Inflammatory Gene Polymorphisms and Risk of Postoperative Myocardial Infarction After Cardiac Surgery

M Podgoreanu

W White

R Morris

J Mathew

M Newman+2 authors

From Departments of Anesthesiology (M.V.P., W.D.W., R.W.M., J.P.M., M.S.-S., I.J.W., H.P.G., M.F.N., D.A.S.), Surgery (C.A.M., D.A.S.), Pharmacology/Cancer Biology (D.A.S.), and Institute for Genome Science and Policy (D.A.S.), Duke University Medical Center, Durham, NC.

Correspondence to Mihai V. Podgoreanu, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. E-mail: ude.ekud@unaerogdop.iahim

M.V.P. and W.D.W. contributed equally to this work.

Abstract

Background

The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery.

Methods and Results

We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level ≥10 × upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P < 0.05; false discovery rate < 10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 −572G > C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G > T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703).

Conclusions

Functional genetic variants in cytokine and leukocyte–endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

Keywords: cardiopulmonary bypass, genetics, inflammation, myocardial infarction, single nucleotide polymorphisms

Abstract

Despite substantial advances in surgical, cardioprotective, and anesthetic techniques, the incidence of perioperative myocardial infarction (PMI) after cardiac surgery remains at 7% to 15%¹ and is associated with reduced long-term survival.² PMI is a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors, suggesting a possible genetic component.

One of the primary mechanisms in the pathogenesis of perioperative myonecrosis is the complex acute inflammatory response to cardiac surgery with cardiopulmonary bypass (CPB). The extent of perioperative systemic inflammation and associated morbidity and mortality have been related to a variety of environmental stimuli including direct surgical trauma, bioincompatibility of the extracorporeal perfusion circuit, endotoxemia, and multi-organ system ischemia-reperfusion injury.³ However, increased evidence for heritability of the pro-inflammatory state suggests that individual genetic background also modulates the magnitude of postoperative systemic inflammatory response after cardiac surgery.⁴ Therefore, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in candidate genes regulating inflammatory pathways are associated with the incidence of postoperative myocardial infarction in a cohort of patients undergoing cardiac surgery with CPB.

Footnotes

Vivien Thomas Young Investigator Award Finalist, American Heart Association Scientific Sessions, Dallas, Texas, 2005.

Presented at the American Heart Association Scientific Sessions, Dallas, Tex, November 13–16, 2005.

Disclosures

None.

Sources of Funding

Footnotes

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