and one-third directly to the patient. We analysed survival (primary outcome) and neurologically favourable survival to discharge, time to first defibrillation shock, and cardiopulmonary resuscitation (CPR) before Emergency Medical Service (EMS) arrival of patients in residences found with ventricular fibrillation (VF), before and after introduction of this text-message alert system. Survival from OHCAs in residences increased from 26% to 39% {adjusted relative risk (RR) 1.5 [95% confidence interval (CI): 1.03-2.0]}. RR for neurologically favourable survival was 1.4 (95% CI: 0.99-2.0). No CPR before ambulance arrival decreased from 22% to 9% (RR: 0.5, 95% CI: 0.3-0.7). Text-message-responders with AED administered shocks to 16% of all patients in VF in residences, while defibrillation by EMS decreased from 73% to 39% in residences (P < 0.001). Defibrillation by first responders in residences increased from 22 to 40% (P < 0.001). Use of public AEDs in residences remained unchanged (6% and 5%) (P = 0.81). Time from emergency call to defibrillation decreased from median 11.7 to 9.3 min; mean difference -2.6 (95% CI: -3.5 to -1.6). CONCLUSION: Introducing volunteer responders directed to AEDs, dispatched by text-message was associated with significantly reduced time to first defibrillation, increased bystander CPR and increased overall survival for OHCA patients in residences found with VF.

Time to Return of Spontaneous Circulation and Survival: When to Transport in out-of-Hospital Cardiac Arrest?

BACKGROUND: In out-of-hospital cardiac arrest (OHCA), 10-50% of patients have return of spontaneous circulation (ROSC) before hospital arrival. It is important to investigate the relation between time-to-ROSC and survival to determine the optimal timing of transport to the hospital in patients without ROSC. Methods: We analyzed data of OHCA patients with a presumed cardiac cause (excluding traumatic and other obvious non-cardiac causes) and ROSC before hospital arrival from the Amsterdam Resuscitation Study (ARREST) database. ROSC included those patients whose ROSC was persistent or transient before or during transport, lasting ≥1 min. Of these data, we analyzed the association between the time of emergency medical services (EMS) arrival until ROSC (time-to-ROSC) and 30-day survival. Results: Of 3632 OHCA patients with attempted resuscitation, 810 patients with prehospital ROSC were included. Of these, 332 (41%) survived 30 days. Survivors had a significant shorter time-to-ROSC compared to non-survivors of median 5 min (IQR 2,10) vs. median 12 min (IQR 9,17) (p < 0.001). Of the survivors, 90% achieved ROSC within 15 min compared to 22 min of non-survivors. In a multivariable model adjusted for known system determinants time-to-ROSC per minute was significantly associated with 30-day survival (OR 0.89; 95%CI 0.86-0.91). A ROC curve showed 8 min as the time-to-ROSC with the best test performance (sensitivity of 0.72 and specificity of 0.77). Conclusion: In OHCA patients with prehospital ROSC survival significantly decreases with increasing time-to-ROSC. Of all patients, 90% of survivors had achieved ROSC within the first 15 min of EMS resuscitation. The optimal time for the decision to transport is between 8 and 15 min after EMS arrival.

Association of beta-blockers and first-registered heart rhythm in out-of-hospital cardiac arrest: real-world data from population-based cohorts across two European countries.

AIMS: Conflicting results have been reported regarding the effect of beta-blockers on first-registered heart rhythm in out-of-hospital cardiac arrest (OHCA). We aimed to establish whether the use of beta-blockers influences first-registered rhythm in OHCA. METHODS AND RESULTS: We included patients with OHCA of presumed cardiac cause from two large independent OHCA-registries from Denmark and the Netherlands. Beta-blocker use was defined as exposure to either non-selective beta-blockers, ß1-selective beta-blockers, or α-ß-dual-receptor blockers within 90 days prior to OHCA. We calculated odds ratios (ORs) for the association of beta-blockers with first-registered heart rhythm using multivariable logistic regression. We identified 23 834 OHCA-patients in Denmark and 1584 in the Netherlands: 7022 (29.5%) and 519 (32.8%) were treated with beta-blockers, respectively. Use of non-selective beta-blockers, but not ß1-selective blockers, was more often associated with non-shockable rhythm than no use of beta-blockers [Denmark: OR 1.93, 95% confidence interval (CI) 1.48-2.52; the Netherlands: OR 2.52, 95% CI 1.15-5.49]. Non-selective beta-blocker use was associated with higher proportion of pulseless electrical activity (PEA) than of shockable rhythm (OR 2.38, 95% CI 1.01-5.65); the association with asystole was of similar magnitude, although not statistically significant compared with shockable rhythm (OR 2.34, 95% CI 0.89-6.18; data on PEA and asystole were only available in the Netherlands). Use of α-ß-dual-receptor blockers was significantly associated with non-shockable rhythm in Denmark (OR 1.21; 95% CI 1.03-1.42) and not significantly in the Netherlands (OR 1.37; 95% CI 0.61-3.07). CONCLUSION: Non-selective beta-blockers, but not ß1-selective beta-blockers, are associated with non-shockable rhythm in OHCA.

COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation.

Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomized clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritized through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterized relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with ≥1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow.

2017 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary.

The International Liaison Committee on Resuscitation has initiated a near-continuous review of cardiopulmonary resuscitation science that replaces the previous 5-year cyclic batch-and-queue approach process. This is the first of an annual series of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations summary articles that will include the cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation in the previous year. The review this year includes 5 basic life support and 1 pediatric Consensuses on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Each of these includes a summary of the science and its quality based on Grading of Recommendations, Assessment, Development, and Evaluation criteria and treatment recommendations. Insights into the deliberations of the International Liaison Committee on Resuscitation task force members are provided in Values and Preferences sections. Finally, the task force members have prioritized and listed the top 3 knowledge gaps for each population, intervention, comparator, and outcome question.

Safety of mechanical chest compression devices AutoPulse and LUCAS in cardiac arrest: a randomized clinical trial for non-inferiority.

AIMS: Mechanical chest compression (CC) during cardiopulmonary resuscitation (CPR) with AutoPulse or LUCAS devices has not improved survival from cardiac arrest. Cohort studies suggest risk of excess damage. We studied safety of mechanical CC and determined possible excess damage compared with manual CC. METHODS AND RESULTS: This is a randomized non-inferiority safety study. Randomization to AutoPulse, LUCAS, or manual CC with corrective depth and rate feedback was performed. We included patients with in-hospital cardiac arrest or with out-of-hospital cardiac arrest arriving with manual CPR at the emergency department. The primary outcome was serious or life-threatening visceral resuscitation-related damage, assessed blind by post-mortem computed tomography scan and/or autopsy or by clinical course until discharge. Non-inferiority hypothesis: mechanical CC compared with manual control does not increase the primary outcome by a risk difference of > 10% [upper 95% confidence interval (CI)]. We included 115 patients treated with AutoPulse, 122 with LUCAS, and 137 patients received manual CC. Safety outcome analysis was possible in 337 of 374 (90.1%) included patients. The primary outcome was observed in 12 of 103 AutoPulse patients (11.6%), 8 of 108 LUCAS patients (7.4%), and 8 of 126 controls (6.4%). Rate difference AutoPulse-control: +5.3% (95% CI - 2.2% to 12.8%), P = 0.15. Rate difference LUCAS-control +1.0% (95% CI - 5.5% to 7.6%), P = 0.75. CONCLUSION: LUCAS does not cause significantly more serious or life-threatening visceral damage than manual CC. For AutoPulse, significantly more serious or life-threatening visceral damage than manual CC cannot be excluded.

Association Between Chest Compression Interruptions and Clinical Outcomes of Ventricular Fibrillation Out-of-Hospital Cardiac Arrest.

BACKGROUND: Minimizing pauses in chest compressions during cardiopulmonary resuscitation is a focus of current guidelines. Prior analyses found that prolonged pauses for defibrillation (perishock pauses) are associated with worse survival. We analyzed resuscitations to characterize the association between pauses for all reasons and both ventricular fibrillation termination and patient survival. METHODS AND RESULTS: In 319 patients with ventricular tachycardia/fibrillation out-of-hospital cardiac arrest, we analyzed recordings from all defibrillators used during resuscitation and measured durations of all cardiopulmonary resuscitation pauses. Median durations were 32 seconds (25th and 75th percentile, 22 and 52 seconds) for the longest pause for any reason, 23 seconds (25th and 75th percentile, 14 and 34 seconds) for the longest perishock pause, and 24 seconds (25th and 75th percentile, 11 and 38 seconds) for the longest nonshock pause. Multivariable regression models showed lower odds for survival per 5-second increase in the longest overall pause (odds ratio, 0.89; 95% confidence interval, 0.83-0.95), longest perishock pause (odds ratio, 0.85; 95% confidence interval, 0.77-0.93), and longest nonshock pause (odds ratio, 0.83; 95% confidence interval, 0.75-0.91). In 36% of cases, the longest pause was a nonshock pause; this subgroup had lower survival than the group in whom the longest pause was a perishock pause (27% versus 44%, respectively; P<0.01) despite a higher chest compression fraction. Preshock pauses were 8 seconds (25th and 75th percentile, 4 and 17 seconds) for shocks that terminated ventricular fibrillation and 7 seconds (25th and 75th percentile, 4 and 13 seconds) for shocks that did not (P=0.18). CONCLUSIONS: Prolonged pauses have a negative association with survival not explained by chest compression fraction or decreased ventricular fibrillation termination rate. Ventricular fibrillation termination was not the mechanism linking pause duration and survival. Strategies shortening the longest pauses may improve outcome.

