Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.

BACKGROUND: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. METHODS: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. RESULTS: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. CONCLUSIONS: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.

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.

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.

Chronic obstructive pulmonary disease and sudden cardiac death: the Rotterdam study.

AIMS: Both sudden cardiac death (SCD) and chronic obstructive pulmonary disease (COPD) are common conditions in the elderly. Previous studies have identified an association between COPD and cardiovascular disease, and with SCD in specific patient groups. Our aim was to investigate whether there is an association between COPD and SCD in the general population. METHODS AND RESULTS: The Rotterdam study is a population-based cohort study among 14 926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a (time dependent) Cox proportional hazard model adjusted for age, sex, and smoking. Of the 13 471 persons included in the analysis; 1615 had a diagnosis of COPD and there were 551 cases of SCD. Chronic obstructive pulmonary disease was associated with an increased risk of SCD (age- and sex-adjusted hazard ratio, HR, 1.34, 95% CI 1.06-1.70). The risk particularly increased in the period 2000 days (5.48 years) after the diagnosis of COPD (age- and sex-adjusted HR 2.12, 95% CI 1.60-2.82) and increased further to a more than three-fold higher risk in COPD subjects with frequent exacerbations during this period (age- and sex-adjusted HR 3.58, 95% CI 2.35-5.44). Analyses restricted to persons without prevalent myocardial infarction or heart failure yielded similar results. CONCLUSION: Chronic obstructive pulmonary disease is associated with an increased risk for SCD. The risk especially increases in persons with frequent exacerbations 5 years after the diagnosis of COPD. This risk indicator could provide new directions for better-targeted actions to prevent SCD.

Assessing Prolongation of the Heart Rate Corrected QT Interval in Users of Tricyclic Antidepressants: Advice to Use Fridericia Rather Than Bazett's Correction.

A prolonged heart rate corrected QT interval (QTc) increases the risk of sudden cardiac death. Some methods of heart rate correction (notably Bazett) overestimate QTc in people with high heart rates. Studies suggest that tricyclic antidepressants (TCAs) can prolong the QTc and increase heart rate. Therefore, we aimed to study whether TCA-induced QTc prolongation is a false-positive observation due to overestimation at high heart rates. For this, we included 12,734 participants from the prospective population-based Rotterdam Study, with a total of 27,068 electrocardiograms (ECGs), of which, 331 during TCA use. Associations between use of TCAs, QTc, and heart rate were studied with linear repeated measurement analyses. QT was corrected for heart rate according to Bazett (QTcBazett), Fridericia (QTcFridericia), or a correction based on regression coefficients obtained from the Rotterdam Study data (QTcStatistical). On ECGs recorded during TCA use, QTcBazett was 6.5 milliseconds (95% confidence interval, 4.0-9.0) longer, and heart rate was 5.8 beats per minute (95% confidence interval, 4.7-6.9) faster than during nonuse. QTcFridericia and QTcStatistical were not statistically significantly longer during TCA use than during nonuse. Furthermore, QTcBazett was similar for ECGs recorded during TCA use and nonuse after statistical adjustment for heart rate. According to our results, TCA use does not seem to be associated with QTc prolongation. Therefore, the current advice of regulatory authorities to restrict the use of these drugs and to do regular checkups of the QTc may need to be revised. Other formulas, like Fridericia's, might be preferred.

Use of selective serotonin re-uptake inhibitors and the heart rate corrected QT interval in a real-life setting: the population-based Rotterdam Study.

AIMS: Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QTc prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults. METHODS: This study, which was part of the prospective Rotterdam Study (period 1991-2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QTc F (QT corrected according to Fridericia) measured during use of individual SSRIs with QTc F measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older. RESULTS: We included 12 589 participants with a total of 26 620 ECGs of which 436 ECGs were made during SSRI use. The mean QTc F was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QTc compared with ECGs recorded during non-use (+12.8 ms, 90% CI 7.5, 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg citalopram. CONCLUSIONS: Although no SSRI class effect was observed, use of citalopram was associated with a longer QTc F, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QTc F prolongation.

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.

Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis.

