A signature of pre-operative biomarkers of cellular senescence to predict risk of cardiac and kidney adverse events after cardiac surgery.

Objective: Understand the potential for pre-operative biomarkers of cellular senescence, a primary aging mechanism, to predict risk of cardiac surgery-associated adverse events. Methods: Biomarkers of senescence were assessed in blood samples collected prior to surgery in 331 patients undergoing CABG +/-valve repair or replacement. Patients were followed throughout the hospital stay and at a 30-day follow-up visit. Logistic regression models for pre-operative risk prediction were built for age-related clinical outcomes with high incidence including KDIGO-defined acute kidney injury (AKI), decline in eGFR ≥25% between pre-op and 30 days, and MACKE30, a composite endpoint of major adverse cardiac and kidney events at 30d. Results: AKI occurred in 19.9% of patients, persistent decline in kidney function at 30d occurred in 11.0%, and MACKE30 occurred in 13.4%. A network of six biomarkers of senescence (p16, p14, LAG3, CD244, CD28 and suPAR) were able to identify patients at risk for AKI (AUC 0.76), kidney decline at 30d (AUC 0.73), and MACKE30 (AUC 0.71). Comparing the top and bottom tertiles of senescence-based risk models, patients in the top tertile had 7.8 (3.3-8.4) higher odds of developing AKI, 4.5 (1.6-12.6) higher odds of developing renal decline at 30d, and 5.7 (2.1-15.6) higher odds of developing MACKE30. All models remained significant when adjusted for clinical variables. Patients with kidney function decline at 30d were largely non-overlapping and clinically distinct from those who experienced AKI, suggesting a different etiology. Typical clinical factors that predispose to AKI (e.g., age, CKD, surgery type) associated with AKI but not the 30d decline endpoint which was instead associated with new-onset atrial fibrillation. Conclusions: A six-member network of biomarkers of senescence, a fundamental mechanism of aging, can identify patients for risk of adverse kidney and cardiac events when measured pre-operatively.

Bedside Allogeneic Erythrocyte Washing with a Cell Saver to Remove Cytokines, Chemokines, and Cell-derived Microvesicles.

BACKGROUND: Removal of cytokines, chemokines, and microvesicles from the supernatant of allogeneic erythrocytes may help mitigate adverse transfusion reactions. Blood bank-based washing procedures present logistical difficulties; therefore, we tested the hypothesis that on-demand bedside washing of allogeneic erythrocyte units is capable of removing soluble factors and is feasible in a clinical setting. METHODS: There were in vitro and prospective, observation cohort components to this a priori planned substudy evaluating bedside allogeneic erythrocyte washing, with a cell saver, during cardiac surgery. Laboratory data were collected from the first 75 washed units given to a subset of patients nested in the intervention arm of a parent clinical trial. Paired pre- and postwash samples from the blood unit bags were centrifuged. The supernatant was aspirated and frozen at -70°C, then batch-tested for cell-derived microvesicles, soluble CD40 ligand, chemokine ligand 5, and neutral lipids (all previously associated with transfusion reactions) and cell-free hemoglobin (possibly increased by washing). From the entire cohort randomized to the intervention arm of the trial, bedside washing was defined as feasible if at least 75% of prescribed units were washed per protocol. RESULTS: Paired data were available for 74 units. Washing reduced soluble CD40 ligand (median [interquartile range]; from 143 [1 to 338] ng/ml to zero), chemokine ligand 5 (from 1,314 [715 to 2,551] to 305 [179 to 488] ng/ml), and microvesicle numbers (from 6.90 [4.10 to 20.0] to 0.83 [0.33 to 2.80] × 106), while cell-free hemoglobin concentration increased from 72.6 (53.6 to 171.6) mg/dl to 210.5 (126.6 to 479.6) mg/dl (P < 0.0001 for each). There was no effect on neutral lipids. Bedside washing was determined as feasible for 80 of 81 patients (99%); overall, 293 of 314 (93%) units were washed per protocol. CONCLUSIONS: Bedside erythrocyte washing was clinically feasible and greatly reduced concentrations of soluble factors thought to be associated with transfusion-related adverse reactions, increasing concentrations of cell-free hemoglobin while maintaining acceptable (less than 0.8%) hemolysis.

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.