Part 3: Adult Basic Life Support and Automated External Defibrillation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.

This review comprises the most extensive literature search and evidence evaluation to date on the most important international BLS interventions, diagnostics, and prognostic factors for cardiac arrest victims. It reemphasizes that the critical lifesaving steps of BLS are (1) prevention, (2) immediate recognition and activation of the emergency response system, (3) early high-quality CPR, and (4) rapid defibrillation for shockable rhythms. Highlights in prevention indicate the rational and judicious deployment of search-and-rescue operations in drowning victims and the importance of education on opioid-associated emergencies. Other 2015 highlights in recognition and activation include the critical role of dispatcher recognition and dispatch-assisted chest compressions, which has been demonstrated in multiple international jurisdictions with consistent improvements in cardiac arrest survival. Similar to the 2010 ILCOR BLS treatment recommendations, the importance of high quality was reemphasized across all measures of CPR quality: rate, depth, recoil, and minimal chest compression pauses, with a universal understanding that we all should be providing chest compressions to all victims of cardiac arrest. This review continued to focus on the interface of BLS sequencing and ensuring high-quality CPR with other important BLS interventions, such as ventilation and defibrillation. In addition, this consensus statement highlights the importance of EMS systems, which employ bundles of care focusing on providing high-quality chest compressions while extricating the patient from the scene to the next level of care. Highlights in defibrillation indicate the global importance of increasing the number of sites with public-access defibrillation programs. Whereas the 2010 ILCOR Consensus on Science provided important direction for the "what" in resuscitation (ie, what to do), the 2015 consensus has begun with the GRADE methodology to provide direction for the quality of resuscitation. We hope that resuscitation councils and other stakeholders will be able to translate this body of knowledge of international consensus statements to build their own effective resuscitation guidelines.

Cardiac arrest and cardiopulmonary resuscitation outcome reports: update of the Utstein Resuscitation Registry Templates for Out-of-Hospital Cardiac Arrest: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian and New Zealand Council on Resuscitation, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, Resuscitation Council of Asia); and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation.

Utstein-style guidelines contribute to improved public health internationally by providing a structured framework with which to compare emergency medical services systems. Advances in resuscitation science, new insights into important predictors of outcome from out-of-hospital cardiac arrest, and lessons learned from methodological research prompted this review and update of the 2004 Utstein guidelines. Representatives of the International Liaison Committee on Resuscitation developed an updated Utstein reporting framework iteratively by meeting face to face, by teleconference, and by Web survey during 2012 through 2014. Herein are recommendations for reporting out-of-hospital cardiac arrest. Data elements were grouped by system factors, dispatch/recognition, patient variables, resuscitation/postresuscitation processes, and outcomes. Elements were classified as core or supplemental using a modified Delphi process primarily based on respondents' assessment of the evidence-based importance of capturing those elements, tempered by the challenges to collect them. New or modified elements reflected consensus on the need to account for emergency medical services system factors, increasing availability of automated external defibrillators, data collection processes, epidemiology trends, increasing use of dispatcher-assisted cardiopulmonary resuscitation, emerging field treatments, postresuscitation care, prognostication tools, and trends in organ recovery. A standard reporting template is recommended to promote standardized reporting. This template facilitates reporting of the bystander-witnessed, shockable rhythm as a measure of emergency medical services system efficacy and all emergency medical services system-treated arrests as a measure of system effectiveness. Several additional important subgroups are identified that enable an estimate of the specific contribution of rhythm and bystander actions that are key determinants of outcome.

Chest compression pauses during defibrillation attempts.

