Thrombotic gene polymorphisms and postoperative outcome after coronary artery bypass graft surgery

<p>Abstract</p> <p>Background</p> <p>Emerging perioperative genomics may influence the direction of risk assessment and surgical strategies in cardiac surgery. The aim of this study was to investigate whether single nucleotide polymorphisms (SNP) affect the clinical presentation and predispose to increased risk for postoperative adverse events in patients undergoing coronary artery bypass grafting surgery (CABG).</p> <p>Methods</p> <p>A total of 220 patients undergoing first-time CABG between January 2005 and May 2008 were screened for factor V gene G1691A (FVL), prothrombin/factor II G20210A (PT G20210A), angiotensin I-converting enzyme insertion/deletion (ACE-ins/del) polymorphisms by PCR and Real Time PCR. End points were defined as death, myocardial infarction, stroke, postoperative bleeding, respiratory and renal insufficiency and event-free survival. Patients were compared to assess for any independent association between genotypes for thrombosis and postoperative phenotypes.</p> <p>Results</p> <p>Among 220 patients, the prevalence of the heterozygous FVL mutation was 10.9% (n = 24), and 3.6% (n = 8) were heterozygous carriers of the PT G20210A mutation. Genotype distribution of ACE-ins/del was 16.6%, 51.9%, and 31.5% in genotypes I/I, I/D, and D/D, respectively. FVL and PT G20210A mutations were associated with higher prevalence of totally occluded coronary arteries (p < 0.001). Furthermore the risk of left ventricular aneurysm formation was significantly higher in FVL heterozygote group compared to FVL G1691G (<it>p </it>= 0.002). ACE D/D genotype was associated with hypertension (<it>p </it>= 0.004), peripheral vascular disease (p = 0.006), and previous myocardial infarction (<it>p </it>= 0.007).</p> <p>Conclusions</p> <p>FVL and PT G20210A genotypes had a higher prevalence of totally occluded vessels potentially as a result of atherothrombotic events. However, none of the genotypes investigated were independently associated with mortality.</p

Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery

<p>Abstract</p> <p>Background</p> <p>In the National Emphysema Treatment Trial (NETT), marked variability in response to lung volume reduction surgery (LVRS) was observed. We sought to identify genetic differences which may explain some of this variability.</p> <p>Methods</p> <p>In 203 subjects from the NETT Genetics Ancillary Study, four outcome measures were used to define response to LVRS at six months: modified BODE index, post-bronchodilator FEV₁, maximum work achieved on a cardiopulmonary exercise test, and University of California, San Diego shortness of breath questionnaire. Sixty-four single nucleotide polymorphisms (SNPs) were genotyped in five genes previously shown to be associated with chronic obstructive pulmonary disease susceptibility, exercise capacity, or emphysema distribution.</p> <p>Results</p> <p>A SNP upstream from glutathione S-transferase pi (<it>GSTP1</it>; p = 0.003) and a coding SNP in microsomal epoxide hydrolase (<it>EPHX1</it>; p = 0.02) were each associated with change in BODE score. These effects appeared to be strongest in patients in the non-upper lobe predominant, low exercise subgroup. A promoter SNP in <it>EPHX1 </it>was associated with change in BODE score (p = 0.008), with the strongest effects in patients with upper lobe predominant emphysema and low exercise capacity. One additional SNP in <it>GSTP1 </it>and three additional SNPs in <it>EPHX1 </it>were associated (p < 0.05) with additional LVRS outcomes. None of these SNP effects were seen in 166 patients randomized to medical therapy.</p> <p>Conclusion</p> <p>Genetic variants in <it>GSTP1 </it>and <it>EPHX1</it>, two genes encoding xenobiotic metabolizing enzymes, were predictive of response to LVRS. These polymorphisms may identify patients most likely to benefit from LVRS.</p

Genome-wide association study of perioperative myocardial infarction after coronary artery bypass surgery.