OBJECTIVE: Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described. DESIGN: Retrospective cohort. SETTING: Single-center university hospital. PARTICIPANTS: A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015. INTERVENTIONS: The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution. MEASUREMENTS AND MAIN RESULTS: Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q3 = 32.6 v CUF < Q1 = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001). CONCLUSIONS: Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.

Intravenous Lidocaine Does Not Improve Neurologic Outcomes after Cardiac Surgery: A Randomized Controlled Trial.

BACKGROUND: Cognitive decline after cardiac surgery occurs frequently and persists in a significant proportion of patients. Preclinical studies and human trials suggest that intravenous lidocaine may confer protection in the setting of neurologic injury. It was hypothesized that lidocaine administration would reduce cognitive decline after cardiac surgery compared to placebo. METHODS: After institutional review board approval, 478 patients undergoing cardiac surgery were enrolled into this multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group trial. Subjects were randomized to lidocaine 1 mg/kg bolus after the induction of anesthesia followed by a continuous infusion (48 µg · kg · min for the first hour, 24 µg · kg · min for the second hour, and 10 µg · kg · min for the next 46 h) or saline with identical volume and rate changes to preserve blinding. Cognitive function was assessed preoperatively and at 6 weeks and 1 yr postoperatively using a standard neurocognitive test battery. The primary outcome was change in cognitive function between baseline and 6 weeks postoperatively, adjusting for age, years of education, baseline cognition, race, and procedure type. RESULTS: Among the 420 allocated subjects who returned for 6-week follow-up (lidocaine: N = 211; placebo: N = 209), there was no difference in the continuous cognitive score change (adjusted mean difference [95% CI], 0.02 (-0.05, 0.08); P = 0.626). Cognitive deficit (greater than 1 SD decline in at least one cognitive domain) at 6 weeks occurred in 41% (87 of 211) in the lidocaine group versus 40% (83 of 209) in the placebo group (adjusted odds ratio [95% CI], 0.94 [0.63, 1.41]; P = 0.766). There were no differences in any quality of life outcomes between treatment groups. At the 1-yr follow-up, there continued to be no difference in cognitive score change, cognitive deficit, or quality of life. CONCLUSIONS: Intravenous lidocaine administered during and after cardiac surgery did not reduce postoperative cognitive decline at 6 weeks.

Temporary autonomic modulation with botulinum toxin type A to reduce atrial fibrillation after cardiac surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) frequently complicates cardiac surgery and is associated with worse outcomes. The cardiac autonomic nervous system is implicated in the pathogenesis of POAF. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of selective cardiac autonomic modulation in preventing POAF. METHODS: In this randomized, double-blind, placebo-controlled trial, adults undergoing cardiac surgery were randomized 1:1 to intraoperative injection of 250 units onabotulinumtoxinA (botulinum toxin type A [BoNTA]) or placebo into epicardial fat pads. The study was powered to detect a 40% reduction in relative risk of POAF. Time to first episode of in-hospital POAF was the primary outcome, evaluated in patients receiving injection. Additionally, incidence of POAF, length of stay (LOS), and adverse events were examined. RESULTS: The trial assigned 145 patients to injection, 15 of whom were dropped before treatment, leaving 130 patients for analysis. Overall, 36.5% (23/63) of BoNTA-treated patients developed POAF compared with 47.8% (32/67) of placebo-treated patients. The time-to-event analysis revealed a hazard ratio of 0.69 (95% confidence interval 0.41-1.19; P = .18) for the BoNTA vs placebo arm. There were no significant differences in postoperative hospital LOS (median [interquartile range] 6.0 [3.4] vs 6.2 [3.7] days; P = .51) or adverse events prolonging LOS (27/63 [42.9%] vs 30/67 [44.8%]; P = .83) in patients receiving BoNTA vs placebo. CONCLUSION: Epicardial injection of onabotulinumtoxinA was without discernible adverse effects, but we failed to detect a significant difference in risk of POAF. Future large-scale studies of epicardial onabotulinumtoxinA injection as a potential POAF prevention strategy should be designed to study smaller, but clinically meaningful, treatment effects.

