Postoperative release of proinflammatory mediators, such as tumor necrosis factor-α (TNFα) and interleukin (IL)-6, is an important mechanism of prolonged mechanical ventilation (PMV) after CABG. Peroxisome proliferator-activated receptor-γ (PPARγ) mediates ligand-dependent transcriptional activation and repression. In in vitro studies PPARγ agonists inhibit TNFα transcription, and are associated with lower levels of TNFα, IL-1β, and IL-6. A C to G transition within the PPARγ-2 gene is associated with substitution of alanine (Ala) for proline (Pro) at position 12 (Pro12Ala). Individuals with this polymorphism had reduced risk of diabetes mellitus, suggesting that this polymorphism may be either functional or a marker for a functional polymorphism.Since PPARγ reduces the proinflammatory mediator release associated with higher risk of PMV post-CABG, we investigated the role of Pro12Ala polymorphism on risk of PMV. The release of inflammatory mediators is higher after on-pump CABG compared to off-pump CABG. Therefore, we examined interaction of surgical technique with the association of Pro12Ala and PMV.
Prospective observational study. Precollected blood was used for gene analysis. Genotype was determined using a modified allele-specific real-time PCR. Primary endpoint was time to extubation.
400 patients and 218 healthy volunteers were enrolled. Patients with Pro12Ala polymorphism had lower risk of PMV (HR=0.56, 95% CI=0.4–0.8, P=0.0028). This association was partially confounded by preoperative and intraoperative risk factors, but remained statistically significant (table 1
Multivariable analysis of risk factors for PMVVariableHazard ratio95% CIP valuePro12Ala0.680.5–0.980.037Female gender1.260.97–1.70.076Renal failure2.41.5–3.90.0003Left main disease > 50%1.41.01–1.850.044Repeat CABG1.51.06–2.20.023Lung disease1.360.98–1.880.052Clinical score2.071.58–2.72<0.0001Diabetes0.80.6–1.070.14). An interaction was seen between surgical technique and the association of Pro12Ala and PMV (P=0.057). The association was seen in patients undergoing on-pump CABG (HR=0.47, P=0.001), but not in those undergoing off-pump surgery (HR=1.08, P=0.8). The association was also independent of previously reported associations between angiotensin-converting enzyme polymorphism and TNF haplotype with PMV.CONCLUSIONS: The Pro12Ala polymorphism is associated with lower risk of PMV after CABG.
Our study demonstrates the important role of PPARγ in post-CABG complications. Patients without the Pro12Ala polymorphism are more likely to benefit by off-pump CABG. Therefore, preoperative genotyping may guide choice of surgical technique.
S. Yende, None.