Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10-3 to <1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

Abstract 17218: Radiation Therapy is not Associated With Incident Atrial Fibrillation in Patients With Thoracic Cancer

Introduction: Radiotherapy for thoracic cancer causes incidental cardiac exposure and increases risk of ischemic heart disease. Less clear is whether radiotherapy similarly increases risk of arrhythmias. Radiotherapy induces cardiac inflammation and fibrosis, which are risk factors for atrial fibrillation (AF). Hypothesis: In patients with thoracic tumors, radiotherapy is associated with incident AF. Methods: We conducted a retrospective study of electronic medical records (EMR) of patients who had a primary tumor of the breast, lung, mediastinum, or esophagus diagnosed between 1994 and 2014, did not have AF at time of diagnosis, and did not have previous thoracic radiotherapy. Patients were followed for incident AF until the end of the EMR or death. Incident AF was determined using a validated algorithm with a positive predictive value of 95.6%. After multiple imputation of missing variables, the association between radiotherapy and incident AF was assessed using Cox proportional hazards models. Results: 4163 patients were included in the analysis. Mean (SD) age was 61.2 (13.3) years and 71% were women; 600 underwent radiotherapy. After a median (25 th -75 th percentile) 796 (255-2032) days of follow-up, the incidence of AF was 6.8% with and 6.2% without radiotherapy (P=0.538). After adjustment for potential confounders, radiotherapy was not associated with incident AF [hazard ratio (HR): 1.02, 95% confidence interval: 0.72-1.44]. Age [HR (per year): 1.05 (1.04-1.06), P=6.0*10 -15 ], male sex [HR: 2.44 (1.80-3.30), P=9.5*10 -9 ], coronary artery disease [HR: 1.42 (1.06-1.92), P=0.02], hypertension [HR: 6.44 (2.04-20.3), P=0.001], and heart failure [HR: 3.20 (2.31-4.44), P=3.4*10 -12 ] were associated with incident AF. Among 3908 patients with unilateral breast or lung tumors, radiotherapy was not associated with incident AF [HR: 1.23 (0.79-1.92)] and tumor laterality did not modify the effect (P for interaction: 0.201). Conclusions: In this large retrospective cohort study, radiotherapy for thoracic tumors was not associated with incident AF. Rather, previously described AF risk factors were the most important drivers of AF risk. Larger studies with extended follow-up may further elucidate whether thoracic radiotherapy is a risk factor for AF. </jats:p

Abstract 17726: Comprehensive Evaluation of QT Interval During Abrupt Changes in Heart Rate and Associated Neurohormonal and Inflammatory Markers

Background: QT interval prolongation and risk of torsades de pointes have been associated with abrupt heart rate (HR) slowing after cardioversion from atrial fibrillation (AF) or AV nodal ablation. The degree to which the QT interval prolongs with abrupt changes in HR, and the underlying mechanisms, are poorly understood. We quantified ΔQT interval during cessation of rapid pacing and examined the relationship between QT and circulating neurohormonal and inflammatory markers. Methods: Eleven subjects with dual chamber pacemakers and intact AV conduction were atrially-paced at 90/min for 10 min, 60 min, and 1 week (Figure). Biomarkers were sampled during and after pacing. The relationships between QT, pacing stage, and biomarker levels were analyzed with a mixed effect model. QT intervals were compared for the 20 RR intervals before and 100 RR intervals after each pacing stage. Results: QT intervals prolonged after cessation of rapid pacing: 6.4 ms (95% confidence interval 4.9-7.8 ms) after 10 min (P&lt;0.0001), 6.1ms (4.6-7.5 ms) after 60 min (P&lt;0.0001), and 2.2ms (0.9-3.6 ms) after 1 week (P=0.002). QT interval was significantly associated with angiotensin II (P=0.002), epinephrine (P&lt;0.0001), norepinephrine (P=0.03), dopamine (P&lt;0.0001), C-reactive protein (P=0.0005), and interleukin-6 (P&lt;0.0001), but not associated with atrial natriuretic peptide (P=0.26), B-type natriuretic peptide (P=0.08), renin (P=0.25), or aldosterone (P=0.42). There were no significant inter-individual differences in biomarker levels drawn before and after pacing (P&gt;0.1 for all comparisons). Conclusion: Abrupt decreases in HR were associated with QT prolongation. QT interval changes correlated with several neuroendocrine and inflammatory biomarkers, though there were no inter-individual differences in biomarker levels before and after pacing. These findings may partially explain the increased risk of torsade de points after restoration of sinus rhythm from AF. </jats:p

Multiple Less Common Genetic Variants Explain the Association of the Cholesteryl Ester Transfer Protein Gene With Coronary Artery Disease

ObjectivesThe objective of this study was to identify associations of the cholesteryl ester transfer protein (CETP) gene with coronary artery disease (CAD) with tagging (t) single nucleotide polymorphisms (SNPs) chosen to optimally account for intra-genic variation.BackgroundThe CETP gene plays a critical role in lipoprotein metabolism, but the common and well-studied TaqIB variant is inconsistently predictive of CAD.MethodsFrom a deoxyribonucleic acid bank of 10,020 individuals, nondiabetic nonsmoking patients (n = 4,811) with angiographically defined, clinically significant CAD (≥70% stenosis) or normal coronaries were genotyped for 11 CETPtSNPs. Myocardial infarction (MI) and lipid levels were evaluated as secondary end points.ResultsAnalysis of single tSNPs, corrected for multiple comparisons (p < 0.00485), identified allele +1086A to be associated with CAD (p = 0.0034). Suggestive allelic and significant genotypic associations were found for −631AA (odds ratio [OR] = 3.95, p = 0.004 vs. CC) and +2389GA (OR = 1.21, p = 0.003 vs. GG). Haplotype analysis by linkage disequilibrium (LD) group revealed a CAD association for LD group B (p = 0.0025 across T+1086A, C+878T, C+408T) and near significance for LD group A (p = 0.013 across C-631A, MspI, G+2389A). A weak protective trend for TaqIB was eliminated by adjustment for other tSNPs, and haplotype analyses suggested that TaqIB was simply a marker for other tSNPs or haplotypes. No tSNP or haplotype associations with MI were found.ConclusionsMultiple, less common SNPs and haplotype variants underlie CETP-related CAD risk, for which the common TaqIB variant is simply a poor marker. The occurrence of risk-related variants on separate haplotypes suggests genetic-risk complexity and allelic heterogeneity. (Database Registry of the Intermountain Heart Collaborative Study; http://clinicaltrials.gov/ct/show/NCT00406185?order=1; NCT00406185)