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Additional file 1: Table S1. Demographics of the study cohort - Amsterdam data. Table S2. Distribution of different types of genetic variants for LQTS 1, 2 and 3 – Amsterdam data. Table S3. Prevalence of specific genetic variants for LQTS 1, 2 and 3 - Amsterdam data. Table S4. Single Lead First ECG model performances for LQTS1 - Amsterdam data. The mean of the collected metrics and the corresponding standard deviation (SD) of the 5-fold cross-validation is reported. The DL models were trained using single leads of the first acquired ECG of control and LQTS1 patients. Table S5. Single Lead First ECG model performances for LQTS2 - Amsterdam data. The mean of the collected metrics and the corresponding standard deviation (SD) of the 5-fold cross-validation is reported. The DL models were trained using single leads of the first acquired ECG of control and LQTS2 patients. Table S6. Single Lead First ECG model performances for LQTS3 - Amsterdam data. The mean of the collected metrics and the corresponding standard deviation (SD) of the 5-fold cross-validation is reported. The DL models were trained using single leads of the first acquired ECG of control and LQTS3 patients. Table S7. Model performances for LQTS 1, 2, and 3 - Amsterdam data. The performance of the DL models for patients whose QTc is within the 10th-90th percentile of the overlapping QTc region is reported. The QTc ranges analyzed are 398-475 ms, 403-477 ms, and 403-475 ms for LQTS 1, 2, and 3, respectively. The automatically measured QTc was used (thresholds used to define prolonged QTc: ≥ 450 ms for males, QTc ≥ 460 ms for females). The mean of the collected metrics and the corresponding standard deviation (SD) of the 5-fold cross-validation is reported. First ECG approach: the DL models were trained using the first acquired 12-lead ECGs. All ECG approach: the DL models were trained using all acquired 12-lead ECGs (not only the first acquired) per patient. Table S8. Demographics of the study cohort (Leuven data). Table S9. Distribution of different types of genetic variants for LQTS 1 and 2 – Leuven data. Table S10. Prevalence of specific genetic variants for LQTS 1 and 2 - Leuven data. Fig. S1. 1DCNN architecture. Schematic representation of the proposed 1DCNN architecture. The model was trained using 12-lead ECGs or single lead. The number 12 in the second column represents the 12-lead ECGs, while the number 1 in the bracket represents the use of the single lead. All 12 leads individually were used. Fig. S2. ECG distribution. Bar plots showing the number of ECGs for LQTS 1, 2, and 3 patients used in the ALL ECG approach. Fig. S3. Probability score distribution of control and LQTS patients. Box plots showing the probability score distribution for A) LQTS1, B) LQTS2, and C) LQTS3 and control patients obtained from the DL models trained on the first acquired 12-lead ECGs. The red dotted line represents the threshold used for the ECG classification. Fig. S4. Probability score distribution of control and LQTS patients. Box plots showing the probability score distribution of A) LQTS1, B) LQTS2, and C) LQTS3 and control patients obtained from the DL models trained on all acquired 12-lead ECGs. The red dotted line represents the threshold used for the ECG classification. Fig. S5. QTc value distribution (Amsterdam data). Top: QTc value distributions of LQTS versus control patients. Bottom: table showing the mean, the lower, and the upper limit of the above QTc value distributions. The automatically measured QTc was used (thresholds used to define prolonged QTc: ≥ 450 ms for males, QTc ≥ 460 ms for females).

Background: Coronavirus disease 2019 (COVID-19) is a systemic disease with cardiovascular involvement, including cardiac arrhythmias. Notably, new-onset atrial fibrillation (AF) and atrial flutter (AFL) during hospitalisation in COVID-19 patients has been associated with increased mortality. However, how this risk is impacted by age and sex is still poorly understood. Methods: For this multicentre cohort study, we extracted demographics, medical history, occurrence of electrical disorders and in-hospital mortality from the large international patient registry CAPACITY-COVID. For each electrical disorder, prevalence during hospitalisation was calculated. Subsequently, we analysed the incremental prognostic effect of developing AF/AFL on in-hospital mortality, using multivariable logistic regression analyses, stratified for sex and age. Results: In total, 5782 patients (64% male; median age 67) were included. Of all patients 11.0% (95% CI 10.2–11.8) experienced AF and 1.6% (95% CI 1.3–1.9) experienced AFL during hospitalisation. Ventricular arrhythmias were rare (

Tables and References supporting ACMG classification of variants identified. (PDF 811 kb)

Objectives The aim of this study was to determine the availability of quinidine throughout the world. Background Quinidine is the only oral medication that is effective for preventing life-threatening ventricular arrhythmias due to Brugada syndrome and idiopathic ventricular fibrillation. However, because of its low price and restricted indication, this medication is not marketed in many countries. Methods We conducted a survey of the availability of quinidine by contacting professional medical societies and arrhythmia specialists worldwide. Physicians were e-mailed questionnaires requesting information concerning the quinidine preparation available at their hospital. We also requested information concerning cases of adverse arrhythmic events resulting from unavailability of quinidine. Results A total of 273 physicians from 131 countries provided information regarding the availability of quinidine. Quinidine was readily available in 19 countries (14%), not accessible in 99 countries (76%), and available only through specific regulatory processes that require 4 to 90 days for completion in 13 countries (10%). We were able to gather information concerning 22 patients who had serious arrhythmias probably related (10 cases) or possibility related (12 cases) to the absence of quinidine, including 2 fatalities possibly attributable to the unavailability of quinidine. Conclusions The lack of accessibility of quinidine is a serious medical hazard at the global level.

To the Editor: Recognition of characteristic changes in an electrocardiogram (ECG) that are associated with acute occlusion of a coronary artery guides decisions regarding immediate reperfusion therapy.1–3 Working from our primary database of percutaneous coronary interventions, which includes records of the ambulance, or admission, ECG (performed on first medical contact with the patient), the preprocedural ECG, and the coronary angiogram, we describe a new ECG pattern without ST-segment elevation that signifies occlusion of the proximal left anterior descending coronary artery (LAD). Instead of the signature ST-segment elevation, the ST segment showed a 1- to 3-mm upsloping ST-segment depression at . . .

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Objectives The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease. Background Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias. Methods Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified. Results Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. Conclusions A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine. (J Am Coll Cardiol 2012;60:144-56) (C) 2012 by the American College of Cardiology Foundation

Tables and References supporting ACMG classification of variants identified. (PDF 811 kb)

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3×10−7, odds ratio = 2, 95% confidence intervals: 1.5–2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p = 3×10−9). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.