Peter A. Noseworthy

Common variants at ten loci influence QT interval duration in the QTGEN Study.

QT interval duration reflecting myocardial repolarization on the electrocardiogram is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of 3 genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study. We observed associations at P < 5×10−8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and Mendelian Long QT Syndromes. Associations at five novel loci included 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RIFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4–6.5% of variation in QT interval. Identifying the causal variants and defining their impact on myocardial repolarization may add incrementally to the prevention of sudden cardiac death and drug-induced arrhythmias.QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 × 10−8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4–6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

The early repolarization pattern in the general population: clinical correlates and heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. RESULTS ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). CONCLUSIONS ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted.

Expedited PublicationThe Early Repolarization Pattern in the General Population: Clinical Correlates and Heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. RESULTS ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). CONCLUSIONS ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted.

Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation

Background In comparison to warfarin, non–vitamin K antagonist oral anticoagulants (NOACs) have the advantages of ease of dosing, fewer drug interactions, and lack of need for ongoing monitoring. We sought to evaluate whether these advantages translate to improved adherence and whether adherence is associated with improved outcomes in patients with atrial fibrillation. Methods and Results We performed a retrospective cohort analysis by using a large US commercial insurance database to identify 64 661 patients with atrial fibrillation who initiated warfarin, dabigatran, rivaroxaban, or apixaban treatment between November 1, 2010, and December 31, 2014. During a median of 1.1 y of follow‐up, 47.5% of NOAC patients had a proportion of days covered of ≥80%, compared with 40.2% in warfarin patients (P<0.001). Patients with CHA 2 DS 2‐VASc (risk based on the presence of congestive heart failure, hypertension age 65–74 y, age ≥75 y, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, sex category) score ≥4 were at increased risk of stroke when they were not taking anticoagulation ≥1 month versus <1 week (1–3 months: hazard ratio [HR] 1.96, 3–6 months: HR 2.64, ≥6 months: HR 3.66; all P<0.001). Patients with CHA 2 DS 2‐VASc score 2 or 3 were at increased risk of stroke when they were not taking anticoagulation ≥6 months (HR 2.73, P<0.001). In these patients with CHA 2 DS 2‐VASc score ≥2, nonadherence was not associated with intracranial hemorrhage. Among patients with CHA 2 DS 2‐VASc score 0 or 1, time not taking anticoagulation was not associated with stroke, but not taking anticoagulation ≥3 months was associated with a significant reduction of bleeding. Conclusions Adherence to anticoagulation is poor in practice and may be modestly improved with NOACs. Adherence to therapy appears to be most important in patients with CHA 2 DS 2‐VASc score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA 2 DS 2‐VASc score 0 or 1.

QTc Prolongation, Torsades de Pointes, and Psychotropic Medications

BACKGROUND Prolongation of the corrected QT (QTc) interval is a key issue for patients who receive psychotropic medications. Such patients may have baseline clinical risk factors for QTc prolongation, and many psychotropic medications may further prolong this interval. This has great clinical relevance, as QTc prolongation is linked with dangerous arrhythmias, especially torsades de pointes (TdP). METHODS We summarize current literature regarding appropriate methods of calculating the QTc interval, the association of the QTc interval with TdP, and risk factors for QTc prolongation. We then review connections between psychiatric medications and QTc prolongation, with a specific focus on antidepressants and antipsychotics. RESULTS QTc interval prolongation is an established, though imperfect, risk marker for TdP. There are no well-controlled studies that assess the risk of TdP associated with psychotropic agents. There are limited data that selective serotonin reuptake inhibitors (SSRIs) as a class are linked to QTc prolongation; citalopram appears more likely than others to induce this phenomenon. Among antipsychotics, thioridazine remains the agent most associated with QTc prolongation; intravenous haloperidol also appears to carry an increased risk. Of the atypical antipsychotics, ziprasidone appears most likely to prolong the QTc interval. CONCLUSIONS The majority of patients in need of psychotropic medications display few risk factors for QTc prolongation and should be considered to be at low risk for TdP. The frequency of cardiac monitoring for patients receiving psychiatric medications should be individually determined, based on the prescribed agent(s) and additional risk factors for TdP.

Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation

Background The introduction of non–vitamin K antagonist oral anticoagulants has been a major advance for stroke prevention in atrial fibrillation; however, outcomes achieved in clinical trials may not translate to routine practice. We aimed to evaluate the effectiveness and safety of dabigatran, rivaroxaban, and apixaban by comparing each agent with warfarin. Methods and Results Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: apixaban versus warfarin (n=15 390), dabigatran versus warfarin (n=28 614), and rivaroxaban versus warfarin (n=32 350). Using Cox proportional hazards regression, we found that for stroke or systemic embolism, apixaban was associated with lower risk (hazard ratio [HR] 0.67, 95% CI 0.46–0.98, P=0.04), but dabigatran and rivaroxaban were associated with a similar risk (dabigatran: HR 0.98, 95% CI 0.76–1.26, P=0.98; rivaroxaban: HR 0.93, 95% CI 0.72–1.19, P=0.56). For major bleeding, apixaban and dabigatran were associated with lower risk (apixaban: HR 0.45, 95% CI 0.34–0.59, P<0.001; dabigatran: HR 0.79, 95% CI 0.67–0.94, P<0.01), and rivaroxaban was associated with a similar risk (HR 1.04, 95% CI 0.90–1.20], P=0.60). All non–vitamin K antagonist oral anticoagulants were associated with a lower risk of intracranial bleeding. Conclusions In patients with nonvalvular atrial fibrillation, apixaban was associated with lower risks of both stroke and major bleeding, dabigatran was associated with similar risk of stroke but lower risk of major bleeding, and rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin.

Genome-wide association analysis identifies multiple loci related to resting heart rate

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Early Repolarization Pattern in Competitive Athletes Clinical Correlates and the Effects of Exercise Training

Background— Inferior lead early repolarization pattern (ERP) recently has been associated with sudden cardiac death. Although ERP is common among athletes, prevalence, ECG lead distribution, clinical characteristics, and effects of physical training remain uncertain. We sought to examine the nonanterior ERP in competitive athletes. Methods and Results— ERP was assessed in a cross-sectional cohort of collegiate athletes (n=879). The relationship between ERP and cardiac structure were then examined in a longitudinal subgroup (n=146) before and after a 90-day period of exercise training. ERP was defined as J-point elevation ≥0.1 mV in at least 2 leads within a nonanterior territory (inferior [II, III, aVF] or lateral territory [I, aVL, V4-V6]). Nonanterior ERP was present in 25.1% (221/879) of athletes, including the inferior subtype in 3.8% (33/879). Exercise training led to significant increases in the prevalence of ERP and the inferior subtype, but there were no associations between ERP and echocardiographic measures of left ventricular remodeling. In a multivariable model, ERP was associated with black race (odds ratio [OR], 5.84; 95% CI, 3.54 to 9.61; P <0.001), increased QRS voltage (OR, 2.08; 95% CI, 1.71 to 2.52; P <0.001), and slower heart rate (OR, 1.54; 95% CI, 1.26 to 1.87; P <0.001). Conclusions— Nonanterior ERP, including the inferior subtype, is common and has strong clinical associations among competitive athletes. The finding of increased ERP prevalence after intense physical training establishes a strong association between exercise and ERP.Background— Inferior lead early repolarization pattern (ERP) recently has been associated with sudden cardiac death. Although ERP is common among athletes, prevalence, ECG lead distribution, clinical characteristics, and effects of physical training remain uncertain. We sought to examine the nonanterior ERP in competitive athletes. Methods and Results— ERP was assessed in a cross-sectional cohort of collegiate athletes (n=879). The relationship between ERP and cardiac structure were then examined in a longitudinal subgroup (n=146) before and after a 90-day period of exercise training. ERP was defined as J-point elevation ≥0.1 mV in at least 2 leads within a nonanterior territory (inferior [II, III, aVF] or lateral territory [I, aVL, V4-V6]). Nonanterior ERP was present in 25.1% (221/879) of athletes, including the inferior subtype in 3.8% (33/879). Exercise training led to significant increases in the prevalence of ERP and the inferior subtype, but there were no associations between ERP and echocardiographic measures of left ventricular remodeling. In a multivariable model, ERP was associated with black race (odds ratio [OR], 5.84; 95% CI, 3.54 to 9.61; P<0.001), increased QRS voltage (OR, 2.08; 95% CI, 1.71 to 2.52; P<0.001), and slower heart rate (OR, 1.54; 95% CI, 1.26 to 1.87; P<0.001). Conclusions— Nonanterior ERP, including the inferior subtype, is common and has strong clinical associations among competitive athletes. The finding of increased ERP prevalence after intense physical training establishes a strong association between exercise and ERP.

