Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium.

BACKGROUND: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. METHOD AND RESULTS: Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65-75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. CONCLUSIONS: For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

Effect of minimally invasive autopsy and ethnic background on acceptance of clinical postmortem investigation in adults.

OBJECTIVES: Autopsy rates worldwide have dropped significantly over the last five decades. Imaging based autopsies are increasingly used as alternatives to conventional autopsy (CA). The aim of this study was to investigate the effect of the introduction of minimally invasive autopsy, consisting of CT, MRI and tissue biopsies on the overall autopsy rate (of CA and minimally invasive autopsy) and the autopsy rate among different ethnicities. METHODS: We performed a prospective single center before-after study. The intervention was the introduction of minimally invasive autopsy as an alternative to CA. Minimally invasive autopsy consisted of MRI, CT, and CT-guided tissue biopsies. Autopsy rates over time and the effect of introducing minimally invasive autopsy were analyzed with a linear regression model. We performed a subgroup analysis comparing the autopsy rates of two groups: a group of western-European ethnicity versus a group of other ethnicities. RESULTS: Autopsy rates declined from 14.0% in 2010 to 8.3% in 2019. The linear regression model showed a significant effect of both time and availability of minimally invasive autopsy on the overall autopsy rate. The predicted autopsy rate in the model started at 15.1% in 2010 and dropped approximately 0.1% per month (ß = -0.001, p < 0.001). Availability of minimally invasive autopsy increased the overall autopsy rate by 2.4% (ß = 0.024, p < 0.001). The overall autopsy rate of people with an ethnic background other than western-European was significantly higher in years when minimally invasive autopsy was available compared to when it was not (22/176 = 12.5% vs. 81/1014 (8.0%), p = 0.049). CONCLUSIONS: The introduction of the minimally invasive autopsy had a small, but significant effect on the overall autopsy rate. Furthermore, the minimally invasive autopsy appears to be more acceptable than CA among people with an ethnicity other than western-European.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Antidepressants and heart-rate variability in older adults: a population-based study.

BACKGROUND: Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may be associated with lower heart rate variability (HRV), a condition associated with increased mortality risk. We aimed to investigate the association between TCAs, SSRIs and HRV in a population-based study. METHOD: In the prospective Rotterdam Study cohort, up to five electrocardiograms (ECGs) per participant were recorded (1991-2012). Two HRV variables were studied based on 10-s ECG recordings: standard deviation of normal-to-normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD). We compared the HRV on ECGs recorded during use of antidepressants with the HRV on ECGs recorded during non-use of any antidepressant. Additionally, we analysed the change in HRV on consecutive ECGs. Those who started or stopped using antidepressants before the second ECG were compared with non-users on two ECGs. RESULTS: We included 23 647 ECGs from 11 729 participants (59% women, mean age 64.6 years at baseline). Compared to ECGs recorded during non-use of antidepressants (n = 22 971), SDNN and RMSSD were lower in ECGs recorded during use of TCAs (n = 296) and SSRIs (n = 380). Participants who started using TCAs before the second ECG had a decrease in HRV and those who stopped had an increase in HRV compared to consistent non-users (p < 0.001). Starting or stopping SSRIs was not associated with HRV changes. CONCLUSION: TCAs were associated with a lower HRV in all analyses, indicating a real drug effect. For SSRIs the results are mixed, indicating a weaker association, possibly due to other factors.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Mapping the domain of medical informatics.

OBJECTIVES: The domain of medical informatics (MI) is not well defined. It covers a wide range of research topics. Our objective is to characterize the field of MI by means of the scientific literature in this domain. METHODS: We used titles and abstracts from MEDLINE records of papers published between July 1993 and July 2008, and extracted uni-, bi- and trigrams as features. Starting with the ISI category of medical informatics, we applied a semi-automated procedure to identify the set of journals and proceedings pertaining to MI. A clustering algorithm was subsequently applied to the articles from this set of publications. RESULTS: MI literature can be divided into three subdomains: 1) the organization, application, and evaluation of health information systems, 2) medical knowledge representation, and 3) signal and data analysis. Over the last fifteen years, the field has remained relatively stable, although most journals have shifted their focus somewhat. CONCLUSIONS: We identified the scientific literature pertaining to the field of MI, and the main areas of research. We were able to show trends in the field, and the positioning of different journals within this field.

Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users.

Several beta-blockers are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6*4 is the main polymorphism leading to decreased enzyme activity. The clinical significance of impaired elimination of beta-blockers is controversial, and most studies suffer from inclusion of small numbers of poor metabolizers (PMs) of CYP2D6. In this study, the association between CYP2D6*4 and blood pressure or heart rate was examined in 1,533 users of beta-blockers in the Rotterdam Study, a population-based cohort study. In CYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (P < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio = 3.86; 95% confidence interval 1.68-8.86; P = 0.0014). The diastolic blood pressure in PMs was 5.4 mm Hg lower in users of beta-blockers metabolized by CYP2D6 (P = 0.017) and 4.8 mm Hg lower in metoprolol users (P = 0.045) compared with EMs. PMs are at increased risk of bradycardia.

Unrecognized myocardial infarction and the risk of stroke: the Rotterdam Study.

OBJECTIVE: To investigate the relationship between unrecognized myocardial infarction and the risk of stroke in a population-based cohort study. METHODS: We followed 6,439 participants from the Rotterdam Study for stroke until January 2002. Participants were free from stroke, and presence of myocardial infarction was assessed at baseline (1990-1993). We calculated hazard ratios of stroke for persons with unrecognized or recognized myocardial infarction compared with persons without myocardial infarction. Analyses were adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 52,915 person-years of follow-up, 505 strokes occurred. Recognized myocardial infarction was only borderline associated with an increased risk of stroke. Unrecognized myocardial infarction increased the risk of stroke by 76% (age- and sex-adjusted hazard ratio 1.76, 95% CI 1.31 to 2.37). Stratification by sex showed that the increased risk was only found in men (hazard ratio for men 2.53, 95% CI 1.68 to 3.81; hazard ratio for women 1.27, 95% CI 0.82 to 1.96). After adjusting for cardiovascular risk factors at baseline, the risk remained significantly increased in men (hazard ratio for stroke 2.13, 95% CI 1.35 to 3.36). Subtyping of strokes revealed that unrecognized myocardial infarction was particularly associated with cortical ischemic strokes (hazard ratio for men 3.57, 95% CI 1.79 to 7.12). CONCLUSIONS: Men with unrecognized myocardial infarction have an increased risk of stroke.

Association between cardiac disorders and a decades-previous history of diphtheria.

A long, prior history of diphtheria is common among middle-aged and elder European adults. The aim of the present study was to determine whether the risk of reduced ventricular function and impaired intraventricular conduction is increased in individuals with a history of diphtheria. A study population of 2,480 subjects (1,222 women) aged 45 years or older who were recruited for the Study of Health in Pomerania were available for the present analyses. Left ventricular function was assessed by echocardiography. Intraventricular conduction blocks were diagnosed using electrocardiograms. Multivariable analyses revealed that individuals with a history of diphtheria had neither an increased odds for reduced fractional shortening (OR 1.21, 95% CI 0.69-2.11; p=0.51) nor an increased odds for intraventricular conduction blocks (OR 0.90, 95% CI 0.55-1.46; p=0.67). However, regression models revealed two-way interactions between the exposure variable and hypertension with respect to both endpoints. A history of diphtheria increased the odds for both endpoints in normotensive but not in hypertensive individuals. The findings show that a history of diphtheria several decades previously in a patient is a risk marker for reduced cardiac function and impaired intraventricular conduction in individuals at low risk for these disorders.

Co-occurrence based meta-analysis of scientific texts: retrieving biological relationships between genes.

