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Strategies for myocardial protection in cardiac surgery are directed at the prevention of procedure-induced ischemia/reperfusion injury as well as metabolic resuscitation in acute ischemic syndromes. Postreperfusion myocardial dysfunction remains a significant clinical problem, most importantly in certain high-risk patient groups. The large body of experimental evidence demonstrating a significant role for sodium-hydrogen exchange activation in myocardial ischemia/reperfusion injury suggests that the ability to pharmacologically inhibit the exchanger presents a promising new approach to current myocardial preservation techniques.

Objective: Sodium–hydrogen exchange (NHE) activation is a major mechanism of cardiac injury produced by ischemia and reperfusion. In addition, NHE may mediate the direct effects of hydrogen peroxide (H2O2) in normally perfused hearts. The present study was done to determine whether H2O2 at low concentrations producing mild myocardial depression affects post-ischemic recovery of function and to determine the ability of the NHE inhibitor HOE 642 to modulate this effect. Methods : Isolated Langendorff-perfused rat hearts with a left ventricular balloon inflated to an initial end-diastolic pressure of 5 mmHg were subjected to 90 min of global zero-flow ischemia followed by 60 min reperfusion. In Study 1, hearts were randomized for perfusion with or without H2O2 (20 μM) for 15 min before ischemia and throughout reperfusion. In Study 2, identical experiments were done except that the hearts were pretreated with the NHE inhibitor HOE 642 (5 μM). Function was assessed by determining intraventricular pressures. Results: Recovery of developed pressure in Study 1 after 10 min reperfusion was 60.3±8% of pre-ischemic values in control hearts whereas this was reduced to 29.9±10% in hearts treated with H2O2 ( P

Objective: The aim was to examine the effects of the Na+/H+ exchange inhibitors amiloride and methylisobutyl amiloride (MIA) in buffer perfused rabbit hearts subjected to one hour of normothermic ischaemia (37 °C) followed by reperfusion. Methods: Experiments were carried out in five groups of Langendorff perfused rabbit hearts: (1) control, (2) amiloride, and (3) MIA (agents in both the preischaemic and reperfusion perfusate), (4) amiloride-R and (5) MIA-R (agents added at reperfusion only). Functional evaluation included serial measurement of resting tension, force, rates of ventricular force development and relaxation, and coronary perfusion pressure. Samples of coronary effluent were obtained for creatine kinase assay and hearts were freeze clamped for metabolite assays. Results: Reperfusion resulted in a marked increase in resting tension in group (1) which was statistically significant compared to groups (2) and (3). Groups (2) and (3) also showed significantly improved recovery of ventricular force, rate of force development, and rate of ventricular relaxation. Addition of either agent only during reperfusion failed to produce a significant beneficial effect. There were no significant differences among the groups with respect to postreperfusion creatine kinase release or end reperfusion metabolite levels. Conclusion: This study shows for the first time that both of the Na+/H+ exchange inhibitors amiloride and MIA produce improved recovery of ventricular function in rabbit hearts subjected to ischaemia and reperfusion, although the beneficial effect was not obtained with drug administration at the time of reperfusion only.

Myocardial infarction that is attributed to native coronary artery spasm in the early postoperative phase has rarely been documented. We report three cases of postoperative myocardial infarction secondary to angiographically demonstrated coronary spasm. Native coronary artery spasm is a rare, but important cause of postoperative ischemia and infarction. Suspicious electrocardiographic changes warrant consideration of transesophageal echocardiography to detect unexpected wall motion abnormalities. Established treatments include intravenous or intracoronary infusion of nitroglycerin and calcium channel antagonists, although several new therapeutic agents may also be beneficial. Prompt coronary angiography is the only definitive modality for early diagnosis and targeted treatment.

Background. Na + /H + exchange represents an important mechanism for pH regulation in the cardiac cell that, however, may paradoxically mediate tissue damage in the reperfused myocardium. We investigated whether inhibition of the exchanger can protect the heart against damage after prolonged hypothermic storage with the use of the selective inhibitor 3-methylsulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694). Methods. After equilibration, isolated rabbit hearts were arrested with a 3 minute infusion of modified St. Thomas' cardioplegic solution and subsequently maintained in ischemic arrest at 4°C for 12 hours before reperfusion at 37°C for 60 minutes. Left ventricular function and creatine kinase release were measured at intervals throughout reperfusion. High-energy phosphate and adenine nucleotide content were determined in hearts before cardioplegia, at the end of the 12-hour storage period, and at the end of reperfusion. HOE 694 (1 μmol/L) was administered either with cardioplegia and throughout reperfusion (study 1) or selectively with either cardioplegia or reperfusion only (study 2). Results. In study 1, systolic function in untreated hearts recovered to less than 40% of preischemic values and was associated with a greater than 1,000% percent sustained elevation in left ventricular end-diastolic pressure. In contrast, systolic recovery in HOE 694-treated hearts was significantly accelerated and improved to approximately 80%, whereas left ventricular end-diastolic pressure increased to only 300% of baseline. Significant protection also occurred in those hearts in which HOE 694 was administered only at reperfusion while the drug was less effective if given only during cardioplegia. Creatine kinase release was not significantly affected except in study 2, where it was significantly lower after 60 minutes of reperfusion in hearts where HOE 694 was added at the time of reperfusion. Tissue metabolite content was not affected by drug treatment. Conclusions. This study shows a marked protective effect of the Na + /H + exchange inhibitor HOE 694 in rabbit hearts subjected to 12 hours of hypothermic ischemia and strongly suggests that antiport inhibitors could play an effective role in myocardial preservation.

