Causes of sudden cardiac death according to age and sex in persons aged 1-49 years.

BACKGROUND: Knowledge of causes of sudden cardiac death (SCD) according to age is important in clinical decision making and to lower the risk of SCD in family members of the deceased. OBJECTIVE: The purpose of this study was to report overall and sex-stratified causes of SCD according to age in persons aged 1-49 years. METHODS: 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. Danish death certificates, discharge summaries, autopsy reports, and data from nationwide registries were used to identify all SCD cases. The SCD cases were divided into 5-year age groups. RESULTS: In the 10-year study period, there were 14,294 deaths, of which 1362 (10%) were classified as SCD. Potentially inherited cardiac disease accounted for a high proportion (43%-78%) of autopsied SCD in all age groups. A significant proportion (19%-54%) of SCD was caused by sudden arrhythmic death syndrome in all age groups. Autopsy rates in both sudden unexpected death cases and SCD cases declined significantly with increasing age (74% in the youngest age group vs 35% in the oldest). CONCLUSION: The proportion of SCD cases that were identified with a potentially inherited cardiac disease postmortem was high in all studied age groups, while autopsy rates in sudden and unexpected death cases declined markedly with increasing age. Our findings indicate that diagnoses of inherited heart disease are likely missed in some SCD cases, along with the opportunity for treatment and prevention in surviving relatives.

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.

Determining a safe upper limit of oxygen supplementation for adult patients: a systematic review.

OBJECTIVE: This systematic review aimed to describe the connection between the inspired oxygen fraction and pulmonary complications in adult patients, with the objective of determining a safe upper limit of oxygen supplementation. METHODS: MEDLINE and Embase were systematically searched in August 2019 (updated July 2020) for studies fulfilling the following criteria: intubated adult patients (Population); high fractions of oxygen (Intervention) versus low fractions of (Comparison); atelectasis, acute respiratory distress syndrome (ARDS), pneumonia and/or duration of mechanical ventilation (Outcome); original studies both observational and interventional (Studies). Screening, data extraction and risk of bias assessment was done by two independent reviewers. RESULTS: Out of 6120 records assessed for eligibility, 12 were included. Seven studies were conducted in the emergency setting, and five studies included patients undergoing elective surgery. Eight studies reported data on atelectasis, two on ARDS, four on pneumonia and two on duration of mechanical ventilation. There was a non-significant increased risk of atelectasis if an oxygen fraction of 0.8 or above was used, relative risk (RR): 1.37 (95% CI 0.95 to 1.96). One study showed an almost threefold higher risk of pneumonia in the high oxygen fraction group (RR: 2.83 (95% CI 2.25 to 3.56)). The two studies reporting ARDS and the two studies with data on mechanical ventilation showed no association with oxygen fraction. Four studies had a high risk of bias in one domain. CONCLUSIONS: In this systematic review, we found inadequate evidence to identify a safe upper dosage of oxygen, but the identified studies suggest a benefit of keeping inspiratory oxygen fraction below 0.8 with regard to formation of atelectases. PROSPERO REGISTRATION NUMBER: CRD42020154242.

Nationwide burden of sudden cardiac death: A study of 54,028 deaths in Denmark.

BACKGROUND: A large proportion of all deaths are sudden cardiac deaths (SCDs). Reliable estimates of nationwide incidence of SCD, however, are missing. OBJECTIVES: The goals of this study were to estimate SCD burden across all age groups in Denmark and to compare it with the estimates of other common causes of death. METHODS: All deaths in Denmark (population of 5.5 million) in 2010 were manually reviewed case by case. Autopsy reports, death certificates, and information from nationwide health registries were systematically examined to identify all SCD cases in 2010. According to the level of detail of the available information, all deaths were categorized as either non-SCD, definite SCD, probable SCD, or possible SCD. RESULTS: There were 54,028 deaths in Denmark in 2010, of which 6867 (13%) were categorized as SCD (591 (9%) definite SCD, 1568 (23%) probable SCD, and 4708 (68%) possible SCD). The incidence rate of definite SCD was 11 (95% confidence interval 10-12) per 100,000 person-years. Including definite, probable, and possible SCD cases, the highest possible overall SCD incidence rate was 124 (95% confidence interval 121-127) per 100,000 person-years. Estimated SCD burden was similar to or greater than the estimates of all other common causes of death. Of all SCD cases, 49% were not diagnosed with cardiovascular disease before death. CONCLUSION: SCD accounted for up to 13% of all deaths. Almost half of all SCD cases occurred in persons without a history of cardiovascular disease. Consequently, the optimization of risk stratification and prevention of SCD in the general population should be given high priority.

Low Birth Weight Increases the Risk of Sudden Cardiac Death in the Young: A Nationwide Study of 2.2 Million People.

