Neutrophil inhibition contributes to cardioprotection by postconditioning.

BACKGROUND: Postconditioning (postcon) reduces infarct size, myocardial superoxide ((•)O(2)) generation, and neutrophil (PMN) accumulation. It is unknown whether inhibition of PMNs influence cardioprotection by postcon. The present study tested the following hypotheses: (1) myocardial salvage by postcon is modified by inhibition of PMNs and (2) postcon directly inhibits PMN (•)O(2) generation. METHODS: For hypothesis 1, a deductive approach was used to determine infarct size in vivo with and without PMNs in rats, and for hypothesis 2, blood sampled from the anterior interventricular vein (AIV) in a canine model was used. Protocol 1: anesthetized rats, subjected to 30 min of coronary artery occlusion and 3 h of reperfusion, were randomized to control (n = 13), postcon (n = 13), PMN-depletion: (n = 9), and postcon in PMN-depleted rats (n = 9). Protocol 2: blood was sampled at baseline, 2 h and 24 h from the AIV, draining the area at risk (AAR) in anesthetized dogs with 60 min coronary occlusion ± postcon; whole blood was analyzed for (•)O(2) by luminol-enhanced chemiluminescence. RESULTS: Postcon and PMN depletion reduced infarct size (42.6 ± 2.1%, P < 0.05 vs. control, and 43.9 ± 3.0%, P < 0.05 vs. control, respectively) vs. control (58.8 ± 0.9%), with no further decrease with postcon in PMN-depleted rats (37.2 ± 2.9%, P = 0.34 vs. postcon). PMN accumulation in AAR was less in postcon (21.2 ± 0.3%, P < 0.05 vs. control) and PMN-depleted (9.4 ± 0.3%, P < 0.05 vs. control) vs. control (30.5 ± 1.2%), with a further decrease in the postcon + PMN depletion group (5.4 ± 0.6%, P < 0.05 vs. control). In dogs, (•)O(2) release by PMNs increased at 2 h and 24 h of R, which was reduced to baseline levels by postcon. CONCLUSIONS: These data imply PMN involvement in cardioprotection by postconditioning.

Off pump coronary artery bypass surgery for significant left ventricular dysfunction: safety, feasibility, and trends in methodology over time--an early experience.

OBJECTIVE: To examine the safety and applicability of off pump coronary artery bypass surgery (OPCAB) in patients with significant left ventricular dysfunction and to discuss the clinical implications for the surgical methods. DESIGN: Retrospective study. SETTING: Tertiary care university affiliated referral centre. PARTICIPANTS: 353 consecutive patients with preoperative left ventricular ejection fraction < or = 35% who underwent coronary artery bypass over a three year period. MAIN OUTCOME MEASURES: Postoperative morbidity and mortality. METHODS: 144 patients operated by OPCAB were compared with 209 patients operated by conventional coronary artery bypass. Multivariate and univariate analyses were performed on the pre- and postoperative variables to predict risk factors associated with hospital morbidity and mortality. RESULTS: Patients in the OPCAB group were more likely to be women and to have congestive heart failure, chronic obstructive pulmonary disease, hypertension, and diabetes; patients in the on pump group were more likely to have had a recent myocardial infarction and to have more severe angina pectoris and an urgent/emergent status. The groups did not differ significantly in length of stay, major postoperative complication rates, or mortality. Comparison of the impact of the procedures on surgical methods over time showed an increase in the use of OPCAB (13% to 67%), without any impact on morbidity or mortality. CONCLUSIONS: OPCAB is feasible and applicable for patients with depressed left ventricular function. This high risk group can potentially benefit from the off pump approach.

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

OBJECTIVES: A 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. METHODS: All 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. RESULTS: Myocardial 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). CONCLUSIONS: Remote 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.

Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: a prospective randomized comparison of two hundred unselected patients undergoing off-pump versus conventional coronary artery bypass grafting.

