Nicorandil ameliorates posttransplant dysfunction in cardiac allografts harvested from non-heart-beating donors

Objective: Warm ischemia is a major cause of cardiac allograft dysfunction in non-heart-beating donors (NHBDs). We evaluated the cardioprotective effects of nicorandil, and adenosine triphosphate-sensitive potassium channel opener, on the early posttransplant left ventricular (LV) function of hearts harvested from asphyxiated canine NHBDs.Methods: Hypoxic cardiac arrest was induced in 12 donor dogs. In 6, nicorandil was administered intravenously at 100 μg/kg+25 μg/kg/min after respiratory arrest and hearts were preserved with nicorandil-supplemented cardioplegic solution (nicorandil group). The remaining 6 did not receive nicorandil at any time during the experiment (control group). Hearts were weaned from cardiopulmonary bypass without inotropic support. In the control group, posttransplant cardiac indices and left ventricular end-systolic pressure (LVESP) decreased significantly, while LV max-dP/dt and Tau increased over pretransplant values. No differences were seen in parameters between pretransplant and posttransplant values in the nicorandil group. Posttransplant cardiac indices, LVESP, and LV max+dP/dt were higher in the nicorandil group than in controls, while posttransplant LV max-dP/dt in the nicorandil group was lower.Conclusions: Our results indicate that pretreatment with nicorandil during hypoxic perfusion before cardiac arrest and subsequent preservation with nicorandil-supplemented cardioplegia ameliorates early posttransplant LV dysfunction of hearts harvested from asphyxiated NHBDs.     

Efficacy of an endothelin-A receptor antagonist in heart transplantation from asphyxiated canine non-heart-beating donors

Objective Hypoxic perfusion before arrest, an indeterminate period of warm ischemia, and subsequent reperfusion are major causes of cardiac allograft dysfunction in non-heart-beating donors (NHBDs). The present study was undertaken to elucidate the cardioprotective effects of ET_A receptor antagonist FR139317 for hearts obtained from asphyxiated NHBDs in a canine transplantation model. Methods Hypoxic cardiac arrest was induced in 17 donor dogs. FR139317 (10 mg/kg) was given to 7 of the dogs over a period of 10 min before disconnecting the ventilator. The hearts were preserved with FR 139317-supplemented cardioplegic solution (FR group). The remaining 10 did not receive FR 139317 at any time during the experiment (control group). Orthotopic transplantation was performed after a mean myocardial ischemic time of 4 h. Results During the agonal period, the highest systolic pulmonary artery pressure in the FR group was lower than that in the control group (47 ± 14 vs. 58 ± 27 mmHg). All animals in the FR group were weaned from cardiopulmonary bypass, whereas only five of the controls were weaned, two of which were identified to have dominant right ventricular failure. After transplantation, recovery rates of the left ventricular end-systolic pressure-volume ratio (Emax) and the maximum first derivative of pressure measured over time (max dP/dt) were not significantly different between the groups, but recovery rates of the cardiac index, left ventricular minimum dP/dt and exponential time constant of LV relaxation (tau) in the FR group were higher than those in the control group. Conclusions The ET_A receptor antagonist FR 139317 reduced pressure overload on the right ventricle by decreasing the peak pulmonary artery pressure before donor arrest. Cardioprotective effects of this agent for heart transplantation from NHBDs are manifested by preserved diastolic properties of the left ventricle.     

Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated beta-adrenergic signaling modulation.

OBJECTIVES: Reperfusion after myocardial ischemia goes together with alteration of the beta-adrenergic (betaAR) signaling. Especially the level and catalytic activity of beta AR kinase (betaARK1) are increased. We hypothesized that myocardial expression of a betaARK1 inhibitor (betaARKct) may protect from post-reperfusion dysfunction. METHODS: Two groups of rabbits were treated by intracoronary delivery of either phosphate-buffered saline (PBS) or a solution of adenovirus carrying the betaARKct transgene (Adeno-betaARKct). At day 5, the hearts were explanted after cold cardioplegic arrest, and preserved at 4 degrees C for 4 h. Reperfusion was hemodynamically standardized on a Langendorff apparatus with oxygenated Krebs solution for 30 min before left ventricular (LV) pressure was recorded using an LV latex balloon connected to a pressure transducer. Non-arrested hearts immediately perfused on the Langendorff apparatus served as controls. RESULTS: LV contractility (LV dP/dt(max), P < 0.05) and relaxation (LV dP/dt(min), P < 0.05) were reduced, and end diastolic pressure (LV EDP) was increased after prolonged exposure to cold preservation solution as compared to normal control hearts, both under basal conditions and when stimulated with the betaAR agonist isoproterenol. However, these parameters remained within a normal range in Adeno-betaARKct-expressing hearts arrested and preserved for 4 h. Biochemical analysis shows a reduced betaAR density and an impaired signaling after reperfusion of hearts arrested for 4 h whereas it is normalized in Adeno-betaARKct-expressing hearts. CONCLUSION: Myocardial gene-mediated inhibition of betaARK1 via betaARKct expression avoids ventricular dysfunction after prolonged preservation. Therefore, this may represent a way of improving early results of cardiac transplantation and perioperative function.     

