Preload Recruitable Stroke Work Area Research Articles

The p38 MAPK Inhibitor SB203580 Blocks Adenosine A1 Receptor-Induced Attenuation of In Vivo Myocardial Stunning

There is considerable evidence implicating a key role for p38 mitogen-activated protein kinase (MAPK) in ischemic and pharmacological preconditioning against myocardial infarction. However, there have been few, if any, studies examining the role of p38 MAPK in the protection of stunned myocardium. The purpose of this study was to determine whether p38 MAPK plays a role in the adenosine A(1) receptor anti-stunning effect in in vivo porcine myocardium. Regional myocardial stunning in anesthetized, open-chest pigs was induced by 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion (RP). Animals were treated with either vehicle (n = 5), AMP579 (70 microg/kg i.v.; 25 microg/kg bolus + 1.5 microg/kg/min for 30 min prior to ischemia, n = 5), the p38 MAPK inhibitor SB203580 (0.25 mg/kg i.v. bolus, n = 4) or a combination of SB203580 plus AMP579 (n = 5). Regional ventricular function was monitored by measurements of segment shortening and load insensitive parameters including preload recruitable stroke work (PRSW) and PRSW area (PRSWA). The ischemic area at risk was similar in all groups and there was no necrosis in any heart. Treatment with AMP579 significantly improved reperfusion regional PRSW and PRSWA compared to vehicle controls. The p38 inhibitor SB203580 alone did not alter the extent of myocardial stunning, but it abolished the beneficial effect of AMP579 pretreatment. These results provide the first evidence that p38 MAPK activation may play an important role in the mechanism by which adenosine agonists attenuate myocardial stunning.

Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning.

The purpose of this study was to determine whether the adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning. Regional stunning was produced by 15 min of coronary artery occlusion and 3 h of reperfusion (RP) in anesthetized open-chest pigs. In acute protection studies, animals were pretreated with saline, low-dose AMP-579 (15 microg/kg iv bolus 10 min before ischemia), or high-dose AMP-579 (50 microg/kg iv at 14 microg/kg bolus + 1.2 microg.kg(-1).min(-1) for 30 min before coronary occlusion). The delayed preconditioning effects of AMP-579 were evaluated 24 h after administration of saline vehicle or high-dose AMP-579 (50 microg/kg iv). Load-insensitive contractility was assessed by measuring regional preload recruitable stroke work (PRSW) and PRSW area. Acute preconditioning with AMP-579 dose dependently improved regional PRSW: 129 +/- 5 and 100 +/- 2% in high- and low-dose AMP-579 groups, respectively, and 78 +/- 5% in the control group at 3 h of RP. Administration of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.7 mg/kg) blocked the acute protective effect of high-dose AMP-579, indicating that these effects are mediated through A1 receptor activation. Delayed preconditioning with AMP-579 significantly increased recovery of PRSW area: 64 +/- 5 vs. 33 +/- 5% in control at 3 h of RP. In isolated perfused rat heart studies, kinetics of the onset and washout of AMP-579 A1 and A2a receptor-mediated effects were distinct compared with those of other adenosine receptor agonists. The unique nature of the adenosine agonist AMP-579 may play a role in its ability to induce delayed preconditioning against in vivo myocardial stunning.

Sodium-hydrogen exchange inhibition attenuates in vivo porcine myocardial stunning

Background Inhibition of the sodium-hydrogen exchanger isoform 1 with HOE-642 (cariporide) has been shown to protect against ischemia-reperfusion injury and to decrease myocardial cell death in numerous animal preparations; however the effects of cariporide in stunned myocardium are not as well understood. We sought to determine whether cariporide attenuated myocardial stunning in vivo. Methods Open chest anesthetized pigs (22–33 kg) were subjected to 15 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Regional ventricular function was assessed by segment shortening. Contractility was measured by stroke work and by load-insensitive preload recruitable stroke work and preload recruitable stroke work area. Vehicle or HOE-642 (1 mg/kg, IV) was administered 10 min before LAD occlusion. Results Cariporide treatment significantly improved postischemic segment shortening, stroke work, preload recruitable stroke work, and preload recruitable stroke work area and had no systemic hemodynamic effects. After 3 h of reperfusion, control animals recovered 33% ± 4% and 33% ± 3% of preischemic LAD segment shortening and preload recruitable stroke work area values, respectively, whereas animals treated with HOE-642 recovered 59% ± 6% and 57% ± 6%, respectively ( p < 0.05). Seven (39%) of 17 control animals exhibited ventricular fibrillation during reperfusion; none of the cariporide-treated pigs fibrillated. Conclusions Sodium–hydrogen exchange inhibition can attenuate postischemic myocardial stunning in addition to its well-described anti-infarct properties. Inhibition of the sodium–hydrogen exchanger may be beneficial in patients susceptible to postischemic myocardial dysfunction associated with cardiac surgery.