OBJECTIVE: Retrospective comparisons of selected patients undergoing off-pump versus conventional on-pump coronary artery bypass grafting have yielded inconsistent results and raised concerns about completeness of revascularization in off-pump coronary artery bypass grafting. METHODS: Two hundred unselected patients referred for elective primary coronary artery bypass grafting were randomly assigned to undergo off-pump coronary artery bypass grafting with an Octopus tissue stabilizer (Medtronic, Inc, Minneapolis, Minn) or conventional coronary artery bypass grafting with cardiopulmonary bypass by a single surgeon. Revascularization intent determined before random assignment was compared with the revascularization performed. All management followed strict, unbiased, criteria-driven protocols. Patients and nonoperative care providers were blinded to surgical group. RESULTS: Baseline characteristics were similar. The number of grafts performed per patient (mean +/- SD 3.39 +/- 1.04 for off-pump coronary artery bypass grafting, 3.40 +/- 1.08 for conventional coronary artery bypass grafting) and the index of completeness of revascularization (number of grafts performed/number of grafts intended, 1.00 +/- 0.18 for off-pump coronary artery bypass grafting, 1.01 +/- 0.09 for conventional coronary artery bypass grafting) were similar. Likewise, the index of completeness of revascularization was similar between groups for the lateral wall. Combined hospital and 30-day mortalities and stroke rates were similar. Postoperative myocardial serum enzyme measures were significantly lower after off-pump coronary artery bypass grafting, suggesting less myocardial injury. Adjusted postoperative thromboelastogram indices, fibrinogen, international normalized ratio, and platelet levels all showed significantly less coagulopathy after off-pump coronary artery bypass grafting. Patients undergoing off-pump coronary artery bypass grafting received fewer units of blood, were more likely to avoid transfusion altogether, and had a higher hematocrit at discharge. Cardiopulmonary bypass was an independent predictor of transfusion (odds ratio 2.42, P =.0073) by multivariate analysis. More patients undergoing off-pump coronary artery bypass grafting were extubated in the operating room and within 4 hours. Postoperative length of stay (in days) was shorter for off-pump coronary artery bypass grafting (5.1 +/- 6.5 for off-pump coronary artery bypass grafting, 6.1 +/- 8.2 for conventional coronary artery bypass grafting, P =.005 by Wilcoxon test). One patient (in the conventional coronary artery bypass grafting group) required angioplasty for graft closure within 30 days. CONCLUSIONS: When compared with conventional coronary artery bypass grafting with cardiopulmonary bypass, off-pump coronary artery bypass grafting achieved similar completeness of revascularization, similar in-hospital and 30-day outcomes, shorter length of stay, reduced transfusion requirement, and less myocardial injury.

Predictors and outcomes associated with early extubation in older adults undergoing coronary artery bypass surgery.

BACKGROUND: Older age has been associated with prolonged mechanical ventilation after coronary artery bypass surgery. Prolonged mechanical ventilation contributes to increased morbidity and mortality and to use of limited financial resources among older adults. OBJECTIVES: To examine selected physiological and pathophysiological variables ofpresurgicalpatients to predict duration of mechanical ventilation in older adults after coronary artery bypass surgery. METHODS: Nonrandomized study of a clinical database of 919 patients (> or =65 years old) who had coronary artery bypass surgery between October 1996 and December 1997. RESULTS: Median elapsed time after coronary artery bypass surgery until extubation was used to sort patients into 2 groups: group 1, 6 hours or fewer (n = 464); and group 2, more than 6 hours (n = 455). With stepwise logistic regression, the physiological model included age (odds ratio, 1.05; P<.001) and female sex (odds ratio, 1.48; P = .005) with weak discrimination by group (concordance statistic = 0.5880). The pathophysiological model, which included renal insufficiency (odds ratio, 3.28; P = .01), previous peripheral vascular surgery (odds ratio, 2.87; P = .03), nonelective preoperative clinical status (odds ratio, 2.8; P = .006), congestive heartfailure (odds ratio, 2.6; P<.001), and reoperation (odds ratio, 2.34; P = .007), showed moderate discrimination bygroup (concordance statistic =0.6755). CONCLUSION: Many older adults were easily extubated and had good outcomes. The variables comorbid conditions and severity of illness provided better discrimination between extubation groups than a physiological model provided. Both predictive models allowed limited discrimination between groups.

All-blood (miniplegia) versus dilute cardioplegia in experimental surgical revascularization of evolving infarction.

