Bo Gregers Winkel

Nationwide study of sudden cardiac death in persons aged 1–35 years

AIMS The aim of this investigation was to study the incidence of sudden cardiac death (SCD) in persons aged 1-35 years in a nationwide setting (5.38 million people) by systematic evaluation of all deaths. METHODS AND RESULTS All deaths in persons aged 1-35 years in Denmark in 2000-06 were included. Death certificates were read independently by two physicians. The National Patient Registry was used to retrieve information on prior medical history. All autopsy reports were read and the cause of death was revised based on autopsy findings. We identified 625 cases of sudden unexpected death (10% of all deaths), of which 156 (25%) were not autopsied. Of the 469 autopsied cases, 314 (67%) were SCD. The most common cardiac cause of death was ischaemic heart disease (13%); 29% of autopsied sudden unexpected death cases were unexplained. In 45% of SCD cases, the death was witnessed; 34% died during sleep; 89% were out-of-hospital deaths. Highest possible incidence rate of SCD in the young was 2.8 per 100 000 person-years including non-autopsied cases of sudden unexpected death. Excluding those, the incidence rate declined to 1.9 per 100 000 person-years. CONCLUSIONS A total of 7% of all deaths in the young can be attributed to SCD, when including non-autopsied cases (autopsy ratio 75%). The incidence rate of SCD in the young of 2.8 per 100 000 person-years is higher than previously reported.

Incidence and etiology of sports-related sudden cardiac death in Denmark—Implications for preparticipation screening

BACKGROUND Studies on incidences of sports-related sudden cardiac death (SrSCD) are few and data are needed for the discussion of preparticipation screening for cardiac disease. OBJECTIVE We sought to chart the incidence and etiology of SrSCD in the young in Denmark (population 5.4 million) and to compare this to the incidence of sudden cardiac death (SCD) in the background population. METHODS All 5,662 death certificates for decedents in the period 2000 to 2006 in the age group 12 to 35 years in Denmark were read independently by 2 physicians to identify cases of SCD. Information from autopsy reports, selected hospital records, and multiple registries was used to identify cases of SCD and SrSCD. SrSCD was defined as SCD occurring during or within 1 hour after exercise in a competitive athlete. The size of the athlete population was estimated from national survey data. RESULTS Fifteen (range 0 to 5 per year) cases of SrSCD were found, 8 of which had antecedent symptoms. The incidence rate was 1.21 (95% confidence interval [CI]: 0.68 to 2.00) per 100,000 athlete person-years. The most common autopsy findings were arrhythmogenic right ventricular cardiomyopathy (n = 4), sudden unexplained death (n = 4), and coronary artery disease (n = 2). The incidence of SCD in the general population age 12 to 35 was 3.76 (95% CI: 3.42 to 4.14) per 100,000 person-years. CONCLUSION In Denmark, SrSCD is a rare occurrence and the incidence rate is lower than that of SCD in the general population. This may imply a low value of preparticipation screening of athletes in Denmark.

High prevalence of genetic variants previously associated with Brugada syndrome in new exome data

More than 300 variants in 12 genes have been associated with Brugada syndrome (BrS) which has a prevalence ranging between 1:2000 and 1:100,000. Until recently, there has been little knowledge regarding the distribution of genetic variations in the general population. This problem was partly solved, when exome data from the NHLI GO Exome Sequencing Project (ESP) was published. In this study, we aimed to report the prevalence of previously BrS‐associated variants in the ESP population. We performed a search in ESP for variants previously associated with BrS. In addition, four variants in ESP were genotyped in a second Danish control population (n = 536) with available electrocardiograms. In ESP, we identified 38 of 355 (10%) variants, distributed on 272 heterozygote carriers and two homozygote carriers. The genes investigated were on average screened in 6258 individuals. This corresponds to a surprisingly high genotype prevalence of 1:23 (274:6258). Genotyping the four common ESP‐derived variants CACNA2D1 S709N, SCN5A F2004L, CACNB2 S143F, and CACNB2 T450I in the Danish controls, we found a genotype prevalence comparable with that found in ESP. We suggest that exome data are used in research, as an additive tool to predict the pathogenicity of variants in patients suspected for BrS.