The intermediary metabolite pyruvate attenuates stunning and reduces infarct size in in vivo porcine myocardium.

The intermediary metabolite pyruvate has been shown to exert significant beneficial effects in in vitro models of myocardial oxidative stress and ischemia-reperfusion injury. However, there have been few reports of the ability of pyruvate to attenuate myocardial stunning or reduce infarct size in vivo. This study tested whether supraphysiological levels of pyruvate protect against reversible and irreversible in vivo myocardial ischemia-reperfusion injury. Anesthetized, open-chest pigs (n = 7/group) underwent 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion to induce stunning. Load-insensitive contractility measurements of regional preload recruitable stroke work (PRSW) and PRSW area (PRSWA) were generated. Vehicle or pyruvate (100 mg/kg i.v. bolus + 10 mg x kg(-1) x min(-1) intra-atrial infusion) was administered during ischemia and for the first hour of reperfusion. In infarct studies, pigs (n = 6/group) underwent 1 h of LAD ischemia and 3 h of reperfusion. Group I pigs received vehicle or pyruvate for 30 min before and throughout ischemia. In group II, the infusion was extended through 1 h of reperfusion. In the stunning protocol, pyruvate significantly improved the recovery of PRSWA at 1 h (50 +/- 4% vs. 23 +/- 3% in controls) and 3 h (69 +/- 5% vs. 39 +/- 3% in controls) reperfusion. Control pigs exhibited infarct sizes of 66 +/- 1% of the area at risk. The pyruvate I protocol was associated with an infarct size of 49 +/- 3% (P < 0.05), whereas the pyruvate II protocol was associated with an infarct size of 30 +/- 2% (P < 0.05 vs. control and pyruvate I). These findings suggest that pyruvate attenuates stunning and decreases myocardial infarction in vivo in part by reduction of reperfusion injury. Metabolic interventions such as pyruvate should be considered when designing the optimal therapeutic strategies for limiting myocardial ischemia-reperfusion injury.

Adenosine A 2a agonist CGS-21680 improves recovery of ventricular function after ischemia-reperfusion in regionally stunned porcine myocardium

Methods: Open chest pigs underwent 15 minute left anterior descending coronary artery (LAD) ischemia followed by 3.5 hours of reperfusion (RP). Control animals (n 5 6) received 0.9 N NaCl (saline) intracoronary (ic) during RP. Treated animals (n 5 6) received saline for the first 2 hr RP, followed by CGS (0.05–0.1 mg/kg/min, ic) for 1 hour and saline for last 30 minutes. Regional stunning was assessed using sonomicrometry to measure load-insensitive preload recruitable stroke work area (PRSWA).

Ischemic preconditioning does not acutely improve load-insensitive parameters of contractility in in vivo stunned porcine myocardium

Objective: Ischemic preconditioning has been shown to have no beneficial effect on segment shortening in in vivo regionally stunned myocardium. The purpose of this study was to determine whether ischemic preconditioning improves the recovery of postischemic ventricular function when contractility is assessed by load-insensitive measurements including end-systolic pressure length relations, preload recruitable stroke work, and preload recruitable stroke work area in in vivo regionally stunned porcine myocardium. Methods: Open chest, pentobarbital-anesthetized pigs were used. Regional ventricular function was monitored by measurements of segment shortening, stroke work, end systolic pressure length relations, preload recruitable stroke work, and preload recruitable stroke work area. The control group was submitted to 15 minutes of left anterior descending coronary artery occlusion and 3 hours of reperfusion. The preconditioned group underwent 2 cycles of 5-minute left anterior descending coronary artery occlusion and 10-minute reperfusion before 15 minutes of occlusion. Results: There was no infarct in either group. The preconditioning protocol significantly depressed preischemic segment shortening but not regional stroke work. Ischemic preconditioning had no significant beneficial effect on regional stroke work, end-systolic pressure length relations, preload recruitable stroke work, or preload recruitable stroke work area. Conclusions: These results confirm that ischemic preconditioning does not ameliorate in vivo porcine myocardial stunning and indicate that ischemic preconditioning may have a limited cardioprotective role during cardiac operation. (J Thorac Cardiovasc Surg 1999;117:810-7)