MOTIVATION: The advent of high-throughput experiments in molecular biology creates a need for methods to efficiently extract and use information for large numbers of genes. Recently, the associative concept space (ACS) has been developed for the representation of information extracted from biomedical literature. The ACS is a Euclidean space in which thesaurus concepts are positioned and the distances between concepts indicates their relatedness. The ACS uses co-occurrence of concepts as a source of information. In this paper we evaluate how well the system can retrieve functionally related genes and we compare its performance with a simple gene co-occurrence method. RESULTS: To assess the performance of the ACS we composed a test set of five groups of functionally related genes. With the ACS good scores were obtained for four of the five groups. When compared to the gene co-occurrence method, the ACS is capable of revealing more functional biological relations and can achieve results with less literature available per gene. Hierarchical clustering was performed on the ACS output, as a potential aid to users, and was found to provide useful clusters. Our results suggest that the algorithm can be of value for researchers studying large numbers of genes. AVAILABILITY: The ACS program is available upon request from the authors.

Prevalence of macrovascular disease amongst type 2 diabetic patients detected by targeted screening and patients newly diagnosed in general practice: the Hoorn Screening Study.

OBJECTIVES: Screening for type 2 diabetes has been recommended and targeted screening might be an efficient way to screen. The aim was to investigate whether diabetic patients identified by a targeted screening procedure differ from newly diagnosed diabetic patients in general practice with regard to the prevalence of macrovascular complications. DESIGN: Cross-sectional population-based study. SETTING: Population study, primary care. SUBJECTS: Diabetic patients identified by a population-based targeted screening procedure (SDM patients), consisting of a screening questionnaire and a fasting capillary glucose measurement followed by diagnostic testing, were compared with newly diagnosed diabetic patients in general practice (GPDM patients). Ischaemic heart disease and prior myocardial infarction were assessed by ECG recording. Peripheral arterial disease was assessed by the ankle-arm index. Intima-media thickness of the right common carotid artery was measured with ultrasound. RESULTS: A total of 195 SDM patients and 60 GPDM patients participated in the medical examination. The prevalence of MI was 13.3% (95% CI 9.3-18.8%) and 3.4% (1.0-11.7%) in SDM patients and GPDM patients respectively. The prevalence of ischaemic heart disease was 39.5% (95% CI 32.9-46.5%) in SDM patients and 24.1% (15.0-36.5%) in GPDM patients. The prevalence of peripheral arterial disease was similar in both groups: 10.6% (95% CI 6.9-15.9%) and 10.2% (4.7-20.5%) respectively. Mean intima-media thickness was 0.85 mm (+/-0.17) in SDM patients and 0.90 mm (+/-0.20) in GPDM patients. The difference in intima-media thickness was not statistically significant. CONCLUSIONS: Targeted screening identified patients with a prevalence of macrovascular complications similar to that of patients detected in general practice, but with a lower degree of hyperglycaemia.

Distribution of information in biomedical abstracts and full-text publications.

MOTIVATION: Full-text documents potentially hold more information than their abstracts, but require more resources for processing. We investigated the added value of full text over abstracts in terms of information content and occurrences of gene symbol--gene name combinations that can resolve gene-symbol ambiguity. RESULTS: We analyzed a set of 3902 biomedical full-text articles. Different keyword measures indicate that information density is highest in abstracts, but that the information coverage in full texts is much greater than in abstracts. Analysis of five different standard sections of articles shows that the highest information coverage is located in the results section. Still, 30-40% of the information mentioned in each section is unique to that section. Only 30% of the gene symbols in the abstract are accompanied by their corresponding names, and a further 8% of the gene names are found in the full text. In the full text, only 18% of the gene symbols are accompanied by their gene names.

Minimum bandwidth requirements for recording of pediatric electrocardiograms.