OBJECTIVE: Currently, there is no consensus on the definition of hyperemesis gravidarum (HG; protracted vomiting in pregnancy) and no single widely used set of diagnostic criteria for HG. The various definitions rely on symptoms, sometimes in combination with laboratory tests. Through a systematic review, we aimed to summarize available evidence on the diagnostic value of biomarkers for HG. This could assist diagnosis and may shed light on the, as yet, not understood cause of the disorder. STUDY DESIGN: We searched Medline and Embase for articles about diagnostic biomarkers for either the presence or severity of HG or nausea and vomiting of pregnancy. We defined HG as any combination of nausea, vomiting, dehydration, weight loss, or hospitalization for nausea and/or vomiting in pregnancy, in the absence of any other obvious cause for these complaints. RESULTS: We found 81 articles on 9 biomarkers. Although 65% of all studies included only HG cases with ketonuria, we did not find an association between ketonuria and presence or severity of HG in 5 studies reporting on this association. Metaanalysis, with the use of the hierarchical summary receiver operating characteristics model, yielded an odds ratio of 3.2 (95% confidence interval, 2.0-5.1) of Heliobacter pylori for HG, as compared with asymptomatic control subjects (sensitivity, 73%; specificity, 55%). Studies on human chorionic gonadotropin and thyroid hormones, leptin, estradiol, progesterone, and white blood count showed inconsistent associations with HG; lymphocytes tended to be higher in women with HG. CONCLUSION: We did not find support for the use of ketonuria in the diagnosis of HG. H pylori serology might be useful in specific patients.

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.].

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

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.

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.

Fifteen Genetic Loci Associated With the Electrocardiographic P Wave.

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

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.

Association of Lipid-Related Genetic Variants with the Incidence of Atrial Fibrillation: The AFGen Consortium.

BACKGROUND: Several studies have shown associations between blood lipid levels and the risk of atrial fibrillation (AF). To test the potential effect of blood lipids with AF risk, we assessed whether previously developed lipid gene scores, used as instrumental variables, are associated with the incidence of AF in 7 large cohorts. METHODS: We analyzed 64,901 individuals of European ancestry without previous AF at baseline and with lipid gene scores. Lipid-specific gene scores, based on loci significantly associated with lipid levels, were calculated. Additionally, non-pleiotropic gene scores for high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were calculated using SNPs that were only associated with the specific lipid fraction. Cox models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of AF per 1-standard deviation (SD) increase of each lipid gene score. RESULTS: During a mean follow-up of 12.0 years, 5434 (8.4%) incident AF cases were identified. After meta-analysis, the HDLc, LDLc, total cholesterol, and triglyceride gene scores were not associated with incidence of AF. Multivariable-adjusted HR (95% CI) were 1.01 (0.98-1.03); 0.98 (0.96-1.01); 0.98 (0.95-1.02); 0.99 (0.97-1.02), respectively. Similarly, non-pleiotropic HDLc and LDLc gene scores showed no association with incident AF: HR (95% CI) = 1.00 (0.97-1.03); 1.01 (0.99-1.04). CONCLUSIONS: In this large cohort study of individuals of European ancestry, gene scores for lipid fractions were not associated with incident AF.

Gene-gene Interaction Analyses for Atrial Fibrillation.

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 × 10-8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10-7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.

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.

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.

Declining incidence of sudden cardiac death from 1990-2010 in a general middle-aged and elderly population: The Rotterdam Study.

BACKGROUND: Although sudden cardiac death (SCD) is relatively common, contemporary data on its incidence are lacking. OBJECTIVE: The purpose of this study was to investigate the current incidence of SCD and its trend over the past 2 decades in a general middle-aged and elderly population. METHODS: This study was performed within the Rotterdam Study, a prospective population-based cohort study of persons aged 45 years and older. Age-standardized incidence rates of SCD were calculated. To study trends in incidence, we compared 2 subcohorts within the total study population, 1 followed from 1990-2000 and the other from 2001-2010. RESULTS: From 1990-2010, 5512 of 14,628 participants died, of whom 583 (4.0%) were classified as SCD. The overall incidence was 4.2 per 1000 person-years. The incidence was higher in men (5.2 per 1000 person-years) than in women (3.6 per 1000 person-years). Age-adjusted hazard ratio (HR) 1.84 (95% confidence [CI] 1.56-2.17) and risk of SCD increased with age (HR 1.10 per year; 95% CI 1.09-1.11). The incidence rate from 1990-2000 was 4.7 per 1000 person-years vs 2.1 per 1000 person-years from 2001-2010 (age- and sex-adjusted HR of SCD 0.60, 95% CI 0.44-0.80). To check for cohort effects, we also analyzed the incidence of total mortality and found an age- and sex-adjusted HR of total mortality of 0.82 (95% CI 0.75-0.90) for the second compared to the first subcohort, which was significantly higher than the decline in SCD incidence. CONCLUSION: We found an incidence of SCD of 4.2 per 1000 person-years. The incidence decreased from 1990-2010, a period during which the diagnosis and treatment of heart disease greatly improved.