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Background: beta-Adrenergic receptor kinase 1 (beta ARK1) mediates beta-adrenergic receptor signaling via receptor phosphorylation, which results in functional uncoupling. The physiological importance of beta ARK1 on cardiac performance in the setting of ischemia and reperfusion injury, however, has not been clearly established. In this study, the effects of beta ARK1 overexpression on myocardial recovery after ischemia and reperfusion injury were evaluated in transgenic mice with the use of an isolated work-performing murine heart preparation and computerized analysis of functional data., Methods and Results: A controlled, experimental study was performed to compare cardiac function in the hearts of both transgenic mice with a 3-fold overexpression of beta ARK1 (n = 6; weight, 25 to 29 g) and littermate controls (n = 9; weight, 25 to 28 g). Preload-dependent cardiac output, contractility, heart rate, stroke work, and stroke volume were evaluated in the 2 groups before and after a 6-minute period of normothermic ischemia. Before ischemia, significant decreases were observed in all parameters of myocardial performance in beta ARK1 mice compared with control mice. After ischemia and reperfusion, significant decreases in cardiac function were observed in both experimental groups; however, significantly lower percentages of myocardial recovery occurred in beta ARK1 hearts compared with control hearts., Conclusions: After global normothermic ischemia, significant decreases in cardiac function were observed in both beta ARK1 and control mice; however, significantly lower percentages of myocardial recovery occurred in beta ARK1 mice. These data suggest that myocardial beta ARK1 overexpression significantly impairs cardiac function in the setting of ischemia and reperfusion injury.

Background: Right ventricular (RV) hypertrophy is an adaptive process that occurs in the setting of chronic pulmonary hypertension (CPH) and can lead to alterations in normal RV diastolic properties. This study was designed to investigate the effects of NO and milrinone on RV diastolic dysfunction in the setting of CPH and RV hypertrophy by use of a canine model of monocrotaline pyrrole (MCTP)-induced CPH., Methods and Results: Sixteen mongrel dogs (22 to 24 kg) were used. Animals underwent percutaneous pulmonary artery (PA) catheterization to measure pulmonary hemodynamics before and 8 weeks after injection of 3 mg/kg MCTP (n=8) or placebo (control, n=8). Eight weeks after injection, all hearts were instrumented with a PA flow probe, sonomicrometric dimension transducers, and micromanometers. Data were collected at baseline and after both NO and milrinone administration. Diastolic properties were quantified by use of the end-diastolic pressure-volume relationship and the time constant of ventricular isovolumic relaxation. Eight weeks after injection, significant increases in the PA pressure and pulmonary vascular resistance were observed in MCTP dogs. Significant worsening of RV diastolic function occurred in association with significant increases in the ratio of RV dry weight to LV+septal dry weight. NO and milrinone administration both led to significant improvements in RV diastolic properties., Conclusions: In the setting of MCTP-induced CPH, significant worsening of RV diastolic function was observed in association with significant increases in the ratio of RV dry weight to LV+septal dry weight, suggesting that these changes are partially due to RV hypertrophy. The significant improvement in RV diastolic properties after both NO and milrinone administration suggests that these agents may be effective forms of pharmacological therapy for improving RV diastolic dysfunction in the setting of CPH.

Background: Right ventricular (RV) failure remains an important risk factor for early morbidity and mortality after orthotopic cardiac transplantation and is most commonly related to preexistent chronic pulmonary hypertension (CPH) in the recipient, which occurs secondary to long-standing congestive heart failure. This study was designed to assess the compensatory mechanisms of the acutely transplanted RV in the setting of recipient CPH using a canine model of bicaval cardiac transplantation (TX) and monocrotaline pyrrole (MCTP)-induced CPH., Methods and Results: Twenty adult mongrel dogs were used for 10 successfully completed TX experiments. Recipients received an injection of 3 mg/kg MCTP 4 months before TX. RV function was assessed with load-insensitive means (preload recruitable stroke work), and Fourier analysis was used to calculate RV hydraulic power and transpulmonary efficiency. At the time of TX, significant increases in the mean pulmonary artery pressure, mean right ventricular pressure, and pulmonary vascular resistance were observed in recipients compared with donors and were further significantly increased after cardiopulmonary bypass. Significant increases in RV preload recruitable stroke work and RV hydraulic power were observed after TX compared with before TX and occurred in association with significant decreases in transpulmonary efficiency., Conclusions: Significant increases in pulmonary hemodynamic indexes occurred after MCTP injection and were further significantly increased after cardiopulmonary bypass. In the setting of recipient CPH, RV performance adapts acutely after bicaval TX with significant increases in power and contractility. However, a significant decrease in transpulmonary efficiency was also observed, which may improve over time as the RV adapts to the increased afterload.