Background Sudden cardiac death (SCD) constitutes a major health problem worldwide. We investigated whether birth weight (BW), small for gestational age (SGA), and large for gestational age are associated with altered risk of SCD among the young (aged 1-36 years). Methods and Results We included all people born in Denmark from 1973 to 2008 utilizing the Danish Medical Birth Register. All SCDs in Denmark in 2000 to 2009 have previously been identified. We defined 5 BW groups, SGA, and large for gestational age as exposure and SCD as the outcome. We estimated the age-specific relative risk of SCD with 95% CI. Additionally, we investigated if SGA and large for gestational age are associated with pathological findings at autopsy. The study population for the BW analyses comprised 2 234 501 people with 389 SCD cases, and the SGA and large for gestational age analyses comprised 1 786 281 people with 193 SCD cases. The relative risk for SCD was 6.69 for people with BW between 1500 and 2499 g (95% CI, 2.38-18.80, P<0.001) and 5.89 for people with BW ≥4500 g (95% CI, 1.81-19.12, P=0.003) at age 5 years. BW 2500 to 3400 g was the reference group. Compared with an appropriate gestational age, the relative risk for SGA was 2.85 (95% CI, 1.35-6.00, P=0.006) at age 10 years. For the autopsied cases, the relative risk of sudden arrhythmic death syndrome at age 5 years was 4.19 for SGA (95% CI, 1.08-16.22, P=0.038). Conclusions We found an association between BW and SCD in the young, with an increased risk among SGA infants. In addition, we found an association between SGA and sudden arrhythmic death syndrome.

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.

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.

Impact of Physician-staffed Helicopters on Pre-hospital Patient Outcomes: A systematic review.

BACKGROUND: Management of pre-hospital patients remains a challenge. In developed countries a physician-staffed helicopter emergency medical service (PS-HEMS) is used in addition to ground emergency medical service (GEMS), but the effect is debated. This systematic review aimed to evaluate the effect of PS-HEMS compared with GEMS on patient outcomes based on the published scientific literature. METHODS: Medline, EMBASE and the Cochrane Library were systematically searched on November 15, 2019 for prospective, interventional studies comparing outcomes of patients transported by either PS-HEMS or GEMS. Outcomes of interest were mortality, time to hospital and quality of life. RESULTS: The majority of 18 studies included were observational and difficult to summarize because of heterogeneity. Meta-analysis could not be carried out. Three studies found reduced mortality in patients transported by PS-HEMS compared with GEMS with Odds ratios (OR) of 0.68 (0.47-0.98); 0.29 (0.10-0.82) and 0.21 (0.06-0.73) respectively. Another two studies found improved survival with OR 1.2 (1.0-1.5) and 6.9 (1.48-32.5) in patients transported by PS-HEMS compared with GEMS. In three studies, PS-HEMS was associated with shorter time to hospital. Three studies reported quality of life and found no benefit of PS-HEMS. CONCLUSION: In this systematic review the studies comparing PS-HEMS with GEMS were difficult to summarize because of heterogeneity. We found a possible survival benefit of PS-HEMS but were unable to conduct a meta-analysis. The overall quality of evidence was low.

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.

Decline in incidence of sudden cardiac death in the young: a 10-year nationwide study of 8756 deaths in Denmark.

AIMS: Sudden cardiac death in the young (SCDY) accounts for a significant proportion of deaths among the young. The aim of this nationwide study was to examine temporal changes in incidence and causes of SCDY in Denmark in 2000-2009. During this 10-year period, several public and private health initiatives were undertaken to decrease morbidity and mortality in Denmark. METHODS AND RESULTS: All deaths among persons aged 1-35 years in Denmark in 2000-2009 (23.7 million person-years) were included. Death certificates, autopsy reports, discharge summaries, and data from nationwide administrative registries were used to identify SCDY cases. Sudden cardiac death in the young incidence rates were age-adjusted and sex-adjusted using direct standardization. Temporal changes in standardized SCDY incidence rates were reported as average annual percent changes. In the 10-year study period, there were 8756 deaths, of which we identified 635 (7%) SCDY cases. For these SCDY cases, median age at death was 29 years and 68% were men. Standardized incidence of SCDY decreased from 3.1 per 100 000 person-years in 2000 [95% confidence interval (CI) 2.4-3.8] to 2.5 per 100 000 person-years in 2009 (95% CI 1.9-3.2). This corresponds to an average annual percent change of -3.0% (95% CI -5.8 to -0.1). The distribution of major causes of SCDY did not change significantly throughout the study period. CONCLUSION: Incidence of SCDY decreased significantly from 2000 through 2009 in Denmark with an average annual percent change of -3%. Further research is needed to elucidate underlying causes of this development.

Nationwide Study of Sudden Cardiac Death in People With Congenital Heart Defects Aged 0 to 35 Years.

