Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis.

BACKGROUND: This study tested the hypothesis that ischemic preconditioning (IP) inhibits myocardial apoptosis after a short period of ischemia and reperfusion. METHODS: In 9 anesthetized dogs, the left anterior descending (LAD) coronary artery was occluded for 30 min and reperfused for 3 h (control), while in 9 others, LAD occlusion was preceded by 5 min of occlusion and 5 min of reperfusion (IP). DNA from frozen myocardial tissue samples was extracted, and apoptosis were identified as "ladders" by agarose gel electrophoresis or confirmed histologically using the terminal transferase UTP nick end-labeling (TUNEL) assay. Neutrophil accumulation was detected by measuring cardiac myeloperoxidase activity. RESULTS: Thirty minutes of LAD occlusion caused a significant decrease in blood flow (colored microspheres), which was comparable between groups. In the control group, DNA ladders occurred in the area at risk (AAR) in six out nine experiments. In contrast, DNA laddering in the AAR was not observed in any of the IP group. AAR in the control group showed a greater percentage of apoptotic cells than IP (6.7 +/- 0.9% vs 1.2 +/- 0.2%; p < 0.01). Cardiac myeloperoxidase activity (U/g tissue) was significantly reduced from 0.07 +/- 0.004 in control to 0.04 +/- 0.01 in IP group (p < 0.05). CONCLUSIONS: We conclude that ischemic preconditioning attenuates apoptosis and neutrophil accumulation in the AAR in a model of nonlethal acute ischemia and reperfusion.

Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass grafting.

OBJECTIVE: Unmodified reperfusion without cardioplegia in minimally invasive direct coronary artery bypass grafting procedures causes endothelial dysfunction that may predispose to polymorphonuclear neutrophil-mediated myocardial injury. This study tested the hypothesis that ischemic preconditioning in a minimally invasive direct coronary artery bypass grafting model attenuates postischemic endothelial dysfunction in coronary vessels. METHODS: In anesthetized dogs, the left anterior descending coronary artery was occluded for 30 minutes and reperfused for 3 hours without ischemic preconditioning (no-ischemic preconditioning; n = 7); in 7 dogs, the left anterior descending occlusion was preceded by 5 minutes occlusion followed by 5 minutes of reperfusion. Relaxation responses to stimulators of nitric oxide synthase were used to evaluate endothelial function in arteries from the ischemic-reperfused (left anterior descending) and nonischemic (left circumflex coronary artery) zones. RESULTS: Stimulated endothelial-dependent relaxation of epicardial left anterior descending artery to incremental concentrations of acetylcholine in the no-ischemic preconditioning animals was shifted to the right, and maximal relaxation was attenuated compared with the nonischemic left circumflex coronary artery (117% +/- 4% vs 138% +/- 5%). In contrast, acetylcholine-induced maximal relaxation was comparable in the left anterior descending artery versus left circumflex coronary artery in the ischemic preconditioning group (130% +/- 6% vs 135% +/- 5%). In 150- to 200- microm left anterior descending microvessels, 50% relaxation occurred with a lower concentration (log[M]) of acetylcholine in ischemic preconditioning versus no-ischemic preconditioning (-8.0 +/- 0.4 vs -7.0 +/- 0.1) with no group differences in smooth muscle relaxation to sodium nitroprusside, suggesting endothelial-specific damage. Adherence of fluorescent labeled polymorphonuclear neutrophils to epicardial coronary artery endothelium, used as an index of basal (unstimulated) anti-polymorphonuclear neutrophil function, was significantly attenuated by ischemic preconditioning versus no-ischemic preconditioning (293 +/- 25 polymorphonuclear neutrophils/mm2 vs 528 +/- 29 polymorphonuclear neutrophils/mm2). CONCLUSION: In this minimally invasive direct coronary artery bypass grafting model, both agonist-stimulated and basal postischemic endothelial dysfunction were attenuated by ischemic preconditioning.

Controlled intermittent asystole: pharmacologic potentiation of vagal-induced asystole.

