Sudden Arrhythmic Death Research Articles

P307Magnetic resonance, electroanatomical mapping, and endomyocardial biopsy to solve the diagnostic and sport eligibility dilemma in a cohort of competitive athletes with ventricular arrhythmias

Abstract Background Ventricular arrhythmias (VAs) are a frequent finding in agonist athletes (athl) at routine sport medicine visits. VAs impact on sport eligibility, their management, and the sudden arrhythmic death risk evaluation in athletes currently represents one of the greatest challenges across both the cardiology and sport medicine field. Purpose To describe how an advanced multi-methodical evaluation allowed diagnosis, risk stratification, targeted therapy and sport eligibility reassessment in a competitive athl cohort with ventricular arrhythmias and pathological findings at magnetic resonance (MR). Methods All consecutive competitive athl with denied sport eligibility due to ventricular arrhythmias that underwent an advanced invasive evaluation at our institute were enrolled. A baseline and stress ECG, and late gadolinium enhanced evaluation (LGE) at MR were performed prior to invasive evaluation in all athl. Invasive evaluation performed in all athl comprised of an electrophysiological study (EPS) to assess arrhythmic inducibility, an endo-cavitary electro-anatomical mapping (EAM), and a EAM and MR guided endo-myocardial biopsy (EMB). A defined diagnosis was postulated in all cases, specific therapeutic interventions were started and sport eligibility status reassessed after 6 months from discharge. Results Thirty-two competitive athl were enrolled in our study (32±6 y.o.; 77% male; 4±1 1h-training session/week); 26 (81%) athl practiced a mixed aerobic-anaerobic, 5 (16%) a pure-aerobic, while only 1 (3%) a pure anaerobic sport. Arrhythmic presentation leading to sport eligibility revoke was: in 13 (40%) athl frequent (>2000/day) premature ventricular contractions (PVCs) at rest, in 2 (6%) PVCs during stress ECG, in 6 (18%) non-sustained ventricular tachycardia (VT), in 8 (25%) sustained VT, and in 3 (11%) ventricular fibrillation/cardiac arrest during sport practice. MR alterations were described in all cases, and LGE at MR was found in 31 (87%) athl; a definite radiological diagnosis was obtained in 13 (40%) athl. A normal myocardium at EMB was found only in 3 (8%) pts; in 15 (45%) a leukocyte infiltrate pattern compatible with myocarditis, in 11 (39%) fibro-fatty replacement, in 2 (5%) a mitochondrial disease and in 1 (3%) a sarcoidosis were proven, and diagnosis were consequently postulated. EPS showed complex VAs inducibility in 8 (25%) cases, while a trans catheter ablation was performed in 10 (31%) athl. A total of 9 (28%) implantable cardioverter devices (ICDs) were implanted, for primary or secondary prevention. According to invasive diagnostic findings and sport medicine guidelines, 8 (25%) athl had their sport eligibility statuts re-instated. Conclusion An invasive multi-methodical assessment allowed in all cases to reach a diagnosis and to start a targeted therapy in a cohort of competitive athl with VA and a pathological MR, granting in a significant (25%) percentage sport eligibility status re-instatement.

4100Exercise related sudden cardiac death in the young in Sweden 2000–2010 – a nationwide study showing decreasing incidence in competitive athletes