Genetic Determinants of Sudden Cardiac Death

Sudden cardiac death (SCD) is the final common end point of multiple disease processes. It results from a complex interplay of structural, metabolic, and genetic determinants. Although epidemiological risk factors such as age, prior myocardial infarction, and low ejection fraction are well established, this syndrome also has a strong genetic component. An understanding of the genetic contributions to risk could add substantially to the prediction and prevention of SCD. In this review, we explore the epidemiology, heritability, and allelic architecture of SCD and provide a detailed overview of the genetics of inherited electrophysiological and structural heart diseases that are potent risk factors for SCD. Each year, SCD claims >300 000 lives in the United States.1 Most cases, ≈80%, are related to underlying coronary artery disease. Fewer cases, ≈10% to 15%, are associated with an underlying nonischemic myopathic process such as hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Approximately 5% are estimated to have a primary defect of cardiac electrophysiology (eg, long-QT syndrome [LQTS] or Brugada syndrome [BS]).2 At the population level, the conventional cardiac risk factors are powerful risk factors for SCD. For example, diabetes mellitus is associated with a marked increase in risk of SCD (odds ratio=1.7 without microvascular disease; odds ratio=2.7 with microvascular disease).3 Among subjects with known coronary artery disease, smoking is linked to an increase in risk of SCD (hazard ratio=2.5).4 In a multivariate analysis from the Paris Prospective Study, a 42-mg/dL increase in total cholesterol (1 SD of the sample variation) was associated with a 23% increased risk of SCD. In the same analysis, an increase of 20 mm Hg in systolic blood pressure was associated with a 23% increase in the risk of SCD.5 Furthermore, data from the Framingham Heart Study demonstrate that left ventricular hypertrophy is a risk …

Meta-Analysis of Selective Serotonin Reuptake Inhibitor–Associated QTc Prolongation

OBJECTIVE To evaluate the association between selective serotonin reuptake inhibitors (SSRIs) and corrected QT interval (QTc) prolongation via meta-analysis of prospective studies. DATA SOURCES PubMed/MEDLINE database (January 1, 1975-August 15, 2012), with additional reports identified using hand searches of reference lists of relevant articles. Key words searched were QT, torsades de pointes, and sudden cardiac death, combined with antidepressants, citalopram, escitalopram, fluoxetine, sertraline, paroxetine, and fluvoxamine. English-, Spanish-, and German-language articles were included. STUDY SELECTION Two reviewers independently identified prospective controlled studies in adults that reported data related to QTc intervals prior to and following treatment with SSRIs. DATA EXTRACTION AND SYNTHESIS Three reviewers independently extracted study-level data including population characteristics, method of QTc measurement and treatment and outcome data. Two independent reviewers critiqued study quality. Publication bias was assessed visually using a funnel plot and quantitatively. Heterogeneity was measured using Cochran Q statistic. RESULTS Sixteen articles (with 25 distinct data subsets) involving 4,292 patients were included. SSRIs were associated with a dose-dependent increase in QTc interval compared to placebo (+6.10 milliseconds; 95% CI, 3.47-8.73; P < .001). Tricyclic antidepressants (TCAs) were associated with a significantly greater QTc increase than SSRIs (TCA prolongation, 7.05 milliseconds; 95% CI, 3.84-10.27 greater than SSRIs; P < .001). With respect to specific SSRI agents, citalopram was associated with significantly greater QTc prolongation than sertraline, paroxetine, and fluvoxamine. CONCLUSIONS SSRIs were associated with a modest but statistically significant increase in the QTc interval, although to a lesser extent than TCAs; this finding was not limited to any single study. Citalopram was associated with more QTc prolongation than most other SSRIs.