Cardiopulmonary bypass is known to cause neutrophil activation, and activated neutrophils appear to be of importance in myocardial reperfusion injury. This study examined the effect of a preischemic infusion of activated neutrophils on the recovery of myocardial function after 40 minutes of hypothermic global ischemia. Studies were carried out in three groups of Langendorff-perfused rabbit hearts: control, control (unactivated) neutrophil infusion, and phorbol myristate acetate-activated neutrophil infusion. The activated neutrophil group showed significant deterioration in function during the activated neutrophil infusion. All three groups demonstrated significant depression of function initially after reperfusion, but the two control groups subsequently recovered to baseline levels. The activated neutrophil group, however, showed a persistent significant depression in ventricular force, rate of ventricular tension development, and rate of ventricular relaxation as well as a significant increase in coronary vascular resistance. It is concluded that activated neutrophils depress myocardial function and contribute to impaired recovery of function after global hypothermic ischemia.

Although use of the internal thoracic artery (ITA) for coronary artery bypass grafting results in superior graft patency and improved patient survival, our initial clinical observations suggested an increased incidence of pleuropulmonary morbidity with its use. One hundred consecutive patients with left ITA grafts were studied prospectively and compared with a consecutive retrospective group of 100 patients undergoing coronary artery bypass grafting with saphenous vein grafts only. Preoperative, postoperative day (POD) 2, POD 6, and postoperative week 8 chest roentgenograms were analyzed for atelectasis and effusion. Postoperative left lower lobe atelectasis was common in both groups on both POD 2 (saphenous vein, 43%, versus ITA, 53%; not significant) and POD 6 (saphenous vein, 40%, versus ITA, 41%; not significant). There was a significantly higher incidence of pleural effusion on POD 6 in the ITA group (84% versus 47%; p less than 0.05) but most of these were small. There was more chest tube drainage (1,413 versus 1,028 mL; p less than 0.01) and a greater need for secondary thoracostomy or thoracentesis (4% versus 0%) in the ITA group. The left pleural space was opened in 67 of the 100 ITA patients but pleurotomy did not appear to influence postoperative morbidity. We conclude that use of the internal thoracic artery for coronary artery bypass grafting results in a small but significant increase in pleuropulmonary morbidity.

Myocardial reperfusion after brief, reversible ischemia is frequently associated with malignant arrhythmias in experimental animals. These observations have been extrapolated to humans despite being restricted to anesthetized, open chest preparations. No data are available regarding the incidence of reperfusion arrhythmias after reversible (less than 20 minutes) ischemia in the conscious state. Thus, reperfusion arrhythmias after a 15 minute occlusion of the left anterior descending coronary artery were compared in 24 open chest dogs (17 anesthetized with pentobarbital and 7 with chloralose plus urethane) and 25 conscious, unsedated, trained dogs. The incidence of all rhythm disorders (single premature ventricular complexes, pairs, ventricular tachycardia and fibrillation) was markedly and significantly lower in conscious than in either pentobarbital- or chloralose-anesthetized dogs. The disparity was not accounted for by differences in coronary collateral flow, coronary reactive hyperemia or occluded bed size. The conscious animals, however, exhibited lower heart rates and arterial pressures during reperfusion than did the open chest dogs, suggesting a lower level of adrenergic stimulation, which might have contributed to the reduced incidence of reperfusion arrhythmias. Coronary reperfusion after 15 minutes of occlusion is unlikely to precipitate ventricular tachyarrhythmias in the conscious, trained dog, even after severe ischemia. The occurrence of these rhythm disorders in anesthetized models may reflect the influence of surgical trauma or excessive adrenergic activity, or both. Reperfusion arrhythmias after reversible ischemia may be considerably less common in the clinical setting than previously postulated on the basis of open chest animal experiments.