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

INTRODUCTION: Thrombocytopenia after cardiac surgery independently predicts stroke, acute kidney injury and death. To understand the underlying risks and mechanisms, we analysed genetic variations associated with thrombocytopenia in patients undergoing coronary artery bypass grafting (CABG) surgery. MATERIALS AND METHODS: Study subjects underwent isolated on-pump CABG surgery at Duke University Medical Center. Post-operative thrombocytopenia was defined as platelet count < 100 × 109/L. Using a logistic regression model adjusted for clinical risk factors, we performed a genome-wide association study in a discovery cohort (n = 860) and validated significant findings in a replication cohort (n = 296). Protein expression was assessed in isolated platelets by immunoblot. RESULTS: A total of 63 single-nucleotide polymorphisms met a priori discovery thresholds for replication, but only 1 (rs9574547) in the intergenic region upstream of sprouty 2 (SPRY2) met nominal significance in the replication cohort. The minor allele of rs9574547 was associated with a lower risk for thrombocytopenia (discovery cohort, odds ratio, 0.45, 95% confidence interval, 0.30-0.67, p = 9.76 × 10-5) with the overall association confirmed by meta-analysis (meta-p = 7.88 × 10-6). Immunoblotting demonstrated expression of SPRY2 and its dynamic regulation during platelet activation. Treatment with a functional SPRY2 peptide blunted platelet extracellular signal-regulated kinase (ERK) phosphorylation after agonist stimulation. CONCLUSION: We identified the association of a genetic polymorphism in the intergenic region of SPRY2 with a decreased incidence of thrombocytopenia after CABG surgery. Because SPRY2-an endogenous receptor tyrosine kinase inhibitor-is present in platelets and modulates essential signalling pathways, these findings support a role for SPRY2 as a novel modulator of platelet responses after cardiac surgery.

Predictive ability of perioperative atrial fibrillation risk indices in cardiac surgery patients: a retrospective cohort study.

PURPOSE: The Multicenter Study of Perioperative Ischemia (McSPI) AFRisk index predicts postoperative atrial fibrillation (POAF) after cardiac surgery, but requires pre-, intra-, and postoperative data. Other more abbreviated risk indices exist, but there is no consensus on which risk index is optimal. We compared the discriminatory capacity of the McSPI AFRisk index with three indices containing only preoperative data (the CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model), hypothesizing that the McSPI AFRisk index would have superior predictive capacity. METHODS: We retrospectively evaluated 783 patients undergoing cardiac surgery using cardiopulmonary bypass. The predictive capacity of each index was assessed by comparing receiver-operating characteristic (ROC) curves, scaled Brier scores, net reclassification indices, and the integrated discrimination indices. RESULTS: The incidence of POAF was 32.6%. The area under the curve (AUC) of the ROC curve were 0.77, 0.58, 0.66, and 0.66 for the McSPI AFRisk index, CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model, respectively. The McSPI AFRIsk index had the highest AUC (P < 0.0001). The scaled Brier scores for the McSPI AFRisk index, CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model were 0.23, 0.02, 0.08, and 0.07, respectively. Both net reclassification indices and integrated discrimination indices showed that the McSPI AFRisk index more appropriately identified patients at high risk of POAF. CONCLUSIONS: The McSPI AFRisk index showed superior ability to predict POAF after cardiac surgery compared with three other indices. When clinicians and investigators wish to measure the risk of POAF after cardiac surgery, they should consider using the McSPI AFRisk index.

Pre- and postoperative anemia, acute kidney injury, and mortality after coronary artery bypass grafting surgery: a retrospective observational study.