BACKGROUND: Previous studies that determined the frequency content of the pediatric ECG had their limitations: the study population was small or the sampling frequency used by the recording system was low. Therefore, current bandwidth recommendations for recording pediatric ECGs are not well founded. We wanted to establish minimum bandwidth requirements using a large set of pediatric ECGs recorded at a high sampling rate. METHODS AND RESULTS: For 2169 children aged 1 day to 16 years, a 12-lead ECG was recorded at a sampling rate of 1200 Hz. The averaged beats of each ECG were passed through digital filters with different cut off points (50 to 300 Hz in 25-Hz steps). We measured the absolute errors in maximum QRS amplitude for each simulated bandwidth and determined the percentage of records with an error >25 microV. We found that in any lead, a bandwidth of 250 Hz yields amplitude errors <25 microV in >95% of the children <1 year. For older children, a gradual decrease in ECG frequency content was demonstrated. CONCLUSIONS: We recommend a minimum bandwidth of 250 Hz to record pediatric ECGs. This bandwidth is considerably higher than the previous recommendation of 150 Hz from the American Heart Association.

Employment of intra-individual variability to improve computerized ECG interpretation.

One of the reasons for the limited practical utility of computer programs for interpretation of electrocardiograms (ECGs) is their susceptibility to intra-individual variability. Two of the most prominent sources of intra-individual variability in ECGs, electrode placement variations and respiration, were studied for their effects on computerized ECG interpretation. Previous research has shown that the effects of intra-individual variability on computerized ECG interpretation depend largely on the individual ECG. To enable the assessment of chest electrode position variations for individual standard 12- lead ECGs, ECGs resulting from simulations of such position variations were interpreted. Variability due to respiration was assessed by interpreting all individual ECG beats instead of an averaged beat. In this paper two methods are presented that employ information about the intra-individual variability in individual ECGs. The first method provides an estimate of the reliability of the interpretation, the second attempts to improve the interpretation itself. In the first method we quantified the variation in interpretation caused by the two sources of intra-individual variability with the use of a stability index, a high index value indicating a low variation in interpretation. This index was subsequently studied using two sets of ECGs. For the first set a â clinical' reference interpretation was obtained from discharge letters. For the second set three cardiologists provided a â cardiologists' reference. The performance of subgroups of ECGs having stability indices higher than a particular value was computed. It appeared that for the â cardiologists' reference, the interpretations of ECGs with a high stability index were more often correct. No effect was found for the â clinical' reference. In the second method we attempted to improve the original interpretation by combining the alternative interpretations into a new interpretation. This was done by taking the median or the average of the quantified alternatives. These combined interpretations proved to perform better than the original interpretation when a cardiologist's interpretation was taken as a reference. This paper shows that intra-individual ECG variability can be used to improve original interpretations. This can be done without having to record multiple ECGs, provided that a model is available to simulate intra-individual variability. The presented methods do not depend on the classification algorithm that is used. They can be used both during classifier design to correct imperfections, and in routine use of the classifier to produce more representative classifications.

The coming of age of computerized ECG processing: can it replace the cardiologist in epidemiological studies and clinical trials?

In spite of decades of research and widespread use of computer programs for the analysis of electrocardiograms (ECGs), the accuracy and usefulness of computerized ECG processing has been questioned. To determine whether ECG computer programs can replace cardiologists in epidemiological studies and clinical trials, we reviewed the literature for evidence, concentrating on one influential ECG measurement, viz. QT interval duration, and one classification method, the Minnesota Code, which is the de facto standard for ECG coding. We compared interobserver variabilities of cardiologists with differences between computer programs and cardiologists, in order not to prejudice against the computer. Studies that contain this type of information indicate that interobserver variabilities are at least as large as differences between computer and cardiologist. This suggests that ECG computer programs perform at least equally well as human observers in ECG measurement and coding, and can replace the cardiologist in epidemiological studies and clinical trials.

Accurate automatic detection of electrode interchange in the electrocardiogram.