Preconditioning prevents myocardial stunning after cardiac transplantation

Background. Preconditioning has been shown to reduce myocardial stunning after reversible global ischemia. To determine whether preconditioning improves functional recovery after cardiac transplantation, 16 sheep were randomly assigned to a preconditioning protocol or to a control group.Methods. Preconditioning was achieved with 5 minutes of global ischemia followed by 10 minutes of reperfusion. The heart was then arrested with 1 L of crystalloid cardioplegia, explanted, stored in a transport cooler, and then transplanted into recipient sheep. The total ischemia time was 2 hours. Pressure-volume loops were used to calculate preload recruitable stroke work, the maximum elastance, and diastolic compliance. Linear regression analysis was used to determine the preload recruitable stroke work, maximum elastance, and diastolic compliance–and end-diastolic volume relationship. The area under the regression curve for preload recruitable stroke work was defined as the preload recruitable stroke work area. Biopsies were taken for high-energy phosphates.Results. Systolic function, represented by preload recruitable stroke work area, was preserved after cardiac transplantation in preconditioned animals. Maximum elastance and diastolic compliance were unaffected by preconditioning or ischemia. High-energy phosphates were better preserved in preconditioned animals.Conclusion. Preconditioning prevented myocardial stunning and preserved high-energy phosphates after experimental cardiac transplantation.

Simultaneous Antegrade And Retrograde Delivery Of Continuous Warm Blood Cardioplegia After Global Ischemia

Objective: Simultaneous delivery of antegrade and retrograde cardioplegia may provide a more homogeneous distribution of cardioplegic solution. It may, however, increase myocardial edema and postcardioplegic myocardial injury. The purpose of this study was to compare simultaneous antegrade-retrograde cardioplegia with antegrade cardioplegia. Methods: After 30 minutes of warm, “unprotected,” global ischemia, pigs were given warm, continuous blood cardioplegia for 45 minutes (antegrade group, n = 8 and simultaneous antegrade-retrograde group, n = 9). All pigs were weaned from cardiopulmonary bypass 45 to 60 minutes after aortic unclamping. Indices of left ventricular function were measured after another 30 minutes with the conductance catheter technique and pressure-volume loops. Results: Global left ventricular function, evaluated by preload recruitable stroke work, decreased from baseline values of 126 (102 to 150) (mean [90% confidence limits]) (antegrade) and 122 (116 to 127) erg/ml × 10 3 (simultaneous) to 75 (61 to 89) ( p = 0.004) and 95 (79 to 112) erg/ml × 10 3 ( p = 0.02), respectively. End-diastolic pressure-volume relation increased from 0.25 (0.21 to 0.28) (antegrade) and 0.30 (0.25 to 0.35) mm Hg/ml (simultaneous) to 0.60 (0.41 to 0.79) ( p = 0.009) and 0.53 (0.35 to 0.71) mm Hg/ml ( p = 0.02), respectively. The time constant of left ventricular pressure relaxation was unchanged. No intergroup difference was observed in preload recruitable stroke work, preload recruitable stroke work area, end-diastolic pressure volume relation, or stiffness constant. Plasma levels of troponin T increased without any difference between groups. Myocardial water content was increased in the simultaneous group (81.1% [80.7% to 81.5%]) versus the antegrade group (80.1% [79.6% to 80.7%], p = 0.01). Conclusion: Despite a small increase in myocardial water content induced by simultaneous blood cardioplegia, no impairment of postcardioplegic cardiac function was observed compared with antegrade cardioplegia. (J Thorac Cardiovasc Surg 1998;115:716-22)

Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia

Cardiopulmonary bypass results in a "euthyroid sick" state. Recently, interest has focused on the relationship between low serum triiodothyronine levels and postoperative cardiovascular hemodynamics. The present study was undertaken to more clearly define the acute effects of triiodothyronine on myocardial mechanics and energetics after hypothermic global ischemia using an ex-vivo canine heart preparation to model the clinical condition. Experiments were performed on isolated hearts subjected to hyperkalemic arrest with 90 minutes of hypothermic (10° C) ischemia. Isolated hearts were cross-perfused by euthyroid support dogs in which triiodothyronine levels spontaneously deceased by 65% to 75% ( p < 0.01) after the initiation of cross-perfusion. In nine heart preparations, triiodothyronine (Triostat) was given as a bolus dose (0.2 μg/kg) after 1 hour of baseline data collection with a subsequent measurable rise in serum triiodothyronine levels ( p < 0.01). In six postischemic hearts, reverse triiodothyronine was given as a 0.2 μg/kg bolus. Triiodothyronine was also administered to a group of eight nonischemic, continuously perfused isolated hearts. Intrinsic myocardial contractility was assessed by analysis of the preload recruitable stroke work area, energetic efficiency from the myocardial oxygen consumption-pressure-volume area relationship, and coronary vascular resistance from analysis of coronary flow and perfusion pressure. Acute administration of triiodothyronine to postischemic hearts improved the preload recruitable stroke work area from 9.5 ± 1.42 to 14.9 ± 2.03 x 10 7 erg/ml, a 56% increase from baseline ( p < 0.001), but had no effect on the preload recruitable stroke work area of the nonischemic hearts. The inotropic response resulting from triiodothyronine treatment did not alter the myocardial oxygen consumption-pressure-volume area relationship. Triiodothyronine treatment was associated with significantly decreased coronary resistance and increased coronary flow through a range of diastolic loading conditions in the postischemic hearts. The biologically inactive thyroid hormone metabolite reverse triiodothyronine was without effect on any of the measured parameters. On the basis of these results, we conclude that the low triiodothyronine state of cardiopulmonary bypass can be reproduced in this isolated heart model and that acute triiodothyronine treatment results in a unique inotropic action manifest only in the postischemic reperfused myocardium and is accomplished without oxygen wasting effects. (J T HORAC C ARDIOVASC S URG 1995; 109: 457-65)

Resuscitative retrograde blood cardioplegia: Are amino acids or continuous warm techniques necessary?

This experiment was designed to determine the relative degree of cardiac functional recovery provided by various forms of resuscitative retrograde blood cardioplegia after global ischemic injuy. Twenty-four dogs were subjected to 20 minutes of normothermic global ischemia followed by 60 minutes of cardioplegic arrest by one of three methods: 1, standard cold blood cardialgia with a cold terminal dose ( n = 8); 2, aspartate-glutamate–enhanced blood with warm induction and terminal enhancement ( n = 8); and group 3, countinous warm blood cardioplegia ( n = 8). Sonomichrometry was used to analyze left ventricular function for maximal elastance and preload recruitable stroke work area. Data were recorded at baseline and preload recruitable stroke work area, but not of maximal elastance, after reperfusion of ischemic differences were detectable among the groups after 60 minutes of unloaded reperfusion. Neither amino acid enchancement nor continuous warm cardioplegia offered a significant advantage in functional recovery over the standard method of cold cardioplegia reperfusion. (J T HORAC C ARDIOVAC S URG 1995;109:242-8)

The effects of amrinone versus dobutamine on myocardial mechanics and energetics after hypothermic global ischemia

The effects on the postischemic myocardium of amrinone and dobutamine were studied in canine hearts that underwent 90 minutes of hypothermic (10 degrees C) arrested ischemia. In an isolated heart preparation cross-circulated by a support dog, left ventricular pressure-volume loops were collected under a constant afterload based on a mock circulatory system and a range of preload conditions controlled by a computerized servo volume pump. Dobutamine (0, 5, 10, 15 micrograms/kg per minute) and amrinone (0, 0.75, 1.5, 3.0 mg/kg) were tested in this order based on the weights of the support dogs in eight experiments. Changes in intrinsic myocardial contractility were analyzed as percent increases in the preload recruitable stroke work area from baselines. Dobutamine exhibited significant dose-related increases in the preload recruitable stroke work area. Amrinone did not produce significant increases in preload recruitable stroke work area at 0.75 mg/kg; amrinone's inotropic effect was equivalent to dobutamine, 5 micrograms/kg per minute at 1.5 mg/kg, and at the maximum dose (3.0 mg/kg) it was equivalent to dobutamine, 10 micrograms/kg per minute. The myocardial energetic efficiency was determined from the analysis of the myocardial oxygen consumption-pressure volume area relationship. The y intercept represents the basal metabolic oxygen requirement of the unloaded beating heart, and the slope is inversely proportional to the rate of energy conversion for increasing loading conditions. Dobutamine significantly increased the y intercepts, but it had no effects on the slopes. These changes demonstrate reduced myocardial efficiencies that are consistent with previous reports. Amrinone (0.75 and 1.50 mg/kg) did not result in change of the y intercepts and the slopes of myocardial oxygen consumption-pressure-volume area relationship from baseline conditions. The y intercept was increased with amrinone (3.0 mg/kg), although still not significantly higher than baseline and not to the extents of the dobutamine group. Dobutamine did not have any primary effect on coronary resistance, while amrinone significantly reduced coronary resistance in all loading conditions at 1.5 and 3.0 mg/kg. This study demonstrates that the inotropic effects of amrinone tested under this constant afterload preparation were lower than those of dobutamine. Amrinone has a superior profile of myocardial efficiency on the postischemic myocardium since it does not produce the oxygen-wasting effects of the traditional inotropic agents such as the beta agonists. This benefit, together with amrinone's coronary dilating effects, critically improves the supply/demand ratio that may be of importance in certain clinical situations.