Background: Acute graft failure is an important cause of morbidity and mortality in cardiac transplantation, and it may be associated with myocardial changes that occur during brain death (BD). This study investigates the changes in biventricular systolic and diastolic function that occur after BD in a validated canine model., Methods and Results: The hearts of 20 mongrel canines (23 to 31 kg) were instrumented with micromanometers, flow probes, and dimension transducers to measure minor/major axes as well as left and right ventricular (LV/RV) septum-to-free wall distances. LV/RV volumes were measured according to the shell subtraction method. LV/RV systolic function was analyzed by ventricular stroke work plotted versus end-diastolic volume during a caval occlusion (preload-independent recruitable systolic work, PRSW). The nonlinear relationships between diastatic pressure (stress) and LV/RV septum-to-free wall distances and volumes (strain) from successive diastoles during caval occlusion were used to evaluate LV/RV diastolic mechanics. The Cushing phenomenon, hyperdynamic response, and diabetes insipidus were observed in each animal after BD. Results are expressed as mean +/- SEM (P < .05 versus baseline, ANOVA, paired two-tailed Student's t test). Biventricular systolic function deteriorated significantly from baseline PRSW 6 to 7 hours after BD. The diastatic LV/RV pressure dimension relationships were significantly different after BD, indicating a decrease in ventricular chamber compliance during diastole., Conclusions: BD causes a significant loss of systolic and diastolic LV/RV function in the brain-dead, heart-beating cadaver, which may contribute to early postoperative cardiac graft failure in the recipient. These findings have significant clinical applications and may help to avoid suboptimal donor/recipient matches.

Background: Myocardial injury after ischemia and reperfusion may be mediated, at least in part, by oxygen-derived free radicals; this supposition is supported by the observation that significant quantities of these radicals are generated during reperfusion. To directly assess the protective effect of extracellular superoxide dismutase (EC-SOD), this study was designed to investigate the ability of EC-SOD overexpression in the hearts of transgenic mice to protect myocardial tissue against ischemiareperfusion injury by use of an isolated work performing murine heart preparation and functional analysis., Methods and Results: Ten transgenic mice (EC.SOD, 28 to 31 g) were studied and compared with 10 control mice (Ctl, 28 to 31 g) in terms of preischemic and postischemic myocardial function. All hearts underwent cardiac harvest and arrest, followed by instrumentation and subsequent reperfusion with warm Krebs-Henseleit solution. Preload-dependent functional analysis was then performed to evaluate cardiac output, contractility (dP/dt), heart rate, stroke work, and stroke volume before and after a 7-minute period of warm ischemia. Results are expressed as mean +/- SEM (ANOVA, paired unpaired t tests). There was no significant difference in preischemic myocardial performance for Ctl and EC-SOD mice. After warm ischemia, cardiac output in EC-SOD was significantly improved compared with Ctl (EC-SOD, 4.55 +/- 0.37 mL/min; Ctl, 2.55 +/- 0.28 mL/min; P < .05). Postischemic dP/dt, stroke work, and stroke volume were also significantly improved in EC-SOD compared with Ctl mice (EC-SOD, 1808 +/- 39 mm Hg/s, 745 +/- 67 dyne.cm, and 13.1 +/- 1.2 microL, respectively; Ctl, 1497 +/- 87 mm Hg/s, 472 +/- 83 dyne.cm, and 8.2 +/- 1.5 microL; P < .05)., Conclusions: EC-SOD overexpressed mice showed significant improvement in postischemic cardiac function compared with Ctl mice. Thus, EC-SOD overexpressed hearts are less susceptible to mild degrees of ischemia-reperfusion injury than normal hearts.