Abstract Background Sudden cardiac death (SCD) is uncommon, but accounts for a majority of natural, unexpected sudden death in the young population. Exercise, although clearly health promoting for the vast majority of individuals, is also historically well known as a potential trigger of SCD. Previous studies have reported varying results concerning the comparative risk of SCD in competitive athletes versus non-athletes. Purpose The aim was to study all exercise related SCD in 10–35 years old in Sweden during the 11-year period 2000–2010, regarding the frequency, etiology, prevalence of symptoms, family history and/or ECG-changes; and to estimate the SCD incidence in the young and specifically in competitive athletes and to compare it with data from the previous decade. Methods We have previously identified all cases of SCD in 1–35 years old during 2000–2010 by systematic search in the Swedish Cause of Death Registry and the database of Forensic Medicine (n=552). From this cohort, we identified 514 cases in 10–35-years old, 373 (73%) men, and 141 (27%) women. For each case, information on circumstances at death, pathogenesis, athletic activity, medical history, symptoms, substance use, and heredity was assembled from autopsy-, police- and medical records. Results Exercise-related SCD occurred in 12% (62/514), a majority being men (56/62; 90%). Two thirds were recreational athletes, one-third competitive athletes. In total, 48% had either previous cardiac disease (27%), family history (27%), symptoms (32%), or an abnormal ECG (45%) before death. The most prevalent diagnosis was sudden arrhythmic death syndrome (SADS) (15/62; 24%). Exercise-related SCD was more frequent in men with hypertrophic cardiomyopathy (p=0.0008) and arrhythmogenic right ventricular cardiomyopathy (p=0.001), compared to non-exercise related SCD. The SCD incidence in competitive athletes was 9.4/million per year in men, and 0.6/million per year in women, which was around half the incidence compared to the years 1992–99. The SCD incidence in the general population was 22.3/million per year in men and 9.6/million per year in women. However, the risk of exercise-related SCD was twice as high in competitive athletes compared to recreational athletes. Conclusions 12% of SCD cases in the young Swedish population are exercise-related, with SADS being the most common etiology. The risk of exercise-related SCD is higher for competitive athletes compared to non-athletes. Specifically, exercise seems to trigger SCD in men with ARVC and HCM. About 50% have a pre-mortal risk profile. Importantly, the incidence of SCD in competitive athletes has been approximately halved in the 2000's compared to the 1990's. Theoretically, increased awareness, safety measures and cardiac screening may all have attributed to this positive development. We advocate a uniform evaluation of all exercise-related SCD in young athletes, including optimal histology and genetic analysis at autopsy. Acknowledgement/Funding Grants from Marcus Borgström, Uppsala University, the Swedish Medical Society, and from Norrbotten County Council

Exercise related sudden cardiac death (SCD) in the young — Pre-mortal characterization of a Swedish nationwide cohort, showing a decline in SCD among athletes

AimsTo study the frequency, etiology, and premortal abnormalities in exercise-related sudden cardiac death (SCD) in the young in Sweden. MethodsAll subjects with SCD in 10–35-year olds in Sweden during 2000–10, were included (n = 514). Information about each case was retrieved from death certifications, autopsy- and medical records. The number of SCD in athletes was compared to national figures from 1992-99. ResultsExercise-related SCD occurred in 12% (62/514) of the SCD-population, a majority being men (56/62; 90%). Cardiopulmonary resuscitation (CPR) was started in 87% (54/62). In total, 48% (30/62), had a cardiac diagnosis, symptoms, family history and/or ECG-changes, before the fatal event. The most prevalent autopsy diagnosis was sudden arrhythmic death syndrome (15/62; 24%). The frequency of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) was significantly higher in exercise-related SCD compared to non-exertional SCD. Exercise-related SCD was more common in athletes (21/29) than in non-athletes (41/485) (P < 0.0001). The total number of SCDs/year in athletes 15–35 years old, are approximately halved in 2000-10 compared to the years 1992–99. ConclusionThe increased risk of exercise-related SCD in HCM and ARVC underlines the importance of early detection and eligibility recommendations. There is a major reduction in deaths among athletes in the 2000s, compared to the previous decade. These results may partly be explained by improved acute preparedness for sudden cardiac arrest (CPR, defibrillation), but as a substantial percentage have preceding risk factors, such as symptoms and ECG-abnormalities, increased cardiac screening and increased general awareness, may also play a role.

