Michael E. Halkos

Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors.

AbstractObjectivesA series of brief coronary artery reperfusions and reocclusions applied during the early minutes of coronary artery reflow (“postconditioning”) attenuates reperfusion injury. However, it is not known whether brief ischemia–reperfusion applied to a distant organ at the onset of myocardial reperfusion (i.e. “remote postconditioning”, remote PostC) reduces infarct size in the reperfused myocardium. In an in vivo anesthetized rat model of myocardial infarction induced by coronary artery occlusion and reperfusion, this study tested the hypothesis that remote postC induced by a single 5 minute episode of renal artery (RA) occlusion and reperfusion applied immediately before the onset of coronary artery reperfusion protects the myocardium from reperfusion injury by mechanisms involving endogenous adenosine receptor activation.MethodsAll rats were subjected to a total of 30 minutes of left coronary artery occlusion (LCAO) and 3 hours of reperfusion. The rats were randomized to one of six groups: 1) Control: LCAO and reperfusion only with no other intervention; 2) Remote PostC: after 24 minutes of LCAO the RA was occluded for 5 minutes and released 1 min before coronary artery reperfusion; 3) Permanent RA occlusion: the RA was permanently occluded after 24 minutes LCAO continuing to the end of reperfusion; 4) Delayed Remote PostC: after 26 minutes LCAO the RA was occluded for 5 minutes, and its release was delayed until 1 min after coronary artery reperfusion; 5) CON + SPT: rats with LCAO and reperfusion received 10 mg/kg IV of the non–selective adenosine receptor antagonist 8–sulfophenyl theophylline [SPT] administered 5 minutes before coronary artery reperfusion; and 6) Remote PostC + SPT: after 24 minutes of LCAO the RA was occluded for 5 minutes and released 1 minute before coronary artery reperfusion in the presence of 10 mg/kg SPT given 5 min before coronary artery reperfusion.ResultsMyocardial infarct size (percentage necrosis/area at risk, mean ± SEM) was reduced by 50% in Remote PostC (25 ± 4%) compared to Control (49 ± 4%, p = 0.003), consistent with a reduction in plasma CK activity (44 ± 5 vs. 67 ± 6 U/ml, p = 0.023). In contrast, permanent RA occlusion before LCAO and reperfusion failed to reduce myocardial infarct size (47 ± 5%) vs Control. Delaying the release of the RA occlusion (delayed Remote PostC) abrogated the myocardial infarct reduction observed with Remote PostC (48 ± 6%). SPT alone had no effect on infarct size (47 ± 4% in CON + SPT vs. 49 ± 4% in CON); however, Remote PostC+SPT abrogated the myocardial infarct size reduction in Remote PostC (50 ± 3% in Remote PostC + SPT vs. 25 ± 4% in Remote PostC).ConclusionsRemote renal postconditioning applied immediately before the onset of coronary artery reperfusion provides potent myocardial infarct size reduction likely exerted during the first minutes of coronary artery reperfusion. This inter–organ remote postconditioning phenomenon is likely mediated in part by release of adenosine by the ischemic–reperfused kidney and subsequent activation of adenosine receptors.

Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury.