Sudden cardiac death in children (1–18 years): symptoms and causes of death in a nationwide setting

AIMS Hitherto, sudden cardiac death in children (SCDc)-defined as sudden cardiac death (SCD) in the 1-18 years old-has been incompletely described in the general population. Knowledge on incidence rates, causes of death and symptoms prior to death is sparse and has been affected by reporting and referral bias. METHODS AND RESULTS In a nationwide setting all deaths in children aged 1-18 years in Denmark in 2000-06 were included. To chart causes of death and incidence rates, death certificates and autopsy reports were collected and read. By additional use of the extensive healthcare registries in Denmark, we were also able to investigate prior disease and symptoms. During the 7-year study period there was an average of 1.11 million persons aged 1-18 years. There were a total of 1504 deaths (214 deaths per year) from 7.78 million person-years. A total of 114 (7.5%) were sudden and unexpected. A cardiac disease was known prior to death in 18% of all sudden unexpected death cases. In two-thirds of all sudden unexpected death cases no previous medical history was registered. Causes of death in autopsied cases were cardiac or unknown in 70%. Unexplained deaths, presumed to be a primary cardiac arrhythmia, accounted for 28% of autopsied sudden unexpected death cases. Autopsy rate was 77%. There were a total of 87 cases of SCDc (5.8% of all deaths). Prodromal symptoms were noted in 26% and antecedent symptoms in 45% of SCDc cases. The most frequent antecedent symptoms were seizures, dyspnoea, and syncope. In total, 61% of SCDc were not known with any prior disease; 23% were known with congenital or other heart disease prior to death. In total, 43 (49%) of all sudden unexpected deaths died of a potential inherited cardiac disease. The incidence rate of sudden unexpected death was 1.5 per 100 000 person-years. The highest possible incidence rate of SCDc was 1.1 per 100 000 person-years. CONCLUSION From a nationwide study of all deaths in a 7-year period more than half of all victims of SCDc experienced antecedent and/or prodromal symptoms prior to death. The incidence rate of sudden death and SCDc was 1.5 and 1.1 per 100 000 person-years, respectively. Cardiac symptoms in young persons should warrant clinical work-up and an autopsy should be performed in all cases of sudden unexpected death in which the deceased was not known with congenital heart disease prior to death. This is pivotal, in the subsequent familial cascade screening, to diagnose and treat potential inherited cardiac diseases in family members.

Sports-related sudden cardiac death in a competitive and a noncompetitive athlete population aged 12 to 49 years: Data from an unselected nationwide study in Denmark

BACKGROUND Preparticipation screening programs have been suggested to reduce the numbers of sports-related sudden cardiac deaths (SrSCD). OBJECTIVE The purpose of this study was to identify and characterize all SrSCD aged 12-49 years and to address the difference in incidence rates between competitive and noncompetitive athletes. METHODS All deaths among persons aged 12-49 years from 2007-2009 were included. Death certificates were reviewed. History of previous admissions to hospital was assessed, and discharge summaries and autopsy reports were read. Sudden cardiac deaths (SCDs) and SrSCD cases were identified. RESULTS In the 3-year period, there were 881 SCDs, of which we identified 44 SrSCD. In noncompetitive athletes aged 12-35 years, the incidence rate of SrSCD was 0.43 (95% confidence interval [CI] 0.16-0.94) per 100,000 athlete person-years vs 2.95 (95% CI 1.95-4.30) in noncompetitive athletes aged 36-49 years. In competitive athletes, the incidence rate of SrSCD was 0.47 (95% CI 0.10-1.14) and 6.64 (95% CI 2.86-13.1) per 100,000 athlete person-years in those aged 12-35 years and 36-49 years, respectively. The incidence rate of SCD in the general population was 10.7 (95% CI 10.0-11.5) per 100.000 person-years. CONCLUSION The incidence rates of SrSCD in noncompetitive and competitive athletes are not different. The study showed an increase in the incidence rate of SrSCD in persons aged 36-49 years in both noncompetitive and competitive athletes compared to those aged 12-35 years. Importantly, SCD in the general population is much more prevalent than is SrSCD in all age groups.

Epilepsy and risk of death and sudden unexpected death in the young: A nationwide study

Patients with epilepsy are at increased risk of premature death from all causes and likely also from sudden unexplained death (SUD). Many patients with epilepsy have significant comorbidity, and it is unclear how much of the increased risk can be explained by epilepsy itself. We aimed to chart the incidence of sudden unexpected death in epilepsy (SUDEP) and estimate the risk of death from all causes and SUD conferred by epilepsy independently.

The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases.

Introduction: Sudden unexplained death account for one‐third of all sudden natural deaths in the young (1–35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long‐QT syndrome (LQTS) genes in the general population. We therefore wanted to investigate the prevalence of mutations in an unselected population of sudden unexplained deaths in a nationwide setting.