Sudden Cardiac Death: A Pediatrician’s Role

1. Benjamin H. Hammond, MD* 2. Kenneth G. Zahka, MD* 3. Peter F. Aziz, MD* 1. *Department of Pediatric Cardiology, Cleveland Clinic Children’s, Pediatric Institute, Cleveland Clinic Foundation, Cleveland, OH * Abbreviations: ACC: : American College of Cardiology AED: : automated external defibrillator ARVC: : arrhythmogenic right ventricular cardiomyopathy CPVT: : catecholaminergic polymorphic ventricular tachycardia ECG: : electrocardiogram HCM: : hypertrophic cardiomyopathy ICD: : implantable cardioverter-defibrillator LQTS: : long QT syndrome LVNC: : left ventricular noncompaction cardiomyopathy LVOT: : left ventricular outflow tract RV: : right ventricle SADS: : sudden arrhythmic death syndrome SCA: : sudden cardiac arrest SCD: : sudden cardiac death TdP: : torsade de pointes VA: : ventricular arrhythmia VT: : ventricular tachycardia 1. There is a broad differential diagnosis to be considered in cases of sudden cardiac arrest, sudden cardiac death. 2. Timely diagnosis can circumvent progression to cardiac arrest in at-risk individuals. 3. All children should be screened and testing should be reserved for those with increased risk. After completing this article, readers should be able to: 1. Assess risk of sudden cardiac arrest/sudden cardiac death (SCA/SCD) with a screening history and physical examination. 2. Identify the mechanisms of distinct etiologies of SCA/SCD. 3. Recognize findings consistent with risk of SCA/SCD on a 12-lead electrocardiogram. 4. Address the concerns and questions of individuals and families after SCA/SCD. Sudden cardiac death (SCD) or sudden cardiac arrest (SCA) may occur in populations known to be at high risk or in individuals previously unrecognized to harbor underlying disease. This review focuses on the pediatrician’s role in identifying the latter group. SCA is a “severe malfunction or cessation of the electrical and mechanical activity of the heart, resulting in almost instantaneous loss of consciousness and collapse” that precedes SCD. (1) SCD is defined as rapid, unexpected death from cardiac causes that occurs within 1 hour of symptoms. (2) SCD that is known to be secondary to a primary arrhythmia is termed sudden arrhythmic death syndrome (SADS) . SCA is a common cause of death in adults, with the annual incidence estimated to be approximately 100 per 100,000, with variation seen with age, sex, and race. (3) These deaths are predominantly associated with coronary artery disease. In individuals younger than 18 years, SCA is much less common, with an estimated annual incidence of out-of-hospital cardiac arrest of 8.3 per 100,000 person-years. (4 …

When is an implantable cardioverter-defibrillator controversial?

When is an implantable cardioverter-defibrillator controversial?

Devices in Heart Failure Patients-Who Benefits From ICD and CRT?

Despite advances in heart failure treatment, this condition remains a relevant medical issue and is associated with a high morbidity and mortality. The cause of death in patients suffering from heart failure is not only a result of hemodynamic failure, but can also be due to ventricular arrhythmias. Implantable cardioverter defibrillators (ICDs) are these days the only tool to significantly reduce arrhythmic sudden death; but not all patients benefit to the same extend. In addition, cardiac resynchronization therapy (CRT) is another tool which is used in patients suffering from heart fialure. Even though both devices have been investigated in large randomized trials, both ICD and CRT remain underutilized in many countries. This brief review focuses on various aspects in this regard including a short overview on upcoming device novelties in the near future.

Whole genome and transcriptome sequencing of post-mortem cardiac tissues from sudden cardiac death victims identifies a gene regulatory variant in NEXN.

