J. David Vega

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.

Off-pump coronary bypass provides reduced mortality and morbidity and equivalent 10-year survival.

BACKGROUND This study compared in-hospital major adverse cardiac events (MACE) and long-term survival after off-pump (OPCAB) vs on-pump (CPB) coronary artery bypass grafting (CABG). METHODS Reviewed were 12,812 consecutive isolated CABG patients from 1997 to 2006. A propensity score (PS), including 40 preoperative risk factors, balanced characteristics between OPCAB and CPB groups. Multiple logistic regression models tested whether gender or surgery type, or their interaction, were associated with in-hospital mortality and MACE. A proportional hazards regression model and Kaplan-Meier curves related long-term survival with gender, surgery type, and their interaction, adjusted for PS and age. RESULTS OPCAB was associated with a significant reduction in operative mortality (adjusted odds ratio [AOR], 0.68; p = 0.045), stroke (AOR, 0.48; p < 0.001), and MACE (AOR, 0.66; p = 0.018). Female gender was associated with higher rates of death (AOR, 1.93), stroke (AOR, 1.82), myocardial infarction (AOR, 2.19), and MACE (AOR, 1.97; each p < 0.001). Women disproportionately benefited from OPCAB in operative mortality (p = 0.04). Odds of death for women on CPB were higher than for women treated with OPCAB (AOR, 2.07, p = 0.005). Odds of death for men on CPB were not significantly higher than for men treated with OPCAB (AOR, 1.16, p = 0.51). Male gender was associated with longer-term survival (p = .011), but surgery type (OPCAB vs CPB) was not (p = 0.23). CONCLUSIONS OPCAB provides significant early mortality and morbidity advantages, especially for women. During the 10-year follow-up, OPCAB and CPB result in similar survival, regardless of gender.

Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection

BACKGROUND Historically, panel reactive antibody (PRA) analysis to detect HLA antibodies has been performed using cell-based complement-dependent cytotoxicity (CDC) techniques. Recently, a flow cytometric procedure (FlowPRA) was introduced as an alternative approach to detect HLA antibodies. The flow methodology, using a solid phase matrix to which soluble HLA class I or class II antigens are attached is significantly more sensitive than CDC assays. However, the clinical relevance of antibodies detected exclusively by FlowPRAhas not been established. In this study of cardiac allograft recipients, FlowPRA was performed on pretransplant sera with no detectable PRA activity as assessed by CDC assays. FlowPRA antibody activity was then correlated with clinical outcome. METHODS PRA analysis by anti-human globulin enhanced (AHG) CDC and FlowPRA was performed on sera corresponding to final cross-match specimens from 219 cardiac allograft recipients. In addition, sera collected 3-6 months posttransplant from 91 patients were evaluated. The presence or absence of antibodies was correlated with episodes of rejection and patient survival. A rejection episode was considered to have occurred based on treatment with antirejection medication and/or histology. RESULTS By CDC, 12 patients (5.5%) had pretransplant PRA >10%. In contrast, 72 patients (32.9%) had pretransplant anti-HLA antibodies detectable by FlowPRA (34 patients with only class I antibodies; 7 patients with only class II antibodies; 31 patients with both class I and class II antibodies). A highly significant association (P<0.001) was observed between pretransplant HLA antibodies detected by FlowPRA and episodes of rejection that occurred during the first posttransplant year. Fifteen patients died within the first year posttransplant. Of nine retrospective flow cytometric cross-matches that were performed, two were in recipients who had no pretransplant antibodies detectable by FlowPRA. Both of these cross-matches were negative. In contrast, five of seven cross-matches were positive among recipients who had FlowPRA detectable pretransplant antibodies. Posttransplant serum specimens from 91 patients were also assessed for antibodies by FlowPRA. Among this group, 58 patients had FlowPRA antibodies and there was a trend (although not statistically significant) for a biopsy documented episode of rejection to have occurred among patients with these antibodies. CONCLUSIONS Collectively, our data suggest that pre- and posttransplant HLA antibodies detectable by FlowPRA and not AHG-CDC identify cardiac allograft recipients at risk for rejection. Furthermore, a positive donor reactive flow cytometric cross-match is significantly associated with graft loss. Thus, we believe that detection and identification of HLA-specific antibodies can be used to stratify patients into high and low risk categories. An important observation of this study is that in the majority of donor:recipient pairs, pretransplant HLA antibodies were not directed against donor antigens. We speculate that these non-donor-directed antibodies are surrogate markers that correspond to previous T cell activation. Thus, the rejection episodes that occur in these patients are in response to donor-derived MHC peptides that share cryptic determinants with the HLA antigens that initially sensitized the patient.

