Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation.

BACKGROUND: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. METHODS: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. RESULTS: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. CONCLUSIONS: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Corrigendum: Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages.

[This corrects the article DOI: 10.3389/fphys.2018.00424.].

Normal Values of QT Variability in 10-s Electrocardiograms for all Ages.

Aims: QT variability is a promising electrocardiographic marker. It has been studied as a screening tool for coronary artery disease and left ventricular hypertrophy, and increased QT variability is a known risk factor for sudden cardiac death. Considering that comprehensive normal values for QT variability were lacking, we set out to establish these in standard 10-s electrocardiograms (ECGs) covering both sexes and all ages. Methods: Ten-second, 12-lead ECGs were provided by five Dutch population studies (Pediatric Normal ECG Study, Leiden University Einthoven Science Project, Prevention of Renal and Vascular End-stage Disease Study, Utrecht Health Project, Rotterdam Study). ECGs were recorded digitally and processed by well-validated analysis software. We selected cardiologically healthy participants, 46% being women. Ages ranged from 11 days to 91 years. After quality control, 13,828 ECGs were available. We assessed three markers: standard deviation of QT intervals (SDqt), short-term QT variability (STVqt), and QT variability index (QTVI). Results: For SDqt and STVqt, the median and the lower limit of normal remained stable with age. The upper limit of normal declined until around age 45, and increased strongly in the elderly, notably so in women. This implies that a subset of the population, small enough not to have appreciable effect on the median, shows a high degree of QT variability with a possible risk of arrhythmias or worse, especially in women. Otherwise, sex differences were negligible in all three measurements. For QTVI, median, and normal limits decreased until age 20, and steadily went up afterwards except for the lower limit of normal, which flattens off after age 65. Conclusion: We report the first set of normal values for QT variability based on 10-s ECGs, for all ages and both sexes.

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages.

Purpose: Heart-rate variability (HRV) measured on standard 10-s electrocardiograms (ECGs) has been associated with increased risk of cardiac and all-cause mortality, but age- and sex-dependent normal values have not been established. Since heart rate strongly affects HRV, its effect should be taken into account. We determined a comprehensive set of normal values of heart-rate corrected HRV derived from 10-s ECGs for both children and adults, covering both sexes. Methods: Five population studies in the Netherlands (Pediatric Normal ECG Study, Leiden University Einthoven Science Project, Prevention of Renal and Vascular End-stage Disease Study, Utrecht Health Project, Rotterdam Study) provided 10-s, 12-lead ECGs. ECGs were stored digitally and analyzed by well-validated analysis software. We included cardiologically healthy participants, 42% being men. Their ages ranged from 11 days to 91 years. After quality control, 13,943 ECGs were available. Heart-rate correction formulas were derived using an exponential model. Two time-domain HRV markers were analyzed: the corrected standard deviation of the normal-to-normal RR intervals (SDNNc) and corrected root mean square of successive RR-interval differences (RMSSDc). Results: There was a considerable age effect. For both SDNNc and RMSSDc, the median and the lower limit of normal decreased steadily from birth until old age. The upper limit of normal decreased until the age of 60, but increased markedly after that age. Differences of the median were minimal between men and women. Conclusion: We report the first comprehensive set of normal values for heart-rate corrected 10-s HRV, which can be of value in clinical practice and in further research.

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10-11) and SCN5A (P=1.1×10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy.

BACKGROUND: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. METHODS: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. RESULTS: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. CONCLUSIONS: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.

Discovery of novel heart rate-associated loci using the Exome Chip.

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Validation of automatic measurement of QT interval variability.

BACKGROUND: Increased variability of beat-to-beat QT-interval durations on the electrocardiogram (ECG) has been associated with increased risk for fatal and non-fatal cardiac events. However, techniques for the measurement of QT variability (QTV) have not been validated since a gold standard is not available. In this study, we propose a validation method and illustrate its use for the validation of two automatic QTV measurement techniques. METHODS: Our method generates artificial standard 12-lead ECGs based on the averaged P-QRS-T complexes from a variety of existing ECG signals, with simulated intrinsic (QT interval) and extrinsic (noise, baseline wander, signal length) variations. We quantified QTV by a commonly used measure, short-term QT variability (STV). Using 28,800 simulated ECGs, we assessed the performance of a conventional QTV measurement algorithm, resembling a manual QTV measurement approach, and a more advanced algorithm based on fiducial segment averaging (FSA). RESULTS: The results for the conventional algorithm show considerable median absolute differences between the simulated and estimated STV. For the highest noise level, median differences were 4-6 ms in the absence of QTV. Increasing signal length generally yields more accurate STV estimates, but the difference in performance between 30 or 60 beats is small. The FSA algorithm proved to be very accurate, with most median absolute differences less than 0.5 ms, even for the highest levels of disturbance. CONCLUSIONS: Artificially constructed ECGs with a variety of disturbances allow validation of QTV measurement procedures. The FSA algorithm provides highly accurate STV estimates under varying signal conditions, and performs much better than traditional beat-by-beat analysis. The fully automatic operation of the FSA algorithm enables STV measurement in large sets of ECGs.

Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study.

BACKGROUND: The association between thyroid function and cardiovascular disease is well established, but no study to date has assessed whether it is a risk factor for sudden cardiac death (SCD). Therefore, we studied the association of thyroid function with SCD in a prospective population-based cohort. METHODS: Participants from the Rotterdam Study ≥45 years with thyroid-stimulating hormone or free thyroxine (FT4) measurements and clinical follow-up were eligible. We assessed the association of thyroid-stimulating hormone and FT4 with the risk of SCD by using an age- and sex-adjusted Cox proportional-hazards model, in all participants and also after restricting the analysis to euthyroid participants (defined by thyroid-stimulating hormone 0.4-4.0 mIU/L). Additional adjustment included cardiovascular risk factors, notably hypertension, serum cholesterol, and smoking. We stratified by age and sex and performed sensitivity analyses by excluding participants with abnormal FT4 values (reference range of 0.85-1.95 ng/dL) and including only witnessed SCDs as outcome. Absolute risks were calculated in a competing risk model by taking death by other causes into account. RESULTS: We included 10 318 participants with 261 incident SCDs (median follow-up, 9.1 years). Higher levels of FT4 were associated with an increased SCD risk, even in the normal range of thyroid function (hazard ratio, 2.28 per 1 ng/dL FT4; 95% confidence interval, 1.31-3.97). Stratification by age or sex and sensitivity analyses did not change the risk estimates substantially. The absolute 10-year risk of SCD increased in euthyroid participants from 1% to 4% with increasing FT4 levels. CONCLUSIONS: Higher FT4 levels are associated with an increased risk of SCD, even in euthyroid participants.

Chronic obstructive pulmonary disease and sudden cardiac death: A systematic review.

Both chronic obstructive pulmonary disease (COPD) and sudden cardiac death (SCD) are major health burdens. A number of studies have addressed their interrelationship, but currently no systematic review has been published. Our objective is to give an overview of the literature of the association between COPD and SCD. A search on PubMed with both MeSH headings and free-text keywords was performed. We selected all original articles of studies in humans that assessed COPD on the one hand and SCD, electrocardiographic markers for SCD, ventricular arrhythmias, or asystole on the other. The electronic search yielded 251 articles, from which 27 full publications were selected after careful evaluation of the full-text articles. In these studies, COPD was associated with a prolonged and shortened QT interval. In patients with a myocardial infarction (MI), COPD was associated with an increased risk of ventricular arrhythmias and decreased survival. COPD was a risk factor for SCD both in cardiovascular patient groups and in community-based studies, independent from cardiovascular risk profile. Studies of the potential impact of respiratory treatment on the occurrence of SCD showed conflicting results. In conclusion, cumulating evidence associates COPD with an increased risk of SCD. Asystole and pulseless electric activity could be more common than VT/VF in deaths associated with COPD. Underlying mechanisms explaining this association require further investigation.

Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram.

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.

Serum Magnesium and the Risk of Death From Coronary Heart Disease and Sudden Cardiac Death.