AbstractReperfusion injury is a complex process involving several cell types (endothelial cells, neutrophils, and cardiomyocytes), soluble proinflammatory mediators, oxidants, ionic and metabolic dyshomeostasis, and cellular and molecular signals. These participants in the pathobiology of reperfusion injury are not mutually exclusive. Some of these events take place during the very early moments of reperfusion, while others, seemingly triggered in part by the early events, are activated within a later timeframe. Postconditioning is a series of brief mechanical interruptions of reperfusion following a specific prescribed algorithm applied at the very onset of reperfusion. This algorithm lasts only from 1 to 3 minutes depending on species. Although associated with re–occlusion of the coronary artery or re–imposition of hypoxia in cell culture, the reference to ischemia has been dropped. Postconditioning has been observed to reduce infarct size and apoptosis as the “end games” in myocardial therapeutics; salvage of infarct size was similar to that achieved by the gold standard of protection, ischemic preconditioning. The cardioprotection was also associated with a reduction in: endothelial cell activation and dysfunction, tissue superoxide anion generation, neutrophil activation and accumulation in reperfused myocardium, microvascular injury, tissue edema, intracellular and mitochondrial calcium accumulation. Postconditioning sets in motion triggers and signals that are functionally related to reduced cell death. Adenosine has been implicated in the cardioprotection of postconditioning, as has e–NOS, nitric oxide and guanylyl cyclase, opening of KATP channels and closing of the mitochondrial permeability transition pore. Cardioprotection by postconditioning has also been associated with the activation of intracellular survival pathways such as ERK1/2 and PI3 kinase – Akt pathways. Other pathways have yet to be identified. Although many of the pathways involved in postconditioning have also been identified in ischemic preconditioning, some may not be involved in preconditioning (ERK1/2). The timing of action of these pathways and other mediators of protection in postconditioning differs from that of preconditioning. In contrast to preconditioning, which requires a foreknowledge of the ischemic event, postconditioning can be applied at the onset of reperfusion at the point of clinical service, i.e. angioplasty, cardiac surgery, transplantation.

Elevated preoperative hemoglobin A1c level is predictive of adverse events after coronary artery bypass surgery

OBJECTIVE Diabetes mellitus has been associated with an increased risk of adverse outcomes after coronary artery bypass grafting. Hemoglobin A1c is a reliable measure of long-term glucose control. It is unknown whether adequacy of diabetic control, measured by hemoglobin A1c, is a predictor of adverse outcomes after coronary artery bypass grafting. METHODS Of 3555 consecutive patients who underwent primary, elective coronary artery bypass grafting at a single academic center from April 1, 2002, to June 30, 2006, 3089 (86.9%) had preoperative hemoglobin A1c levels obtained and entered prospectively into a computerized database. All patients were treated with a perioperative intravenous insulin protocol. A multivariable logistic regression model was used to determine whether hemoglobin A1c, as a continuous variable, was associated with in-hospital mortality, renal failure, cerebrovascular accident, myocardial infarction, and deep sternal wound infection after coronary artery bypass grafting. Receiver operating characteristic curve analysis identified the hemoglobin A1c value that maximally discriminated outcome dichotomies. RESULTS In-hospital mortality for all patients was 1.0% (31/3089). An elevated hemoglobin A1c level predicted in-hospital mortality after coronary artery bypass grafting (odds ratio 1.40 per unit increase, P = .019). Receiver operating characteristic curve analysis revealed that hemoglobin A1c greater than 8.6% was associated with a 4-fold increase in mortality. For each unit increase in hemoglobin A1c, there was a significantly increased risk of myocardial infarction and deep sternal wound infection. By using receiver operating characteristic value thresholds, renal failure (threshold 6.7, odds ratio 2.1), cerebrovascular accident (threshold 7.6, odds ratio 2.24), and deep sternal wound infection (threshold 7.8, odds ratio 5.29) occurred more commonly in patients with elevated hemoglobin A1c. CONCLUSION Elevated hemoglobin A1c level was strongly associated with adverse events after coronary artery bypass grafting. Preoperative hemoglobin A1c testing may allow for more accurate risk stratification in patients undergoing coronary artery bypass grafting.

Elevated Preoperative Hemoglobin A1c Level is Associated With Reduced Long-Term Survival After Coronary Artery Bypass Surgery

