Background

Prolongation of the QT interval has been associated with an increased risk of developing atrial fibrillation (AF), but the responsible mechanism remains unknown.

Objectives

The aims of this study were to subdivide the QT interval into its components and identify the resultant electrocardiographic interval(s) responsible for the association with AF.

Methods

Predefined QT-interval components were assessed for association with incident AF in the Atherosclerosis Risk in Communities study using Cox proportional hazards models. Hazard ratios (HRs) were calculated per 1-SD increase in each component. Among QT-interval components exhibiting significant associations, additional analyses evaluating long extremes, defined as greater than the 95^th percentile, were performed.

Results

Of the 14,625 individuals, 1505 (10.3%) were diagnosed with incident AF during a mean follow-up period of 17.6 years. After multivariable adjustment, QT-interval components involved in repolarization, but not depolarization, exhibited significant associations with incident AF, including a longer ST segment (HR 1.27; 95% confidence interval [CI] 1.14-1.41; P < .001) and a prolonged T-wave onset to T-wave peak (T-onset to T-peak) (HR 1.13; 95% CI 1.07-1.20; P < .001). Marked prolongation of the ST segment (HR 1.31; 95% CI 1.04-1.64; P = .022) and T-onset to T-peak (HR 1.36; 95% CI 1.09-1.69; P = .006) was also associated with an increased risk of incident AF.

Conclusion

The association between a prolonged QT interval and incident AF is primarily explained by components involved in ventricular repolarization: prolongation of the ST segment and T-onset to T-peak. These observations suggest that prolongation of phases 2 and 3 of the cardiac action potential drives the association between the QT interval and AF risk.

The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation.

Background

The prediction of atrial fibrillation (AF) following catheter ablation of atrial flutter (Afl) would be helpful to facilitate targeted arrhythmia monitoring and anti-coagulation strategies. A single nucleotide polymorphism, rs2200733, is strongly associated with AF. We sought to characterize the association between rs2200733 and prevalent Afl and to determine if the variant could predict AF after cavotricuspid isthmus ablation.

Methods and results

We performed a genetic association study of 295 patients with Afl and/or AF and 469 controls using multivariable logistic regression. The variant was then assessed as a predictor of incident AF after cavotricuspid isthmus ablation in 87 consecutive typical Afl patients with Cox proportional hazards models. The rs2200733 rare allele was associated with an adjusted 2.06-fold increased odds of isolated Afl (95% CI: 1.13-3.76, P = 0.019) and an adjusted 2.79-fold increased odds of a combined phenotype of AF and Afl (95% CI: 1.81-4.28, P < 0.001). Following catheter ablation for Afl, carrier status of rs2200733 failed to predict an increased risk of AF either among all subjects (adjusted HR: 0.94; 95% CI: 0.58-1.53, P = 0.806) or among those with isolated Afl (adjusted HR: 1.29; 95% CI: 0.51-3.26, P = 0.585).

Conclusions

Our study demonstrates that Afl, whether occurring in isolation or along with AF, is associated with the rs2200733 AF risk allele. Genetic carrier status of rs2200733 failed to predict an increased risk of incident or recurrent AF following catheter ablation for Afl. These findings suggest that the causal mechanism associated with rs2200733 is germane to both AF and Afl.

Background

Studies of ≤15 atrial fibrillation (AF) patients have identified atrial-specific mutations within connexin genes, suggesting that somatic mutations may account for sporadic cases of the arrhythmia. We sought to identify atrial somatic mutations among patients with and without AF using targeted deep next-generation sequencing of 560 genes, including genetic culprits implicated in AF, the Mendelian cardiomyopathies and channelopathies, and all ion channels within the genome.

Methods and results

Targeted gene capture and next-generation sequencing were performed on DNA from lymphocytes and left atrial appendages of 34 patients (25 with AF). Twenty AF patients had undergone cardiac surgery exclusively for pulmonary vein isolation and 17 had no structural heart disease. Sequence alignment and variant calling were performed for each atrial-lymphocyte pair using the Burrows-Wheeler Aligner, the Genome Analysis Toolkit, and MuTect packages. Next-generation sequencing yielded a median 265-fold coverage depth (interquartile range, 64-369). Comparison of the 3 million base pairs from each atrial-lymphocyte pair revealed a single potential somatic missense mutation in 3 AF patients and 2 in a single control (12 versus 11%; P=1). All potential discordant variants had low allelic fractions (range, 2.3%-7.3%) and none were detected with conventional sequencing.