BACKGROUND: Minimally invasive direct coronary artery bypass graft operations have, to date, displayed a higher rate of early graft failure than conventional coronary artery bypass procedures using extracorporeal technology. Construction of the coronary artery anastomosis on a beating heart versus a quiescent heart is likely an important factor in this difference between the two approaches. Controlled intermittent asystole induced by vagal stimulation to give transient nonchemically induced asystole for brief intervals sufficient for placement of coronary artery sutures might improve the precision of minimally invasive direct coronary artery bypass graft anastomoses and reduce graft failure while increasing the technical ease of operation. METHODS: The feasibility of producing transient, reversible asystole with combined vagus nerve stimulation and treatment with a pharmacologic regimen of (1) an acetylcholinesterase inhibitor (pyridostigmine, 0.5 mg/kg), (2) a beta-adrenergic receptor blocker (propranolol, 80 microg/kg), and (3) a calcium-channel blocker (verapamil, 50 microg/kg) was studied in a sheep model. Seven animals underwent right vagus nerve stimulation in two modes: (1) a single continuous 60-second impulse and (2) multiple sequential 15-second impulses. RESULTS: Vagal stimulation alone achieved bradycardia without consistent and reproducible cardiac arrest. After drug administration 6 animals displayed significant potentiation of vagal-induced asystole in the 60-second stimulation protocol (1.6+/-0.9 seconds non-drug-treated versus 52.0+/-5.6 seconds drug-treated; p < 0.05). In the sequential 15-second impulse protocol after drug treatment, 6 animals achieved consistent, escape-free asystole during five to six sequential 15-second stimulations versus a brief pause and bradycardia produced without drug treatment. CONCLUSIONS: Increased acetylcholine activity by acetylcholinesterase inhibition and prevention of electromechanical escape activity by beta-adrenergic receptor and calcium-channel blockade during vagal stimulation produced a marked potentiation of vagal-induced asystole and a means of achieving controlled intermittent asystole. Controlled intermittent asystole achieved by pharmacologic potentiation of vagal-induced asystole may be a useful technique for enhancing technical ease in minimally invasive direct coronary artery bypass graft operations.

Preconditioning during simulated MIDCABG attenuates blood flow defects and neutrophil accumulation.

BACKGROUND: Ischemic preconditioning (IP) may be cardioprotective in minimally invasive direct coronary artery bypass where cardioplegia is not used. This study tested the hypothesis that IP of the area at risk (AAR) would attenuate postischemic injury from transient coronary artery occlusion. METHODS: In 19 anesthetized dogs, the left anterior descending coronary artery was occluded for 30 minutes (simulating coronary occlusion during anastomosis) followed by 3 hours of reperfusion. In 10 dogs, occlusion was preceded by 5 minutes of occlusion and 5 minutes of reperfusion (IP), whereas 9 other dogs had no IP (control, C). RESULTS: Thirty minutes of left anterior descending occlusion caused comparable dyskinesis (systolic shortening, sonomicrometry) in the AAR in C (baseline, 29% +/- 3% to 3% +/- 2%) and in IP (baseline, 29% +/- 2% to -0.3% +/- 2%). After 3 hours of reperfusion, systolic shortening was significantly depressed in C (20% +/- 4%), and was not significantly improved by IP (24% +/- 3%, p = 0.8 versus C). Postischemic diastolic stiffness in the AAR was not altered by IP versus C (0.60 +/- 0.12 versus 0.41 +/- 0.13). Plasma creatine kinase activity was similar between C and IP at the end of reperfusion (20 +/- 11 versus 16 +/- 5 U/g). Postischemic AAR blood flow (in milliliters per minute per gram of tissue) at 180 minutes of reperfusion decreased by 56% versus baseline in C (from 1.04 +/- 0.4 to 0.46 +/- 0.12; p < 0.05) compared with no change in IP (from 0.74 +/- 0.23 to 0.60 +/- 0.10), but there was no significant group difference at this time. Myeloperoxidase activity as an index of neutrophil accumulation in AAR was decreased in IP versus C (0.4 +/- 0.09 versus 0.7 +/- 0.04 U/microg tissue). CONCLUSIONS: Ischemic preconditioning does not decrease postischemic wall motion and only modestly increases postischemic blood flow abnormalities in the AAR, but does significantly inhibit neutrophil accumulation.

Angiogenesis as a predictor of survival after surgical resection for stage I non-small-cell lung cancer.