BACKGROUND: The advantages of blood cardioplegia include the oxygen-carrying capacity, superior oncotic and buffering properties, and endogenous antioxidants contained in blood. However, the partial dilution of blood in 4:1 (blood:crystalloid) cardioplegic solutions may nullify these advantages and progressively dilute blood during continuous retrograde delivery. This study tested the hypothesis that all-blood (66:1) cardioplegia provides superior myocardial protection compared with dilute (4:1) cardioplegia delivered in a continuous retrograde modality during surgical reperfusion of evolving myocardial infarction. METHODS AND RESULTS: After 60 minutes of left anterior descending coronary artery (LAD) occlusion, anesthetized canines were placed on cardiopulmonary bypass and randomized to either all-blood cardioplegia (AB group) or dilute blood cardioplegia (Dil group). After cross clamping, arrest was induced with 5 minutes of tepid (30 degrees C) antegrade potassium all-blood or dilute blood cardioplegia and maintained with tepid retrograde coronary sinus cardioplegia for a total of 1 hour. The LAD was released after 30 minutes of arrest, simulating revascularization. The cardioplegia hematocrit for the Dil group was lower than that for the AB group (7+/-1% versus 12+/-2%, P<0.05); at the end of bypass, systemic hematocrit was lower in the Dil group than in the Ab group (15+/-1% versus 20+/-1%, P<0.05). Infarct size (triphenyltetrazolium chloride staining) was comparable between the AB and Dil groups (29.6+/-2.9% versus 30.3+/-3.9% of area at risk), and there was no difference in area-at-risk myocardium systolic shortening (by sonomicrometry, -0.3+/-1% versus -0.4+/-1%). Tissue edema after bypass tended to be greater in the Dil group compared with the AB group in the heart (82+/-0% versus 81+/-1%), lung (79+/-1% versus 78+/-1%), liver (75+/-1% versus 74+/-0%), and skeletal muscle (76+/-1% versus 73+/-2%) and was significantly greater in the duodenum (80+/-1% versus 79+/-1%, P<0.05) and kidney (82+/-1% versus 79+/-1%, P<0.05). Postexperimental endothelial function (relaxation of acetylcholine) was impaired in LADs of the AB group versus the Dil group (59+/-6% versus 77+/-5%, P<0.05). CONCLUSIONS: Both all-blood cardioplegia and dilute cardioplegia have disadvantages, but these do not have an impact on the pathogenesis of infarct size or recovery of regional contractile function.

Electroplegia: an alternative to blood cardioplegia for arresting the heart during conventional (on-pump) cardiac operation.

BACKGROUND: Aortic cross-clamping is contraindicated in patients with severe atherosclerosis of the ascending aorta, and administration of chemical cardioplegia may be cumbersome in these patients. In this study, we demonstrate an alternative method of achieving cardioplegia by electrical stimulation of the vagus nerve. METHODS: In anesthetized canines, the left anterior descending coronary artery was reversibly ligated for 90 minutes, followed by cardiopulmonary bypass (CPB) and randomization to three groups (n = 8 each): (1) BCP group: 1 hour of intermittent hypothermic (4 degrees C) blood cardioplegia infusion; (2) CPB group: 1 hour of CPB alone; (3) EP group (group receiving electroplegia): 1 hour of intermittent vagal stimulation (total of 60 20-second electrical stimuli at 40 Hz, 6 to 10 V) with adjunctive pyridostigmine (0.5 mg/kg), verapamil (50 microg/kg), and propranolol (80 microg/kg) to potentiate hyperpolarization and suppress ectopic escape beats. RESULTS: The EP group achieved consistent intervals of arrest with 3.8 +/- 1.2 escape beats per 20-second stimulation period. After 2 hours of reperfusion off CPB, the left anterior descending coronary artery segmental shortening was reduced from baseline in all groups, but the segmental shortening recovered to a greater extent in the EP group than in either the CPB or BCP group (2.4% +/- 1.4% versus -1.3% +/- 1.3% versus -4.0% +/- 0.8%, p < 0.05). Infarct size (TTC stain, percentage of area at risk) was comparable among groups (EP: 20.9% +/- 4.7%; CPB: 29.6% +/- 3.2%; BCP: 25.1% +/- 5.7%). Postischemic left anterior descending coronary artery endothelial function (percent maximum relaxation to acetylcholine) was depressed in the EP group (68.6% +/- 7.6% versus 102.3% +/- 6.4%, p < 0.05), but was comparable versus nonischemic circumflex function in the BCP group (77.1% +/- 11.9% versus 100.4% +/- 10.0%, p = 0.15) and the CPB group (93.8% +/- 6.6% versus 93.3% +/- 6.6%). CONCLUSIONS: Electroplegia achieves elective intermittent cardiac arrest, avoids hypothermia, chemical cardioplegia, and aortic cross-clamping, with physiological outcomes comparable to blood cardioplegia.

Active perfusion of coronary grafts facilitates complex off-pump coronary artery bypass surgery.

BACKGROUND: Hemodynamic stability during cardiac manipulation for complex, multivessel off-pump coronary artery bypass grafting (OPCAB) remains problematic. METHODS: A servo-controlled pump has been utilized to deliver warm whole blood to coronary grafts prior to construction of proximal anastomoses. RESULTS: This technique may avoid detrimental hemodynamic decompensation, which may accompany regional coronary ischemia during cardiac displacement. It may also allow precise infusion of supplemental additives leading to coronary vasodilatation, myocardial resuscitation, and enhancement of myocardial contractility. CONCLUSION: In this report, three complex OPCAB cases are described which were successfully performed with active graft perfusion and which might not otherwise have been technically feasible by conventional OPCAB techniques.

Progressively developed myocardial apoptotic cell death during late phase of reperfusion.

