Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Whole-Exome Sequencing Implicates Neuronal Calcium Channel with Familial Atrial Fibrillation.

Background: Atrial Fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, responsible for considerable morbidity and mortality. The heterogenic and complex pathogenesis of AF remains poorly understood, which contributes to the current limitation in effective treatments. We aimed to identify rare genetic variants associated with AF in patients with familial AF. Methods and results: We performed whole exome sequencing in a large family with familial AF and identified a rare variant in the gene CACNA1A c.5053G > A which co-segregated with AF. The gene encodes for the protein variants CaV2.1-V1686M, and is important in neuronal function. Functional characterization of the CACNA1A, using patch-clamp recordings on transiently transfected mammalian cells, revealed a modest loss-of-function of CaV2.1-V1686M. Conclusion: We identified a rare loss-of-function variant associated with AF in a gene previously linked with neuronal function. The results allude to a novel link between dysfunction of an ion channel previously associated with neuronal functions and increased risk of developing AF.

Fascicular heart blocks and risk of adverse cardiovascular outcomes: Results from a large primary care population.

BACKGROUND: Fascicular heart blocks can progress to complete heart blocks, but this risk has not been evaluated in a large general population. OBJECTIVE: The purpose of this study was to investigate the association between various types of fascicular blocks diagnosed by electrocardiographic (ECG) readings and the risk of incident higher degree atrioventricular block (AVB), syncope, pacemaker implantation, and death. METHODS: We studied primary care patients referred for ECG recording between 2001 and 2015. Cox regression models were used to estimate hazard ratios (HRs) as well as absolute risks of cardiovascular outcomes. RESULTS: Of 358,958 primary care patients (median age 54 years; 55% women), 13,636 (3.8%) had any type of fascicular block. Patients were followed up to 15.9 years. We found increasing HRs of incident syncope, pacemaker implantation, and third-degree AVB with increasing complexity of fascicular block. Compared with no block, isolated left anterior fascicular block (LAFB) was associated with 0%-2% increased 10-year risk of developing third-degree AVB (HR 1.6; 95% confidence interval [CI] 1.25-2.05), whereas right bundle branch block combined with LAFB and first-degree AVB was associated with up to 23% increased 10-year risk (HR 11.0; 95% CI 7.7-15.7), depending on age and sex group. Except for left posterior fascicular block (HR 2.09; 95% CI 1.87-2.32), we did not find any relevant associations between fascicular block and death. CONCLUSION: We found that higher degrees of fascicular blocks were associated with increasing risk of syncope, pacemaker implantation, and complete heart block, but the association with death was negligible.

Genome-wide association study identifies 18 novel loci associated with left atrial volume and function.

AIMS: Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data. METHODS AND RESULTS: We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14]. CONCLUSION: We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.

[Evident decline in mortality from ischaemic heart disease in Denmark from 1970 to 2015].

The decline in mortality from ischaemic heart disease (IHD) of 81% from 1990 to 2015 is dramatic and one of the greatest successes of Danish public health care. Improved treatment regimes and changes in modifiable risk factors contribute equally to the decline in mortality (47% vs. 44%). The standardised rate of cardiac mortality per 100,000 Danes for both women and men under 65 years of age were in 2017 so modest (4 vs 15), that a transformation from heart disease to heart healthy seems realistic.

Early-onset atrial fibrillation patients show reduced left ventricular ejection fraction and increased atrial fibrosis.

Atrial fibrillation (AF) has traditionally been considered an electrical heart disease. However, genetic studies have revealed that the structural architecture of the heart also play a significant role. We evaluated the functional and structural consequences of harboring a titin-truncating variant (TTNtv) in AF patients, using cardiac magnetic resonance (CMR). Seventeen early-onset AF cases carrying a TTNtv, were matched 1:1 with non-AF controls and a replication cohort of early-onset AF cases without TTNtv, and underwent CMR. Cardiac volumes and left atrial late gadolinium enhancement (LA LGE), as a fibrosis proxy, were measured by a blinded operator. Results: AF cases with TTNtv had significantly reduced left ventricular ejection fraction (LVEF) compared with controls (57 ± 4 vs 64 ± 5%, P < 0.001). We obtained similar findings in early-onset AF patients without TTNtv compared with controls (61 ± 4 vs 64 ± 5%, P = 0.02). We furthermore found a statistically significant increase in LA LGE when comparing early-onset AF TTNtv cases with controls. Using state-of-the-art CMR, we found that early-onset AF patients, irrespective of TTNtv carrier status, had reduced LVEF, indicating that early-onset AF might not be as benign as previously thought.

Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.

Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse.

AIMS: Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. METHODS AND RESULTS: We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10-1.17, P = 5.8 × 10-15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15-1.46, P = 1.68 × 10-5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. CONCLUSION: We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.

Genetic variants on chromosomes 7p31 and 12p12 are associated with abnormal atrial electrical activation in patients with early-onset lone atrial fibrillation.

BACKGROUND: Abnormal P-wave morphology (PWM) has been associated with a history of atrial fibrillation (AF) in earlier studies. Although lone AF is believed to have substantial genetic basis, studies on associations between single nucleotide polymorphisms (SNP) linked to lone AF and PWM have not been reported. We aimed to assess whether SNPs previously associated with lone AF (rs2200733, rs13376333, rs3807989, and rs11047543) are also linked to P-wave abnormalities. METHODS: Four SNPs were studied in 176 unrelated individuals with early-onset lone AF (age at onset <50 years), median age 38 years (19-63 years), 149 men. Using sinus rhythm ECG, orthogonal PWM was classified as Type 1-positive in leads X and Y and negative in lead Z, Type 2-positive in leads X and Y and biphasic (-/+) in lead Z, Type 3-positive in lead X and biphasic in lead Y (+/-), and the remaining as atypical. RESULTS: Two SNPs were found to be significantly associated with altered P-wave morphology distribution: rs3807989 near the gene CAV1/CAV2 and rs11047543 near the gene SOX5. Both SNPs were associated with a higher risk of non-Type 1 P-wave morphology (rs3807989: OR = 4.8, 95% CI = 2.3-10.2, p < 0.001; rs11047543: OR = 4.7, 95% CI = 1.1-20.5, p = 0.04). No association was observed for rs2200733 and rs13376333. CONCLUSION: In this study, the two variants rs3807989 and rs11047543, previously associated with PR interval and lone AF, were associated with altered P-wave morphology distribution in patients with early-onset lone AF. These findings suggest that common genetic variants may modify atrial conduction properties.

Associations between common ECG abnormalities and out-of-hospital cardiac arrest.

Background: Out-of-hospital cardiac arrest (OHCA) is often the first manifestation of unrecognised cardiac disease. ECG abnormalities encountered in primary care settings may be warning signs of OHCA. Objective: We examined the association between common ECG abnormalities and OHCA in a primary care setting. Methods: We cross-linked individuals who had an ECG recording between 2001 and 2011 in a primary care setting with the Danish Cardiac Arrest Registry and identified OHCAs of presumed cardiac cause. Results: A total of 326 227 individuals were included and 2667 (0,8%) suffered an OHCA. In Cox regression analyses, adjusted for age and sex, the following ECG findings were strongly associated with OHCA: ST-depression without concomitant atrial fibrillation (HR 2.79; 95% CI 2.45 to 3.18), left bundle branch block (LBBB; HR 3.44; 95% CI 2.85 to 4.14) and non-specific intraventricular block (NSIB; HR 3.15; 95% CI 2.58 to 3.83). Also associated with OHCA were atrial fibrillation (HR 1.89; 95% CI 1.63 to 2.18), Q-wave (HR 1.75; 95% CI 1.57 to 1.95), Cornell and Sokolow-Lyon criteria for left ventricular hypertrophy (HR 1.56; 95% CI 1.33 to 1.82 and HR 1.27; 95% CI 1.12 to 1.45, respectively), ST-elevation (HR 1.40; 95% CI 1.09 to 1.54) and right bundle branch block (HR 1.29; 95% CI 1.09 to 1.54). The association between ST-depression and OHCA diminished with concomitant atrial fibrillation (HR 1.79; 95% CI 1.42 to 2.24, p < 0.01 for interaction). Among patients suffering from OHCA, without a known cardiac disease at the time of the cardiac arrest, 14.2 % had LBBB, NSIB or ST-depression. Conclusions: Several common ECG findings obtained from a primary care setting are associated with OHCA.

Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts.

We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified ~2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.

Clinical implications of electrocardiographic bundle branch block in primary care.

OBJECTIVES: Electrocardiographic bundle branch block (BBB) is common but the prognostic implications in primary care are unclear. We sought to investigate the relationship between electrocardiographic BBB subtypes and the risk of cardiovascular (CV) outcomes in a primary care population free of major CV disease. METHODS: Retrospective cohort study of primary care patients referred for electrocardiogram (ECG) recording between 2001 and 2011. Cox regression models were used to estimate hazard ratios (HR) as well as absolute risks of CV outcomes based on various BBB subtypes. RESULTS: We included 202 268 individuals with a median follow-up period of 7.8 years (Inter-quartile range [IQR] 4.9-10.6). Left bundle branch block (LBBB) was associated with heart failure (HF) in both men (HR 3.96, 95% CI 3.30 to 4.76) and women (HR 2.51, 95% CI 2.15 to 2.94) and with CV death in men (HR 1.80, 95% CI 1.38 to 2.35). Right bundle branch block (RBBB) was associated with pacemaker implantation in both men (HR 3.26, 95% CI 2.74 to 3.89) and women (HR 3.69, 95% CI 2.91 to 4.67), HF in both sexes and weakly associated with CV death in men. Regarding LBBB, we found an increasing hazard of HF with increasing QRS-interval duration (HR 1.25, 95% CI 1.11 to 1.42 per 10 ms increase in men and HR 1.23, 95% CI 1.08 to 1.40 per 10 ms increase in women). Absolute 10-year risk predictions across age-specific and sex-specific subgroups revealed clinically relevant differences between having various BBB subtypes. CONCLUSIONS: Opportunistic findings of BBB subtypes in primary care patients without major CV disease should be considered warnings of future HF and pacemaker implantation.

Visit-to-Visit Variability of Hemoglobin A1c in People Without Diabetes and Risk of Major Adverse Cardiovascular Events and All-Cause Mortality.

OBJECTIVE: We aimed to study whether visit-to-visit variability of glycated hemoglobin A1c (HbA1c) is associated with incident major adverse cardiovascular events (MACE), all-cause mortality, and type 2 diabetes in people without diabetes. RESEARCH DESIGN AND METHODS: We included primary care patients with no history of diabetes or cardiovascular disease and with three annual HbA1c measurements within normal range (<6.5% [48 mmol/mol]). For each individual, we measured the HbA1c variability as the SD of the residuals obtained from a linear regression on the three HbA1c measurements. From the linear regression, we also obtained the estimated index HbA1c (intercept) and the trend over time (slope). Follow-up began at the date of the third measurement. Associations between HbA1c variability and outcome were analyzed using Cox regression, adjusted for traditional risk factors, intercept, and trend and reported as hazard ratio per SD increase in variability (HRSD). RESULTS: In total, 6,756 individuals were included. During a median follow-up time of 6.3 years, 996 developed MACE, 856 died, and 1,267 developed type 2 diabetes. We found a significant association between increasing HbA1c variability and incident MACE (HRSD 1.09 [95% CI 1.03-1.15]) and all-cause mortality (HRSD 1.13 [95% CI 1.07-1.20]), whereas there were no associations with type 2 diabetes (HRSD 1.00 [95% CI 0.95-1.05]). We calculated 5-year absolute risks of MACE and all-cause mortality and found clinically relevant differences across several age, sex, comorbidity, and HbA1c variability-defined subgroups. CONCLUSIONS: In a primary care population free of diabetes and cardiovascular disease, high HbA1c variability was associated with increased risks of MACE and all-cause mortality.

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

Brugada Syndrome-Associated Genetic Loci Are Associated With J-Point Elevation and an Increased Risk of Cardiac Arrest.