OBJECTIVES: Some patients with surgically resected stage I non-small-cell lung cancer eventually have metastatic disease. A histologic marker of metastatic potential and diminished survival for stage I non-small-cell lung cancer may distinguish this patient population. This study evaluates the degree of angiogenesis as a predictor of cancer-related death after operation for stage I non-small-cell lung cancer. METHODS: Demographic, surgical, and histopathologic data, including presence of vascular invasion, were reviewed for 106 patients with stage I non-small-cell lung cancer from 1985 through 1990. Visual quantitation of microvessels immunostained with factor VIII-related antigen and CD31 in 5 microm sections from the paraffin blocks of tissue defined rumor angiogenesis. RESULTS: Follow-up was 95.1% complete, mean 5.2 +/- 3.0 years. Lung cancer-related mortality rate was 24.4% at 5 years. Mean microvessel counts were 20.7 +/- 11.2 for FVIII and 29.6 +/- 18.1 for CD31. Univariate analysis revealed an FVIII count of at least 20 (p = 0.025) and blood vessel invasion (p = 0.017) to be significant predictors of disease-related death. After adjustment for other patient and tumor characteristics, multivariate Cox regression analysis found an FVIII count of at least 20 (hazard ratio 2.9) and blood vessel invasion (hazard ratio 3.7) to be significant independent correlates of lung cancer death (p = 0.018 and p = 0.011, respectively). CD31 quantitation did not predict survival on univariate or multivariate analyses and did not correlate strongly with FVIII quantitation (Spearman's rank correlation r = 0.19). CONCLUSIONS: This analysis reveals a significant association between tumor neovascularization and cancer-related mortality rate among patients with stage I non-small-cell lung cancer. Microvessel quantitation of FVIII, as an indicator of tumor angiogenesis and metastatic potential, may define a subset of patients with stage I non-small-cell lung cancer who could benefit from adjuvant therapy after surgical resection.

Esophageal perforation: emphasis on management.

BACKGROUND: Perforation of the esophagus is a deadly injury that requires expert management for survival. METHODS: We performed a retrospective clinical review of 66 patients treated at Emory University affiliated hospitals for esophageal perforation between 1973 and 1993. RESULTS: Iatrogenic perforations accounted for 48 injuries (73%), barogenic perforations occurred in 12 patients (17%), trauma was causative in 3 (5%), and 3 patients had esophageal infection and other causes. Lower-third injuries occurred in 43 cases (65%), middle third in 14 (21%), and upper third in 9 (14%). Early contained perforations were managed successfully by limiting oral intake and giving parenteral antibiotics in 12 patients. Cervical perforations were drained without attempt at closure of the leak. Perforations with mediastinal or pleural contamination recognized early were managed by primary closure and drainage in 28 patients. Reinforcement of the primary closure using stomach fundus, pleural, diaphragmatic, or pericardial flap was performed in 16 patients. Those perforations that escaped early recognition required thoughtful management, using generous debridement and drainage and sometimes esophageal resection. The esophageal T tube provided control of leaks in 3 of these patients and was a useful adjunct. Using these management principles, we achieved a 76% survival rate for all patients. Six patients with perforations complicating endoesophageal management of esophageal varices were a high-risk subset with an 83% mortality rate. CONCLUSIONS: Esophageal perforation remains an important thoracic emergency. Aggressive operative therapy remains the mainstay for treatment; however, conservative management may be preferred for contained perforations and the esophageal T tube may be used for late perforations.

Myocardial protection for coronary artery bypass in patients with acute myocardial infarction: resuscitation of ischemic myocardium.

An increasing body of evidence suggests that the majority of myocardial injury that occurs during ischemia and reperfusion is effected during the reperfusion phase. There is also convincing evidence that controlling the conditions of reperfusion and composition of the reperfusate can markedly minimize the ultimate injury following an ischemic insult. Medical reperfusion (PTCA, thrombolytics) has the disadvantage of reperfusing with unmodified whole blood under uncontrolled conditions, whereas surgical reperfusion allows very stringent control of both. A brief review of the pathophysiology of ischemia and reperfusion is presented to gain insight into the mechanisms of injury that can be counteracted by controlling the conditions of reperfusion and composition of the reperfusate. Surgical protocols that have been developed independently at two separate institutions are outlined, along with the experimental data supporting each method, and the advantages and disadvantages of each method. This information should allow implementation of a rational plan of myocardial protection for resuscitation of the ischemic myocardium when performing coronary artery bypass grafting in the setting of acute myocardial ischemia and infarction.

Neurologic events after coronary bypass grafting: further observations with warm cardioplegia.