Myocardial apoptosis is primarily triggered during reperfusion (R). The aim of this study was to test the hypothesis that R-induced apoptosis develops progressively during the late phase of R, and that R-induced apoptosis is associated with changes in expression of anti- and pro-apoptotic proteins and infiltrated inflammatory cells. Thirty-one dogs were subjected to 60 min of left anterior descending coronary occlusion followed by 6, 24, 48, and 72 h R, respectively. There was no group difference in collateral blood flow, measured by colored microspheres during ischemia. Necrotic cell death (TTC staining) was significantly increased during R, starting at 27 +/- 2% at 6 h R and increasing to 41 +/- 2% at 24 h R. There was no further change at 48 (37 +/- 3%) and 72 (36 +/- 6%) h R, respectively. TUNEL positive cells (% total normal nuclei) in the peri-necrotic zone progressively increased from 6 (26 +/- 2) to 24 (38 +/- 1), 48 (48 +/- 3) and 72 (59 +/- 4) h R, respectively. The number of detected TUNEL positive cells at these time points was consistent with an increased intensity of DNA ladders, identified by agarose gel electrophoresis. Compared with normal tissue, western blot analysis showed persistent reduction in expression of anti-apoptotic protein Bcl-2 from 6 (16 +/- 0.8%) to 72 h R (78 +/- 2%), and increase in expression of pro-apoptotic proteins including Bax from 6 (30 +/- 3%) to 72 h R (66 +/- 3%), and p53 from 6 (12 +/- 1%) to 72 h R (91 +/- 2%), respectively. Immunohistochemical staining revealed that infiltrated neutrophils (mm(2) myocardium) were significantly correlated with development of necrotic and apoptotic cell death from 6 to 24 h R, respectively (P < 0.05), while large macrophage infiltration seen during 48 to 72 h R were correlated with apoptotic cell death (P < 0.05). These results indicate that 1) necrosis peaked at 24 h R when apoptosis was still progressively developing during later R; 2) changes in Bcl-2 family and p53 proteins may participate in R-induced myocardial apoptosis; 3) inflammatory cells may play a role in triggering cell death during R. P < 0.05 vs. normal nuclei and tissue; P < 0.01 vs. 6 h R.

Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive off-pump coronary bypass patients.

BACKGROUND: This retrospective study compared clinical outcomes and resource utilization in patients having off-pump coronary artery bypass grafting (OPCAB) versus conventional coronary artery bypass grafting (CABG). Angiographic patency was documented in the OPCAB group. METHODS: From April 1997 through November 1999, OPCAB was performed in 200 consecutive patients, and the results were compared with those in a contemporaneous matched control group of 1,000 patients undergoing CABG. Patients were matched according to age, sex, preexisting disease (renal failure, diabetes, pulmonary disease, stroke, hypertension, peripheral vascular disease, previous myocardial infarction, and primary or redo status. Follow-up in the OPCAB patients was 93% and averaged 13.4 months. RESULTS: Hospital death (1.0%), postoperative stroke (1.5%), myocardial infarction (1.0%), and re-entry for bleeding (1.5%) occurred infrequently in the OPCAB group. There were reductions in the rates of transfusion (33.0% versus 70.0%; p < 0.001) and deep sternal wound infection (0% versus 2.2%; p = 0.067) in the OPCAB group compared with the CABG group. Angiographic assessment of 421 grafted arteries was performed in 167 OPCAB patients (83.5%) prior to hospital discharge. All but five were patent (98.8%) (93.3% FitzGibbon A, 5.5% FitzGibbon B, 1.2% FitzGibbon O). All 163 internal mammary artery grafts were patent. Off-pump coronary artery bypass grafting reduced postoperative hospital stay from 5.7 +/- 5.3 days in the CABG group to 3.9 +/- 2.6 days (p < 0.001), with a decrease in hospital cost of 15.0% (p < 0.001). CONCLUSIONS: Off-pump coronary artery bypass grafting reduces hospital cost, postoperative length of stay, and morbidity compared with CABG on cardiopulmonary bypass. Off-pump coronary bypass grafting is safe, cost effective, and associated with excellent graft patency and clinical outcomes.

Myocardial protection for off-pump coronary artery bypass surgery.

Myocardial protection during off-pump coronary artery bypass surgery (OPCAB) is a multifactorial problem. Careful, individualized choice of graft sequence and maintenance of stable systemic hemodynamics are of central importance. Recently refined techniques for atraumatic rotation of the heart and visualization of coronary anastomoses allow precise and controlled grafting of all coronary territories without cardiopulmonary bypass in the large majority of cases. Perfusion-assisted direct coronary artery bypass (PADCAB) techniques, in which coronary perfusion pressure is independent of systemic arterial pressure, can avoid or abort a downward hemodynamic spiral, which may occasionally occur during complex, multivessel OPCAB. PADCAB promotes collateral myocardial perfusion and avoids the cumulative global effect of sequential episodes of regional ischemia, improving myocardial protection during OPCAB.

