Risk of sports-related sudden cardiac death in women.

Sudden cardiac death (SCD) is a tragic incident accountable for up to 50% of deaths from cardiovascular disease. Sports-related SCD (SrSCD) is a phenomenon which has previously been associated with both competitive and recreational sport activities. SrSCD has been found to occur 5-33-fold less frequently in women than in men, and the sex difference persists despite a rapid increase in female participation in sports. Establishing the reasons behind this difference could pinpoint targets for improved prevention of SrSCD. Therefore, this review summarizes existing knowledge on epidemiology, characteristics, and causes of SrSCD in females, and elaborates on proposed mechanisms behind the sex differences. Although literature concerning the aetiology of SrSCD in females is limited, proposed mechanisms include sex-specific variations in hormones, blood pressure, autonomic tone, and the presentation of acute coronary syndromes. Consequently, these biological differences impact the degree of cardiac hypertrophy, dilation, right ventricular remodelling, myocardial fibrosis, and coronary atherosclerosis, and thereby the occurrence of ventricular arrhythmias in male and female athletes associated with short- and long-term exercise. Finally, cardiac examinations such as electrocardiograms and echocardiography are useful tools allowing easy differentiation between physiological and pathological cardiac adaptations following exercise in women. However, as a significant proportion of SrSCD causes in women are non-structural or unexplained after autopsy, channelopathies may play an important role, encouraging attention to prodromal symptoms and family history. These findings will aid in the identification of females at high risk of SrSCD and development of targeted prevention for female sport participants.

Nationwide study of mortality and sudden cardiac death in young persons diagnosed with chronic kidney disease.

AIMS: The aim of this study was to compare short- and long-term risk of sudden cardiac death (SCD) among persons aged 18-49 years with and without chronic kidney disease (CKD). METHODS AND RESULTS: Using Danish nationwide health registries, all persons aged 18-49 years diagnosed with earlier stages of CKD or chronic kidney failure from 1 July 1995 through 2009 were identified. Non-exposed subjects matched on sex and birth-year were identified. All SCD in the Danish population aged 18-49 years in 2000-2009 have previously been identified using information from the Danish nationwide health registries, death certificates, and autopsy reports. In total, 9308 incident cases of earlier stage CKD and 1233 incident cases of chronic kidney failure were included. Among patients with earlier stage CKD, the absolute risk of SCD 1, 5, and 10 years after diagnosis was 0.14%, 0.37%, and 0.68%, respectively. Compared with age- and sex-matched subjects the corresponding relative risk (RR) was 20.3 [95% confidence interval (CI) 8.4-48.8], 7.1 (95% CI 4.2-12.0), and 6.1 (95% CI 3.8-9.7), respectively. Among patients with chronic kidney failure, the absolute 1-, 5-, and 10-year risk of SCD was 0.17%, 0.56%, and 2.07%, respectively. The corresponding RR was 12.5 (95% CI 1.4-111.6), 7.9 (95% CI 2.3-27.0), and 10.1 (95% CI 4.5-22.6). CONCLUSION: Persons with earlier stage CKD and chronic kidney failure had increased risk of SCD compared with the background population with a 6- to 20-fold increased risk of SCD. These findings underline the importance of early cardiovascular risk monitoring and assessment in persons with CKD.

Witnessed and unwitnessed sudden cardiac death: a nationwide study of persons aged 1-35 years.

AIMS: The aim of this study is to compare clinical characteristics and causes of death among witnessed and unwitnessed sudden cardiac death (SCD) cases aged 1-35 years. METHODS AND RESULTS: In this retrospective nationwide study, all deaths in persons aged 1-35 years in Denmark during 2000-09 were included (23.7 million person-years). Using the in-depth descriptive Danish death certificates and Danish nationwide registries, 860 cases of sudden, unexpected death were identified. Through review of autopsy reports and register data, we identified 635 cases of SCD of which 266 (42%) were witnessed and 326 (51%) were unwitnessed. In 43 cases (7%), witnessed status was missing. Clinical characteristics were overall similar between the two groups. We found a male predominance among unwitnessed SCD compared to witnessed SCD (71% and 62%, respectively, P-value 0.012), as well as more psychiatric comorbidity (20% and 13%, respectively, P-value 0.029). Unwitnessed SCD more often occurred during sleep whereas witnessed SCD more often occurred while the individual was awake and relaxed (P-value < 0.001). The autopsy rate among all SCD cases was 70% with no significant difference in autopsy rate between the two groups. Sudden unexplained death, which was the leading autopsy conclusion in both groups, was more frequent among unwitnessed SCD (P-value 0.001). CONCLUSION: Several clinical characteristics and autopsy findings were similar between witnessed and unwitnessed SCD cases. Our data support the inclusion of both witnessed and unwitnessed cases in epidemiological studies of SCD cases aged 1-35 years, although the risk of misclassification is higher among unwitnessed and non-autopsied cases of SCD.

