Cullen D. Morris

Off-Pump Coronary Artery Bypass Disproportionately Benefits High-Risk Patients

BACKGROUND It is not known which patient subgroups may benefit most from off-pump coronary artery bypass grafting (OPCAB) rather than coronary artery bypass grafting on cardiopulmonary bypass (CPB). METHODS The Society of Thoracic Surgeons database was queried for all isolated, primary coronary artery bypass graft cases between January 1, 1997, and December 31, 2007, at a US academic center. The Society of Thoracic Surgeons Predicted Risk of Mortality (PROM) was calculated by a formula based on 30 preoperative risk factors. It was used in three ways to compare 30-day operative mortality between patients treated with OPCAB versus CPB. First, patients were divided into quartiles based on their PROM, and mortality rates were compared between OPCAB and CPB patients within each PROM quartile. Second, a logistic regression model tested for an interaction between surgery type and PROM; a significant interaction would indicate that the relative mortality risk of OPCAB versus CPB varied with different PROM levels. Finally, locally smoothed kernel regression curves were used to visually estimate a threshold PROM point at which mortality rates diverge for the surgery types. RESULTS There were 14,766 consecutive patients, 7,083 OPCAB (48.0%) and 7,683 CPB (52.0%). There was no difference in operative mortality between OPCAB and CPB for patients in the lower two risk quartiles. In the higher risk quartiles there was a mortality benefit for OPCAB (odds ratio, 0.62 and 0.45 for OPCAB in the third and fourth risk quartiles). Logistic regression analysis confirmed a significant interaction between surgery type and PROM (p = 0.005) meaning that OPCAB is especially beneficial to patients with higher PROM. This benefit is most significant for patients with PROM values above 2.5% to 3%, where mortality curves sharply diverge. CONCLUSIONS Off-pump coronary artery bypass grafting is associated with lower operative mortality than coronary artery bypass grafting on CPB for higher risk patients. This mortality benefit increases with increasing PROM.

Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion

OBJECTIVE Myocardial apoptosis is primarily triggered during reperfusion (R) through various mechanisms that may involve endonuclease to cleavage genomic DNA in the internucleosomal linker regions. However, the relative contribution of myocardial apoptosis to development of myocardial injury during R remains unknown. In the present study, we examined whether inhibition of apoptosis with aurintricarboxylic acid (ATA), an endonuclease inhibitor, during R reduces infarct size and improves regional contractile function. METHODS AND RESULTS In two groups of chronically-instrumented dogs, 1 h of left anterior descending (LAD) coronary occlusion was followed by 24 h of R with infusion of saline (control, n=8) or ATA (1 mg/kg/h, n=8) into the left atrium starting 5 min before R and continuing for 2 h. ATA significantly reduced apoptotic cells (TUNEL staining) in the peri-necrotic myocardium (12+/-1%* vs. 36+/-4%), consistent with the absence of DNA laddering. To confirm inhibition of apoptosis with ATA, densitometrically, Bcl-2 (% of normal myocardium) was significantly increased vs. control (102+/-12* vs. 68+/-9) and Bax as well as the activated caspase-3 were significantly reduced vs. control (108+/-17* vs. 194+/-42 and -29+/-4* vs. 174+/-43, respectively). ATA significantly improved segmental shortening (3.3+/-1.2* vs. -1.8+/-0.7%) and segmental work (79.3+/-11.3* vs. 7.1+/-5.8 mmHg/mm) in area at risk myocardium, and reduced infarct size (TTC staining, 27+/-0.2* vs. 37+/-0.5%), confirmed by lower plasma creatine kinase activity. In addition, myocardial blood flow (0.9+/-0.1* vs. 0.4+/-0.1 ml/min/g) and endothelial-dependent maximal vascular relaxation (119+/-6* vs. 49+/-8%) were significantly improved. Myeloperoxidase activity in area at risk myocardium, a marker for neutrophil accumulation, was also significantly reduced (17+/-4* vs. 138+/-28 Delta Abs/min). CONCLUSIONS These data suggest that the inhibition of apoptosis during R is associated with a reduction in infarction, improvement in regional contractile and vascular endothelial functions as well as augmentation in myocardial blood flow. *P<0.05 vs. control group.

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.

Predictors of outcome in thymectomy for myasthenia gravis

BACKGROUND Factors determining predictability of response to thymectomy for myasthenia gravis (MG) vary in the literature. METHODS A 25-year retrospective review (1974 to 1999) of all thymectomies performed at a single institution was undertaken. RESULTS In 113 consecutive thymectomies for MG, women comprised 79% (89 of 113 patients), and mean age was 40+/-15 years. Complications occurred in 14% of patients (16 of 113). In-hospital mortality was 0, but 90-day hospital mortality was 0.88% (1 of 113 patients). Follow-up was obtained in 81% (92 of 113 patients) at a mean of 51+/-59 months postoperatively. Complete remission was achieved in 21% of patients (19 of 92), and marked improvement of MG in 54% (50 of 92), for a total benefit rate of 75%. Fourteen percent (13 of 92) were unchanged, and 11% (10 of 92) were worse. Using univariate analysis, sex, age, and pathology correlated significantly with outcome (p < 0.05): 80% of women (57 of 70) benefited from the procedure, versus 57% of men (12 of 21). Eighty percent (57 of 70) of patients less than 51 years of age were improved or in remission, versus 57% (12 of 22) older than 50. Twenty-three percent (5 of 22) of patients with thymoma deteriorated, versus 7.1% (5 of 70) without thymoma. Sex did not significantly correlate in the multivariate model. CONCLUSIONS Sex, age, and thymic pathology are potential predictors of outcome in thymectomy for MG, and may shape treatment decisions and target higher-risk patients.