Sudden cardiac death (SCD) is a major public health problem and constitutes a diagnostic and preventive challenge in forensic pathology, especially for cases with structural normal hearts at autopsy, so-called sudden arrhythmic death syndrome (SADS). The identification of new genetic risk factors that predispose to SADS is important, because they may contribute to establish the diagnosis and increase the understanding of disease pathways underlying SADS. Pathogenic mutations in the protein coding regions of cardiac genes were found in relation to SADS. However, much remains unknown about variants in non-coding regions of the genome. In this study, we explored the potential of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to find DNA variants in SCD victims with structural normal hearts. With focus on the non-coding regulatory regions, we re-examined a cohort of 13 SADS and sudden unexplained death in infancy (SUDI) victims without disease causing DNA variants in recognized cardiac genes. The genetic re-examination of DNA was carried out using frozen tissue samples and WTS was carried out using five distinct formalin fixed and paraffin embedded (FFPE) cardiac tissue samples from each individual, including anterior and posterior walls of the left ventricle, ventricular papillary muscle, septum, and the right ventricle. We identified 23 candidate variants in regulatory sequences of cardiac genes, including a variant in the promotor region of NEXN, c.-194A>G, that was found to be statistically significantly (p < 0.05) associated with decreased expression of NEXN and cardiac hypertrophy. With the use of post-mortem FFPE tissues, we highlight the potential of using WTS investigations and compare gene expression levels with DNA variation in regulatory non-coding regions of the genome for a better understanding of the genetics of cardiac diseases leading to SCD.

Children with wearable cardioverter defibrillators: Examining activity levels via accelerometer

The wearable cardioverter defibrillator can be used to protect against sudden cardiac arrhythmic death in at risk children. The wearable cardioverter defibrillator provides clinicians with multiple types of information such as activity level while wearing the device. The current study examined physical activity in pediatric populations while wearing the wearable cardioverter defibrillator and compared age, sex, and diagnostic groups in activity levels. The study sample included 231 children, aged 8–17, who wore a wearable cardioverter defibrillator between 2009 and 2017. All device based information and activity counts were retrieved from the data sent via remote monitoring. Pediatric patients were active for 73 min per day, with a median step count of 7361. These data were collected during their average of 39 days of wear time over an average of 21 h daily. There were no associations between sex, diagnostic groups, or end of use reason and wear time or activity; however, age was negatively associated with changes in activity level for patients aged 8–11. Results indicated significant increases in step count over the first three weeks of wear in all ages χF2 (3, n = 50) = 34.27, p < .001. Pediatric patients are relatively active and increase levels of physical activity over the first month of use. These results are encouraging in that pediatric patients with wearable cardioverter defibrillator are potentially improving both physically and mentally over time with the wearable cardioverter defibrillator.

Abstract 102: Molecular, Cellular and Systemic Mechanism of Nonlinear Dynamic Patterns of Ventricular Repolarization and Spontaneous Arrhythmic Sudden Death in Non-ischemic Heart Failure

Introduction: Sudden cardiac death (SCD) is the leading cause of death in USA. Heart failure (HF) confers high SCD risk, but most SCD victims do not have HF or well-defined genetic abnormalities. The underlying mechanisms are poorly understood, precluding the design of more effective strategies for risk stratification and therapy. We previously showed that distinct non-linear patterns of cardiac repolarization strongly and independently predict SCD in HF patients [PMID: 27044982]. We also showed in a unique guinea pig HF model that increased levels of mitochondrial reactive oxygen species (mROS) drive spontaneous SCD, even before HF onset [PMID: 29898892]. Herein, we further dissect the underlying mechanisms. Hypothesis: Increased mROS levels in pressure overloaded hearts reduce K+ currents, destabilize the resting membrane potential, increase repolarization lability and cause SCD. Methods: Guinea pigs were randomized to Sham, aortic banding (AC), or AC with daily brief low-dose β-adrenergic stress (ACi) with and without in vivo mROS scavenger MitoTEMPO (ACi+MT). We performed time series analyses on recordings of: (1) 24-hour ECG QT interval in freely ambulating animals before sacrifice at 4 weeks; (2) pressure-volume and electrophysiology (EP) in excised perfused hearts; and (3) duration of action potential (APd), calcium transient (CaTd) and sarcomere shortening (SSd) in isolated LV myocytes. Results: About 50% of ACi animals had SCD by 4 weeks. Increased QT entropy in ACi (at 1 week) predicted SCD over followup, similar to HF patients. Compared to Sham and ACi+MT, LV myocytes isolated from AC and ACi had reduced inward (IK1) and delayed slow (IKs) and rapid (IKr) rectifier currents; and increased beat-to-beat lability in APd, CaTd and SSd. The late Na and L-type Ca currents were similar between models. Acute exposure to isoproterenol (Iso) and carbachol (CCh) increased lability in LV myocytes compared to Iso or CCh alone. Conclusions: High mROS levels reduce repolarization reserve in LV myocytes and contribute, at least in part, to the non-linear dynamics of ventricular repolarization (reflected by high QT entropy), leading to spontaneous arrhythmic SCD. These findings provide important new mechanistic insight with direct clinical implications.