BACKGROUND: Preoperative and postoperative anemia have been identified individually as potential risk factors for postoperative complications after coronary artery bypass grafting (CABG) surgery. Their interrelationship with acute kidney injury (AKI) and long-term mortality, however, has not been clearly defined and was the purpose of this study. METHODS: We retrospectively evaluated 6,130 adult patients undergoing CABG surgery performed at a single large academic medical center. Preoperative and postoperative hemoglobin concentrations were used as continuous predictors of postoperative AKI and mortality. Additionally, sex-specific preoperative (< 13 g·dL-1 in men and < 12 g·dL-1 in women) and postoperative anemia (the median of the lowest in-hospital values) were used as categorical predictors. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines, when serum creatinine rose ≥ 50% during the period between day of surgery and postoperative day ten, or when a 0.3 mg·dL-1 (26.5 µmol·L-1) increase was detected in a rolling 48-hr window from the day of surgery to the tenth postoperative day. The association of preoperative and postoperative hemoglobin levels and anemia patterns with postoperative AKI and mortality were assessed via univariable and multivariable Cox proportional hazard analyses with time-varying effects for postoperative serum hemoglobin concentrations. RESULTS: The median preoperative and median minimum postoperative serum hemoglobin concentrations were 13.1 g·dL-1 and 8.8 g·dL-1, respectively. The incidence of AKI was 58%. Overall, 1,880 (30.7%) patients died an average of 6.8 yr after surgery. After adjusting for differences in baseline and clinical characteristics, on any given day, patients with preoperative anemia (multivariable hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.13 to 1.33; P < 0.001) and those with a combination of preoperative and postoperative anemia (multivariable HR, 1.24; 95% CI, 1.09 to 1.40; P < 0.0008) were at an elevated risk for developing postoperative AKI and mortality (preoperative anemia: multivariable HR, 1.29; 95% CI, 1.15 to 1.44; P < 0.001; preoperative and postoperative anemia: multivariable HR, 1.50; 95% CI, 1.25 to 1.79; P < 0.001). CONCLUSIONS: Our findings suggest that preoperative anemia alone and preoperative anemia combined with postoperative anemia are associated with AKI and mortality after CABG surgery.

Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats.

Resolution agonists, including lipid mediators and peptides such as annexin A1 (ANXA1), are providing novel approaches to treat inflammatory conditions. Surgical trauma exerts a significant burden on the immune system that can affect and impair multiple organs. Perioperative cerebral injury after cardiac surgery is associated with significant adverse neurological outcomes such as delirium and postoperative cognitive dysfunction. Using a clinically relevant rat model of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), we tested the pro-resolving effects of a novel bioactive ANXA1 tripeptide (ANXA1sp) on neuroinflammation and cognition. Male rats underwent 2 h CPB with 1 h DHCA at 18°C, and received vehicle or ANXA1sp followed by timed reperfusion up to postoperative day 7. Immortalized murine microglial cell line BV2 were treated with vehicle or ANXA1sp and subjected to 2 h oxygen-glucose deprivation followed by timed reoxygenation. Microglial activation, cell death, neuroinflammation, and NF-κB activation were assessed in tissue samples and cell cultures. Rats exposed to CPB and DHCA had evident neuroinflammation in various brain areas. However, in ANXA1sp-treated rats, microglial activation and cell death (apoptosis and necrosis) were reduced at 24 h and 7 days after surgery. This was associated with a reduction in key pro-inflammatory cytokines due to inhibition of NF-κB activation in the brain and systemically. Treated rats also had improved neurologic scores and shorter latency in the Morris water maze. In BV2 cells treated with ANXA1sp, similar protective effects were observed including decreased pro-inflammatory cytokines and cell death. Notably, we also found increased expression of ANXA1, which binds to NF-κB p65 and thereby inhibits its transcriptional activity. Our findings provide evidence that treatment with a novel pro-resolving ANXA1 tripeptide is neuroprotective after cardiac surgery in rats by attenuating neuroinflammation and may prevent postoperative neurologic complications.

Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: ≥2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) × 10/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 × 10/L, 100 to 150 × 10/L, and <100 × 10/L, respectively. The risk for stroke increased by 12% on a given postoperative day for every 30 × 10/L decrease in platelet counts (adjusted hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01-1.24; P= .0255). On a given day, patients with moderate to severe thrombocytopenia were almost twice as likely to develop stroke (adjusted HR, 1.89; 95% CI, 1.13-3.16; P= .0155) as patients with nadir platelet counts >150 × 10/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (≥2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48-5.41; P= .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery.

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial.