Long-Term Outcomes After Isolated Aortic Valve Replacement in Octogenarians: A Modern Perspective

BACKGROUND With the recent advent of percutaneous valve therapy, an increased need for the evaluation of outcomes after open aortic valve replacement (AVR) in elderly patients is warranted. This study compares the short- and long-term survival outcomes of octogenarians after AVR with younger age groups in the modern surgical era. METHODS A retrospective review was performed on patients who underwent isolated, primary AVR from 1996 to 2006 at the Emory Healthcare Hospitals. Five-hundred fifteen patients were divided into three age groups: 60 to 69 (n = 206), 70 to 79 (n = 221), and 80 to 89 years of age (n = 88). Outcomes were compared among the age groups using logistic regression and analysis of variance techniques. Long-term survival between age groups was compared using the Cox proportional hazards model. Kaplan-Meier plots were used to determine survival rates. RESULTS The groups were similar with respect to in-hospital mortality (p = 0.66) and hospital length of stay (p = 0.08). Preoperative predictors of in-hospital mortality included stroke (odds ratio [OR] 5.36), chronic lung disease (OR 4.51), and renal failure (OR 1.39). As expected, age significantly impacted long-term survival (hazard ratio [HR] 1.06). Other predictors of long-term survival included stroke (HR 2.15), current smoker (HR 2.03), diabetes (HR 1.53), and renal failure (HR 1.4). The Kaplan-Meier estimate of median survival for octogenarians was 7.4 years. CONCLUSIONS In the modern era, octogenarians have acceptable short- and long-term results after open AVR. Comparisons of less invasive techniques for AVR should rely on outcomes based in the modern era and decisions regarding surgical intervention in patients requiring AVR should not be based on age alone.

Moderate Hypothermia and Unilateral Selective Antegrade Cerebral Perfusion: A Contemporary Cerebral Protection Strategy for Aortic Arch Surgery

BACKGROUND Cerebral protection techniques during aortic arch surgery include deep hypothermic circulatory arrest, retrograde cerebral perfusion, and (or) antegrade cerebral perfusion. It is unclear whether unilateral selective antegrade cerebral perfusion (uSACP) in the setting of moderate hypothermic circulatory arrest (MHCA) constitutes an effective cerebral protective strategy during aortic arch reconstruction. METHODS A retrospective review was performed for all aortic arch cases involving uSACP between January 2004 and December 2009. Of these 412 patients, 97 (24%) were treated emergently. Adverse outcomes included operative mortality, permanent neurologic dysfunction, temporary neurologic dysfunction, and renal failure requiring dialysis. Potential selection bias was controlled by the inclusion of 11 covariates. Multivariable logistic regression analysis was used to model adverse outcome as a function of MHCA and the covariates. Adjusted odds ratios were formulated along with 95% confidence intervals. RESULTS Three hundred forty-four patients underwent hemiarch reconstruction and 68 patients underwent total arch replacement. The mean core body temperature at the initiation of uSACP was 25.7 degrees C + or - 2.8 degrees C with a uSACP time of 30 + or - 15 minutes. Overall operative mortality occurred in 29 (7.0%) patients. The incidence of permanent neurologic dysfunction and temporary neurologic dysfunction were 3.6% and 5.1%, respectively. Nineteen (4.6%) patients suffered postoperative renal failure requiring dialysis. In the adjusted analysis, MHCA was not found to be an independent predictor of mortality, permanent neurologic dysfunction, temporary neurologic dysfunction, or renal failure requiring dialysis. CONCLUSIONS The MHCA with adjunctive uSACP is not an independent risk factor for adverse outcomes after aortic arch surgery. These data suggest that MHCA combined with uSACP represents an effective cerebral protective strategy in patients undergoing arch reconstruction in both the elective and emergent settings.

Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress

AIMS CYP1A1 and CYP1B1, members of the cytochrome P450 protein family, are regulated by fluid shear stress. This study describes the effects of duration, magnitude and pattern of shear stress on CYP1A1 and CYP1B1 expressions in human endothelial cells, towards the goal of understanding the role(s) of these genes in pro-atherogenic or anti-atherogenic endothelial cell functions. METHODS AND RESULTS We investigated CYP1A1 and CYP1B1 expressions under different durations, levels, and patterns of shear stress. CYP1A1 and CYP1B1 mRNA, protein, and enzymatic activity were maximally up-regulated at > or =24 h of arterial levels of shear stress (15-25 dynes/cm2). Expression of both genes was significantly attenuated by reversing shear stress when compared with 15 dynes/cm2 steady shear stress. Small interfering RNA knockdown of CYP1A1 resulted in significantly reduced CYP1B1 and thrombospondin-1 expression, genes regulated by the aryl hydrocarbon receptor (AhR). Immunostaining of human coronary arteries showed constitutive CYP1A1 and CYP1B1 protein expressions in endothelial cells. Immunostaining of mouse aorta showed nuclear localization of AhR and increased expression of CYP1A1 in the descending thoracic aorta, whereas reduced nuclear localization of AhR and attenuated CYP1A1 expression were observed in the lesser curvature of the aortic arch. CONCLUSION CYP1A1 and CYP1B1 gene and protein expressions vary with time, magnitude, and pattern of shear stress. Increased CYP1A1 gene expression modulates AhR-regulated genes. Based on our in vitro reversing flow data and in vivo immunostained mouse aorta, we suggest that increased expression of both genes reflects an anti-atherogenic endothelial cell phenotype.

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.

Clopidogrel (Plavix®) and cardiac surgical patients: implications for platelet function monitoring and postoperative bleeding

The use of clopidogrel (Plavix), an inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation, has been proven to reduce ischemic events in cardiovascular patients, but little information is available for optimal monitoring of platelet function in patients receiving the drug preoperatively. In the first part of the study we compared different testing modalities (thrombelastography (TEG), platelet aggregometry, and whole blood aggregation) to assess platelet ADP receptor inhibition. Because clopidogrel is a pro-drug, we used an in vitro model of ADP inhibition with 5‵-p-fluorosulfonylbenzoyladenosine (FSBA). FSBA at final concentration of 80 μM completely inhibited platelet aggregation but had no effect on TEG maximum amplitude (MA). In the second part of the study, antiplatelet effects of clopidogrel were clinically assessed and correlated to postoperative bleeding in 18 coronary bypass surgery patients. Preoperative TEG results were normal or hypercoagulable in clopidogrel-treated patients, although platelet aggregation responses to ADP were inhibited. Clopidogrel-treated patients who underwent cardiopulmonary bypass had a high incidence (84.6%) of platelet transfusion therapy due to increased chest tube drainage. In conclusion, we have demonstrated that normal preoperative TEG-MA does not preclude clopidogrel-induced ADP receptor blockade; however, TEG can be a reliable monitor for CPB-induced platelet dysfunction related to GPIIb/IIIa. For monitoring clopidogrel, it is necessary to perform more specific platelet function tests (aggregometry or platelet count ratio) using ADP as an activator.

Preferential Activation of SMAD1/5/8 on the Fibrosa Endothelium in Calcified Human Aortic Valves - Association with Low BMP Antagonists and SMAD6

Background Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification. Methods and Results Human calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFβ pathway) did not show any difference. Interestingly, we found that BMP-2/4/6 expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both disease states. Moreover, significant expression of inhibitory SMAD-6 expression was found only in the non-calcified ventricularis endothelium. Conclusions SMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of BMP antagonists and inhibitory SMAD6. These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs.

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts

BACKGROUND A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.