Charlotte Glinge

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.

Incidence and Risk Factors of Ventricular Fibrillation Before Primary Angioplasty in Patients With First ST-Elevation Myocardial Infarction: A Nationwide Study in Denmark

Background We aimed to investigate the incidence and risk factors for ventricular fibrillation (VF) before primary percutaneous coronary intervention (PPCI) among patients with ST‐segment elevation myocardial infarction (STEMI) in a prospective nationwide setting. Methods and Results In this case‐control study, patients presenting within the first 12 hours of first STEMI who survived to undergo angiography and subsequent PPCI were enrolled. Over 2 years, 219 cases presenting with VF before PPCI and 441 controls without preceding VF were enrolled. Of the 219 case patients, 182 (83%) had STEMI with out‐of‐hospital cardiac arrest due to VF, and 37 (17%) had cardiac arrest upon arrival to the emergency room. Medical history was collected by standardized interviews and by linkage to national electronic health records. The incidence of VF before PPCI among STEMI patients was 11.6%. Multivariable logistic regression analysis identified novel associations between atrial fibrillation and alcohol consumption with VF. Patients with a history of atrial fibrillation had a 2.80‐fold odds of experiencing VF before PPCI (95% CI 1.10 to 7.30). Compared with nondrinkers, patients who consumed 1 to 7 units, 8 to 14 units, or >15 units of alcohol per week had an odds ratio (OR) of 1.30 (95% CI, 0.80 to 2.20), 2.30 (95% CI, 1.20 to 4.20), or 3.30 (95% CI, 1.80 to 5.90), respectively, for VF. Previously reported associations for preinfarction angina (OR 0.46; 95% CI 0.32 to 0.67), age of <60 years (OR 1.75; 95% CI 1.20 to 2.60), anterior infarction (OR 2.10; 95% CI 1.40 to 3.00), preprocedural thrombolysis in myocardial infarction flow grade 0 (OR 1.65; 95% CI 1.14 to 2.40), and family history of sudden death (OR 1.60; 95% CI 1.10 to 2.40) were all associated with VF. Conclusion Several easily assessed risk factors were associated with VF occurring out‐of‐hospital or on arrival at the emergency room before PPCI in STEMI patients, thus providing potential avenues for investigation regarding improved identification and prevention of life‐threatening ventricular arrhythmias.

Stability of Circulating Blood-Based MicroRNAs - Pre-Analytic Methodological Considerations.

Background and aim The potential of microRNAs (miRNA) as non-invasive diagnostic, prognostic, and predictive biomarkers, as well as therapeutic targets, has recently been recognized. Previous studies have highlighted the importance of consistency in the methodology used, but to our knowledge, no study has described the methodology of sample preparation and storage systematically with respect to miRNAs as blood biomarkers. The aim of this study was to investigate the stability of miRNAs in blood under various relevant clinical and research conditions: different collection tubes, storage at different temperatures, physical disturbance, as well as serial freeze-thaw cycles. Methods Blood samples were collected from 12 healthy donors into different collection tubes containing anticoagulants, including EDTA, citrate and lithium-heparin, as well as into serum collection tubes. MiRNA stability was evaluated by measuring expression changes of miR-1, miR-21 and miR-29b at different conditions: varying processing time of whole blood (up to 72 hours (h)), long-term storage (9 months at -80°C), physical disturbance (1 and 8 h), as well as in a series of freeze/thaw cycles (1 and 4 times). Results Different collection tubes revealed comparable concentrations of miR-1, miR-21 and miR-29b. Tubes with lithium-heparin were found unsuitable for miRNA quantification. MiRNA levels were stable for at least 24 h at room temperature in whole blood, while separated fractions did show alterations within 24 h. There were significant changes in the miR-21 and miR-29b levels after 72 h incubation of whole blood at room temperature (p<0.01 for both). Both miR-1 and miR-21 showed decreased levels after physical disturbance for 8 h in separated plasma and miR-1 in serum whole blood, while after 1 h of disturbance no changes were observed. Storage of samples at -80°C extended the miRNA stability remarkably, however, miRNA levels in long-term stored (9 months) whole blood samples were significantly changed, which is in contrast to the plasma samples, where miR-21 or miR-29b levels were found to be stable. Repetitive (n = 4) freeze-thaw cycles resulted in a significant reduction of miRNA concentration both in plasma and serum samples. Conclusion This study highlights the importance of proper and systematic sample collection and preparation when measuring circulating miRNAs, e.g., in context of clinical trials. We demonstrated that the type of collection tubes, preparation, handling and storage of samples should be standardized to avoid confounding variables influencing the results.