Conclusions

Using high-depth next-generation sequencing and state-of-the art somatic mutation calling approaches, no pathogenic atrial somatic mutations could be confirmed among 25 AF patients in a comprehensive cardiac arrhythmia genetic panel. These findings indicate that atrial-specific mutations are rare and that somatic mosaicism is unlikely to exert a prominent role in AF pathogenesis.

Several reports have demonstrated that prolongation of the QT interval is associated with sudden cardiac death (SCD). However, it is unknown whether any of the components within the QT interval are responsible for its association with SCD. We examined the association of the individual QT-interval components (R-wave onset to R-peak, R-peak to R-wave end, ST-segment, T-wave onset to T-peak, and T-peak to T-wave end) with SCD in 12 241 participants (54±5.7 years; 26% black; 55% women) from the ARIC study (Atherosclerosis Risk in Communities). The QT interval and its components were measured at baseline (1987-1989) from 12-lead ECGs. SCD cases were adjudicated by a group of physicians through December 31, 2012. During a median follow-up of 23.6 years, a total of 346 cases of SCD were identified. Although prolongation of the QT interval was associated with a 49% increased risk of SCD (hazard ratio, 1.49; 95% confidence interval, 1.01-2.18), only the T-wave onset to T-peak component (per 1-SD increase: hazard ratio, 1.19; 95% confidence interval, 1.06-1.34) was associated with SCD and not any of the other components in separate models. When all of the QT-interval components were included in the same model, T-wave onset to T-peak remained the strongest predictor of SCD (per 1-SD increase: hazard ratio, 1.21; 95% confidence interval, 1.06-1.37). The risk of SCD with the QT interval is driven by prolongation of the T-wave onset to T-peak component. This suggests that shifting the focus from the overall QT interval to its individual components will refine SCD prediction in the community.

Background

Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

Methods and results

Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.

Conclusions

Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable arrhythmia syndrome entailing a high risk of sudden cardiac death. Discernment from benign arrhythmia disorders, particularly right ventricular outflow tract ventricular tachycardia (RVOT VT), may be challenging, providing an impetus to explore alternative modalities that may facilitate evaluation of patients with suspected ARVC.

Objective

We evaluated the role of equilibrium radionuclide angiography (ERNA) as a diagnostic tool for ARVC.

Methods

ERNA measures of ventricular synchrony-synchrony (S) and entropy (E)-were examined in patients with ARVC (n = 16), those with RVOT VT (n = 13), and healthy controls (n = 49). The sensitivity and specificity of ERNA parameters for ARVC diagnosis were compared with those of echocardiography (ECHO) and cardiovascular magnetic resonance (CMR).

Results

ERNA right ventricular synchrony parameters in patients with ARVC (S = 0.91 ± 0.07; E = 0.61 ± 0.1) differed significantly from those in patients with RVOT VT (S = 0.99 ± 0.01 [P = .0015]; E = 0.46 ± 0.05 [P < .001]) and healthy controls (S = 0.97 ± 0.02 [P = .003]; E = 0.48 ± 0.07 [P = .001]). The sensitivity of ERNA synchrony parameters for ARVC diagnosis (81%) was higher than that for ECHO (38%; P = .033) and similar to that for CMR (69%; P = .162), while specificity was lower for ERNA (89%) than that for ECHO and CMR (both 100%; P = .008).

Conclusion

ERNA right ventricular synchrony parameters can distinguish patients with ARVC from controls with structurally normal hearts, and its performance is comparable to that of ECHO and CMR for ARVC diagnosis. These findings suggest that ERNA may serve as a valuable imaging tool in the diagnostic evaluation of patients with suspected ARVC.

Background

Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.

Methods

We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.

Results

Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.

Conclusions

Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.

Importance

White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.

Objectives

To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.

Design, setting, and participants

Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.

Main outcomes and measures

Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.

Results

A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4%; 95% CI, 2.9%-29.9%) and ARIC (31.7%; 95% CI, 16.0%-53.0%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.

Conclusions and relevance

The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.