PURPOSE: Postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. The pathophysiology of POCD remains elusive, but previous work showed that intravenous lidocaine may be protective against POCD, possibly by modulating cerebral inflammation. We hypothesized that intravenous lidocaine would attenuate the cerebral inflammatory response to cardiopulmonary bypass (CPB) by reducing the transcerebral activation gradients of platelets, leukocytes, and/or platelet-leukocyte conjugates. METHODS: We studied 202 patients undergoing cardiac surgery with CPB in this prospective randomized double-blinded placebo-controlled trial. Subjects were randomized to receive either intravenous lidocaine (bolus + 48-hr infusion) or placebo (identical infusion volume and duration). Paired jugular venous and radial arterial blood samples were drawn at several time points and analyzed by fluorescence-activated cell sorting to identify activated platelets and platelet-leukocyte conjugates. Transcerebral activation gradients were calculated by subtracting arterial values from venous values and were compared between groups using repeated measures regression models with covariate adjustment for age, sex, surgery type, and CPB duration. RESULTS: Beginning after aortic cross-clamp release and peaking ten minutes after the termination of CPB, the mean (SD) transcerebral activation gradient of platelet-monocyte conjugates decreased in lidocaine-treated vs placebo-treated patients [-1.84 (11.47) mean linear fluorescence intensity (MLFI) vs 1.46 (13.88) MLFI, respectively; mean difference, -4.08 MLFI; 95% confidence interval, -7.86 to -0.29; P = 0.03). No difference was seen at any time point for activated platelets or for platelet-neutrophil conjugates. CONCLUSION: While lidocaine did not affect the systemic or transcerebral activation of platelets or leukocytes, we did observe a reduction in the transcerebral activation of platelet-monocyte conjugates after aortic cross-clamp release. This may be a manifestation of reduced cerebral inflammation during cardiopulmonary bypass in response to treatment with lidocaine. This trial was registered at ClinicalTrials.gov (NCT00938964).

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

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-1ß (IL1ß), 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 IL1ß in modulating susceptibility to postoperative QTc prolongation after cardiac surgery.

Gene signatures of postoperative atrial fibrillation in atrial tissue after coronary artery bypass grafting surgery in patients receiving ß-blockers.

Atrial tissue gene expression profiling may help to determine how differentially expressed genes in the human atrium before cardiopulmonary bypass (CPB) are related to subsequent biologic pathway activation patterns, and whether specific expression profiles are associated with an increased risk for postoperative atrial fibrillation (AF) or altered response to ß-blocker (BB) therapy after coronary artery bypass grafting (CABG) surgery. Right atrial appendage (RAA) samples were collected from 45 patients who were receiving perioperative BB treatment, and underwent CABG surgery. The isolated RNA samples were used for microarray gene expression analysis, to identify probes that were expressed differently in patients with and without postoperative AF. Gene expression analysis was performed to identify probes that were expressed differently in patients with and without postoperative AF. Gene set enrichment analysis (GSEA) was performed to determine how sets of genes might be systematically altered in patients with postoperative AF. Of the 45 patients studied, genomic DNA from 42 patients was used for target sequencing of 66 candidate genes potentially associated with AF, and 2,144 single-nucleotide polymorphisms (SNPs) were identified. We then performed expression quantitative trait loci (eQTL) analysis to determine the correlation between SNPs identified in the genotyped patients, and RAA expression. Probes that met a false discovery rate<0.25 were selected for eQTL analysis. Of the 17,678 gene expression probes analyzed, 2 probes met our prespecified significance threshold of false discovery rate<0.25. The most significant probe corresponded to vesicular overexpressed in cancer - prosurvival protein 1 gene (VOPP1; 1.83 fold change; P=3.47×10(-7)), and was up-regulated in patients with postoperative AF, whereas the second most significant probe, which corresponded to the LOC389286 gene (0.49 fold change; P=1.54×10(-5)), was down-regulated in patients with postoperative AF. GSEA highlighted the role of VOPP1 in pathways with biologic relevance to myocardial homeostasis, and oxidative stress and redox modulation. Candidate gene eQTL showed a trans-acting association between variants of G protein-coupled receptor kinase 5 gene, previously linked to altered BB response, and high expression of VOPP1. In patients undergoing CABG surgery, RAA gene expression profiling, and pathway and eQTL analysis suggested that VOPP1 plays a novel etiological role in postoperative AF despite perioperative BB therapy.

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.

Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery.