Paradigm of Sudden Death Prevention in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a worldwide genetic heart disease and a common cause of sudden death in the young. Penetration of the implantable cardioverter-defibrillator (ICD) into this patient population over the past 20 years has made accurate selection of patients for primary prevention ICDs a priority. Consequently, a new paradigm has emerged in the management of this complex disease with ICD therapy responsible for a substantial decrease in overall HCM-related mortality (to 0.5%/y) and independent of patient age. Selection of candidates for ICDs has matured substantially with the formulation of an enhanced risk stratification algorithm. One or more contemporary risk markers judged major within a given patient's clinical profile, in association with physician judgment and shared decision-making, is sufficient to consider a primary prevention ICD implant. An enhanced American College of Cardiology/American Heart Association risk factor model (including new contrast-magnetic resonance-based markers, such as left ventricular apical aneurysm) used prospectively to make ICD decisions proved to be 95% sensitive for identifying patients who would experience ≥1 appropriate device therapies terminating ventricular tachycardia/fibrillation. The number of HCM patients required to treat with ICDs to save 1 patient with abolition of lethal ventricular tachyarrhythmias was 6:1, similar to randomized defibrillator trials in other cardiomyopathies. In contrast to patients with ischemic heart disease, after ICD shock HCM patients rarely experience transformation to heart failure deterioration or sudden arrhythmic death. The mathematically derived risk score model proposed by the European Society of Cardiology was inferior for identifying high-risk patients susceptible to arrhythmic sudden death with a sensitivity of only 33%, leaving many patients exposed to the possibility of sudden death without ICDs. In conclusion, introduction of the ICD associated with a matured risk stratification algorithm has altered management strategy and clinical course of many HCM patients, making the likelihood of sudden death prevention a reality and fulfilling the aspiration of preservation of life and reduced mortality for this vulnerable patient population.

Current challenges in sudden cardiac death prevention.

Ischemic heart disease and non-ischemic dilated cardiomyopathy are the most common causes of arrhythmic sudden cardiac death (SCD). Implantable cardioverter defibrillator (ICD) therapy is the only strategy that proved to be effective in preventing SCD in high-risk individuals while the role of antiarrhythmic drugs is limited to symptoms relief. Current guidelines recommend selecting candidates to ICD implantation based on etiology, symptoms of heart failure (NYHA class), and severely depressed left ventricular ejection fraction, but these parameters are neither sensitive nor specific. The review addresses the mechanisms of SCD in patients with heart failure of either ischemic or non-ischemic etiology, risk stratification, and strategies for prevention of SCD in the clinical practice (including optimization of heart failure therapy, avoidance of triggering factors, antiarrhythmic drugs, ICD therapy, early resuscitation, and public access defibrillators).

Next-generation sequencing using microfluidic PCR enrichment for molecular autopsy

BackgroundWe aimed to determine the mutation yield and clinical applicability of “molecular autopsy” following sudden arrhythmic death syndrome (SADS) by validating and utilizing low-cost high-throughput technologies: Fluidigm Access Array PCR-enrichment with Illumina HiSeq 2000 next generation sequencing (NGS).MethodsWe validated and optimized the NGS platform with a subset of 46 patients by comparison with Sanger sequencing of coding exons of major arrhythmia risk-genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2). A combined large multi-ethnic international SADS cohort was sequenced utilizing the NGS platform to determine overall molecular yield; rare variants identified by NGS were subsequently reconfirmed by Sanger sequencing.ResultsThe NGS platform demonstrated 100% sensitivity for pathogenic variants as well as 87.20% sensitivity and 99.99% specificity for all substitutions (optimization subset, n = 46). The positive predictive value (PPV) for NGS for rare substitutions was 16.0% (27 confirmed rare variants of 169 positive NGS calls in 151 additional cases). The overall molecular yield in 197 multi-ethnic SADS cases (mean age 22.6 ± 14.4 years, 68% male) was 5.1% (95% confidence interval 2.0–8.1%), representing 10 cases carrying pathogenic or likely pathogenic risk-mutations.ConclusionsMolecular autopsy with Fluidigm Access Array and Illumina HiSeq NGS utilizing a selected panel of LQTS/BrS and CPVT risk-genes offers moderate diagnostic yield, albeit requiring confirmatory Sanger-sequencing of mutational variants.