Symptoms Preceding Sports-Related Sudden Cardiac Death in Persons Aged 1-49 Years.

PURPOSE OF REVIEW: Sports-related sudden cardiac death (Sr-SCD) is a leading natural cause of death in young athletes. To prevent Sr-SCD in athletes, it is important to identify individuals at risk. This review sought to summarize the current knowledge of symptoms prior to Sr-SCD in athletes aged 1-49 years. RECENT FINDINGS: Cardiovascular screening of athletes is a subject of interest. However, the cost of ECG screening in a young population is relatively high compared to potential benefits, and systematic screening of athletes is heavily debated. In the background population, both cardiac and non-specific symptoms are often present prior to SCD. Both cardiac and non-specific symptoms are present in up to 74% prior to Sr-SCD. The main symptoms are syncope, chest pain, palpitations and dizziness. Knowledge of symptoms could potentially be used in combination with non-invasive prediction models to prevent Sr-SCD and treat athletes at risk.

Sudden cardiac death among persons with diabetes aged 1-49 years: a 10-year nationwide study of 14 294 deaths in Denmark.

AIMS: The aim of this study was to compare nationwide incidence rate (IR) of sudden cardiac death (SCD) in persons aged 1-49 years with and without diabetes mellitus (DM). METHODS AND RESULTS: The study population consisted of all persons in Denmark aged 1-49 years in 2000-09, which equals 27.1 million person-years. All 14 294 deaths in the 10-year period were included. By using the highly descriptive Danish death certificates, 1698 cases of sudden and unexpected death were identified. Through review of autopsy reports, discharge summaries, and the Danish registries, we identified 1363 cases of SCD. The Danish Register of Medicinal Product Statistics was used to identify persons with type 1 DM and type 2 DM. Among the 14 294 decedents, there were 669 with DM, of which 118 suffered SCD (9% of all SCD), making SCD the leading cause of death among young persons with DM. Among those aged 1-35 years, the IR of SCD-DM was 21.9 per 100 000 person-years compared to 2.6 per 100 000 person-years among persons without DM [IR ratio 8.6, 95% confidence interval (CI) 5.8-28.6]. Within the age range 36-49 years, the IR among persons with DM was 119.8 per 100 000 person-years compared to 19.7 per 100 000 person-years among persons without DM (IR ratio 6.1, 95% CI 4.7-7.8). CONCLUSION: We found that young persons with DM aged 1-35 years had >8-fold higher SCD IR compared to young persons without DM. Our study highlights the need for early cardiovascular risk monitoring and assessment in young persons with DM.

Diabetes and the Risk of Sudden Cardiac Death.

PURPOSE OF REVIEW: Persons with diabetes mellitus (DM) have increased morbidity and mortality rates compared with persons without DM. Sudden cardiac death (SCD) is a leading cause of death, and multiple studies have found an increased risk of SCD among individuals with DM. This review sought to collect the latest knowledge of the epidemiological and pathophysiological interplay between DM and SCD. RECENT FINDINGS: Persons with DM have a two- to tenfold increased risk of SCD compared with persons without DM. The underlying mechanisms for the increased risk of SCD are complex and multifactorial. The main pathophysiological contributors are DM-induced cardiac autonomic neuropathy (CAN), metabolic changes, silent ischemia, and polypharmacy. Persons with DM have an increased risk of SCD. Future studies should focus on CAN and the combined risk of QT prolongation from the interplay between CAN, hypoglycemia, and polypharmacy. Genes and pathways involved in control of the autonomic nervous system and cardiac ion channels could be a future focal point.