Experimental off-pump coronary artery revascularization with adenosine-enhanced reperfusion.

OBJECTIVE: Although beating heart coronary artery bypass grafting has recently gained popularity, it eliminates the protective strategies (ie, cardioplegia) developed for use in conventional cardiac operations. We recently introduced the technique of perfusion-assisted direct coronary artery bypass to perfuse the grafted vessels during multivessel off-pump coronary artery bypass grafting. In the present study we tested the hypothesis that intracoronary reperfusion with the cardioprotective agent adenosine during simulated perfusion-assisted direct coronary artery bypass attenuates reperfusion injury. METHODS: In anesthetized dogs the heart was exposed, and the left anterior descending coronary artery was ligated for 75 minutes. Reperfusion was achieved through a catheter in the left anterior descending coronary artery by means of a computer-controlled pump. Intracoronary left anterior descending coronary artery perfusion pressure was continuously matched to mean arterial blood pressure. In one group (adenosine group) 10 micromol/L adenosine was added to the blood during the first 30 minutes of reperfusion, whereas another group (vehicle group) received a comparable volume of saline solution. RESULTS: During the first 30 minutes of reperfusion, blood flow through the left anterior descending coronary artery was significantly greater (P <.05) in the adenosine group than in the vehicle group (150.6 +/- 21.9 vs 50.2 +/- 11.3 mL/min at 15 minutes of reperfusion). Although there were no group differences in postischemic wall motion, infarct size was significantly smaller in the adenosine group than in the vehicle group (11.1% +/- 3.0% vs. 28.0% +/- 4.0% of area at risk, P <.05). Myeloperoxidase activity in the necrotic tissue, an index of neutrophil accumulation, tended to be lower in the adenosine group than in the vehicle group (58.6 +/- 14.2 vs. 91.0 +/- 21.6 DeltaAbs Units x min(-1) x g(-1) tissue). In isolated postischemic left anterior descending coronary artery rings, the maximal relaxation response to the endothelium-dependent vasodilator acetylcholine was significantly greater in the adenosine group than in the vehicle group (97.9% +/- 5.6% vs. 64.7% +/- 6.5%, P<.05). CONCLUSION: This novel reperfusion strategy for off-pump coronary artery bypass grafting can be used not only in cases requiring multiple grafting but also to attenuate necrosis and endothelial dysfunction in acute evolving infarction.

In vivo hemodynamic, histologic, and antimineralization characteristics of the Mosaic bioprosthesis.

BACKGROUND: Performance of bioprosthetic valves is limited by tissue degeneration due to calcification with reduced performance and longevity. The Mosaic bioprosthetic valve (Medtronic Heart Valves, Inc, Minneapolis, MN) combines zero pressure fixation, antimineralization properties of alpha-amino oleic acid (AOA), and a proven stent design. We tested the hypothesis that AOA treatment of Mosaic valves improves hemodynamics, antimineralization properties, and survival in a chronic ovine model. METHODS: Mitral valves were implanted in juvenile sheep with Mosaic valves with AOA treatment (n = 8) or without AOA treatment (non-AOA, n = 8), or Hancock I (HAN, n = 4) tissue valves, and explanted at 20 postoperative weeks. RESULTS: Survival was equivalent in AOA and non-AOA (140 +/- 0.4 and 129 +/- 30 days), but was significantly less in HAN (82 +/- 35). Leaflet calcium (microgCa/mg tissue) was less in AOA (9.6 +/- 13.9; p < 0.05 versus non-AOA and HAN) than non-AOA (96.3 +/- 63.8) and HAN (130.8 +/- 43.2). Explant valve orifice area (cm2) was significantly preserved in the AOA group compared with the non-AOA group (1.5 +/- 0.7 vs 0.8 +/- 0.3; p < 0.05 versus non-AOA and HAN). CONCLUSIONS: We conclude that AOA treatment of Mosaic valves reduces leaflet calcification and valve gradient in juvenile sheep, and that the Mosaic design and fixation features may offer survival advantages that must be confirmed in extended trials.

Adenosine attenuates reperfusion-induced apoptotic cell death by modulating expression of Bcl-2 and Bax proteins.