The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

The American College of Medical Genetics and Genomics (ACMG) has previously published policy statements on the reporting of secondary findings in clinical exome and genome sequencing (ACMG SF v1.0 and ACMG SF v2.0), also known as the “ACMG 56” and “ACMG 59,” respectively.1.Green R.C. Berg J.S. Grody W.W. et al.ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.1:CAS:528:DC%2BC3sXhtVKku73K10.1038/gim.2013.73Genet Med. 2013; 15: 565-574Google Scholar,2.Kalia S.S. Adelman K. Bale S.J. et al.Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.10.1038/gim.2016.190Genet Med. 2017; 19: 249-255Google Scholar These recommendations specifically stated that “reporting some incidental [a.k.a. secondary] findings would likely have medical benefit for the patients and families of patients undergoing clinical sequencing” (ACMG board’s emphasis). The ACMG SF v2.0 list of genes was not validated for general population screening. The use of ACMG SF v2.0 for purposes other than reporting incidental findings after clinical sequencing is not endorsed by ACMG. Many of the ACMG SF v2.0 genes have uncertain penetrance when identified in asymptomatic individuals (e.g., SCN5A and Brugada syndrome).3.Hosseini M. Kim R. Udupa S. et al.Reappraisal of reported genes for sudden arrhythmic death: an evidence based evaluation of gene validity for Brugada syndrome.10.1161/CIRCULATIONAHA.118.035070Circulation. 2018; 138: 1195-1205Google Scholar This policy statement is meant to reduce unproven interventions based solely on genotype information. In the absence of penetrance data that can only be obtained through robust genotype–phenotype correlation, the medical ethical principle of nonmaleficence should dominate.•The ACMG strongly discourages any reference to the term ACMG SF v2.0 (or ACMG 59) outside of the reporting of incidental findings after clinical sequencing.•Further, ACMG SF™, ACMG 59™, ACMG 56™, and related words and designs incorporating ACMG™, are trademarks of the American College of Medical Genetics and Genomics and may not be used without permission.•The ACMG encourages further ascertainment of genotype–phenotype correlation and research to establish the efficacy of interventions in asymptomatic patients with pathogenic and likely pathogenic variants in known associated genes. The authors declare no conflicts of interest. Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. The Board of Directors of the American College of Medical Genetics and Genomics approved this statement on 16 October 2018 Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Refining the World Health Organization Definition: Predicting Autopsy-Defined Sudden Arrhythmic Deaths Among Presumed Sudden Cardiac Deaths in the POST SCD Study.