Toxicology Screening in Sports-Related Sudden Cardiac Death: A Multinational Observational Study.

BACKGROUND: Knowledge of toxicological findings among sports-related sudden cardiac death (SrSCD) is scarce. OBJECTIVES: This study aimed to describe postmortem toxicology findings in a multinational cohort of young SrSCD. METHODS: Patients with sudden cardiac death (SCD) aged 12 to 49 years with a complete post mortem were included from Denmark, Spain, and Australia. Postmortem findings were compared between SrSCD and non-SrSCD, and toxicology findings in SrSCD were assessed. RESULTS: We included 3,189 SCD, of which 219 (7%) were sports-related. SrSCD patients were younger (36 years vs 41 years; P < 0.001) and of male predominance (96% vs 75%; P < 0.001), and their death was more often caused by structural cardiac disease (68% vs 61%; P = 0.038). Positive toxicology screenings were significantly less likely among SrSCD than non-SrSCD (12% vs 43%; P < 0.001), corresponding to 82% lower odds of a positive toxicology screening in SrSCD. Patient characteristics were similar between SrSCDs with positive and negative toxicology screenings, but deaths were more often unexplained (59% vs 34%). Nonopioid analgesics were the most common finding (3%), and SCD-associated drugs were detected in 6% of SrSCD. SUD was more prevalent among the SrSCD with positive toxicology (59% vs 34%). CONCLUSIONS: Sports-related SCD mainly occurred in younger men with structural heart disease. They had a significantly lower prevalence of a positive toxicology screening compared with non-SrSCD, and detection of SCD-associated drugs was rare.

Differences among young unwitnessed sudden cardiac death, according to time from last seen alive: Insights from a 15-year nationwide study.

BACKGROUND: More than half of all sudden cardiac deaths (SCDs) are unwitnessed, but the composition of the unwitnessed SCD population is poorly described. OBJECTIVE: The purpose of this study was to compare clinical and autopsy characteristics of young unwitnessed SCD subjects, based on the time from last contact to being found dead. METHODS: All unwitnessed SCD subjects aged 1-35 years in Denmark from 2000-2014 identified through a multisource approach were included. Time from last seen alive to being found dead was dichotomized to <1 hour or 1-24 hours. Clinical characteristics and autopsy results were compared, and predictors of autopsy were assessed by logistic regression. RESULTS: Of 440 unwitnessed SCD subjects, 366 (83%) had not been seen alive within 1 hour of being found dead. Comorbidities differed between the groups, with more epilepsy (17% vs 5%) and psychiatric diseases (13% vs 7%) in the 24-hour group. Patients in the 24-hour group died more frequently during sleep (64% vs 23%), the autopsy rate was higher (75% vs 61%), and deaths were more often unexplained after autopsy (69% vs 53%). Having been seen within 1 hour of death independently decreased the chance of being autopsied (odds ratio 0.51; 95% confidence interval 0.27-1.00; P = .0497). CONCLUSION: The majority of unwitnessed SCD subjects had not been seen alive within 1 hour of being found dead. Clinical- and autopsy-related characteristics differed between the 2 groups. Differences were mainly attributable to death-related circumstances and comorbidities. Excluding SCD cases not seen alive within 1 hour of being found dead would severely underestimate the burden of SCD.

Outcomes after out-of-hospital cardiac arrest in immigrants vs natives in Denmark.