This study tests the hypothesis that infarct reduction with adenosine (Ado) is associated with inhibition of apoptotic cell death by modulating expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins and reducing neutrophil accumulation. In three groups of dogs, the left anterior descending coronary artery was occluded for 60 min and reperfused for 6 h. Either saline (Control, n=8), Ado (140 microg/kg/min, n=8) or CGS21680, an adenosine A2A receptor analogue, (0.2 microg/kg/min, n=7) were infused during the first 2 h of reperfusion. Myocardial apoptosis was detected by histological TUNEL staining and DNA laddering. Expression of Bcl-2 and Bax proteins was analyzed using Western blot assay. Neutrophil localization was detected by immunohistochemistry with monoclonal anti-neutrophil CD18 antibody. There was no group difference in collateral blood flow (colored microspheres) during ischemia. Intra-left atrial administration of Ado and CGS21680 significantly decreased infarct size from 26+/-2% in Control to 13+/-1%* and 16+/-3%*, respectively. TUNEL positive cells in the peri-necrotic zone of the ischemic myocardium were also significantly reduced from 16+/-2% in Control group to 9+/-1%* and 10+/-2%*, respectively, consistent with the absence of DNA laddering in these two groups. Densitometrically, Ado and CGS21680 at reperfusion significantly increased the expression (% of normal myocardium) of downregulated Bcl-2 from 45+/-6% in Control group to 78+/-12%* and 69+/-10%*, respectively, and attenuated expression of upregulated Bax from 198+/-16% in Control group to 148+/-10%* and 158+/-12%*, respectively. Furthermore, the number of positive CD18 cells (mm(2) myocardium), which was significantly correlated with TUNEL positive cells in peri-necrotic zone, was significantly reduced from 403+/-42 in Control group to 142+/-18* in Ado group and 153+/-20%* in CGS21680 group, respectively. In conclusion, the present study suggests that inhibition of apoptosis by Ado at reperfusion involves alterations in anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins and neutrophil accumulation, primarily mediated by an adenosine A2A receptor. * P<0.05 v Control group.

Brief pretreatment of radial artery conduits with phenoxybenzamine prevents vasoconstriction long term.

BACKGROUND: Radial artery bypass conduits are prone to early vasospasm or "string sign" with use of vasopressor therapy intraoperatively and postoperatively, causing increased resistance in coronary artery grafts. Current intraoperative treatment with papaverine fails to provide sustained inhibition of vasoconstriction. We tested the hypothesis that a 30-minute pretreatment of radial artery segments with the alpha-adrenergic antagonist phenoxybenzamine (PB) or the putative protein phosphatase 2,3-butadione monoxime (BDM) attenuates vasoconstriction induced by the vasopressors phenylephrine or norepinephrine for as long as 48 hours compared with papaverine. METHODS: Canine radial arteries were harvested, incubated in control buffer or solutions of papaverine 10(-6) M, BDM 10(-6) M or phenoxybenzamine 10(-6) M for 30 minutes, washed, and stored in drug-free culture medium for 2, 24, or 48 hours. After storage, constriction was induced by norepinephrine at incremental concentrations ranging from 0.7 to 3.5 micromol/L or by phenylephrine (0.300 to 1.5 micromol/L) with or without the inhibitors, and the degree of vasoconstriction was quantified in organ chambers. Responses to norepinephrine or phenylephrine were compared to constriction with receptor-independent potassium chloride KC1 (30 mmol/L). RESULTS: Maximum responses to phenylephrine and norepinephrine were comparable at 2, 24, and 48 hours after harvest in the control group (phenylephrine: 67% +/- 4%, 62% +/- 6%, 65% +/- 6% of KC1 response; norepinephrine: 75% +/- 4%, 62% +/- 1%, 58% +/- 7%, respectively). Papaverine failed to attenuate constriction to phenylephrine and norepinephrine 2, 24, or 48 hours posttreatment. Pretreatment with BDM did not reduce vasoconstriction responses to phenylephrine or norepinephrine 2 hours after incubation but did reduce constriction responses thereafter. In contrast, phenoxybenzamine completely attenuated constriction to both phenylephrine (19% +/- 8%, 1% +/- 4%, -12% +/- 4%) and norepinephrine (7.1% +/- 1%, -5% +/- 5%, -20% +/- 5%) at 2, 24, and 48 hours posttreatment, respectively. Phenoxybenzamine did not alter endothelial function relative to controls at any time point. CONCLUSIONS: Thirty-minute pretreatment of RA conduits with 10(-6) M phenoxybenzamine completely inhibits vasoconstriction to phenylephrine and norepinephrine for as long as 48 hours. Soaking radial artery grafts briefly in phenoxybenzamine solution before implantation may be effective in preventing postoperative vasospasm caused by two common alpha-adrenergic agonists used in postoperative hemodynamic management.

Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion.

