Objective To report the incidence rate of osmotic demyelination syndrome (ODS), associated risk factors, treatment, and long‐term outcomes in a nationwide cohort. Methods We conducted a retrospective study of individuals diagnosed with central pontine myelinolysis (ICD‐10 code G37.2) in the Swedish National Patient Register during 1997‐2011. Results During the study period, we identified 83 individuals with ODS, 47 women and 36 men. Median age at diagnosis was 55 years. The incidence rate of ODS for the entire study period was 0.611 (95% CI: 0.490‐0.754) per million person‐years and increased during the study period from 0.271 (95% CI: 0.147‐0.460) in 1997‐2001 to 0.945 (95% CI: 0.677‐1.234) individuals per million person‐years in 2007‐2011. Most cases (86.7%) were hyponatremic with a median sodium level at admission of 104 mmol/L. All hyponatremic cases were chronic. The cause of hyponatremia was multifactorial, including drugs (56.9%), polydipsia (31.9%), and vomiting or diarrhea (41.7%). A majority of patients (69.9%) were alcoholics. Hyponatremic patients were predominantly treated with isotonic saline (93.1%) and only 4.2% with hypotonic fluids. The median correction rate was 0.72 mmol/L/h. Only six patients were corrected in accordance with national guidelines (≤8 mmol/L/24/h). At three months, 7.2% had died and 60.2% were functionally independent (modified Rankin Scale 0‐2). Interpretation We found an increasing incidence during the study period, which could partly be explained by increased access to magnetic resonance imaging. ODS occurs predominantly in patients with extreme chronic hyponatremia which is corrected too fast with isotonic saline. Most patients survived and became functionally independent.

Aims The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10−20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

Aims Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications. Methods and results This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders. Conclusion The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.

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Background Long‐QT syndrome (LQTS) is a cardiac repolarization abnormality that can lead to sudden cardiac death. The most common causes are rare coding variants in the genes KCNQ1 , KCNH2 , and SCN5A . The data on LQTS epidemiology are limited, and information on expressivity and penetrance of pathogenic variants is sparse. Methods and Results We screened for rare coding variants associated with the corrected QT (QTc) interval in Iceland. We explored the frequency of the identified variants, their penetrance, and their association with severe events. Twelve variants were associated with the QTc interval. Five in KCNQ 1, 3 in KCNH2 , 2 in cardiomyopathy genes MYBPC3 and PKP2 , and 2 in genes where coding variants have not been associated with the QTc interval, ISOC1 and MYOM2. The combined carrier frequency of the 8 variants in the previously known LQTS genes was 530 per 100 000 individuals (1:190). p.Tyr315Cys and p.Leu273Phe in KCNQ1 were associated with having a mean QTc interval longer than 500 ms ( P =4.2×10 −7 ; odds ratio [OR], 38.6; P =8.4×10 −10 , OR, 26.5; respectively), and p.Leu273Phe was associated with sudden cardiac death ( P =0.0034; OR, 2.99). p.Val215Met in KCNQ1 was carried by 1 in 280 Icelanders, had a smaller effect on the QTc interval ( P =1.8×10 −44 ; effect, 22.8 ms), and did not associate with severe clinical events. Conclusions The carrier frequency of associating variants in LQTS genes was higher than previous estimates of the prevalence of LQTS. The variants have variable effects on the QTc interval, and carriers of p.Tyr315Cys and p.Leu273Phe have a more severe disease than carriers of p.Val215Met. These data could lead to improved identification, risk stratification, and a more precise clinical approach to those with QTc prolongation.

Introduction: AV nodal re-entry tachycardia (AVNRT) is the most common type of paroxysmal supraventricular tachycardia. At present, the underlying etiology of AVNRT is unclear. Hypothesis: In a genome-wide association study (GWAS), we aimed to identify common genetic variants associated with AVNRT. Methods: We performed a GWAS meta-analysis of Danish patients diagnosed with AVNRT verified by invasive electrophysiological study. An Icelandic population of AVNRT patients was used for replication. We performed conditional analysis by adjusting our analysis for atrial fibrillation (AF) genetics and transcriptome-wide analyses (TWAS) to assess associations between gene expression and AVNRT. Electrophysiological consequences were investigated in CRISPR-Cas9 modified zebrafish. Results: A total of 1,515 AVNRT patients and 38,428 controls were available for meta-analysis. Two genetic loci associated with AVNRT; at chromosome 5q35.1, close to the NKX2-5 gene (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.38-1.58, P = 2.6 х 10 -13 ), and at 14q11.2 in the MYH6 gene (OR 1.26, 95% CI 1.18-1.34, P = 2.3 х 10 -8 ). We found similar effect sizes and direction of effect for both loci in the Icelandic AVNRT cohort. Using conditional analyses, we found that these loci were associated with AVNRT independent of AF. Analyses of loss of Nkx2-5 zebrafish showed no difference with regards to electrocardiographic parameters and transmission electron microscopy of atrial tissue compared with wildtype. Conclusion: This is, to our knowledge, the first GWAS on AVNRT. We identified two genetic loci that associated with AVNRT.