Cardiac symptoms before sudden cardiac death caused by coronary artery disease: a nationwide study among young Danish people

Objective The aim of this nationwide case–control study was to identify and characterise symptoms before sudden death of young persons who had died due to coronary artery disease (CAD). Methods We have previously investigated the incidence of sudden cardiac death (SCD) in young Danish people aged 1–35 years in Denmark during 2000–2006. We included all deaths (n=6629) and identified 314 autopsied cases of SCD, 40 of whom (13%) died from CAD. To compare symptoms before death, the CAD case group was sex- and age-matched 1:2 with a control group randomly sampled from a population of 1497 individuals who had died in accidents. We used data from the National Patient Registry on previous contacts with the healthcare system for all persons and read all available patient records, including death certificates and autopsy reports. Results A total of 31 (79%) persons with CAD-SCD had cardiac symptoms such as angina pectoris (n=24, 62%) and dyspnoea during the 12 months before death, and this was significantly higher than in the control group (p<0.001). In the case group, 18 persons (46%) had contacts with the healthcare system for cardiac symptoms before death, and this was also significantly higher than the control group (p<0.001). Conclusions In this nationwide study we found that 62% of young persons with SCD experienced angina before death, and nearly half of them who died of CAD had sought medical attention within the last year before death.

Gender differences in sudden cardiac death in the young-a nationwide study

BackgroundHitherto, sudden cardiac death (SCD) in the young has been described with no distinction between genders. SCD occurs more often in men (SCDm) than women (SCDw), but this disparity is not understood and has not been investigated systematically in a nationwide setting. Our objective was to report gender differences in SCD in the young in a nationwide (Denmark) setting.MethodsAll deaths in persons aged 1–35 years nationwide in Denmark between 2000 and 2009 were included. Death certificates and autopsy reports were obtained. The extensive health care registries in Denmark were used to investigate any known disease prior to death. SCDw were compared to SCDm.ResultsDuring the 10-year study period there were a total of 8756 deaths in 23.7 million person-years. In total, 635 deaths were SCD. SCDw constituted 205 deaths (32%). Women had a higher proportion of witnessed deaths (51 vs. 41%, p = 0.02) and died less often in a public place (16 vs. 26%, p = 0.01). Age at death, ratios of autopsies and sudden unexplained deaths, and comorbidities, did not differ. Causes of SCD were largely comparable between genders. The incidence rate of SCDw was half of that of SCDm (1.8 vs. 3.6 per 100,000 person-years, incidence rate ratio 2.0 (95% CI 1.7–2.4), p < 0.01).ConclusionsIncidence rate ratio of SCDm vs SCDw is 2. Young SCDw and SCDm are equally investigated, have comparable comorbidity, and causes of SCD. SCD due to potentially inherited cardiac diseases is less often in young women and could reflect a protection of female gender.

Sudden cardiac death in young adults with previous hospital-based psychiatric inpatient and outpatient treatment: a nationwide cohort study from Denmark.