Burden of Sudden Cardiac Death in Persons Aged 1 to 49 Years Nationwide Study in Denmark

Background—Knowledge of the burden and causes of sudden cardiac death (SCD) is sparse in persons aged <50 years; better understanding is needed to lower the risk of SCD. The aim of this study was to report SCD incidence rates and autopsy findings in persons aged 1 to 49 years. Methods and Results—All deaths in persons aged 1 to 49 years were included in 2007 to 2009. Death certificates were reviewed by 2 physicians. History of previous admissions to hospital was assessed, and discharge summaries were read. Sudden unexpected death cases were identified and autopsy reports were collected. In the 3-year study period, there were 7849 deaths of which we identified 893 (11%) SCD cases. The annual incidence rate per 100 000 persons increased from 2.3 (95% confidence interval, 2.0–2.7) to 21.7 (95% confidence interval, 20.2–23.4) in persons aged 1 to 35 and 36 to 49 years, respectively. Coronary artery disease was the most common cause of death and was found in 158 (36%) autopsied cases, followed by 135 (31%) cases of sudden unexplained death. Conclusions—In a nationwide cohort of persons aged <50 years, the annual incidence rate of SCD was ≈10× higher in persons aged 36 to 49 years than in persons aged 1 to 35 years. Notably, coronary artery disease was the most common cause of SCD, followed by unexplained deaths. These findings may help in developing strategies to prevent SCD in the future.

Mutations in Genes Encoding Cardiac Ion Channels Previously Associated With Sudden Infant Death Syndrome (SIDS) Are Present With High Frequency in New Exome Data

BACKGROUND Sudden infant death syndrome (SIDS) is the leading cause of death in the first 6 months after birth in the industrialized world. The genetic contribution to SIDS has been investigated intensively and to date, 14 cardiac channelopathy genes have been associated with SIDS. Newly published data from National Heart, Lung, and Blood Institute Grand Opportunity (NHLBI GO) Exome Sequencing Project (ESP) provided important knowledge on genetic variation in the background population. Our aim was to identify all variants previously associated with SIDS in ESP to improve the discrimination between plausible disease-causing mutations and variants most likely to be false-positive. METHODS The PubMed database was searched to identify SIDS-associated channelopathy variants and the prevalence of these in the ESP population (6500 individuals) were obtained. In silico prediction tools were applied to variants present in ESP and 6 SIDS-associated variants (CAV3 p.C72W, p.T78M; KCNH2 p.R148W, and SCN5A p.S216L, p.V1951L, p.F2004L) were genotyped in our own control population. RESULTS Nineteen different missense variants previously associated with SIDS were identified in ESP affecting 225 of 6424 alleles. This corresponds to 1:29 individuals in the ESP population being carriers of a SIDS-associated variant. Genotyping of 6 SIDS-associated variants in our own controls revealed frequencies comparable with those found in ESP. CONCLUSIONS A very high prevalence of previously SIDS-associated variants was identified in exome data from population studies. Our findings indicate that the suggested disease-causing role of some of these variants is questionable. A cautious interpretation of these variants must be made when found in SIDS victims.

Risk of cardiovascular disease in family members of young sudden cardiac death victims

AIMS Descriptive and genetic studies suggest that relatives of sudden cardiac death (SCD) victims have an increased risk of several cardiovascular diseases (CVDs). Given the severe consequences of undiagnosed CVD and the availability of effective treatment, the potential for prevention in this group is enormous if they do have an increased CVD risk. This nationwide prospective population-based cohort study described the risk of CVDs in relatives of young SCD victims, compared with the general population. METHODS AND RESULTS All SCD victims aged 1-35 years in Denmark, 2000-2006, were identified (n = 470), along with their first- and second-degree relatives (n = 3073). We compared the incidence of CVD in those relatives with that in the background population using standardized incidence ratios (SIRs). The observed number of CVDs over 11 years of follow-up was 292, compared with 219 expected based on national rates [SIR 1.33, 95% confidence interval (CI) 1.19-1.50]. Risks varied significantly with age; the SIR for those <35 years was 3.53 (95% CI 2.65-4.69), compared with SIRs of 1.59 (95% CI 1.35-1.89) and 0.91 (95% CI 0.75-1.10) for those aged 35-60 years or >60 years, respectively (P(homogeneity) < 0.0001). For first-degree relatives <35 years, SIRs for ischaemic heart disease, cardiomyopathy, and ventricular arrhythmia were 5.99 (95% CI 1.95-0.13.98), 17.91 (95% CI 4.88-45.87), and 19.15 (95% CI 7.70-39.45), respectively. CONCLUSION CVDs co-aggregated significantly with SCD in families, with young first-degree relatives at greatest risk. Results clearly indicate that family members of young SCD victims should be offered comprehensive and systematic screening, with focus on the youngest relatives.