Interleukin-1β gene variants are associated with QTc interval prolongation following cardiac surgery: a prospective observational study

Abstract

Background: We characterized cardiac surgery-induced dynamic changes of the corrected QT (QTc) interval and tested the hypothesis that genetic factors are associated with perioperative QTc prolongation independent of clinical and procedural factors.

Methods: All study subjects were ascertained from a prospective study of patients who underwent elective cardiac surgery during August 1999 to April 2002. We defined a prolonged QTc interval as > 440 msec, measured from 24-hr pre- and postoperative 12-lead electrocardiograms. The association of 37 single nucleotide polymorphisms (SNPs) in 21 candidate genes -involved in modulating arrhythmia susceptibility pathways with postoperative QTc changes- was investigated in a two-stage design with a stage I cohort (n = 497) nested within a stage II cohort (n = 957). Empirical P values (Pemp) were obtained by permutation tests with 10,000 repeats.

Results: After adjusting for clinical and procedural risk factors, we selected four SNPs (P value range, 0.03-0.1) in stage I, which we then tested in the stage II cohort. Two functional SNPs in the pro-inflammatory cytokine interleukin-1β (IL1β), rs1143633 (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.53 to 0.95; Pemp = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; Pemp = 0.04), remained independent predictors of postoperative QTc prolongation. The ability of a clinico-genetic model incorporating the two IL1B polymorphisms to classify patients at risk for developing prolonged postoperative QTc was superior to a clinical model alone, with a net reclassification improvement of 0.308 (P = 0.0003) and an integrated discrimination improvement of 0.02 (P = 0.000024).

Conclusion: The results suggest a contribution of IL1β in modulating susceptibility to postoperative QTc prolongation after cardiac surgery.

Fig. 1

Frequency distributions of changes (in msec) from preoperative to postoperative QTc intervals in patients undergoing cardiac surgery. (A) stage I cohort (n = 497); (B) stage II cohort (n = 957)

Fig. 2

Perioperative serum concentrations of interleukin-1β in patients undergoing cardiac surgery (n = 288). Sampling time points are preoperative (base), and four hours, 24 hr, and 48 hr after aortic cross-clamp removal. Results at each time point are expressed as mean (SD) in all patients (A), stratified by IL1B rs1143633 genotypes (homozygous major allele GG and heterozygous AG vs homozygous minor allele AA carriers, recessive inheritance model) (B), and by IL1B rs16994 genotypes (homozygous minor allele TT and heterozygous CT vs homozygous major allele CC carriers, dominant inheritance pattern) (C). Patients carrying either the rs1143633G allele and/or the rs16994T allele are high interleukin-1β producers. *P < 0.01 difference compared with preoperative (base) values. IL = interleukin