PURPOSE OF REVIEW: This article summarizes current knowledge of the causes and consequences of interruption of chest compressions during cardiopulmonary resuscitation. RECENT FINDINGS: Pauses in chest compressions occur during analysis of the heart rhythm, delivery of ventilation, interventions such as intubation, and gaining intravenous access, but pauses may also be unprompted. Pauses related to defibrillation are because of preshock pauses for rhythm analysis and charging, and postshock pauses to evaluate the outcome of the shock. Prolonged pauses, mainly preshock pauses (>10 s) are associated with decreased survival to discharge in retrospective analyses. Measures to reduce preshock and postshock pauses include resuming chest compressions during defibrillator charging, continued chest compression during defibrillation by mechanical chest compression devices or during manual chest compression with sufficiently insulating gloves for the rescuer, and eliminating postshock rhythm and pulse checks. New filtering techniques may allow rhythm analysis during chest compressions. SUMMARY: It is important to avoid any unnecessary pause in chest compressions before and after a defibrillation shock. Pauses should be kept to an absolute minimum, preferably to less than 10 s.

Improving usual care after sudden death in the young with focus on inherited cardiac diseases (the CAREFUL study): a community-based intervention study.

AIMS: Inherited cardiac diseases play an important role in sudden death (SD) in the young. Autopsy and cardiogenetic evaluation of relatives of young SD victims identifies relatives at risk. We studied the usual care after SD in the young aimed at identifying inherited cardiac disease, and assessed the efficacy of two interventions to improve this usual care. METHODS AND RESULTS: We conducted a community-based intervention study to increase autopsy rates of young SD victims aged 1-44 years and referral of their relatives to cardiogenetic clinics. In the Amsterdam study region, a 24/7 central telephone number and a website were available to inform general practitioners and coroners. In the Utrecht study region, they were informed by a letter and educational meetings. In two control regions usual care was monitored. Autopsy was performed in 169 of 390 registered SD cases (43.3%). Cardiogenetic evaluation of relatives was indicated in 296 of 390 cases (75.9%), but only 25 of 296 families (8.4%) attended a cardiogenetics clinic. Autopsy rates were 38.7% in the Amsterdam study region, 45.5% in the Utrecht study region, and 49.0% in the control regions. The proportion of families evaluated at cardiogenetics clinics in the Amsterdam study region, the Utrecht study region, and the control regions was 7.3, 9.9, and 8.8%, respectively. CONCLUSIONS: The autopsy rate in young SD cases in the Netherlands is low and few families undergo cardiogenetic evaluation to detect inherited cardiac diseases. Two different interventions did not improve this suboptimal situation substantially.

Improved survival after out-of-hospital cardiac arrest and use of automated external defibrillators.

BACKGROUND: In recent years, a wider use of automated external defibrillators (AEDs) to treat out-of-hospital cardiac arrest was advocated in The Netherlands. We aimed to establish whether survival with favorable neurologic outcome after out-of-hospital cardiac arrest has significantly increased, and, if so, whether this is attributable to AED use. METHODS AND RESULTS: We performed a population-based cohort study, including patients with out-of-hospital cardiac arrest from cardiac causes between 2006 and 2012, excluding emergency medical service-witnessed arrests. We determined survival status at each stage (to emergency department, to admission, and to discharge) and examined temporal trends using logistic regression analysis with year of resuscitation as an independent variable. By adding each covariable subsequently to the regression model, we investigated their impact on the odds ratio of year of resuscitation. Analyses were performed according to initial rhythm (shockable versus nonshockable) and AED use. Rates of survival with favorable neurologic outcome after out-of-hospital cardiac arrest increased significantly (N=6133, 16.2% to 19.7%; P for trend=0.021), although solely in patients presenting with a shockable initial rhythm (N=2823; 29.1% to 41.4%; P for trend<0.001). In this group, survival increased at each stage but was strongest in the prehospital phase (odds ratio, 1.11 [95% CI, 1.06-1.16]). Rates of AED use almost tripled during the study period (21.4% to 59.3%; P for trend <0.001), thereby decreasing time from emergency call to defibrillation-device connection (median, 9.9 to 8.0 minutes; P<0.001). AED use statistically explained increased survival with favorable neurologic outcome by decreasing the odds ratio of year of resuscitation to a nonsignificant 1.04. CONCLUSIONS: Increased AED use is associated with increased survival in patients with a shockable initial rhythm. We recommend continuous efforts to introduce or extend AED programs.

Duration of ventilations during cardiopulmonary resuscitation by lay rescuers and first responders: relationship between delivering chest compressions and outcomes.