BACKGROUND: Low serum magnesium has been implicated in cardiovascular mortality, but results are conflicting and the pathway is unclear. We studied the association of serum magnesium with coronary heart disease (CHD) mortality and sudden cardiac death (SCD) within the prospective population-based Rotterdam Study, with adjudicated end points and long-term follow-up. METHODS AND RESULTS: Nine-thousand eight-hundred and twenty participants (mean age 65.1 years, 56.8% female) were included with a median follow-up of 8.7 years. We used multivariable Cox proportional hazard models and found that a 0.1 mmol/L increase in serum magnesium level was associated with a lower risk for CHD mortality (hazard ratio: 0.82, 95% CI 0.70-0.96). Furthermore, we divided serum magnesium in quartiles, with the second and third quartile combined as reference group (0.81-0.88 mmol/L). Low serum magnesium (≤0.80 mmol/L) was associated with an increased risk of CHD mortality (N=431, hazard ratio: 1.36, 95% CI 1.09-1.69) and SCD (N=217, hazard ratio: 1.54, 95% CI 1.12-2.11). Low serum magnesium was associated with accelerated subclinical atherosclerosis (expressed as increased carotid intima-media thickness: +0.013 mm, 95% CI 0.005-0.020) and increased QT-interval, mainly through an effect on heart rate (RR-interval: -7.1 ms, 95% CI -13.5 to -0.8). Additional adjustments for carotid intima-media thickness and heart rate did not change the associations with CHD mortality and SCD. CONCLUSIONS: Low serum magnesium is associated with an increased risk of CHD mortality and SCD. Although low magnesium was associated with both carotid intima-media thickness and heart rate, this did not explain the relationship between serum magnesium and CHD mortality or SCD. Future studies should focus on why magnesium associates with CHD mortality and SCD and whether intervention reduces these risks.

Subclinical Abnormalities in Echocardiographic Parameters and Risk of Sudden Cardiac Death in a General Population: The Rotterdam Study.

BACKGROUND: Subclinical cardiac dysfunction has been associated with increased mortality, and heart failure increases the risk of sudden cardiac death (SCD). Less well known is whether subclinical cardiac dysfunction is also a risk factor for SCD. Our objective was to assess the association between echocardiographic parameters and SCD in a community-dwelling population free of heart failure. METHODS AND RESULTS: We computed hazard ratios (HRs) for left atrium diameter, left ventricular (LV) end-diastolic dimension, LV end-systolic dimension, LV mass, qualitative LV systolic function, LV fractional shortening, and diastolic function. During a median follow-up of 6.3 years in 4,686 participants, 68 participants died because of SCD. Significant associations with SCD were observed for qualitative LV systolic function and LV fractional shortening. For moderate/poor qualitative LV systolic function, the HR for SCD was 2.54 (95% confidence interval [CI] 1.10-5.87). Each standard deviation decrease in LV fractional shortening was associated with an HR of 1.36 (95% CI 1.09-1.70). CONCLUSIONS: Subclinical abnormalities in LV systolic function were associated with SCD risk in this general population. Although prediction of SCD remains difficult and traditional cardiovascular risk factors are of greatest importance, this knowledge might guide future directions to prevent SCD in persons with subclinical cardiac dysfunction.

ABCB1 gene variants, digoxin and risk of sudden cardiac death in a general population.

OBJECTIVE: The ATP-binding cassette B1 (ABCB1) gene encodes P-glycoprotein, a transport protein, which plays an important role in the bioavailability of digoxin. We aimed to investigate the interaction between variants within the ABCB1 gene and digoxin on the risk of sudden cardiac death (SCD). METHODS: Within the Rotterdam Study, a population-based cohort study in persons 45 years of age and older, we used Cox regression to analyse the association between three polymorphisms that have been associated with digoxin bioavailability, extracted from 1000-Genomes imputed ABCB1 genotypes and the risk of SCD, stratified by digoxin use. RESULTS: In a total study population of 10,932 persons, 419 SCDs occurred during a median follow-up of 9.8 years. In non-users of digoxin, the risk of SCD was not different across genotypes. In digoxin users, homozygous T allele carriers of C1236T (HR 1.90; 95% CI 1.09 to 3.30; allele frequency 0.43), G2677T (HR 1.89; 95% CI 1.10 to 3.24; allele frequency 0.44) and C3435T (HR 1.72; 95% CI 1.03 to 2.87; allele frequency 0.53) had a significantly increased risk of SCD in a recessive model. Interaction between the ABCB1 polymorphisms and digoxin use was significant for C1236T and G2677T in the age-adjusted and sex-adjusted model. CONCLUSIONS: In this study, we showed that in digoxin users variant alleles at each of the three loci in the ABCB1 gene were associated with an increased risk of SCD compared with digoxin users with none or one T allele. If replicated, the findings imply that the ABCB1 genotype modifies the risk of cardiac digoxin toxicity.

Drugs and ventricular repolarization in a general population: the Rotterdam Study.