The prolonged myocardial dysfunction observed after reversible ischemia (stunned myocardium) has been postulated to result from an inability of the myocytes to replenish ATP stores. Accordingly, one would expect inotropic stimulation to result in minimal increase in contractile function, or possibly even further deterioration. To test this hypothesis, studies were performed in open-chest dogs undergoing a 15-minute occlusion of the left anterior descending coronary artery (LAD) followed by 4 hours of reperfusion. Systolic wall thickening, an index of regional myocardial function, was measured in the LAD-dependent territory with ultrasonic crystals. Thickening fraction was 20.8 +/- 3.0% (mean +/- standard error of the mean) under baseline conditions, decreased to -18.6 +/- 1.6% during LAD occlusion, and was still severely depressed after 3 hours of reperfusion (2.6 +/- 3.4%). Thickening fraction remained stable between 3 and 4 hours of reperfusion in 5 untreated control dogs. In 9 treated dogs, isoproterenol (0.1 microgram/kg/min intravenously for 30 minutes starting 3 hours after reperfusion) increased thickening fraction to values (24.8 +/- 4.5%) that were similar to those at baseline. Thirty minutes after discontinuation of isoproterenol administration, thickening fraction had returned to pre-isoproterenol levels. Thus, reperfused, severely depressed myocardium responds dramatically to beta-adrenergic stimulation without subsequent adverse effects on function in the short-term. These findings imply that the stunned myocardium can generate ATP, and therefore do not support the view that an inability to replenish ATP stores is the cause of postischemic dysfunction. More important, this study suggests that postischemic dysfunction in humans may be effectively reversed with inotropic therapy without short-term deleterious sequelae.

Myocardial reperfusion after reversible regional ischemia is known to result in delayed recovery of contractile function, but the mechanism responsible for this phenomenon remains unclear. We examined the ability of N-2-mercaptopropionylglycine, a synthetic thiol compound with oxygen free radical scavenging properties, to attenuate postischemic dysfunction in open chest dogs undergoing a 15 minute occlusion of the left anterior descending coronary artery followed by 4 hours of re-perfusion. Treated animals received an infusion of N-2-mercaptopropionylglycine (50 mg/kg per h) for 4 hours starting 15 minutes before coronary occlusion. Collateral flow, as determined with radioactive microspheres after 10 minutes of ischemia, was 0.07 ± 0.01 ml/min per g (mean ± SE) in both control (n = 20) and treated (n = 13) groups. The occluded vascular bed, as determined by postmortem perfusion, averaged 26.1 ± 1.2% of the weight of the left ventricle in control and 29.6 ± 1.3% in treated animals.Systolic wall thickening (an index of regional function) was assessed with an epicardial pulsed Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesia during ischemia. Nevertheless, recovery of function (expressed as percent of baseline) was considerably greater in the treated dogs at 1 hour (44.6 versus 12.8%, p = 0.05), 2 hours (64.0 versus 31.6%, p < 0.02), 3 hours (77.1 versus 36.7%, p < 0.01) and 4 hours of reperfusion (75.0 versus 40.0%, p < 0.05).Thus, N-2-mercaptopropionylglycine produced a significant and sustained improvement in recovery of contractile function after a brief episode of regional myocardial ischemia. These results suggest that oxygen free radicals play a significant role in myocardial postishemic dysfunction. Because N-2-mercaptopropionylgly-cine is potentially available for oral prophylactic therapy, these results have significant therapeutic implications.

We examined biventricular function in patients with the adult respiratory distress syndrome (ARDS) by a combination of invasively determined pressures and flows and concomitant radionuclide angiography. Right (RVEF) and left (LVEF) ventricular ejection fractions were measured; right and left ventricular end-diastolic (EDVI) and end-systolic (ESVI) volume indices were calculated from the respective ejection fraction and measured thermodilution stroke volume. With an increase in the outflow pressure load on the right ventricle, measured as the mean pulmonary artery pressure (PAP), the RVEF fell (Y = 66.25 -1.01X; r2 = .42; p less than .001) and both the RVEDVI (y = 13.39 + 3.66X; r2 = .33; p less than .001) and RVESVI (Y = 23.9 + 3.57X; r2 = .41; p less than .001) increased. Progressive increases in the PAP also seemed associated with a change in left ventricular end-diastolic pressure-volume relationships: without pulmonary artery hypertension (PAP less than 20 mm Hg) the mean LVEDVI was 87.2 +/- 31.3 ml/m2 (mean +/- SD) and the mean PCWP was 5.0 +/- 2.8 mm Hg; with a mean PAP exceeding 30 mm Hg, the LVEDVI remained constant (90.4 +/- 26.9 ml/m2) although the PCWP was greater than previous (18.5 +/- 5.7 mm Hg; p less than .01). Analysis of right ventricular peak-systolic pressure end-systolic volume ratios implied a concurrent depression in right ventricular contractility at high levels of PAP. However, right ventricular "pump" function to maintain an adequate left ventricular preload remained unaltered regardless of the presence of pulmonary artery hypertension.