Background: Total orthotopic heart transplantation was recently introduced into clinical practice as an alternative technique for orthotopic cardiac transplantation. Total cardiac transplantation uses separate bicaval and left and right pulmonary anastomoses, whereas the standard technique of cardiac transplantation uses atrioplasty. Because the anatomic differences between total and standard orthotopic heart transplantation occur at the atrial level, this study compares atrial systolic function and biventricular filling (dV/dt) between the standard and total transplantation techniques., Methods and Results: Forty-eight mongrel canines (23 to 31 kg) were used for 12 total and 12 standard orthotopic cardiac transplantations. Right and left ventricular (RV/LV) function and AV synchrony were analyzed with micromanometry, sonomicrometry, ultrasonic flow meters, and intraoperative echocardiography. Results are expressed as mean +/- SEM (ANOVA, paired and unpaired t tests, and chi 2 test). There were no significant differences in baseline function (pretransplantation), bypass times, and cardiac ischemic times between the two groups. Posttransplantation sinus rhythm was preserved in all total (P < 0025) and in only one standard transplantation recipient (all required atrial diastole pacing). Significant decreases in RV/LV dV/dt from 113 +/- 13 and 123 +/- 14 mL/s to 69 +/- 6 and 85 +/- 10 mL/s after transplantation were measured in the standard group. No significant changes occurred in the total group after transplantation with respect to RV/LV diastolic filling. After transplantation, left atrial contractility and relaxation (-dP/dt) decreased significantly in the standard group by 43% and 70%, respectively, whereas in the total transplantation group, there were no observed changes in left atrial contractility and-dP/dt. A significant increase in the septum to RV free wall dimension in the standard group suggests altered geometry., Conclusions: Total AV transplantation is a feasible alternative to standard cardiac transplantation and conserves both normal sinus rhythm and synchronized beating of the atria and ventricles. Ischemic and bypass times are comparable in patients undergoing either method. These data suggest that RV/LV diastolic function and geometry and atrial systole are better preserved in the total AV transplantation technique.

Background: Cardiac failure remains an important problem after heart transplantation and may be associated with events that occur during brain death (BD) before transplantation. In this study, cardiac function is studied after BD, and biochemical evaluation of myocardial high-energy phosphates and the beta-adrenergic receptor system is presented., Methods and Results: The hearts of 17 mongrel dogs (23 to 31 kg) were instrumented with flow probes, micromanometers, and ultrasonic dimension transducers to measure ventricular pressure and volume relationships. In a validated canine BD model, systolic right and left ventricular (RV/LV) function was analyzed by load-insensitive measurements during caval occlusion (preload-recruitable stroke work, PRSW). The beta-adrenergic receptor (BAR) density, adenylate cyclase (AC) activity, and myocardial ATP and creatine phosphate (CP) were measured before and 6 to 7 hours after BD. Results are expressed as mean +/- SEM (*P < .05 versus baseline, paired two-tailed Student's t test). Myocardial function deteriorated significantly from baseline PRSW (RV, 22 +/- 1 erg x 10(3); LV, 75 +/- 4 erg x 10(3)) by 37 +/- 10% for the RV (P < .001) and 22 +/- 7% for the LV (P < .001). BAR density increased from 282 +/- 42 to 568 +/- 173 fmol/mg for the RV and from 291 +/- 64 to 353 +/- 56 fmol/mg for the LV. Isoproterenol-stimulated AC activity was also significantly enhanced after BD. ATP and CP, however, remained unchanged after BD compared with baseline values before BD., Conclusions: BD causes significant systolic biventricular dysfunction. The loss of ventricular function after BD was more prominent in the right ventricle and may contribute to early postoperative RV failure in the recipient. These injuries occurred despite BAR system upregulation after BD. Global myocardial ischemia is unlikely, since ATP and CP remained normal before and after BD.