BACKGROUND: Myocardial injury during early reperfusion (R) has been well documented. However, the extent and time course of myocardial injury during late R are still unclear. The purpose of this study was to determine the extent of regional contractile and endothelial dysfunction and myocardial blood flow (MBF) defect as well as extension of infarction in association with neutrophil (PMN) actions during R. MATERIALS AND METHODS: A total of 29 dogs underwent a protocol of 1 h LAD ischemia followed by 6, 24, 48, and 72 h of R, respectively. Regional contractile function (sonomicrometry), MBF (colored microspheres), infarct size (triphenyltetrazolium chloride staining), and PMN localization (immunohistochemistry) were determined. RESULTS: Percentage segmental shortening at 6, 24, 48, and 72 h of R was significantly blunted (-1.8 +/- 1.2,* - 0.37 +/- 0. 6,* 0.04 +/- 0.2,* and 5.9 +/- 1.2* vs baseline 17.7 +/- 0.8). MBF (ml/min/g) was attenuated at 24 (0.27 +/- 0.03*), 48 (0.46 +/- 0. 07*), and 72 h of R (0.48 +/- 0.06*) vs 6 h of R (0.65 +/- 0.06). Infarct size increased from 6 (27 +/- 2%) to 24 h of R (41 +/- 2%*) with no further increase at 48 and 72 h of R, consistent with a peak of creatine kinase activity. PMN adherence (mm(2) endothelium) to left anterior descending coronary artery (LAD) segments was increased after 6 h of R (63 +/- 3*) vs nonischemic left circumflex coronary artery (LCX) segments (42 +/- 2) with a peak at 48 h of R (111 +/- 5*). Endothelium-dependent vascular relaxation in the LAD was also blunted at 6, 24, and 48 h of R. Immunostaining revealed CD18-positive PMNs were mainly accumulated in intravascular space during 6 h of R with an increase in migration of PMNs seen at 24 h of R, consistent with a peak of myeloperoxidase release. Myeloperoxidase activity in a given area at risk sample was significantly correlated with infarct extension during the first 24 h of R. CONCLUSIONS: These results provide pathologic evidence for myocardial injury during the extended R and a basis for exploration of interventions designed to limit myocardial injury after ischemia. (*P < 0.05 vs Baseline, 6 h of R and LCX segments.)

Glutathione reverses endothelial damage from peroxynitrite, the byproduct of nitric oxide degradation, in crystalloid cardioplegia.

BACKGROUND: NO has been advocated as an adjunct to cardioplegia solutions. However, NO undergoes a rapid biradical reaction with superoxide anions to produce peroxynitrite (ONOO(-)). ONOO(-) in crystalloid cardioplegia solution induces injury to coronary endothelium and to systolic function after cardioplegia and reperfusion. However, ONOO(-) may be degraded to less lethal or cardioprotective intermediates with glutathione (GSH) in reactions separate from its well known antioxidant effects. We hypothesized that GSH detoxifies ONOO(-) and reverses defects in endothelial function and systolic function when present in crystalloid cardioplegia. METHODS AND RESULTS: In anesthetized dogs on cardiopulmonary bypass, a 45-minute period of global normothermic ischemia was followed by 60 minutes of intermittent cold crystalloid cardioplegia (Plegisol) and 2 hours of reperfusion. The cardioplegia solution contained 5 micromol/L authentic ONOO(-); catalase was included to attenuate the potential antioxidant effects of GSH and to unmask the effects on ONOO(-). In 1 group (CP+GSH, n=5), the cardioplegia contained 500 micromol/L GSH, whereas 1 group received crystalloid cardioplegia without GSH (CCP, n=6). There were no group differences in postcardioplegia left ventricular systolic function (end-systolic pressure-volume relation, impedance catheter: CCP 10.0+/-2.4 versus CP+GSH 10.6+/-1.3 mm Hg/mL) or diastolic chamber stiffness (ss-coefficient: CCP 0.35+/-0.2 versus CP+GSH 0.31+/-0.18). Myocardial neutrophil accumulation (myeloperoxidase activity) was attenuated in CP+GSH versus CCP (2.2+/-0.7 versus 5.4+/-1.2, P:<0.05). In postexperimental coronary arteries, maximal endothelium-dependent relaxation was greater in CP+GSH than in CCP (118+/-6% versus 92+/-5%, P:<0.05), with a smaller EC(50) value (-7. 10+/-0.05 versus -6.98+/-0.03, respectively, P:<0.05). Smooth muscle relaxation was complete in both groups. The adherence of neutrophils to postexperimental coronary arteries as a measure of endothelial function was less in CP+GSH than in CCP (98+/-18 versus 234+/-36 neutrophils/mm(2), P:<0.05). Nitrosoglutathione, a byproduct of the reaction between ONOO(-) and GSH, was greater in CP+GSH than in CCP (4.1+/-2.3 versus 0.4+/-0.2 microg/mL, P:<0.05). CONCLUSIONS: GSH in crystalloid cardioplegia detoxifies ONOO(-) and forms cardioprotective nitrosoglutathione, resulting in attenuated neutrophil adherence and selective endothelial protection through the inhibition of neutrophil-mediated damage.

Influence of concomitant CABG and urgent/emergent status on mitral valve replacement surgery.