BACKGROUND The predictive role of hemoglobin A1c (HbA1c) on long-term outcomes after coronary artery bypass surgery has not been evaluated. METHODS Preoperative HbA1c levels were obtained in 3,201 patients undergoing primary, elective coronary artery bypass surgery at Emory Healthcare Hospitals from January 2002 to December 2006 and entered prospectively into a computerized database. Long-term survival status was determined by cross-referencing patient records with the Social Security Death Index. Log-rank (unadjusted) and Cox proportional hazards regression models (adjusted) were employed to determine whether HbA1c and diabetes mellitus were independent risk factors for reduced long-term survival, adjusted for 29 covariates. Hazard ratios for each unit increase in continuous HbA1c were calculated. RESULTS Patients with HbA1c of 7% or greater had lower unadjusted 5-year survival compared with patients with HbA1c less than 7% (p = 0.001). Similarly, patients with diabetes mellitus had lower unadjusted 5-year survival compared with patients without diabetes (p < 0.001). After multivariable adjustment, higher HbA1c (measured as a continuous variable) was associated with reduced long-term survival for each unit increase in HbA1c (hazard ratio 1.15, p < 0.001), but preoperative diagnosis of diabetes was not associated with reduced long-term survival after coronary artery bypass surgery (p = 0.41). Other multivariable predictors of reduced long-term survival included age, cerebrovascular disease, elevated serum creatinine, renal insufficiency, congestive heart failure, previous myocardial infarction, chronic lung disease, and peripheral vascular disease. CONCLUSIONS Poor preoperative glycemic control, as measured by an elevated HbA1c, is associated with reduced long-term survival after coronary artery bypass surgery. Optimizing glucose control in these patients may improve long-term survival.

Selective antegrade cerebral perfusion via right axillary artery cannulation reduces morbidity and mortality after proximal aortic surgery

INTRODUCTION Selective antegrade cerebral perfusion is a well-described neuroprotective technique used in proximal aortic surgery. This study investigated whether selective antegrade cerebral perfusion is associated with improved outcomes in both emergency and elective settings compared with deep hypothermic circulatory arrest alone. METHODS Retrospective review was performed for all cases of proximal aortic surgery between January 2004 and May 2007. Of these 271 patients, 105 had emergency and 166 had elective operation. Selection bias was controlled using propensity scoring methods. Multivariable logistic regression analysis was used to model adverse outcomes as a function of selective antegrade cerebral perfusion, emergency status, and their interaction, adjusted for the propensity score. Adjusted odds ratios were formulated with 95% confidence intervals. RESULTS Operative mortality occurred in 12.1% (33/271) of patients: 8.8% (18/205) in patients with selective antegrade cerebral perfusion versus 22.7% (15/66) in those with deep hypothermic circulatory arrest alone (P = .003). Temporary neurologic dysfunction occurred in 5.9% (15/255) of patients: 4.5% (9/198) in selective antegrade cerebral perfusion versus 10.5% (6/57) in deep hypothermic circulatory arrest alone (P = .09). Stroke occurred in 4.3% (11/255) of patients with no difference between groups. In the elective setting, selective antegrade cerebral perfusion was associated with a significant decrease in operative mortality compared with deep hypothermic circulatory arrest alone. Overall, selective antegrade cerebral perfusion was associated with shorter intensive care unit and ventilator times and fewer renal and pulmonary complications. Significant multivariable predictors of operative mortality were emergency status, previous coronary surgery, and cardiopulmonary bypass time. CONCLUSIONS Use of selective antegrade cerebral perfusion confers a survival advantage during proximal aortic surgery that is most apparent in the elective setting. Improved resource utilization and fewer pulmonary and renal complications were observed in patients with selective antegrade cerebral perfusion.

Hybrid Coronary Revascularization Versus Off-Pump Coronary Artery Bypass Grafting for the Treatment of Multivessel Coronary Artery Disease

BACKGROUND Hybrid coronary revascularization (HCR) combines a minimally invasive (3-cm anterolateral thoracotomy), sternal-sparing, off-pump left internal mammary artery-left anterior descending (LIMA-LAD) coronary artery anastomosis with percutaneous coronary intervention (PCI) to non-LAD coronary arteries. We compared outcomes of HCR versus traditional off-pump coronary artery bypass grafting (OPCAB) for the treatment of multivessel coronary artery disease (CAD). METHODS Between October 8, 2003 and April 23, 2010, 147 patients with multivessel coronary disease were treated with HCR at a US academic center. These were matched 4:1 to 588 contemporaneous patients treated with multivessel OPCAB by sternotomy using an optimal matching algorithm with 8 preoperative variables: age, gender, ejection fraction, presence of diabetes, myocardial infarction (MI), number of diseased vessels, left main coronary artery disease, and Society of Thoracic Surgeons (STS) predicted risk of mortality (PROM) score. In-hospital major adverse events (MACCE) and the need for repeated revascularization during follow-up were compared between groups. All-cause mortality was determined using the Social Security Death Index (SSDI). RESULTS Matching produced groups with similar coronary anatomy and statistically similar preoperative risk factors. The incidence of MACCE was similar between groups (3/147 HCR versus 12/588 OPCAB). During a median 3.2 years of follow up, the need for repeated revascularization was higher for HCR than for OPCAB (18/147 [12.2%] versus 22/588 [3.7%]; p < 0.001). The incidence of blood transfusion was higher for the OPCAB group. Estimated 5-year survival was similar between groups (OPCAB, 84.3% versus HCR, 86.8%; p = 0.61). CONCLUSIONS Hybrid coronary revascularization is a minimally invasive treatment for multivessel CAD. Although repeated revascularization was greater with HCR, both in-hospital and midterm outcomes were comparable with those of traditional OPCAB. Further investigation into the comparative effectiveness of this alternative strategy is warranted.