BACKGROUND: Postoperative atrial fibrillation (AF) is a potentially life-threatening complication after coronary artery bypass graft (CABG) surgery. Genetic predisposition may predict risk for developing postoperative AF. METHODS: Study subjects underwent CABG surgery with cardiopulmonary bypass at Duke University Medical Center. In a discovery cohort of 877 individuals from the Perioperative Genetics and Safety Outcomes Study, we performed a genome-wide association study using a logistic regression model with a covariate adjustment for AF risk index. Single-nucleotide polymorphisms (SNPs) that met a P < 5 × 10(-5) were further tested using a replication dataset of 304 individuals from the CATHeterization GENetics biorepository, followed by meta-analysis. Potential pathways related to postoperative AF were identified through gene enrichment analysis using the top genome-wide association study SNPs (P < 10(-4)). RESULTS: Nineteen SNPs met the a priori defined discovery threshold for replication, but only 3 met nominal significance (P < .05) in the CATHeterization GENetics group, with only one-rs10504554, in the intronic region in lymphocyte antigen 96 (LY96)-showing the same direction of the effect for postoperative AF (odds ratio [OR] 0.48, 95% CI 0.34-0.68, P = 2.9 × 10(-5) vs OR 0.55, 95% CI 0.31-0.99, P = .046) and strong overall association by meta-analysis (meta-P = 4.0 × 10(-6)). Gene enrichment analysis highlighted the role of LY96 in pathways of biologic relevance to activation and modulation of innate immune responses. Our analysis also showed potential association between LY96 and nuclear factor κ-B interaction and postoperative AF through their relevance to inflammatory signaling pathways. CONCLUSIONS: In patients undergoing CABG surgery, we found genetic polymorphisms in LY96 associated with decreased risk of postoperative AF.

Intraoperative Magnesium Administration Does Not Reduce Postoperative Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Hypomagnesemia has been associated with an increased risk of postoperative atrial fibrillation (POAF). Although previous studies have suggested a beneficial effect of magnesium (Mg) therapy, almost all of these are limited by small sample size and relatively low Mg dose. We hypothesized that high-dose Mg decreases the occurrence of new-onset POAF, and we tested this hypothesis by using data from a prospective trial that assessed the effect of Mg on cognitive outcomes in patients undergoing cardiac surgery. METHODS: A total of 389 patients undergoing cardiac surgery were enrolled in this double-blind, placebo-controlled trial. Subjects were randomized to receive Mg as a 50-mg/kg bolus immediately after induction of anesthesia followed by another 50 mg/kg as an infusion given over 3 hours (total dose, 100 mg/kg) or placebo. We tested the effect of Mg therapy on POAF with logistic regression, adjusting for the risk of atrial fibrillation (AF) by using the Multicenter Study of Perioperative Ischemia risk index for Atrial Fibrillation after Cardiac Surgery. RESULTS: Among the 363 patients analyzed, after we excluded patients with chronic or acute preoperative AF (placebo: n = 177; Mg: n = 186), the incidence of new-onset POAF was 42.5% (95% confidence interval [CI], 35%-50%) in the Mg group compared with 37.9% (95% CI, 31%-45%) in the placebo group (P = 0.40). The 95% CI for this absolute risk difference of 4.6% is -5.5% to 14.7%. The time to onset of POAF also was identical between the groups, and no significant effect of Mg was found in logistic regression analysis after we adjusted for AF risk (odds ratio, 1.09; 95% CI, 0.69-1.72; P = 0.73). CONCLUSIONS: High-dose intraoperative Mg therapy did not decrease the incidence of new-onset POAF after cardiac surgery.

Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci.

Acute kidney injury (AKI) is a common, serious complication of cardiac surgery. Since prior studies have supported a genetic basis for postoperative AKI, we conducted a genome-wide association study (GWAS) for AKI following coronary bypass graft (CABG) surgery. The discovery data set consisted of 873 nonemergent CABG surgery patients with cardiopulmonary bypass (PEGASUS), while a replication data set had 380 cardiac surgical patients (CATHGEN). Single-nucleotide polymorphism (SNP) data were based on Illumina Human610-Quad (PEGASUS) and OMNI1-Quad (CATHGEN) BeadChips. We used linear regression with adjustment for a clinical AKI risk score to test SNP associations with the postoperative peak rise relative to preoperative serum creatinine concentration as a quantitative AKI trait. Nine SNPs meeting significance in the discovery set were detected. The rs13317787 in GRM7|LMCD1-AS1 intergenic region (3p21.6) and rs10262995 in BBS9 (7p14.3) were replicated with significance in the CATHGEN data set and exhibited significantly strong overall association following meta-analysis. Additional fine mapping using imputed SNPs across these two regions and meta-analysis found genome-wide significance at the GRM7|LMCD1-AS1 locus and a significantly strong association at BBS9. Thus, through an unbiased GWAS approach, we found two new loci associated with post-CABG AKI providing new insights into the pathogenesis of perioperative AKI.