Methods

TexGen is a collaborative, prospective genetic registry that enrolls patients with any personal or family history of cardiovascular disease who seek care at several institutions within the Texas Medical Center system, including the University of Texas Health Science Center, the University of Texas M. D. Anderson Cancer Center, and Baylor College of Medicine and their affiliated hospitals, and the Texas Heart Institute at St. Luke’s Episcopal Hospital. The cohort included patients admitted with acute coronary syndrome, stroke, or transient ischemic attack, those undergoing percutaneous coronary interventions or CABG, and those undergoing vascular surgical procedures.

For the present analyses, we restricted the population to TexGen patients undergoing CABG (with or without valve surgery procedures) from September 2001 through September 2008, who had self-reported their race as white to avoid the issue of population stratification.

The preoperative, intraoperative, and postoperative characteristics of the patients were obtained through a database maintained at the St. Luke’s Episcopal Hospital. This research database is used to prospectively collect information on patients enrolled in TexGen. The database has written documentation for each field that is coded and has systems in place to ensure the reliability of the data, including range edit limits for every data field, consistency checks between fields, and periodic inter-rater reliability. The data from the patient charts were abstracted by 3 trained abstractors, with 95% agreement among the abstractors. Monthly electronic quality control checks were conducted to detect logical errors. When verification coding (recoding the same admission) was performed on a minimum of 10 admissions per month, it was found that 95% of the data collected were correct.

The variables used in our analysis included age, gender, history of acute coronary syndromes, hypertension, diabetes mellitus, concomitant valve surgery, history of AF, reduced left ventricular ejection fraction (defined as <0.35), New York Heart Association functional class at surgery, preoperative BB, antiarrhythmic medication, or statin use, and aortic cross-clamp and total bypass time.

The prospective follow-up of outcomes included annual follow-up telephone calls by the TexGen research nurses and annual surveys mailed to each patient. In addition, any hospitalization for patients enrolled in the database was also verified using the hospitalization records.

Genotyping of rs2200733 and rs10033464 variants was performed using validated TaqMan assays (Applied Biosystems, Life Technologies, Carlsbad, California). These 2 polymorphisms on chromosome 4q25 were chosen a priori because these polymorphisms have been the ones extensively studied thus far. Polymerase chain reaction product was amplified using 0.9 μm each of the forward and reverse primers, 0.2 μm each of the fluorescein amidite and VIC minor groove binder sequence-specific probes, 3 ng DNA, 5.0 mM MgCl ₂ , and 1× TaqMan Universal PCR Master Mix containing AmpliTaq gold DNA polymerase in a 5.5-μl reaction volume. Both the SNPs had a call rate of >99%. A Hardy-Weinberg equilibrium of p >0.05 was calculated using a chi-square goodness-of-fit model. The quality control concordance for 37 samples was 100%.

Our primary outcomes of interest included the development of postoperative AF after CABG and long-term development of AF after discharge. Postoperative AF was defined as the occurrence of any AF during hospitalization for the index surgery. All patients were monitored with continuous telemetry (either in the intensive care unit or on the telemetry floors) throughout their hospital stay, and any episode of AF was included in the present analysis. The long-term development of AF after the index hospitalization for CABG included any new AF that either necessitated hospitalization or was noted on an electrocardiogram for a hospitalization for a reason other than AF. We also performed exploratory analyses to assess whether the associations between these polymorphisms and the risk of postoperative AF could be modulated by age, gender, or the type of preoperative therapy (preoperative BB, statin, or antiarrhythmic) used.

Our secondary outcomes of interest included the development of postoperative stroke, the development of stroke during long-term follow-up, and long-term survival. Stroke was defined as clinical evidence of a focal neurologic deficit and a radiologic defect on the computed tomographic or magnetic resonance imaging scan of the brain. The vital status of these patients was ascertained using data from the Texas State Bureau of Vital Statistics.

The categorical and continuous variables were compared between the groups using the Pearson chi-square test or Wilcoxon rank-sum test, respectively. The Hardy-Weinberg equilibrium expectation of allelic frequencies was tested using a chi-square goodness-of-fit model.

For the development of postoperative AF, we initially performed univariate analyses to study the associations between each SNP, rs2200733 and rs10033464, and the risk of postoperative AF development. Logistic regression analyses were subsequently performed using a limited adjustment model that included age and gender, followed by a more extensive adjustment model that included age, gender, history of AF, hypertension, preoperative BB, statin, or antiarrhythmic use, and concomitant valve surgery as covariates to ascertain whether the polymorphisms of interest were independent predictors of postoperative AF in the fully adjusted models.

For long-term risk of AF, we initially performed a log-rank test to study the association between rs2200733 and rs10033464 and the interval to the development of AF. Cox proportional hazards models (adjusting for age, gender, and hypertension) were subsequently used to determine whether polymorphisms in rs2200733 and rs10033464 were independently associated with the long-term development of AF. Similarly, logistic and Cox regressions analyses were used to determine whether rs2200733 and rs10033464 were associated with development of postoperative stroke or the long-term development of stroke, respectively. The associations between rs2200733 and rs10033464 and survival were analyzed using the log-rank test.

For all these analyses, a dominant model was used to study the associations between polymorphisms in rs2200733 and rs10033464 and the outcomes of interest. Statistical analyses were performed using SAS statistical software, version 9.1 (SAS Institute, Cary, North Carolina). All analyses were performed using 2-tailed tests for significance. Because we were evaluating these polymorphisms on an a priori basis, a p value of <0.05 was considered statistically significant, and adjustments were not made for multiple comparisons.

Results

Of the patients undergoing CABG enrolled in the TexGen database (n = 1,568), 1,166 patients identified their race as white. This group represented the final population included in the present analyses. The baseline characteristics of these patients are listed in Table 1 . The mean age of the cohort was 65 years, and the proportion of men was greater. The prevalence of hypertension and patients with New York Heart Association functional class III-IV symptoms was high, and 10% of the patients reported a history of AF.

The frequencies for rs2200733 and rs10033464 in the TexGen sample are listed in Table 2 . Overall, 22% of the patients carried ≥1 risk allele (T) for rs2200733, and roughly 16% of the patients carried ≥1 risk allele (T) for rs10033464.

Overall, the incidence of in-hospital AF after CABG in our cohort was 36.45%. The odds ratios for the risk of the development of postoperative AF after univariate analyses and after adjustment for the covariates of interest using the dominant model are listed in Table 3 . Carriers of the risk allele (TT or CT) for rs2200733 had a 41% greater risk of developing postoperative AF in the fully adjusted model. In contrast, the presence of the minor allele for rs10033464 (TT or GT) was associated with a 47% increased risk of the development of postoperative AF. Similar results were obtained after excluding the 117 patients with a history of AF ( Supplemental Table 1 ).

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