OBJECTIVES: Identification of patient subpopulations susceptible to develop myocardial infarction (MI) or, conversely, those displaying either intrinsic cardioprotective phenotypes or highly responsive to protective interventions remain high-priority knowledge gaps. We sought to identify novel common genetic variants associated with perioperative MI in patients undergoing coronary artery bypass grafting using genome-wide association methodology. SETTING: 107 secondary and tertiary cardiac surgery centres across the USA. PARTICIPANTS: We conducted a stage I genome-wide association study (GWAS) in 1433 ethnically diverse patients of both genders (112 cases/1321 controls) from the Genetics of Myocardial Adverse Outcomes and Graft Failure (GeneMAGIC) study, and a stage II analysis in an expanded population of 2055 patients (225 cases/1830 controls) combined from the GeneMAGIC and Duke Perioperative Genetics and Safety Outcomes (PEGASUS) studies. Patients undergoing primary non-emergent coronary bypass grafting were included. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome variable was perioperative MI, defined as creatine kinase MB isoenzyme (CK-MB) values ≥10× upper limit of normal during the first postoperative day, and not attributable to preoperative MI. Secondary outcomes included postoperative CK-MB as a quantitative trait, or a dichotomised phenotype based on extreme quartiles of the CK-MB distribution. RESULTS: Following quality control and adjustment for clinical covariates, we identified 521 single nucleotide polymorphisms in the stage I GWAS analysis. Among these, 8 common variants in 3 genes or intergenic regions met p<10(-5) in stage II. A secondary analysis using CK-MB as a quantitative trait (minimum p=1.26×10(-3) for rs609418), or a dichotomised phenotype based on extreme CK-MB values (minimum p=7.72×10(-6) for rs4834703) supported these findings. Pathway analysis revealed that genes harbouring top-scoring variants cluster in pathways of biological relevance to extracellular matrix remodelling, endoplasmic reticulum-to-Golgi transport and inflammation. CONCLUSIONS: Using a two-stage GWAS and pathway analysis, we identified and prioritised several potential susceptibility loci for perioperative MI

Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. METHODS: The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. RESULTS: The median postoperative nadir platelet count was 121 × 10/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 × 10/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). CONCLUSION: The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery

Discriminative accuracy of genomic profiling comparing multiplicative and additive risk models

Genetic prediction of common diseases is based on testing multiple genetic variants with weak effect sizes. Standard logistic regression and Cox Proportional Hazard models that assess the combined effect of multiple variants on disease risk assume multiplicative joint effects of the variants, but this assumption may not be correct. The risk model chosen may affect the predictive accuracy of genomic profiling. We investigated the discriminative accuracy of genomic profiling by comparing additive and multiplicative risk models. We examined genomic profiles of 40 variants with genotype frequencies varying from 0.1 to 0.4 and relative risks varying from 1.1 to 1.5 in separate scenarios assuming a disease risk of 10%. The discriminative accuracy was evaluated by the area under the receiver operating characteristic curve. Predicted risks were more extreme at the lower and higher risks for the multiplicative risk model compared with the additive model. The discriminative accuracy was consistently higher for multiplicative risk models than for additive risk models. The differences in discriminative accuracy were negligible when the effect sizes were small (<1.2), but were substantial when risk genotypes were common or when they had stronger effects. Unraveling the exact mode of biological interaction is important when effect sizes of genetic variants are moderate at the least, to prevent the incorrect estimation of risks

Preoperative statin is associated with decreased operative mortality in high risk coronary artery bypass patients

<p>Abstract</p> <p>Background</p> <p>Statins are widely prescribed to patients with atherosclerosis. A retrospective database analysis was used to examine the role of preoperative statin use in hospital mortality, for patients undergoing isolated coronary artery bypass grafting (CABG.)</p> <p>Methods</p> <p>The study population comprised 2377 patients who had isolated CABG at Allegheny General Hospital between 2000 and 2004. Mean age of the patients was 65 ± 11 years (range 27 to 92 years). 1594 (67%) were male, 5% had previous open heart procedures, and 4% had emergency surgery. 1004 patients (42%) were being treated with a statin at the time of admission. Univariate, bivariate (Chi², Fisher's Exact and Student's t-tests) and multivariate (stepwise linear regression) analyses were used to evaluate the association of statin use with mortality following CABG.</p> <p>Results</p> <p>Annual prevalence of preoperative statin use was similar over the study period and averaged 40%. Preoperative clinical risk assessment demonstrated a 2% risk of mortality in both the statin and non-statin groups. Operative mortality was 2.4% for all patients, 1.7% for statin users and 2.8% for non-statin users (p < 0.07). Using multivariate analysis, lack of statin use was found to be an independent predictor of mortality in high-risk patients (n = 245, 12.9% vs. 5.6%, p < 0.05).</p> <p>Conclusions</p> <p>Between 2000 and 2004 less than 50% of patients at this institution were receiving statins before admission for isolated CABG. A retrospective analysis of this cohort provides evidence that preoperative statin use is associated with lower operative mortality in high-risk patients.</p

Association entre les variantes génétiques de l’interleukine-1β et une prolongation de l’intervalle QTc après une chirurgie cardiaque: une étude observationnelle prospective

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 (P(emp)) 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; P(emp) = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; P(emp) = 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