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1.  Expression of Uncoupling Protein-2 Remains Increased Within Hibernating Myocardium Despite Successful Coronary Artery Bypass Grafting at 4 Weeks Post-Revascularization 
The Journal of surgical research  2014;193(1):15-21.
We have previously shown that mitochondrial uncoupling protein-2 (UCP-2) is increased in a swine model of hibernating myocardium (HM). Although UCP-2 reduces oxidant stress, it can promote inefficiency of the electron transport chain. In this study, we tested whether UCP-2 remains increased in revascularized HM (RHM) following coronary artery bypass grafting (CABG).
Seven swine underwent thoracotomy with placement of a constrictor on the left anterior descending artery (LAD). Twelve weeks later, a left internal mammary artery (LIMA) graft was placed on the distal LAD. Four weeks post-CABG, CT angiography documented patent grafts and function. At the terminal study, blood flow to the LAD and remote territories were assessed during high-dose dobutamine and mitochondria isolated from both regions for analysis. Comparisons were made to a group of swine with HM who underwent constrictor placement without bypass grafting (n=4).
During dobutamine infusion, RHM demonstrated lower blood flows (2.44±0.23 versus 3.43±0.30 ml/min/g; P<0.05) and reduced wall thickening (33±9% versus 52±13%; P<0.05) compared with remote regions. RHM had lower respiratory control indices (3.7±0.3 versus 4.3±0.4; P<0.05) with persistently increased UCP-2 content.
Despite patent grafts, RHM demonstrates a submaximal response to dobutamine infusion and increased mitochondrial UCP-2 expression. These data support the notion that recovery of the mitochondria in RHM is delayed early post-CABG and may contribute to impaired oxygen consumption and contractile reserve during catecholamine challenges.
PMCID: PMC4268234  PMID: 25199570
2.  Perioperative Outcomes after On- and Off-Pump Coronary Artery Bypass Grafting 
Texas Heart Institute Journal  2014;41(2):144-151.
Although numerous reports describe the results of off-pump coronary artery bypass grafting (CABG) at specialized centers and in select patient populations, it remains unclear how off-pump CABG affects real-world patient outcomes. We conducted a large, multicenter observational cohort study of perioperative death and morbidity in on-pump (ON) versus off-pump (OFF) CABG.
We reviewed Veterans Affairs Surgical Quality Improvement Program data for all patients (N=65,097) who underwent isolated CABG from October 1997 through April 2011 (intention-to-treat data were available from 2005 onward). The primary outcome was perioperative (30-day or in-hospital) death; the secondary outcomes were perioperative stroke, dialysis dependence, reoperation for bleeding, mechanical circulatory support, myocardial infarction, ventilator support ≥48 hr, and mediastinitis. Propensity scores calculated from age, 17 preoperative risk factors, and year of surgery were used to match 8,911 OFF with 26,733 ON patients.
In the complete cohort, compared with the ON patients (n=53,468), the OFF patients (n=11,629) had less perioperative death (2.02% vs 2.53%, P=0.0012) and lower incidences of all morbidities except perioperative myocardial infarction. In the matched cohort, perioperative death did not differ significantly between OFF and ON patients (1.94% vs 2.28%, P=0.06), but the OFF group had lower incidences of all morbidities except for perioperative myocardial infarction and mediastinitis. A subgroup intention-to-treat analysis yielded similar but smaller outcome differences between the ON and OFF groups.
Off-pump CABG might be associated with decreased operative morbidity but did not affect operative death, compared with on-pump CABG. Future studies should examine the effect of off-pump CABG on long-term outcomes.
PMCID: PMC4004490  PMID: 24808773
Cardiac surgical procedures/adverse effects/methods/mortality; coronary artery bypass/adverse effects/methods/mortality; morbidity; mortality; outcome assessment
3.  Uncoupling Protein-2 Expression and Effects on Mitochondrial Membrane Potential and Oxidant Stress in Heart Tissue 
Translational Research  2011;159(5):383-390.