BACKGROUND: The 2010 guidelines for cardiopulmonary resuscitation allow 5 seconds to give 2 breaths to deliver sufficient chest compressions and to keep perfusion pressure high. This study aims to determine whether the recommended short interruption for ventilations by trained lay rescuers and first responders can be achieved and to evaluate its consequence for chest compressions and survival. METHODS AND RESULTS: From a prospective data collection of out-of-hospital cardiac arrest, we used automatic external defibrillator recordings of cardiopulmonary resuscitation by rescuers who had received a standard European Resuscitation Council basic life support and automatic external defibrillator course. Ventilation periods and total compressions delivered per minute during each 2 minutes of cardiopulmonary resuscitation cycle were measured, and the chest compression fraction was calculated. Neurological intact survival to discharge was studied in relation to these factors and covariates. We included 199 automatic external defibrillator recordings. The median interruption time for 2 ventilations was 7 seconds (25th-75th percentile, 6-9 seconds). Of all rescuers, 21% took <5 seconds and 83% took <10 seconds for a ventilation period; 97%, 88%, and 63% of rescuers were able to deliver >60, >70, and >80 chest compressions per minute, respectively. The median chest compression fraction was 65% (25th-75th percentile, 59%-71%). Survival was 25% (49 of 199), not associated with long or short ventilation pauses when controlled for covariates. CONCLUSIONS: The great majority of rescuers can give 2 rescue breaths in <10 seconds and deliver at least 70 compressions in a minute. Longer pauses for ventilations are not associated with worse outcome. Guidelines may allow longer pauses for ventilations with no detriment to survival.

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community.

AIMS: Non-cardiac drugs that impair cardiac repolarization (electrocardiographic QT prolongation) are associated with an increased sudden cardiac arrest (SCA) risk. Emerging evidence suggests that non-cardiac drugs that impair cardiac depolarization and excitability (electrocardiographic QRS prolongation) also increase the risk for SCA. Nortriptyline, which blocks the SCN5A-encoded cardiac sodium channel, may exemplify such drugs. We aimed to study whether nortriptyline increases the risk for SCA, and to establish the underlying mechanisms. METHODS AND RESULTS: We studied QRS durations during rest/exercise in an index patient who experienced ventricular tachycardia during exercise while using nortriptyline, and compared them with those of 55 controls with/without nortriptyline and 24 controls with Brugada syndrome (BrS) without nortriptyline, who carried an SCN5A mutation. We performed molecular-genetic (exon-trapping) and functional (patch-clamp) experiments to unravel the mechanisms of QRS prolongation by nortriptyline and the SCN5A mutation found in the index patient. We conducted a prospective community-based study among 944 victims of ECG-documented SCA and 4354-matched controls to determine the risk for SCA associated with nortriptyline use. Multiple mechanisms may act in concert to increase the risk for SCA during nortriptyline use. Pharmacological (nortriptyline), genetic (loss-of-function SCN5A mutation), and/or functional (sodium channel inactivation at fast heart rates) factors conspire to reduce the cardiac sodium current and increase the risk for SCA. Nortriptyline use in the community was associated with a 4.5-fold increase in the risk for SCA [adjusted OR: 4.5 (95% CI: 1.1-19.5)], particularly when other sodium channel-blocking factors were present. CONCLUSIONS: Nortriptyline increases the risk for SCA in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel.

Exercise-related out-of-hospital cardiac arrest in the general population: incidence and prognosis.

AIMS: Although regular physical activity has beneficial cardiovascular effects, exercise can trigger an acute cardiac event. We aimed to determine the incidence and prognosis of exercise-related out-of-hospital cardiac arrest (OHCA) in the general population. METHODS AND RESULTS: We prospectively collected all OHCAs in persons aged 10-90 years from January 2006 to January 2009 in the Dutch province North Holland. The relation between exercise during or within 1 h before OHCA and outcome was analysed using multivariable logistic regression, adjusted for age, gender, location, bystander witness, bystander cardiopulmonary resuscitation (CPR), automated external defibrillator (AED) use, initial rhythm, and Emergency Medical System response time. Of 2524 OHCAs, 143 (5.7%) were exercise related (7 ≤35 years, 93% men). Exercise-related OHCA incidence was 2.1 per 100 000 person-years overall and 0.3 per 100 000 person-years in those ≤35 years. Survival after exercise-related OHCA was distinctly better than after non-exercise related OHCA (46.2 vs. 17.2%) [unadjusted odds ratio (OR) 4.12; 95%CI 2.92-5.82; P < 0.001], even after adjustment for abovementioned variables (OR 2.63; 95%CI, 1.23-5.54; P = 0.01). In the 69 victims aged ≤35 years, exercise was not associated with better survival: 14.3 vs. 17.7% in non-exercise-related OHCA (OR 0.77; 95%CI 0.08-7.08; P = 0.82). CONCLUSION: Exercise-related OHCA has a low incidence, particularly in the young. Cardiac arrests occurring during or shortly after exercise carry a markedly better prognosis than non-exercise-related arrests in persons >35 years. This study establishes the favourable outcome of exercise-related OHCA and should have direct implications for public health programs to prevent exercise-related sudden death.