Warm heart surgery has documented myocardial protection benefit, but with an added neurologic threat. It is hypothesized that moderately hypothermic aerobic heart surgery will maintain the myocardial protection and reduce neurologic risk. This study compared 493 patients undergoing coronary artery bypass graft operations with normothermic (35 degrees to 37% degrees C) continuous blood cardioplegia and normothermic perfusion to 379 coronary artery bypass grafting patients with hypothermic (33 degrees to 29 degrees C) continuous blood cardioplegia and hypothermic perfusion to test this hypothesis. There was no difference in age, sex, prior myocardial infarction, hypertension, prior neurologic event, congestive failure, or diabetes. The hypothermic group had more reoperations (24% versus 14%; p = 0.0002), class III/IV angina (83% versus 71%; p = 0.002), a trend to more triple-vessel (54% versus 47%; p = 0.10) and left main disease (18% versus 14%; p = 0.10), lower ejection fractions (0.52 +/- 0.15 versus 0.55 +/- 0.13), more grafts placed (3.6 +/- 1.1 versus 3.4 +/- 1.1; p = 0.04), but fewer internal mammary arteries (62% versus 78%; p < 0.0001). Postoperative myocardial infarction rate was 1.2% in the hypothermic group and 1.3% in the normothermic group (p = not significant). Intraaortic balloon pump requirement was 3.4% with hypothermic and 1.4% with normothermic groups (p = 0.05). The incidence of postoperative neurologic events was significantly higher in the normothermic group (4.7% versus 1.8%; p = 0.038). The multivariate correlates of stroke were older age and normothermic cardioplegia, whereas the only multivariate correlate of death was older age.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary sinus pressure and arterial venting do not affect retrograde cardioplegia distribution.

Retrograde techniques for the administration of cardioplegia solutions are of interest because of their relative practical convenience, and because of the possibility that they provide better delivery to myocardial regions jeopardized by coronary stenosis than can be achieved with traditional antegrade techniques. This study was designed to test the following three hypotheses about how the distribution of cardioplegia by retrograde techniques might be optimized: (1) venting an occluded coronary artery improves the distribution of cardioplegia to the myocardial region originally supplied by it; (2) increasing the coronary sinus perfusion pressure makes the distribution of cardioplegia through the myocardium more uniform; and (3) increasing the driving pressure, as achieved by increasing the coronary sinus perfusion pressure or occluding a left coronary artery, improves the distribution of flow to the right ventricular free wall and interventricular septum. Tracer microspheres infused retrogradely with cardioplegia solution into canine hearts in vitro showed that the distribution of flow through the coronary sinus is consistently and significantly nonuniform, and is not significantly altered by coronary arterial occlusion and venting, or by increases in coronary sinus perfusion pressure.

Aerobic blood cardioplegia for revascularization of acute infarct: effects of delivery temperature.

The effects of different cardioplegia temperatures on myocardial protection with continuous aerobic blood cardioplegia were studied in a canine model of acute regional injury after left anterior descending coronary artery occlusion and subsequent revascularization. Twenty-five animals underwent 90 minutes of occlusion followed by revascularization during 60 minutes of electromechanical arrest with continuous retrograde blood cardioplegia delivered at one of three temperatures: 18 degrees C (n = 8), 28 degrees C (n = 8), and 37 degrees C (n = 9). Left ventricular protection was assessed in a right heart bypass model in terms of the left ventricular pressure-volume relationships, myocardial oxygen consumption, regional myocardial blood flow, adenosine trisphosphate concentration, and water content. The preload recruitable stroke work relationship at 90 minutes after reperfusion was better in the 18 degrees C and 28 degrees C groups than that in the 37 degrees C group (18 degrees C, 85 +/- 14 erg x 10(3)/mL; 28 degrees C, 77 +/- 17 erg x 10(3)/mL; 37 degrees C, 58 +/- 13 erg x 10(3)/mL; p < 0.05). The maximum elastance and stress-strain relationships showed there were no significant differences between the groups at 90 minutes. The myocardial oxygen consumption was greatest in the 37 degrees C group during the first hour after reperfusion (18 degrees C, 5.4 +/- 1.4 mL O2.min-1.100 g-1; 28 degrees C, 4.7 +/- 1.1 mL O2.min-1.100 g-1; 37 degrees C, 6.3 +/- 1.6 mL O2.min-1.100 g-1; p < 0.05). The regional myocardial blood flow, adenosine triphosphate concentration, and myocardial water content were similar in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)