Introduction: A previous genome-wide association study found three genetic loci, rs9388451, rs10428132, and rs11708996, to increase the risk of Brugada Syndrome (BrS). Since the effect of these loci in the general population is unknown, we aimed to investigate the effect on electrocardiogram (ECG) parameters and outcomes in the general population. Materials and Methods: A cohort of 6,161 individuals (median age 45 [interquartile range (IQR) 40-50] years, 49% males), with available digital ECGs, was genotyped and subsequently followed for a median period of 13 [IQR 12.6-13.4] years. Data on outcomes were collected from Danish administrative healthcare registries. Furthermore, ~400,000 persons from UK Biobank were investigated for associations between the three loci and cardiac arrest/ventricular fibrillation (VF). Results: Homozygote carriers of the C allele in rs6800541 intronic to SCN10A had a significantly larger J-point elevation (JPE) compared with wildtype carriers (11 vs. 6 µV, P < 0.001). There was an additive effect of carrying multiple BrS-associated risk alleles with an increased JPE in lead V1. None of the BrS-associated genetic loci predisposed to syncope, atrial fibrillation, or total mortality in the general Danish population. The rs9388451 genetic locus adjacent to the HEY2 gene was associated with cardiac arrest/VF in an analysis using the UK Biobank study (odds ratio = 1.13 (95% confidence interval: 1.08-1.18), P = 0.006). Conclusions: BrS-associated risk alleles increase the JPE in lead V1 in an additive manner, but was not associated with increased mortality or syncope in the general population of Denmark. However, the HEY2 risk allele increased the risk of cardiac arrest/VF in the larger population study of UK Biobank indicating an important role of this common genetic locus.

Risk Prediction of Atrial Fibrillation Based on Electrocardiographic Interatrial Block.

BACKGROUND: The electrocardiographic interatrial block (IAB) has been associated with atrial fibrillation (AF). We aimed to test whether IAB can improve risk prediction of AF for the individual person. METHODS AND RESULTS: Digital ECGs of 152 759 primary care patients aged 50 to 90 years were collected from 2001 to 2011. We identified individuals with P-wave ≥120 ms and the presence of none, 1, 2, or 3 biphasic P-waves in inferior leads. Data on comorbidity, medication, and outcomes were obtained from nationwide registries. We observed a dose-response relationship between the number of biphasic P-waves in inferior leads and the hazard of AF during follow-up. Discrimination of the 10-year outcome of AF, measured by time-dependent area under the curve, was increased by 1.09% (95% confidence interval 0.43-1.74%) for individuals with cardiovascular disease at baseline (CVD) and 1.01% (95% confidence interval 0.40-1.62%) for individuals without CVD, when IAB was added to a conventional risk model for AF. The highest effect of IAB on the absolute risk of AF was observed in individuals aged 60 to 70 years with CVD. In this subgroup, the 10-year risk of AF was 50% in those with advanced IAB compared with 10% in those with a normal P-wave. In general, individuals with advanced IAB and no CVD had a higher risk of AF than patients with CVD and no IAB. CONCLUSIONS: IAB improves risk prediction of AF when added to a conventional risk model. Clinicians may consider monitoring patients with IAB more closely for the occurrence of AF, especially for high-risk subgroups.

Functional consequences of genetic variation in sodium channel modifiers in early onset lone atrial fibrillation.

AIM: We investigated the effect of variants in genes encoding sodium channel modifiers SNTA1 and GPD1L found in early onset atrial fibrillation (AF) patients. PATIENTS & METHODS: Genetic screening in patients with early onset lone AF revealed three variants in GPD1L and SNTA1 in three AF patients. Functional analysis was performed by patch-clamp electrophysiology. RESULTS: Co-expression of GPD1L or its p.A326E variant with NaV1.5 did not alter INa density or current kinetics. SNTA1 shifted the peak-current by -5 mV. The SNTA1-p.A257G variant significantly increased INa. SNTA1-p.P74L did not produce functional changes. CONCLUSION: Although genetic variation of sodium channel modifiers may contribute to development of AF at a molecular level, it is unlikely a monogenic cause of the disease.

Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes.

Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.

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.