QRS interval on the electrocardiogram reflects ventricular depolarization and conduction time, and is a risk factor for mortality, sudden death, and heart failure. We performed a genome-wide association meta-analysis in 40,407 European-descent individuals from 14 studies, with further genotyping in 7170 additional Europeans, and identified 22 loci associated with QRS duration (P < 5 × 10−8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors, and calcium-handling proteins, but also point to novel biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a gene at our most significant locus, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Sununary.We previously reported that mortality due to ischaemic heart disease was lower in haemophilia patients than in the general male population. To support the hypothesis that this could be attributed to a protective effect of the clotting defect in haemophilia and not to differences in cardiovascular risk factors, we performed a second study. We examined 95 haemophilia patients for the presence of major risk factors for ischaemic heart disease and compared their risk factor profile with the data of epidemiologic surveys of the general Dutch population.Haemophilia patients had on average higher blood pressures than the comparison population, were more often hypertensive and used antihypertensive drugs twice äs often.The mean serum cholesterol level of the patients was markedly lower than in the comparison population (4-8 versus 5-6 mmol/1, 95% confidence interval of the difference: 0-5-Mmmol/l).The risk factors were weighted into one theoretical risk raüo for ischaemic heart disease by application of logistic regression coefficients. The theoretical risk ratio based on the risk factor profile was 0-78. This risk ratio can only explain a moderate reduction in the incidence of ischaemic heart disease, much smaller than the mortality ratio of 0-20 we reported previously. Therefore these data support the hypothesis of a direct protective effect of haemophilia on the development of ischaemic heart disease.

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In order to test the diagnostic performance of various ECG computer programs a reference library of ECGs is being established and evaluation methods are being developed in an international co-operative project. A pilot study was undertaken in which 250 validated electrocardiograms (ECG) and vectorcardiograms (VCG) comprising seven diagnostic groups i.e., normal, left, right and bi-ventricular hypertrophy, anterior, inferior and combined infarction have been analysed independently by 11 different computer programs as well as by six cardiologists. A coding scheme was applied to assign individual diagnostic statements to a common set and to obtain combined program and cardiologist interpretation results. Preliminary results indicate that the accuracy of classification by different programs varies widely. Total accuracy varied between 57.2% and 75.8% (median 69.4%). The cardiologists had a higher accuracy (median 74.3%) than the majority of programs, at least when using the standard ECG. As it is considered premature to stress individual program results, in view of the current sample size, the enhancement in diagnostic accuracy obtained by combining interpretation results is highlighted. Indeed combined cardiologist and program results demonstrated the highest accuracy i.e., respectively 78.7% and 76.1%, higher than the result of any individual reader or program. The combined result of the five most accurate programs was 78.4%, that of the six least accurate was 71.5%, which is again higher than the respective individual components. These findings demonstrate that the combination of expert knowledge of computer programs can, similar to panel review and group analysis in clinical practice, enhance diagnostic accuracy.