Randomized Controlled Trial of Intensive Versus Conservative Glucose Control in Patients Undergoing Coronary Artery Bypass Graft Surgery: GLUCO-CABG Trial

OBJECTIVE The optimal level of glycemic control needed to improve outcomes in cardiac surgery patients remains controversial. RESEARCH DESIGN AND METHODS We randomized patients with diabetes (n = 152) and without diabetes (n = 150) with hyperglycemia to an intensive glucose target of 100–140 mg/dL (n = 151) or to a conservative target of 141–180 mg/dL (n = 151) after coronary artery bypass surgery (CABG) surgery. After the intensive care unit (ICU), patients received a single treatment regimen in the hospital and 90 days postdischarge. Primary outcome was differences in a composite of complications, including mortality, wound infection, pneumonia, bacteremia, respiratory failure, acute kidney injury, and major cardiovascular events. RESULTS Mean glucose in the ICU was 132 ± 14 mg/dL (interquartile range [IQR] 124–139) in the intensive and 154 ± 17 mg/dL (IQR 142–164) in the conservative group (P < 0.001). There were no significant differences in the composite of complications between intensive and conservative groups (42 vs. 52%, P = 0.08). We observed heterogeneity in treatment effect according to diabetes status, with no differences in complications among patients with diabetes treated with intensive or conservative regimens (49 vs. 48%, P = 0.87), but a significant lower rate of complications in patients without diabetes treated with intensive compared with conservative treatment regimen (34 vs. 55%, P = 0.008). CONCLUSIONS Intensive insulin therapy to target glucose of 100 and 140 mg/dL in the ICU did not significantly reduce perioperative complications compared with target glucose of 141 and 180 mg/dL after CABG surgery. Subgroup analysis showed a lower number of complications in patients without diabetes, but not in patients with diabetes treated with the intensive regimen. Large prospective randomized studies are needed to confirm these findings.

Impact of preoperative renal dysfunction on long-term survival for patients undergoing aortic valve replacement.

BACKGROUND The impact of the degrees of renal dysfunction (RD) after aortic valve replacement (AVR) has not been well described. The purpose of this study was to compare patients undergoing AVR with a range of renal function from normal to dialysis-dependence. METHODS A retrospective review of 2,408 patients undergoing AVR with or without coronary artery bypass graft surgery (CABG) from January 1996 to March 2009 was performed. Glomerular filtration rate (GFR) was estimated for patients using the Modification of Diet in Renal Disease formula. Multivariable logistic and Cox regression methods were used to determine the independent association of GFR with outcomes. Adjusted odds ratios were calculated for in-hospital outcomes, and Kaplan-Meier curves were created to estimate long-term survival. RESULTS In all, 1,512 patients (62.8%) had isolated AVR, and 896 (37.2%) underwent AVR plus CABG. Preoperative RD was common among all patients: 1,148 of 2,408 (47.7%) with mild RD (GFR 60 to 90 mL·min(-1)·1.73 m(-2)), 644 of 2,408 (26.7%) moderate RD (GFR 30 to 59 mL·min(-1)·1.73 m(-2)), 59 of 2,408 (2.5%) severe RD (GFR 15 to 30 mL·min(-1)·1.73 m(-2)), and 114 (4.7%) with kidney failure (GFR<15) or requiring dialysis. In-hospital mortality generally rose with RD, from 2.9% for patients with no RD to 15.8% for patients with severe RD, and 17.3% for patients requiring dialysis. Patients with severe RD or preoperative dialysis were associated with significantly poorer outcomes. Adjusted long-term survival is progressively worse across levels of RD, as was postoperative length of stay (p<0.001). CONCLUSIONS Preoperative RD is common among the AVR population and is associated with diminished long-term survival. The association between RD and worse outcomes after AVR surgery has significant clinical implications.