Ischemic tolerance of the arrested heart during warm cardioplegia.

Normothermic blood cardioplegia has recently generated interest as an alternative method of myocardial protection during cardiopulmonary bypass (CPB) surgery. One disadvantage is the obligatory interruption of coronary flow during the distal coronary anastomosis. This study was designed to determine the safe normothermic ischemic time of the arrested and decompressed heart. Under normothermic CPB (37 degrees C), initial cardioplegic arrest was induced with 750 cc of warm (37 degrees C) hyperkalemic blood cardioplegia in 21 adult dogs. The heart then received warm blood cardioplegia either continuously (50 cc/min), every 5 min (250 cc each) or every 10 min (350 cc each) for a total equivalent ischemic time of 30 min (n = 7 in each group). Left ventricular pressure-volume (PV) loops were measured by micromanometer and conductance (volume) catheters before, at 60 and 90 min after aortic cross-clamping. Systolic function was measured as the preload recruitable stroke work area derived from the stroke work-end diastolic volume relationship, and the diastolic stiffness constant (k) was derived from the exponential diastolic PV relationship. The q5 min group sustained minor deterioration in diastolic function while its systolic function was well maintained during recovery. There were significant reductions in both the diastolic and systolic functions in the q10 min group. The maximum drops in the septal wall pH during aortic cross-clamping were 0.05 +/- 0.02 (not significant), 0.19 +/- 0.06 (P < 0.05), and 0.40 +/- 0.09 (P < 0.01) for the continuous, q5 min and q10 min groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Superiority of the University of Wisconsin solution over simple crystalloid for extended heart preservation

To compare the effects of the University of Wisconsin solution with those of an extracellular crystalloid solution, Krebs-Ringer bicarbonate, as cardiac preservation media, we studied 35 adult dogs in an isolated heart preparation. Four groups of seven hearts were preserved in University of Wisconsin solution for 6 or 12 hours or in Krebs-Ringer bicarbonate solution for 6 or 12 hours. An additional group of seven hearts with no ischemia was used for a control group. In the four preservation groups, hearts were arrested by electrolyte solution (Normosol with potassium chloride, 20 mEq/L, added, 4 degrees C), flushed with 200 ml of the preservation solution, and then stored in the same solution at 1 degree to 2 degrees C. The hearts were mounted on an isolated heart preparation equipped with a computer-controlled servo-pump system that used a mock arterial system to modulate the aortic input impedance presented to the left ventricle. Left ventricular pressure-volume loops were measured on-line for 2 hours of reperfusion with autologous warm oxygenated blood. Elastance was derived from the end-systolic pressure-volume relationship, and diastolic compliance was derived from the end-diastolic pressure-volume relationship. The total left ventricular performance was assessed by the preload recruitable stroke work area, the slope, and its x-intercept, all of which derived from the stroke work (pressure-volume area)-end-diastolic volume relationship. Extended global ischemia had more deleterious effects on the end-diastolic than the end-systolic pressure-volume relationship. In confirmation with other studies, elastance did not accurately reflect the level of ventricular contractile dysfunction because of the significant amount of diastolic dysfunction. The preservation of myocardial systolic and diastolic functions, as demonstrated by the preload recruitable stroke work area and diastolic compliance, was better in the University of Wisconsin solution groups than in the Krebs-Ringer bicarbonate solution groups after 6 and 12 hours of preservation. In addition, 6 hours of preservation with University of Wisconsin solution maintained normal systolic and diastolic functions as compared with those of the control group. Preservation with University of Wisconsin solution prevented any myocardial edema formation; by contrast, this was significantly increased after 12 hours in Krebs-Ringer bicarbonate solution. Groups preserved with University of Wisconsin solution had less reperfusion injury as evidenced by the release of coronary sinus creatine kinase during reperfusion; they also had improved oxygen use during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)