Conventional definitions of sudden cardiac death (SCD) presume cardiac cause. We studied the World Health Organization-defined SCDs autopsied in the POST SCD study (Postmortem Systematic Investigation of SCD) to determine whether premortem characteristics could identify autopsy-defined sudden arrhythmic death (SAD) among presumed SCDs. Between January 2, 2011, and January 4, 2016, we prospectively identified all 615 World Health Organization-defined SCDs (144 witnessed) 18 to 90 years in San Francisco County for medical record review and autopsy via medical examiner surveillance. Autopsy-defined SADs had no extracardiac or acute heart failure cause of death. We used 2 nested sets of premortem predictors-an emergency medical system set and a comprehensive set adding medical record data-to develop Least Absolute Selection and Shrinkage Operator models of SAD among witnessed and unwitnessed cohorts. Of 615 presumed SCDs, 348 (57%) were autopsy-defined SAD. For witnessed cases, the emergency medical system model (area under the receiver operator curve 0.75 [0.67-0.82]) included presenting rhythm of ventricular tachycardia/fibrillation and pulseless electrical activity, while the comprehensive (area under the receiver operator curve 0.78 [0.70-0.84]) added depression. If only ventricular tachycardia/fibrillation witnessed cases (n=48) were classified as SAD, sensitivity was 0.46 (0.36-0.57), and specificity was 0.90 (0.79-0.97). For unwitnessed cases, the emergency medical system model (area under the receiver operator curve 0.68 [0.64-0.73]) included black race, male sex, age, and time since last seen normal, while the comprehensive (area under the receiver operator curve 0.75 [0.71-0.79]) added use of β-blockers, antidepressants, QT-prolonging drugs, opiates, illicit drugs, and dyslipidemia. If only unwitnessed cases <1 hour (n=59) were classified as SAD, sensitivity was 0.18 (0.13-0.22) and specificity was 0.95 (0.90-0.97). Our models identify premortem characteristics that can better specify autopsy-defined SAD among presumed SCDs and suggest the World Health Organization definition can be improved by restricting witnessed SCDs to ventricular tachycardia/fibrillation or nonpulseless electrical activity rhythms and unwitnessed cases to <1 hour since last normal, at the cost of sensitivity.

Sudden cardiac death associated to substances of abuse and psychotropic drugs consumed by young people: A population study based on forensic autopsies

BackgroundToxic substances are one of the main risk factors for sudden cardiac death (SCD) in young people. However, there is limited information about this matter based on clinical research. The aim of this study was to analyze the use of substances of abuse (legal and illicit) and prescribed psychotropic drugs in young people who died by SCD. MethodsA population-based study performed in 15–35-year-olds who died by SCD in Biscay (Basque-Country) between 1991 and 2016. Cases were analyzed prospectively by a complete autopsy, toxicological and histopathological studies. A case was considered positive for exposure to cardiotoxic substances if smoking status was diagnosed or if toxicological analysis detected any drug associated with increased risk of SCD. ResultsThere were 204 SCD; 98 (48%) were exposed to a cardiotoxic substance, including smoking status (n = 72) and/or positive toxicology (n = 58). Illicit drugs (n = 29, mainly cannabis and cocaine), ethanol (n = 25), and prescribed psychotropic drugs (n = 11) were detected. Positive cases were more frequent in males than in females (54% vs. 19%). They were also more common in subjects who died by acute (86%) and chronic (71%) ischemic heart disease than in myocardial diseases (33%) and sudden arrhythmic death syndrome (36%). All positive cases of illicit drugs were males. Smoking status was very high in deaths due to acute ischemic heart disease. ConclusionsThe proportion of users of substances of abuse was unexpectedly high, even more prevalent than other cardiovascular risk factors. Toxic substances could play an important role as triggers of SCD in young people.

MicroRNA-directed cardiac repair after myocardial infarction in pigs.

Viral vector delivery of microRNA-199a after myocardial infarction in pigs can stimulate endogenous myocardial repair mechanisms and improve cardiac function; however, persistent expression of the miRNA leads to sudden arrhythmic death.

MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs.

Prompt coronary catheterization and revascularization have dramatically improved the outcome of myocardial infarction, but also have resulted in a growing number of survived patients with permanent structural damage of the heart, which frequently leads to heart failure. Finding new treatments for this condition is a largely unmet clinical need 1, especially because of the incapacity of cardiomyocytes to replicate after birth and thus achieve regeneration of the lost contractile tissue 2. Here we show that expression of human microRNA-199a in infarcted pig hearts is capable of stimulating cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, the treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. At longer follow-up, however, persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however this therapy needs to be tightly dosed.