Clinical outcomes after hybrid coronary revascularization versus coronary artery bypass surgery: a meta-analysis of 1,190 patients

BACKGROUND Hybrid coronary revascularization (HCR) represents a minimally invasive revascularization strategy in which the durability of the internal mammary artery to left anterior descending artery graft is combined with percutaneous coronary intervention to treat remaining lesions. We performed a systematic review and meta-analysis to compare clinical outcomes after HCR with conventional coronary artery bypass graft (CABG) surgery. METHODS A comprehensive EMBASE and PUBMED search was performed for comparative studies evaluating in-hospital and 1-year death, myocardial infarction (MI), stroke, and repeat revascularization. RESULTS Six observational studies (1 case control, 5 propensity adjusted) comprising 1,190 patients were included; 366 (30.8%) patients underwent HCR (185 staged and 181 concurrent), and 824 (69.2%) were treated with CABG (786 off-pump, 38 on-pump). Drug-eluting stents were used in 328 (89.6%) patients undergoing HCR. Hybrid coronary revascularization was associated with lower in-hospital need for blood transfusions, shorter length of stay, and faster return to work. No significant differences were found for the composite of death, MI, stroke, or repeat revascularization during hospitalization (odds ratio 0.63, 95% CI 0.25-1.58, P = .33) and at 1-year follow-up (odds ratio 0.49, 95% CI 0.20-1.24, P = .13). Comparisons of individual components showed no difference in all-cause mortality, MI, or stroke, but higher repeat revascularization among patients treated with HCR. CONCLUSIONS Hybrid coronary revascularization is associated with lower morbidity and similar in-hospital and 1-year major adverse cerebrovascular or cardiac events rates, but greater requirement for repeat revascularization compared with CABG. Further exploration of this strategy with adequately powered randomized trials is warranted.

Influence of On-Pump Versus Off-Pump Techniques and Completeness of Revascularization on Long-Term Survival After Coronary Artery Bypass

BACKGROUND Off-pump coronary artery bypass graft surgery (OPCABG) may be associated with reduced morbidity and in-hospital mortality. In this study, we report the influence of surgery type, number of grafts, and the Index of Completeness of Revascularization (ICOR), namely, the number of grafts/number diseased vessel systems, on long-term survival. METHODS From 1997 to 2006, 12,812 consecutive patients underwent isolated CABG at a single academic center. Ten-year survival data were obtained by cross-referencing patients with the national Social Security Death Index. A propensity score analysis of 46 preoperative characteristics balanced risk factors between surgical groups. A proportional hazards regression analysis modeled the hazard of death as a function of surgery type (on versus off), distal group (1 to 3 versus 4 to 7 vessels), ICOR, and propensity score. RESULTS Proportional hazards regression analysis showed no significant influence of surgery type or number of grafts on long-term survival within the four groups: OPCABG 1 to 3 grafts (n = 3,946; ICOR 1.11), OPCABG 4 to 7 grafts (n = 1,721; ICOR 1.56), on-pump CABG 1 to 3 grafts (n = 3,380; ICOR 1.21), and on-pump CABG 4 to 7 grafts (n = 3,765; ICOR 1.64). Irrespective of technique of revascularization, there was a survival advantage for patients with higher ICOR. CONCLUSIONS Long-term survival was similar for patients receiving 1 to 3 or 4 to 7 grafts by either on-pump or off-pump techniques. However, higher ICOR was associated with improved long- term survival within all groups.