In recording an electrocardiogram (ECG), an interchange of electrodes may easily go unnoticed. Automatic detection would be desirable, but current algorithms, when dealing with more than left arm-right arm reversal, have moderate sensitivity. We propose a novel approach that uses the redundancy of information in the standard 12-lead ECG. We assume that each of the 8 independent electrocardiographic leads can be reconstructed from the 7 others in reasonable approximation. The correlation between any electrocardiographic lead and its reconstruction should be higher if the electrodes are correctly placed than when some interchange were present. The difference in correlation should have discriminative power. This was verified on a set of 3,305 ECGs for 14 common electrode interchange errors. The material was split in a learning and test set, and general reconstruction coefficients were computed from the learning set. For each interchange, electrode-error ECGs were derived by rearranging leads of the unaltered ECGs. Correlations between the actual leads and their reconstructions were computed for all ECGs. From the differences in lead correlation, decision rules were derived for each kind of interchange. All 14 rules had specificities of > or =99.5% in the test set. Sensitivities were > or =93% for 11 rules, and left arm-left leg electrode reversal scored low.

Computerized ST depression analysis improves prediction of all-cause and cardiovascular mortality: the strong heart study.

BACKGROUND: Nonspecific ST depression assessed by standard visual Minnesota coding (MC) has been demonstrated to predict risk. Although computer analysis has been applied to digital ECGs for MC, the prognostic value of computerized MC and computerized ST depression analyses have not been examined in relation to standard visual MC. METHODS: The predictive value of nonspecific ST depression as determined by visual and computerized MC codes 4.2 or 4.3 was compared with computer-measured ST depression >or= 50 microV in 2,127 American Indian participants in the first Strong Heart Study examination. Computerized MC and ST depression were determined using separate computerized-ECG analysis programs and visual MC was performed by an experienced ECG core laboratory. RESULTS: The prevalence of MC 4.2 or 4.3 by computer was higher than by visual analysis (6.4 vs 4.4%, P < 0.001). After mean follow-up of 3.7 +/- 0.9 years, there were 73 cardiovascular deaths and 227 deaths from all causes. In univariate Cox analyses, visual MC (relative risk [RR] 4.8, 95% confidence interval [CI] 2.6-9.1), computerized MC (RR 6.0, 95% CI 3.5-10.3), and computer-measured ST depression (RR 7.6, 95% CI 4.5-12.9) were all significant predictors of cardiovascular death. In separate multivariate Cox regression analyses that included age, sex, diabetes, HDL and LDL cholesterol, body mass index, systolic and diastolic blood pressure, microalbuminuria, smoking, and the presence of coronary heart disease, computerized MC (RR 3.0, 95% CI 1.6-5.6) and computer-measured ST depression (RR 3.1, 95% CI 1.7-5.7), but not visual MC, remained significant predictors of cardiovascular mortality. When both computerized MC and computer-measured ST depression were entered into the multivariate Cox regression, each variable provided independent risk stratification (RR 2.1, 95% CI 1.0-4.4, and RR 2.1, 95% CI 1.0-4.4, respectively). Similarly, computerized MC and computer-measured ST depression, but not visual MC, were independent predictors of all-cause mortality after controlling for standard risk factors. CONCLUSIONS: Computer analysis of the ECG, using computerized MC and computer-measured ST depression, provides independent and additive risk stratification for cardiovascular and all-cause mortality, and improves risk stratification compared with visual MC. These findings support the use of routine computer analysis of ST depression on the rest ECG for assessment of risk and suggest that computerized MC can replace visual MC for this purpose.

New normal limits for the paediatric electrocardiogram.

AIMS: Previous studies that determined the normal limits for the paediatric ECG had their imperfections: ECGs were recorded at a relatively low sampling rate, ECG measurements were conducted manually, or normal limits were presented for only a limited set of parameters. The aim of this study was to establish an up-to-date and complete set of clinically relevant normal limits for the paediatric ECG. METHODS AND RESULTS: ECGs from 1912 healthy Dutch children (age 11 days to 16 years) were recorded at a sampling rate of 1200 Hz. The digitally stored ECGs were analysed using a well-validated ECG computer program. The normal limits of all clinically relevant ECG measurements were determined for nine age groups. Clinically significant differences were shown to exist, compared with previously established normal limits. Sex differences could be demonstrated for QRS duration and several amplitude measurements. CONCLUSIONS: These new normal limits differ substantially from those commonly used and suggest that diagnostic criteria for the paediatric ECG should be adjusted.