PURPOSE: Prolonged ventricular repolarization (measured as heart-rate corrected QT (QTc) prolongation or JT-interval prolongation) is a risk factor for ventricular arrhythmias and can be drug-induced. Drugs can be classified as having known or possible QTc-prolonging properties. Regulatory agencies recommend avoiding concomitant use of multiple QTc-prolonging drugs, but evidence is lacking to what degree ventricular repolarization is influenced by concomitant use of these drugs. METHODS: Within a population-based cohort of persons aged 45 years and older, with up to five electrocardiograms recorded per participant between 1991 and 2010, we used generalised estimating equations to study the association between concomitant use of multiple QTc-prolonging drugs and repolarization duration. RESULTS: The study population consisted of 13 009 participants with 26 908 electrocardiograms. With the addition of a second or third QTc-prolonging drug there was no substantial increase in QTc and JT interval and no increased risk of a prolonged QTc interval, compared to use of one QTc-prolonging drug. There was a large difference between the effect of one known or one possible QTc-prolonging drugs on QTc interval: 15 ms for known, and 3 ms for possible QTc-prolonging drugs. CONCLUSIONS: In this study, the added prolongation in users of two or three QTc-prolonging drugs on QTc was small. There was a large difference in QTc prolongation between known and possible QTc-prolonging drugs. Further research in larger or high-risk populations is needed to establish whether it is safe to use multiple QTc-prolonging drugs concomitantly to prevent that the current advice might unnecessarily withhold beneficial drugs from patients.

Consistency of heart rate-QTc prolongation consistency and sudden cardiac death: The Rotterdam Study.

BACKGROUND: A prolonged heart rate-corrected QT (QTc) interval is a well-known risk indicator for sudden cardiac death (SCD) and a contraindication for drugs with potentially arrhythmogenic adverse effects. OBJECTIVE: We aimed to study the consistency of QTc interval prolongation and whether a consistent QTc interval prolongation correlates differently with SCD than does an inconsistently prolonged QTc interval. METHODS: We used a population-based cohort study of persons 55 years and older. We excluded participants using QTc-prolonging drugs or with bundle branch block. The QT interval was corrected for heart rate using Bazett and Fridericia formulas. Using a Cox regression model, we assessed the association between QTc interval prolongation consistency and the occurrence of SCD. RESULTS: A total of 3484 participants had electrocardiograms (ECGs) recorded on 2 consecutive visits. In 96%-98% of participants with a normal QTc interval on the first ECG, the QTc interval remained normal, but only in 27%-35% of those with a prolonged QTc interval, the QTc interval was prolonged on the second ECG after a median of 1.8 years. A consistently prolonged QTc interval was associated with an increased risk of SCD as compared with a consistently normal QTc interval (Bazett: hazard ratio 2.23; 95% confidence interval 1.17-4.24, Fridericia: hazard ratio 6.67; 95% confidence interval 2.96-15.06). A prolonged QTc interval preceded or followed by a normal QTc interval was not significantly associated with an increased risk of SCD. CONCLUSION: Persons with an inconsistently prolonged QTc interval did not have a higher risk of SCD than those with a consistently normal QTc interval. Persons with a consistently prolonged QTc interval did have a higher risk of SCD. Our results suggest that repeated measurements of the QTc interval could enhance risk stratification.

Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update.

A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of drugs from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient. Identifying genetic variants associated with drug-induced QT prolongation might add to tailored pharmacotherapy and prevent beneficial drugs from being withdrawn unnecessarily. In this review, our objective was to provide an overview of the genetic background of drug-induced QT prolongation, distinguishing pharmacokinetic and pharmacodynamic pathways. Pharmacokinetic-mediated genetic susceptibility is mainly characterized by variation in genes encoding drug-metabolizing cytochrome P450 enzymes or drug transporters. For instance, the P-glycoprotein drug transporter plays a role in the pharmacokinetic susceptibility of drug-induced QT prolongation. The pharmacodynamic component of genetic susceptibility is mainly characterized by genes known to be associated with QT interval duration in the general population and genes in which the causal mutations of congenital long QT syndromes are located. Ethnicity influences susceptibility to drug-induced QT interval prolongation, with Caucasians being more sensitive than other ethnicities. Research on the association between pharmacogenetic interactions and clinical endpoints such as sudden cardiac death is still limited. Future studies in this area could enable us to determine the risk of arrhythmias more adequately in clinical practice.