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* From Methodist Healthcare and University of Tennessee, Memphis, TN.
Correspondence to: Sachin Yende, MD, 501 Crews Wing, Methodist Healthcare, 1265 Union Ave, Memphis, TN 38104; e-mail: yende{at}juno.com
A potential source of complications after coronary artery bypass
graft surgery (CABG) includes release of proinflammatory and
anti-inflammatory cytokines like tumor necrosis factor (TNF)-
and
interleukin (IL)-10, respectively. These are released secondary to
ischemia-reperfusion injury, exposure of blood to bypass circuit,
products of complement system, and/or endotoxin release from the GI
tract. The G 
A transitions at - 308 site within the promoter
region of the TNF- gene and + 250 site within the first intron of
the TNF-ß gene is associated with elevated levels of TNF-.
Similarly, the G A transition at - 1082 site within the
promoter region of the IL-10 gene is associated with lower IL-10
levels. We hypothesize that polymorphisms within these genes will be
associated with variable outcomes after CABG.
This was a prospective observational study. Patients were weaned by a standardized respiratory protocol and assessed at 8 h, 24 h, and 48 h for failure to wean. Precollected blood was used for gene analysis using polymerase chain reaction and restriction enzyme digestion (for TNF sites) or heteroduplex generation (IL-10 sites) as described previously. The primary end points were duration of mechanical ventilation and need for transfusion of blood products after surgery. The secondary end point was 30-day mortality. To explore the potential role of preoperative genotyping, we examined the role of a scoring system based on preoperative risk factors (SS) by Spivack et al1 and TNF haplotype to predict risk of prolonged mechanical ventilation (PMV).
Three hundred fifty-five patients (262 patients undergoing conventional CABG) were enrolled. Patients with TNF+ 250G/-308G (TNF-GG) haplotype had longer duration of mechanical ventilation compared to those without this haplotype (30.3 h vs 12.7 h, p = 0.006). Patients with the TNF-GG haplotype were less likely to be extubated at 48 h (8.5% vs 2%, p = 0.006). This association of the TNF-GG haplotype was independent of preoperative risk factors. The TNF haplotypes had no effect on bleeding complications and mortality after CABG. The TNF-GG haplotype was associated with PMV in patients undergoing conventional CABG only (34.8 h vs 17.5 h, p = 0.006) with no effect on patients undergoing off-pump CABG (OPCAB) [13.2 h vs 10.8 h, p = not significant]. Using Bayesian analysis and pretest probability of 6.5%, patients with SS < 0 (n = 121) had a posttest probability of 1.4% (low risk). In patients with SS > 0 (n = 141), posttest probability was 10.7%. Gene analysis of patients with SS > 0 resulted in posttest probability of 3.5% (low risk) for AA genotype (n = 59) and 16.1% (high risk) for non-AA genotypes (n = 82). Risk of PMV for patients undergoing OPCAB (n = 93) was 3.2% regardless of genotypes or SS. The IL-10 polymorphisms had no effect on either of the primary end points. The G allele was associated with a higher mortality rate compared to A allele (7.4% vs 2.7%, p < 0.05).
In conclusion, the + 250G/-308G haplotype is associated with PMV and the GG genotype at - 1082 site is associated with higher mortality after CABG. SS and TNF haplotype may be used in combination to predict risk of PMV after CABG. Low-risk patients may proceed to surgery. In high-risk patients, OPCAB may be performed to reduce risk of PMV.
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