BACKGROUND: Congenital heart defects (CHD) are among the leading causes of sudden cardiac death (SCD) in the young. Nationwide incidence of SCD in people with CHD (SCD-CHD) has not been established in the young general population. The aims of this study were to investigate incidence of SCD-CHD and whether incidence of SCD-CHD in infants declined after implementation of nationwide fetal ultrasound screening in Denmark. METHODS: All deaths (n=11 451) among people aged 0 to 35 years in Denmark in 2000 to 2009 (24.4 million person-years) were included. Danish death certificates, autopsy reports, records from hospitals and general practitioners, and data from nationwide Danish registries were used to identify SCD-CHD cases. RESULTS: We identified 90 (11%) cases of SCD-CHD from 809 SCD. The incidence rate of SCD-CHD was 0.4 per 100 000 person-years among people aged 0 to 35 years. In total, 53 (59%) were diagnosed with CHD before death. Incidence of SCD was 9.6× higher among patients with CHD compared with people without CHD (P<0.01). Annual incidence of physical activity-related SCD-CHD among patients aged 2 to 35 years diagnosed with CHD was 0.9 per 100 000. The annual incidence rate of SCD-CHD in infants declined after implementation of nationwide fetal ultrasound screening (incidence rate ratio, 3.8; P<0.01). CONCLUSIONS: The proportion of SCD-CHD in the young was 11%, which is higher than previously reported. Physical activity-related SCD-CHD was a rare event among patients with CHD. We observed an ≈4-fold lower incidence of SCD-CHD among infants born after implementation of nationwide screening.

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.

Sudden unexpected death caused by stroke: A nationwide study among children and young adults in Denmark.

Background Stroke is the fifth leading cause of death in young individuals globally. Data on the burden of sudden death by stroke are sparse in the young. Aims The aim of this study was to report mortality rates, cause of death, stroke subtype, and symptoms in children and young adults who suffered sudden death by stroke. Methods We conducted a retrospective, nationwide study including all deaths within Danish borders between 2000-2009 and 2007-2009 in persons aged 1-35 years and 36-49 years, respectively. Two physicians identified all sudden death cases through review of all death certificates. All available autopsy reports and records from hospitals and general practitioners were retrieved and a neurologist identified all sudden death by stroke cases. Results Of the 14,567 deaths in the 10-year period, there were 1,698 sudden death cases, of which 52 (3%) were sudden death by stroke. There was a male predominance (56%) and the median age was 33 years. The incidence of sudden death by stroke in individuals aged 1-49 years was 0.19 deaths per 100,000 person-years. Stroke was hemorrhagic in 94% of cases, whereof subarachnoid hemorrhage was the cause of death in 63% of cases. Seventeen (33%) cases contacted the healthcare system because of neurological symptoms, whereof one was suspected of having a stroke (6%). Conclusions Sudden death by stroke in children and young adults occurs primarily due to hemorrhagic stroke. We report a high frequency of neurological symptoms prior to sudden death by stroke. Increased awareness among healthcare professionals towards stroke symptoms in children and young adults may lead to earlier detection of stroke, and thereby potentially lowering the incidence of sudden death by stroke.

Febrile seizures prior to sudden cardiac death: a Danish nationwide study.

Aims: Febrile seizure (FS) is a common disorder affecting 2-5% of children up to 5 years of age. The aim of this study was to determine whether FS in early childhood are over-represented in young adults dying from sudden cardiac death (SCD). Methods and results: We included all deaths (n = 4595) nationwide and through review of all death certificates, we identified 245 SCD in Danes aged 1-30 years in 2000-09. Through the usage of nationwide registries, we identified all persons admitted with first FS among SCD cases (14/245; 5.7%) and in the corresponding living Danish population (71 027/2 369 785; 3.0%) and also in victims of transport accidents (26/917; 2.8%). The frequency of FS among SCD cases was significantly increased by an odds ratio of 1.96 [95% confidence interval (CI) 1.14-3.36; P = 0.021] compared with the living Danish population and with an odds ratio of 2.08 (95% CI 1.07-4.04; P = 0.046) compared with transport accident victims. SCD cases did not differ statistically in birth year (P = 0.272), age at SCD (P = 0.667) or prior medical conditions, except for epilepsy (P < 0.001), when comparing SCD with and without prior FS. The most common cause of death in autopsied SCD cases with FS was sudden arrhythmic death syndrome (5/8; 62.5%). Conclusion: In conclusion, this study demonstrates a significantly two-fold increase in the frequency of FS prior to death in young SCD cases compared with the two control groups, suggesting that FS could potentially contribute in a risk stratification model for SCD and warrant further studies.

Association of common genetic variants related to atrial fibrillation and the risk of ventricular fibrillation in the setting of first ST-elevation myocardial infarction.