Impact of Effective Management Strategies on Patients With the Most Extreme Phenotypic Expression of Hypertrophic Cardiomyopathy

Advances in treatment options for hypertrophic cardiomyopathy (HC) have proven effective in many patients for promoting favorable long-term outcomes. Whether this expectation is similar for patients with the most extreme expression of massive left ventricular (LV) hypertrophy, a particularly aggressive form of the disease is unresolved. Of 1,766 consecutive HC patients presenting to Tufts HC Institute (2004 to 2015), 92 were identified with extreme LV wall thickness (30 to 48 mm), and compared with 1,674 HC patients with less marked hypertrophy (13 to 29 mm). Follow-up assessment was over 5.3 ± 3.4 years. Patients with massive LV hypertrophy (n = 92) had higher sudden death event rates (3.0%/year) than did patients with lesser hypertrophy (0.8%/year; p <0.001). In 16 of the 92 patients (17%), potentially lethal ventricular tachyarrhythmia were successfully aborted by primary prevention implantable cardioverter defibrillator (ICD) therapy at 30 ± 13 years (n = 11), or by resuscitated cardiac arrest with external defibrillation (n = 5) and later by secondary prevention interventions (n = 3); no patient experienced arrhythmic sudden death. Aborted sudden death events (3.0%/year) exceeded HC-related mortality by 7-fold (n = 2; 0.4%/year; p <0.001). European Society of Cardiology risk score would have failed to identify 60% of patients with arrhythmic sudden death events, leaving them exposed to sudden death without ICDs. In addition, 35 patients required surgical myectomy for progressive heart failure due to LV outflow obstruction (improved to NYHA I/II in 30). Eighty-eight (96%) of the 92 patients have survived to age 38 ± 14 years (23% ≥ 50 years). All-cause mortality did not differ from an age and gender-matched general population (p = 0.62). In conclusion, in this referral-based population, patients with the most extreme expression of HC are at increased arrhythmic sudden death risk reliably prevented with prophylactic ICDs. Progressive heart failure secondary to outflow obstruction was reversible with surgical myectomy. Despite extreme phenotypic expression, with contemporary treatment interventions young HC patients have an opportunity to achieve extended survival with good quality of life.

Response by Wilde and Gollob to Letter Regarding Article, “Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome”

Response by Wilde and Gollob to Letter Regarding Article, “Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome”

Sudden arrhythmia death syndrome in young victims: a five-year retrospective review and two-year prospective molecular autopsy study by next-generation sequencing and clinical evaluation of their first-degree relatives.

Sudden arrhythmia death syndrome (SADS) accounts for about 30% of causes of sudden cardiac death (SCD) in young people. In Hong Kong, there are scarce data on SADS and a lack of experience in molecular autopsy. We aimed to investigate the value of molecular autopsy techniques for detecting SADS in an East Asian population. This was a two-part study. First, we conducted a retrospective 5-year review of autopsies performed in public mortuaries on young SCD victims. Second, we conducted a prospective 2-year study combining conventional autopsy investigations, molecular autopsy, and cardiac evaluation of the first-degree relatives of SCD victims. A panel of 35 genes implicated in SADS was analysed by next-generation sequencing. There were 289 SCD victims included in the 5-year review. Coronary artery disease was the major cause of death (35%); 40% were structural heart diseases and 25% were unexplained. These unexplained cases could include SADS-related conditions. In the 2-year prospective study, 21 SCD victims were examined: 10% had arrhythmogenic right ventricular cardiomyopathy, 5% had hypertrophic cardiomyopathy, and 85% had negative autopsy. Genetic analysis showed 29% with positive heterozygous genetic variants; six variants were novel. One third of victims had history of syncope, and 14% had family history of SCD. More than half of the 11 first-degree relatives who underwent genetic testing carried related genetic variants, and 10% had SADS-related clinical features. This pilot feasibility study shows the value of incorporating cardiac evaluation of surviving relatives and next-generation sequencing molecular autopsy into conventional forensic investigations in diagnosing young SCD victims in East Asian populations. The interpretation of genetic variants in the context of SCD is complicated and we recommend its analysis and reporting by qualified pathologists.