INTRODUCTION Psychiatric patients have premature mortality compared to the general population. The incidence of sudden cardiac death (SCD) in psychiatric patients is unknown in a nationwide setting. The aim of this study was to compare nationwide SCD incidence rates in young individuals with and without previous psychiatric disease. METHOD Nationwide, retrospective cohort study including all deaths in people aged 18-35 years in 2000-2006 in Denmark. The unique Danish death certificates and autopsy reports were used to identify SCD cases. Psychiatric disease was defined as a previous psychiatric hospital contact and was identified using The Danish Psychiatric Central Research Register. All diagnoses in Danish registries are coded according to ICD-8 or ICD-10. All hospital records were retrieved manually. RESULTS Among 5,178 deaths, 395 were due to SCD and autopsies were performed on 262 (66%). In 77 SCD cases, a previous psychiatric hospital contact was identified. The SCD incidence rate in psychiatric patients was 14.8 (95% CI, 11.7-18.5) per 100,000 person-years versus 3.8 (95% CI, 3.4-4.3) per 100,000 person-years in individuals without psychiatric hospital contact (incidence rate ratio = 3.9; 95% CI, 3.0-5.0; P < .01). Incidence rates per 100,000 persons-years were the highest in patients with schizophrenia-spectrum disorders (38.9; 95% CI, 26.4-55.2) and substance-related disorders (31.6; 95% CI, 19.3-48.8). SCDs in psychiatric patients compared to nonpsychiatric patients were more often unexplained (65% vs 40%, P = .02), and cardiac symptoms were reported prior to death in 46% of psychiatric patients. CONCLUSIONS Patients with prior psychiatric hospital contact have a 4-fold increased risk of SCD. Since almost 50% had possible cardiac symptoms prior to death, cardiovascular risk monitoring and management in the mentally ill are essential.

Epidemiology and genetics of ventricular fibrillation during acute myocardial infarction

Sudden cardiac death (SCD) from ventricular fibrillation (VF) during coronary artery disease (CAD) is a leading cause of total and cardiovascular mortality, and in more than half of SCD cases VF occurs as the first symptom of CAD. Several epidemiological studies have shown that sudden death of a family member is a risk factor for SCD and VF during acute myocardial infarction (MI), independent of traditional risk factors including family history of MI, suggesting a genetic component in the susceptibility to VF. To prevent SCD and VF due to MI, we need a better understanding of the genetic and molecular mechanisms causing VF in this apparently healthy population. Even though new insights and technologies have become available, the genetic predisposition to VF during MI remains poorly understood. Findings from a variety of different genetic studies have failed to reach reproducibility, although several genetic variants, both common and rare variants, have been associated to either VF or SCD. For this review, we searched PubMed for potentially relevant articles, using the following MeSH-terms: “sudden cardiac death”, “ventricular fibrillation”, “out-of-hospital cardiac arrest”, “myocardial infarction, myocardial ischemia”, “coronary artery disease”, and “genetics”. This review describes the epidemiology and evidence for genetic susceptibility to VF due to MI.

Post-mortem toxicology in young sudden cardiac death victims: A nationwide cohort study

Aims Several drugs increase the risk of ventricular fibrillation and sudden cardiac death (SCD). We aimed to investigate in detail the toxicological findings of all young SCD throughout Denmark. Methods and results Deaths in persons aged 1-49 years were included over a 10-year period. Death certificates and autopsy reports were retrieved and read to identify cases of sudden death and establish cause of death. All medico-legal autopsied SCD were included and toxicological reports collected. Positive toxicology was defined as the presence of any substance (licit and/or illicit). All toxicological findings had previously been evaluated not to have caused the death (i.e. lethal concentrations were excluded). We identified 620 medico-legal autopsied cases of SCD, of which 77% (n = 477) were toxicologically investigated post-mortem, and 57% (n = 270) had a positive toxicology profile. Sudden cardiac death with positive toxicology had higher rates of sudden arrhythmic death syndrome (SADS), compared with SCD with negative toxicology (56% vs. 42%, P < 0.01). In total, 752 agents were detected, and polypharmacy (defined as the presence of more than one drug) was present in 61% (n = 164), all substances combined. Psychotropic drugs were the most frequent (62%, n = 467), and 82% (n = 385) were in pharmacological or subpharmacological levels. Conclusion We found that more than half of all toxicologically investigated SCD victims have positive post-mortem toxicological findings, and polypharmacy is displayed in a considerable proportion. SCD with positive toxicology had higher rate of SADS, suggesting that the compounds may play a proarrhythmic role in these cases.