BACKGROUND: Cohort studies have revealed an increased risk for ventricular fibrillation (VF) and sudden cardiac death (SCD) in patients with atrial fibrillation (AF). In this study, we hypothesized that single nucleotide polymorphisms (SNP) previously associated with AF may be associated with the risk of VF caused by first ST-segment elevation myocardial infarction (STEMI). METHODS: We investigated association of 24 AF-associated SNPs with VF in the prospectively assembled case-control study among first STEMI-patients of Danish ancestry. RESULTS: We included 257 cases (STEMI with VF) and 537 controls (STEMI without VF). The median age at index infarction was 60 years for the cases and 61 years for the controls (p = 0.100). Compared to the control group, the case group was more likely to be male (86% vs. 75%, p = 0.001), have a history of AF (7% vs. 2%, p = 0.006) or hypercholesterolemia (39% vs. 31%, p = 0.023), and a family history of sudden death (40% vs. 25%, p < 0.001). All 24 selected SNPs have previously been associated with AF. None of the 24 SNPs were associated with the risk of VF after adjustment for age and sex under additive genetic model of inheritance in the logistic regression model. CONCLUSION: In this study, we found that the 24 AF-associated SNPs may not be involved in increasing the risk of VF. Larger VF cohorts and use of new next generation sequencing and epigenetic may in future identify additional AF and VF risk loci and improve our understanding of genetic pathways behind the two arrhythmias.

Differences in clinical characteristics in patients with first ST-segment elevation myocardial infarction and ventricular fibrillation according to sex.

PURPOSE: We aimed to assess sex differences in clinical characteristics, circumstances of arrest, and procedural characteristics in ST-elevation myocardial infarction (STEMI) patients with ventricular fibrillation (VF) prior to angioplasty. METHODS: Cases of VF with first STEMI (n = 329; 276 men and 53 women) were identified from the GEVAMI study, which is prospectively assembled case-control study among first STEMI patients in Denmark. RESULTS: Compared to men, women experienced symptoms for a longer time interval prior to angioplasty (140 vs. 166 min, p = 0.020), and were more likely to present with VF later during transport to the hospital rather than prior to emergency medical services arrival (36 vs. 52%, p = 0.040). Prior to VF, women had a significantly lower income (p = 0.002) and education level (p = 0.008), were less likely to consume alcohol (3 vs. 6 units, p = 0.040), more likely to smoke (71 vs. 52%, p = 0.007), and more likely to have depression (25 vs. 10%, p = 0.002) or a history of angina (59 vs. 42%, p = 0.030). Even though women had more angina within a year prior to VF, no difference was observed in self-reported contact with the healthcare system (p = 0.200). In multivariable logistic regression models, history of angina (OR = 2.70; p = 0.006), low educational level (OR = 2.80, p = 0.012) and low income (OR = 6.00, p = 0.005) remained significantly associated with female sex. There were no differences in procedural characteristics between men and women. CONCLUSIONS: We found several sex differences in clinical characteristics and circumstances of arrest. The importance of seeking acute medical attention when experiencing angina should be emphasized in women, especially in women with low socioeconomic status.

Sudden cardiac death and coronary disease in the young: A nationwide cohort study in Denmark.

BACKGROUND: Sudden cardiac death caused by coronary artery disease (CAD-SCD) is the most frequent cause of SCD in persons <50years. The aim of this study was to examine differences in clinical characteristics and autopsy findings of the heart among 18-35 and 36-49year old CAD-SCD cases. METHODS: We have previously identified all sudden cardiac deaths in Denmark through review of death certificates and autopsy reports including all deaths between 2000 and 2006 in individuals aged 18-35years and all deaths between 2007 and 2009 in individuals aged 18-49years. In this study we included the 197 autopsied CAD-SCD cases. Full autopsy report and medical records from general practitioners and hospitals were obtained. RESULTS: There was a male predominance (n=151, 76%) and the median age was 42years. In witnessed cases, 51% had a shockable rhythm and 9 cases returned to spontaneous circulation briefly, CAD-SCD victims aged 36-49years had more severe atherosclerosis in all coronary arteries, more multi-vessel disease (29% vs. 15%, p=0.049) and less commonly (38% vs. 54%, p=0.039) acute coronary occlusion than victims <36years. Sixty-eight percent(n=133) of CAD-SCD victims had cardiac symptoms prior to death. CONCLUSION: This nationwide study found several differences in the pathologic lesions of the heart in victims aged 18-35 and 36-49years, which might be associated with different disease progression leading to death in these age groups. We also report a high frequency of cardiac symptoms prior to death in young CAD-SCD cases, which may enable clinicians to prevent these tragic deaths.

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.

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.

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

BACKGROUND: Hitherto, 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. METHODS: All 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. RESULTS: During 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). CONCLUSIONS: Incidence 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.