BACKGROUND: Outcomes and resource utilization of patients undergoing mitral valve replacement (MVR) with or without concomitant coronary artery bypass grafting (CABG) were reviewed. METHODS: Data for 1,844 patients undergoing isolated primary MVR at Emory University Hospitals between 1980 and 1997 were recorded prospectively in a computerized database. RESULTS: The four groups included patients undergoing elective MVR with (n = 360) or without CABG (n = 1332) and urgent/emergent MVR with (n = 66) or without CABG (n = 86). Length of stay was significantly higher in patients undergoing elective MVR with CABG (15 days) than in those without CABG (11 days) but was not significantly different in patients undergoing urgent/emergent MVR with CABG (17 days) than in those without CABG (19 days). In-hospital mortality was significantly higher for patients undergoing elective (14%) or urgent/emergent (41%) MVR with CABG than in those undergoing MVR without CABG (elective:6%; urgent/emergent:20%). The 19-year survival rate was 32% for patients undergoing elective MVR with CABG compared with 51% for those without CABG and 28% for patients undergoing urgent/emergent MVR with CABG compared with 46% for those without CABG. Multivariate correlates of long-term mortality included older age, concomitant CABG, and urgent/emergent status. Hospital costs were significantly higher for patients undergoing elective MVR with ($33,216) than for those without ($23,890) CABG. No significant difference in cost were noted between patients undergoing urgent/emergent MVR with ($40,535) and without ($31,981) CABG. CONCLUSIONS: The addition of CABG or urgent/emergent status to patients undergoing MVR significantly increases morbidity, mortality, and costs. Careful scrutiny of the benefits versus resource utilization is required for patients undergoing high risk MVR.

Ten-year trends in heart valve replacement operations.

BACKGROUND: There has been increasing concern in recent years about the quality and cost of heart valvular replacement procedures. The purpose of this study is to examine the profile of patients undergoing valvular operations during the past decade, and to look at trends in outcome and resource utilization over that period. METHODS: Clinical and procedural data of 2,972 patients undergoing heart valve replacement at Emory University Hospitals between 1988 and 1997 were recorded prospectively on standardized forms by trained medical personnel and entered into a computerized database. RESULTS: There were 1,802 patients undergoing aortic valve replacement (AVR), 966 undergoing mitral valve replacement (MVR), and 204 undergoing combined aortic and mitral valve procedures (AVR + MVR). No patients were excluded. There was a statistically significant trend for patients undergoing AVR, MVR, or AVR + MVR over time to be older and sicker by multiple criteria. Nonetheless, procedural outcome and inhospital mortality for patients undergoing AVR remained unchanged. Cost and length of stay increased from 1988 to 1992 when a concerted effort to decrease resource utilization began. Between 1992 and 1997 for AVR, length of stay decreased from 13.4 to 8.0 days and cost from $37,047 to $21,856. Similarly, between 1992 and 1997 for MVR, length of stay decreased from 15.6 to 8.1 days and cost from $45,072 to $21,747. The net result over the time period from 1988 to 1997 was an average decline in the cost of operation of $785 a year, adjusted for other factors. CONCLUSIONS: This study reveals that outcome of valvular replacement during the period from 1988 to 1997 has remained constant despite the patients becoming older and sicker during the same period. This constant outcome has been accomplished, but length of stay has decreased significantly. Hospital costs increased during the first years of the study period, but then decreased to levels in 1997 that were equal to or significantly less than 1988 levels.

Outcome of coronary revascularization in patients on renal dialysis.

Previous retrospective studies showed high periprocedure mortality rate and poor outcome after percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) among renal dialysis patients. The purpose of this study was to compare mortality and clinical event rates in renal dialysis patients after PTCA or CABG. We identified 252 patients from the Emory Cardiovascular Database who were on dialysis and who received PTCA (122 patients) or CABG (130 patients) at Emory University Hospital and Crawford W. Long Hospital between March 1987 and December 1997. Baseline and angiographic characteristics, in-hospital, and 1-year outcome were compared between the 2 groups. Left main disease and 3-vessel coronary artery disease were significantly more common in the CABG group. There was a higher periprocedure and in-hospital mortality in the CABG group (6.9% vs 1.6%, p = 0.04). Patients in the PTCA group underwent repeat revascularization 11 times more frequently within 1 year (22% vs 2%). At 1 year, mortality was 23% in the PTCA group and 27% in the CABG group, with no statistical difference between the 2 groups. This nonrandomized comparison reveals that PTCA and CABG can be performed in selected renal dialysis patients with an acceptable in-hospital major complication rate; however, 1-year mortality remains high in dialysis patients after coronary revascularization. Therefore, attempts at improving outcome in dialysis patients should focus on the prevention and treatment of coronary artery disease before they require coronary revascularization.