Risk factors and causes of sudden noncardiac death: A nationwide cohort study in Denmark

BACKGROUND On the performance of an autopsy, sudden deaths may be divided into 2 classifications: (1) sudden cardiac deaths and (2) sudden noncardiac deaths (SNCDs). Families of SNCD victims should not be followed up as a means of searching for cardiac disease. OBJECTIVE The purpose of this study was to report the risk factors and causes of SNCD. METHODS We conducted a retrospective, nationwide study including all deaths between 2000 and 2006 of individuals aged 1-35 years and all deaths between 2007 and 2009 of individuals aged 1-49 years. Two physicians identified all sudden death cases through review of death certificates. Autopsy reports were collected. A multivariable logistic regression model was used to identify both clinical characteristics and risk factors associated with SNCD. RESULTS We identified 1039 autopsied cases of sudden death, of which 286 (28%) were classified as SNCD. The median age in the SNCD death population was 32 years. Increasing age was inversely associated with SNCD (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.87-0.98). Female sex, in-hospital location, and the absence of cardiac comorbidities were positively associated with SNCD (OR 1.7, 95% CI 1.3-2.3; OR 3.0, 95% CI 2.0-4.4; and OR 4.3, 95% CI 2.5-7.4, respectively). The most common cause of SNCD was pulmonary disease (n = 115 [40%]). CONCLUSION Sudden death among individuals aged <50 years was caused by noncardiac diseases in 28% of cases. Risk factors were female sex, age, and the absence of cardiac comorbidities. These data may guide future strategies for the follow-up of family members of nonautopsied sudden death victims, improve risk stratification, and influence public health strategies.

A Common Variant in SCN5A and the Risk of Ventricular Fibrillation Caused by First ST-Segment Elevation Myocardial Infarction

Background Several common genetic variants have been associated with either ventricular fibrillation (VF) or sudden cardiac death (SCD). However, replication efforts have been limited. Therefore, we aimed to analyze whether such variants may contribute to VF caused by first ST-elevation myocardial infarction (STEMI). Methods We analyzed 27 single nucleotide polymorphisms (SNP) previously associated with SCD/VF in other cohorts, and examined whether these SNPs were associated with VF caused by first STEMI in the GEnetic causes of Ventricular Arrhythmias in patients with first ST-elevation Myocardial Infarction (GEVAMI) study on ethnical Danes. The GEVAMI study is a prospective case-control study involving 257 cases (STEMI with VF) and 537 controls (STEMI without VF). Results Of the 27 candidate SNPs, one SNP (rs11720524) located in intron 1 of SCN5A which was previously associated with SCD was significantly associated with VF caused by first STEMI. The major C-allele of rs11720524 was present in 64% of the cases and the C/C genotype was significantly associated with VF with an odds ratio (OR) of 1.87 (95% CI: 1.12–3.12; P = 0.017). After controlling for clinical differences between cases and controls such as age, sex, family history of sudden death, alcohol consumption, previous atrial fibrillation, statin use, angina, culprit artery, and thrombolysis in myocardial infarction (TIMI) flow, the C/C genotype of rs11720524 was still significantly associated with VF with an OR of 1.9 (95% CI: 1.05–3.43; P = 0.032). Marginal associations with VF were also found for rs9388451 in HEY2 gene. The CC genotype showed an insignificant risk for VF with OR = 1.50 (95% CI: 0.96–2.40; P = 0.070). Conclusion One common intronic variant in SCN5A suggested an association with VF caused by first STEMI. Further studies into the functional abnormalities associated with the noncoding variant in SCN5A may lead to important insights into predisposition to VF during STEMI.