Comparative study of AMP579 and adenosine in inhibition of neutrophil-mediated vascular and myocardial injury during 24 h of reperfusion

OBJECTIVE The purpose of this study was to compare protective effects of AMP579 and adenosine (Ado) at reperfusion (R) on inhibition of polymorphonuclear neutrophil (PMN) activation, PMN-mediated injury to coronary artery endothelium, and final infarct size. METHODS In anesthetized dogs, 1 h of left anterior descending coronary artery occlusion was followed by 24 h R and drugs were administered at R. Control (n=8, saline control), AMPI (n=7, AMP579, 50 microg/kg i.v. bolus followed by 3 microg/kg/min for 2 h), AMPII (n=7, AMP579, 50 microg/kg i.v. bolus), AMPIII (n=7, AMP579, 3 microg/kg/min i.v. for 2 h), and Ado (n=7, adenosine, 140 microg/kg/min i.v. for 2 h). RESULTS AMP579 in vitro directly inhibited superoxide radical (O(-)(2)) generation (nM/5x10(6) PMNs) from PMNs dose-dependently (from 17+/-1* at 10 nM to 2+/-0.2* at 10 microM vs. activated 30+/-2). However, inhibition of O(-)(2) generation by Ado at each concentration was significantly less than for AMP579. The IC(50) value for AMP579 (0.09+/-0.02 microM) on O(-)(2) generation was significantly less than that of Ado (3.9+/-1. 1 microM). Adherence of unstimulated PMN to postischemic coronary artery endothelium (PMNs/mm(2)) was attenuated in AMPI and AMPIII vs. Control (60+/-3* and 58+/-3* vs. Control 110+/-4), while Ado partially attenuated PMN adherence (98+/-3*). Accordingly, endothelial-dependent vascular relaxation was significantly greater in AMPI and AMPIII vs. Ado. At 24 h R, myocardial blood flow (MBF, ml/min/g) in the area at risk (AAR), confirmed by colored microspheres, in AMPI and AMPIII was significantly improved (0.8+/-0. 1* and 0.7+/-0.1* vs. Control 0.3+/-0.04). Infarct size (IS, TTC staining) in AMPI and AMPIII was significantly reduced from 38+/-3% in Control to 21+/-4%* and 22+/-3%*, respectively, confirmed by lower plasma creatine kinase activity (I.U./g protein) in these two groups (27+/-6* and 32+/-2* vs. 49+/-3). Cardiac myeloperoxidase activity (MPO, Abs/min) in the AAR was significantly reduced in AMPI and AMPIII vs. Control (36+/-11* and 35+/-10* vs. 89+/-10). However, changes in MBF, IS and MPO were not significantly altered by Ado. CONCLUSIONS These data suggest that continuous infusion of AMP579 at R is more potent than adenosine in attenuating R injury, and AMP579-induced cardioprotection involves inhibition of PMN-induced vascular and myocardial tissue injury. *P<0.05 vs. Control.

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.

Adenosine in myocardial protection in on-pump and off-pump cardiac surgery

Adenosine is most well known for its potent vasodilation of the vasculature. However, it also promotes glycolysis, and activates potassium-sensitive adenosine triphosphate (K(ATP)) channels. Adenosine also strongly inhibits neutrophil function such as superoxide anion production, protease release, and adherence to coronary endothelial cells. Hence adenosine attenuates ischemic injury as well as neutrophil-mediated reperfusion injury. Adenosine has also been implicated in the cardioprotective phenomenon of ischemic preconditioning. Accordingly experimental evidence shows that adenosine reduces postischemic injury when administered before ischemia and at the onset of reperfusion. Clinical studies in cardiology and cardiac surgery show cardioprotective trends with adenosine treatment but the effects are not as dramatic as those reported by experimental studies.

Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Dysfunction

BACKGROUND The purpose of this study was to assess the impact of left ventricular dysfunction and other risk factors on short- and mid-term outcomes after aortic valve replacement for aortic stenosis. METHODS From January 1, 2002, to December 31, 2007, 773 consecutive patients underwent primary aortic valve replacement for aortic stenosis at a single institution; concomitant coronary artery bypass graft surgery (CABG) was performed in 45.4% (351 of 773). Multivariable regression analysis was used to identify predictors of in-hospital mortality, with ejection fraction (EF) as the primary variable of interest. After discharge, survival status was determined using the Social Security Death Index. A Cox proportional hazards regression model was used to identify predictors of mid-term mortality. RESULTS On univariable analysis, EF (odds ratio [OR] 0.979, 95% confidence interval [CI]: 0.960 to 0.999, p = 0.044) but not concomitant CABG emerged as a predictor of in-hospital mortality. However, on multivariable analysis, neither EF nor concomitant CABG was associated with increased in-hospital mortality. Multivariable predictors of in-hospital mortality included age, emergent status, and prolonged bypass time. On univariable analysis, mid-term mortality was associated with EF and concomitant CABG (OR 0.979, 95% CI: 0.966 to 0.991, p = 0.001, and OR 1.61, 95% CI: 1.11 to 2.36, p = 0.013, respectively). However, after multivariable adjustment, only EF was associated with mid-term mortality (adjusted OR 0.985, 95% CI: 0.970 to 1.00, p = 0.049). Other multivariable predictors of mid-term mortality included age, dialysis-dependent renal failure, previous stroke, and peripheral vascular disease. CONCLUSIONS Left ventricular dysfunction, in addition to other patient comorbidities, may negatively impact survival after aortic valve replacement. Careful consideration of the cumulative effect of these multiple risk factors is necessary to optimize patient outcomes.

Long-term survival for patients with preoperative renal failure undergoing bioprosthetic or mechanical valve replacement.

BACKGROUND The objective of this study was to assess short-term and long-term outcomes after valve replacement with biologic or mechanical prostheses in patients with preoperative end-stage renal disease on chronic dialysis. METHODS A retrospective review of patients with end-stage renal disease undergoing valve replacement from January 1996 through March 2008 at Emory Healthcare Hospitals was performed. Outcomes were compared using χ(2) tests and 2-sample t tests. Adjusted long-term survival up to 10 years was assessed with Kaplan-Meier plots and compared between biologic and mechanical replacements using the Cox proportional hazards model. RESULTS A total of 202 patients underwent 211 valve replacement operations. Patient age was 20 to 83 years (mean age, 54.8 ± 14.0); 115 of 211 (54.5%) were male. Operations included the following: 100 of 211 (47.4%) isolated aortic; 49 of 211 (23.2%) isolated mitral; 4 of 211 (1.9%) isolated tricuspid; and 58 of 211 (27.5%) combined replacements. Thirteen (6.2%) patients underwent reoperative valve replacements. Most patients received bioprosthetic valves (143 of 211, 67.8%), while 68 of 211 (32.2%) received mechanical valves. Concomitant coronary artery bypass was performed in 53 of 211 (25.1%) patients. Thirty-day mortality was in 42 of 211 patients (19.9%) and was not different between bioprosthetic and mechanical replacements. Overall 10-year survival was 18.1% for all patients and was not influenced by valve type implanted. CONCLUSIONS For patients with end-stage renal disease treated with dialysis, valve replacement carries acceptable operative mortality. Long-term survival is similar among patients receiving bioprosthetic versus mechanical valve replacement. Careful risk assessment and choice of valve prosthesis should be performed prior to surgical intervention in this high-risk patient population.

Racial Disparity Persists After On-Pump and Off-Pump Coronary Artery Bypass Grafting

Background— Race has been shown to be an independent risk factor for operative mortality after coronary artery bypass grafting (CABG). This study sought to determine the extent to which race is a risk factor for adverse events, long-term mortality, and whether off-pump surgery (OPCAB) modifies that risk. Methods and Results— The Society of Thoracic Surgeons Adult Cardiac Database at Emory Healthcare affiliated hospitals was queried for all primary isolated CABG records from 1997 to 2007. A propensity score was formulated to balance the patient groups with respect to treatment assignment (OPCAB or CABG on cardiopulmonary bypass). Multivariable logistic regression was used to assess the impact of black race and OPCAB on in-hospital outcomes (death, stroke, myocardial infarction, and their composite, major adverse cardiac events). Cox proportional hazards regression model and Kaplan–Meier curves determined whether black race affected long-term all-cause mortality. Interaction terms were constructed to test whether OPCAB surgery influences surgical results differently in black patients than in white patients. There were 12 874 consecutive CABG patients, including 2033 (15.8%) blacks and 10 841 (84.2%) whites. Survival at 3, 5, and 10 years for blacks (87.5%, 81.4%, 63.8%) was significantly lower than for whites (90.7%, 85.2%, 67.1%, P<0.001). Blacks (adjusted odds ratio, 0.77; 95% CI, 0.44 to 1.36) and whites (adjusted odds ratio, 0.72; 95% CI, 0.53 to 0.99) who had OPCAB had lower risk-adjusted odds of major adverse cardiac events than their racial counterparts who had CABG on cardiopulmonary bypass. Conclusions— Short- and long-term outcomes are significantly worse in black than in white patients undergoing primary isolated CABG. OPCAB does not narrow the disparity in outcomes between blacks and whites.