Myocardial uncoupling protein (UCP)-2 is increased with chronic peroxisome proliferator-activated receptor γ (PPARγ) stimulation but the effect on membrane potential and superoxide is unclear. Wild type (WT) and UCP-2 knock-out (KO) mice were given a 3-week diet of control (C) or the PPAR γ agonist pioglitazone (50 μg/gram-chow per day) (PIO). In isolated mitochondria, UCP-2 content by Western blots, membrane potential (ΔΨm) by tetraphenylphosphonium (TPP) and relative superoxide levels by dihydroethidium (DHE) were measured. Oxygen respiration was determined at baseline and following 10 minutes anoxia-reoxygenation. PIO induced a 2-fold increase in UCP-2 and nuclear-bound PGC1α in WT mice with no UCP-2 expression in KO mice. Mitochondrial ΔΨm from WT mice on C and PIO diets was −166±4 mv and −147±6 mV respectively (P<0.05) and were lower than UCP-2 KO mice on C and PIO (−180±4 and −180±4 mv respectively; P<0.05). Maximal complex III inhibitable superoxide from WT mice on C and PIO diets was 22.5±1.3 and 17.8±1.1 AU respectively (P<0.05) and were lower than UCP-2 KO on C and PIO (32.9±2.3 and 29.2±1.9 AU respectively; P<0.05). Post-anoxia, the respiratory control index (RCI) in mitochondria from WT mice with and without PIO was 2.5±0.3 and 2.4±0.2 respectively and exceeded that of UCP-2 KO mice on C and PIO (1.2±0.1 and 1.4±0.1 respectively (P<0.05). In summary, chronic PPARγ stimulation leads to depolarization of the inner membrane and reduced superoxide of isolated heart mitochondria, which was critically dependent upon increased expression of UCP-2. UCP-2 expression affords resistance to brief anoxia-reoxygenation.
PMCID: PMC3328031  PMID: 22500511
4.  Utility of nuclear stress imaging for detecting coronary artery bypass graft disease 
The value of Single Photon Emission Computed Tomography stress myocardial perfusion imaging (SPECT-MPI) for detecting graft disease after coronary artery bypass surgery (CABG) has not been studied prospectively in an unselected cohort.
Radial Artery Versus Saphenous Vein Graft Study is a Veterans Affairs Cooperative Study to determine graft patency rates after CABG surgery. Seventy-nine participants agreed to SPECT-MPI within 24 hours of their coronary angiogram, one-year after CABG. The choice of the stress protocol was made at the discretion of the nuclear radiologist and was either a symptom-limited exercise test (n = 68) or an adenosine infusion (n = 11). The SPECT-MPI results were interpreted independent of the angiographic results and estimates of sensitivity, specificity and accuracy were based on the prediction of a graft stenosis of ≥70% on coronary angiogram.
A significant stenosis was present in 38 (48%) of 79 patients and 56 (22%) of 251 grafts. In those stress tests with an optimal exercise heart rate response (>80% maximum predicted heart rate) (n = 26) sensitivity, specificity and accuracy of SPECT-MPI for predicting the graft stenosis was 77%, 69% and 73% respectively. With adenosine (n = 11) it was 75%, 57% and 64%, respectively. Among participants with a suboptimal exercise heart rate response, the sensitivity of SPECT-MPI for predicting a graft stenosis was <50%. The accuracy of SPECT-MPI for detecting graft disease did not vary significantly with ischemic territory.
Under optimal stress conditions, SPECT-MPI has a good sensitivity and accuracy for detecting graft disease in an unselected patient population 1 year post-CABG.
PMCID: PMC3469356  PMID: 22862805
Coronary artery bypass grafts; CABG; Coronary artery imaging; Cardiac catheterization/intervention
5.  Dose dependent effect of statins on postoperative atrial fibrillation after cardiac surgery among patients treated with beta blockers 
Previous studies on the effects of Statins in preventing atrial fibrillation (AF) after cardiac surgery have shown conflicting results. Whether statins prevent AF in patients treated with postoperative beta blockers and whether the statin-effect is dose related are unknown.
We retrospectively studied 1936 consecutive patients who underwent coronary artery bypass graft (CABG) (n = 1493) or valve surgery (n = 443) at the Minneapolis Veterans Affairs Medical Center. All patients were in sinus rhythm before the surgery. Postoperative beta blockers were administered routinely (92% within 24 hours postoperatively).
Mean age was 66+10 years and 68% of the patients were taking Statins. Postoperative AF occurred in 588 (30%) patients and led to longer length of stay in the intensive care unit versus those without AF (5.1+7.6 days versus 2.5+2.3 days, p < 0.0001). Patients with a past history of AF had a 5 times higher risk of postoperative AF (odds ratio 5.1; 95% confidence interval 3.4 to 7.7; p < 0.0001). AF occurred in 31% of patients taking statins versus 29% of the others (p = 0.49). In multivariable analysis, statins were not associated with AF (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.7 to 1.2; p = 0.59). However, in a subgroup analysis, the patients treated with Simvastatin >20 mg daily had a 36% reduction in the risk of postoperative AF (OR 0.64, 95% CI 0.43 to 0.6; p = 0.03) in comparison to those taking lower dosages.
Among cardiac surgery patients treated with postoperative beta blockers Statin treatment reduces the incidence of postoperative AF when used at higher dosages
PMCID: PMC2777853  PMID: 19889221

Results 1-5 (5)