AIMS: Ethnic disparities subsist in out-of-hospital cardiac arrest (OHCA) outcomes in the US, yet it is unresolved whether similar inequalities exist in European countries. This study compared survival after OHCA and its determinants in immigrants and non-immigrants in Denmark. METHODS: Using the nationwide Danish Cardiac Arrest Register, 37,622 OHCAs of presumed cardiac cause between 2001 and 2019 were included, 95% in non-immigrants and 5% in immigrants. Univariate and multiple logistic regression was used to assess disparities in treatments, return of spontaneous circulation (ROSC) at hospital arrival, and 30-day survival. RESULTS: Immigrants were younger at OHCA (median 64 [IQR 53-72] vs 68 [59-74] years; p < 0.05), had more prior myocardial infarction (15% vs 12%, p < 0.05), more diabetes (27% vs 19%, p < 0.05), and were more often witnessed (56% vs 53%; p < 0.05). Immigrants received similar bystander cardiopulmonary resuscitation and defibrillation rates to non-immigrants, but more coronary angiographies (15% vs 13%; p < 0.05) and percutaneous coronary interventions (10% vs 8%, p < 0.05), although this was insignificant after age-adjustment. Immigrants had higher ROSC at hospital arrival (28% vs 26%; p < 0.05) and 30-day survival (18% vs 16%; p < 0.05) compared to non-immigrants, but adjusting for age, sex, witness status, first observed rhythm, diabetes, and heart failure rendered the difference non-significant (odds ratios (OR) 1.03, 95% confidence interval (CI) 0.92-1.16 and OR 1.05, 95% CI 0.91-1.20, respectively). CONCLUSIONS: OHCA management was similar between immigrants and non-immigrants, resulting in similar ROSC at hospital arrival and 30-day survival after adjustments.

Use of Nonrecommended Drugs in Patients With Brugada Syndrome: A Danish Nationwide Cohort Study.

Background Patients with Brugada syndrome (BrS) are recommended to avoid drugs that may increase their risk of arrhythmic events. We examined treatment with such drugs in patients with BrS after their diagnosis. Methods and Results All Danish patients diagnosed with BrS (2006-2018) with >12 months of follow-up were identified from nationwide registries. Nonrecommended BrS drugs were grouped into drugs to "avoid" or "preferably avoid" according to http://www.brugadadrugs.org. Cox proportional hazards analyses were performed to identify factors associated with any nonrecommended BrS drug use, and logistic regression analyses were performed to examine associated risk of appropriate implantable cardioverter defibrillator therapy, mortality, and a combined end point indicating an arrhythmic event of delayed implantable cardioverter defibrillator implantation, appropriate implantable cardioverter defibrillator therapy, and mortality. During a median follow-up of 6.8 years, 93/270 (34.4%) patients with BrS (70.4% male, median age at diagnosis 46.1 years [interquartile range, 32.6-57.4]) were treated with ≥1 nonrecommended BrS drugs. No difference in any nonrecommended BrS drug use was identified comparing time before BrS diagnosis (12.6%) with each of the 5 years following BrS diagnosis (P>0.05). Factors associated with any nonrecommended BrS drug use after diagnosis were female sex (hazard ratio [HR]) 1.83 [95% CI, 1.15-2.90]), psychiatric disease (HR, 3.63 [1.89-6.99]), and prior use of any nonrecommended BrS drug (HR, 4.76 [2.45-9.25]). No significant association between any nonrecommended BrS drug use and implantable cardioverter defibrillator therapy (n=20/97, odds ratio [OR], 0.7 [0.2-2.4]), mortality (n=10/270, OR, 3.4 [0.7-19.6]), or the combined end point (n=38/270, OR, 1.7 [0.8-3.7]) was identified. Conclusions One in 3 patients with BrS were treated with a nonrecommended BrS drug after BrS diagnosis, and a BrS diagnosis did not change prescription patterns. More awareness of nonrecommended drug use among patients with BrS is needed.

Sex differences in sudden cardiac death in a nationwide study of 54 028 deaths.

OBJECTIVE: Sudden cardiac death (SCD) is a leading cause of death and is more common among males than females. Epidemiological studies of sex differences in SCD cases of all ages are sparse. The aim of this study was to examine differences in incidence rates, clinical characteristics, comorbidities and autopsy findings between male and female SCD cases. METHODS: All deaths in Denmark in 2010 (54 028) were reviewed. Autopsy reports, death certificates, discharge summaries and nationwide health registries were reviewed to identify cases of SCD. Based on the available information, all deaths were subcategorised into definite, probable and possible SCD. RESULTS: A total of 6867 SCD cases were identified, of which 3859 (56%) were males and 3008 (44%) were females. Incidence rates increased with age and were higher for male population across all age groups in the adult population. Average age at time of SCD was 71 years among males compared with 79 among females (p<0.01). The greatest difference in SCD incidence between males and females was found among the 35-50 years group with an incidence rate ratio of 3.7 (95% CI: 2.8 to 4.8). Compared with female SCD victims, male SCD victims more often had cardiovascular diseases and diabetes mellitus (p<0.01). CONCLUSION: This is the first nationwide study of sex differences in SCD across all ages. Differences in incidence rates between males and females were greatest among young adults and the middle-aged. Incidence rates of SCD among older female population approached that of the male population, despite having significantly more cardiovascular disease and diabetes in male SCD cases.

Ethnic disparities in out-of-hospital cardiac arrest: A population-based cohort study among adult Danish immigrants.

Background: Ethnicity might impact out-of-hospital cardiac arrest (OHCA) risk, but it has scarcely been studied in Europe. We aimed to assess whether ethnicity influenced the risk of OHCA of cardiac cause in Danish immigrants and its interplay with risk factors for OHCA and socioeconomic status. Methods: This nationwide study included all immigrants between 18 and 80 years present in Denmark at some point between 2001 and 2020. Regions of origin were defined as Africa, Arabic countries, Asia, Eastern Europe, Latin America, and Western countries. OHCAs with presumed cardiac cause were identified from the Danish Cardiac Arrest Registry. Findings: Overall, among 1,011,565 immigrants, a total of 1,801 (0.2%) OHCAs (median age 64 (Q1-Q3 53-72) years, 72% males) occurred. The age- and sex- standardized (reference: Western countries) incidence of OHCA (/1,00,000 person-years) was 34.6 (27.8-43.4) in African, 34.1 (30.4-38.4) in Arabic, 33.5 (29.3-38.2) in Asian, 35.6 (31.9-39.6) in Eastern European, and 16.2 (9.0-27.2) in Latin American immigrants. When selecting Western origin as a reference, and after adjusting on OHCA risk factors, Arabic (HR 1.18, 95%CI 1.04-1.35; P=0.01), Eastern European (HR 1.28, 95%CI 1.13-1.46; P<0.001), and African origin (HR 1.34, 95%CI 1.10-1.63; P<0.01) were associated with higher risk of OHCA, whereas Latin American origin (HR 0.58, 95%CI 0.35-0.0.96; P=0.03) was associated with lower risk of OHCA. Comparable results were observed when adjusting on education level and economic status. Interpretation: This study emphasizes that ethnicity is associated with OHCA risk, even when considering traditional cardiac arrest risk factors. Funding: R Garcia received a grant from the Fédération Française de Cardiologie for his post-doctoral fellowship and this work was supported by the Novo Nordisk Foundation Tandem Programme 2022 (grant# 31364).

Cause-specific mortality in children and young adults with diabetes mellitus: A Danish nationwide cohort study.

AIMS: Persons with diabetes mellitus have increased all-cause mortality compared with the general population. Nationwide studies on causes of death and mortality among young persons with diabetes mellitus are sparse. The aim of this study was to examine all-cause and cause-specific mortality in children and young adults with and without diabetes. METHODS AND RESULTS: The study population consisted of all persons in Denmark aged 1-35 years in 2000-2009 and 36-49 years in 2007-2009, which equals 27.1 million person-years. All 14,294 deaths in the 10-year period were included and cause of death was established based on information from autopsy reports and death certificates. The Danish Register of Medicinal Product Statistics was used to identify persons with type 1 diabetes and type 2 diabetes. During the study period, which included 153,070 diabetic person-years, 669 (5% of all deceased) persons with diabetes mellitus died, of which 70% had type 1 and 30% had type 2 diabetes. Persons with diabetes mellitus had an all-cause mortality rate (ASMR) of 327 per 100,000 person-years compared with 74 per 100,000 person-years among persons without diabetes mellitus (ASMR ratio 4, p < 0.001). The leading cause of death among persons with diabetes mellitus was cardiac diseases (n = 230, 34%) with an ASMR ratio of 8 (95% confidence interval 6-9). CONCLUSIONS: Young persons with diabetes mellitus had four-fold increased all-cause mortality and eight-fold increased cardiovascular mortality compared with persons without diabetes mellitus. Focus on cardiovascular risk monitoring and management among young persons with diabetes mellitus is warranted to prevent premature death in diabetes mellitus.