The effect of short-term coronary perfusion using a perfusion apparatus on canine heart transplantation from non-heart-beating donors.

BACKGROUND: We investigated the effects of briefly perfusing hearts from non-heart-beating donors (NHBDs) with a Celsior solution before cardiac transplantation. METHODS: Donor hearts were left in situ for 20 minutes after cardiac arrest was induced by rapid exsanguination. Twelve donor-recipient pairs of mongrel dogs were divided into 2 groups, the simple immersion (SI, n = 6) group and the coronary perfusion (CP, n = 6) group. Both groups underwent coronary flushing with Celsior, after which hearts from the SI group were stored using simple immersion for 4 hours and hearts from the CP group underwent 1 hour of further perfusion followed by storage for 3 hours. Orthotopic transplantation was then performed. We measured cardiac output, end-systolic maximal elastance (E(max)), left ventricular pressure, and rate pressure product 1 and 2 hours after weaning from cardiopulmonary bypass (CPB). Two hours after weaning from CPB, the hearts were harvested for histopathologic study and to determine the percentage of water content. RESULTS: The cardiac output (CO) recovery rate was significantly higher in the CP group than in the SI Group 1 hour after weaning from CPB (p < 0.05). The CO recovery rate, E(max), and rate pressure product were significantly higher and the percentage of water content was significantly lower in the CP group than in the SI Group 2 hours after weaning from CPB (p < 0.05). Histopathologic damage was more severe in the SI group. CONCLUSIONS: The results of this study suggest that short-term coronary perfusion with a Celsior solution may be useful for heart transplantation from NHBDs.     

Changes in left ventricular function after cardiac arrest and reperfusion in hypertropheral hearts.

Hypertrophied hearts may be more susceptible to ischemia/reperfusion during cardiac surgery than normal hearts, so we designed to compare the alterations in left ventricular function after ischemia/reperfusion, in hypertrophied hearts (Group H) with those in normal hearts (Group C), using a rabbit heart model of hypertrophy induced by banding of the ascending thoracic aorta. The pre and postischemic left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), positive and negative dP/dt, and coronary flow were measured. The percent recovery of coronary flow and negative dP/dt were significantly lower in Group H than in Group C (p < 0.05). The LVEDP was significantly greater in Group H, and the LVEDP increased significantly from the base line value in Group H (p < 0.05). There was no significant difference in other value between two groups. These findings demonstrated that LV diastolic dysfunction rather than LV systolic dysfunction occurred in the early ischemic stage, especially to hypertrophied hearts, indicating that better protection is required for these hearts.     

Enhanced functional recovery with venting during cardioplegic arrest in chronically damaged hearts

Thirty dogs with experimental myocardial infarction underwent cardiopulmonary bypass, hypothermic asanguineous K+ cardioplegia (1 hour), and reperfusion (30 minutes). Ten hearts were vented throughout, 5 only during arrest, and 5 only during reperfusion; 10 were not vented. Left ventricular (LV) performance and compliance were assessed by isovolumic (LV balloon) indexes before bypass and after reperfusion. Vented hearts recovered 116 +/- 8.3% of prearrest developed LV systolic pressure (DLVSP) and 131 +/- 13.6% of prearrest rate of rise of LV pressure (dP/dt). Nonvented hearts allowed to develop pressure during arrest (11.6 +/- 1.6 mm Hg) and reperfusion (65 +/- 4 mm Hg) recovered 50 +/- 3.9% of prearrest DLVSP and 55 +/- 5% of prearrest dP/dt (p less than 0.05). Reduction in LV compliance was comparable in both groups. Mitochondrial architecture (electron microscopy) was preserved in vented hearts, but was modestly disrupted in nonvented hearts, thus suggesting slight metabolic impairment. Functional recovery was nearly complete in hearts vented only during reperfusion (DLVSP, 94 +/- 10.4%; dP/dt, 89 +/- 12.6%), but venting only during arrest led to functional depression (DLVSP, 50 +/- 6.6%; dP/dt, 51 +/- 8%; p = 0.01). We conclude that venting chronically infarcted hearts during cardiac operations affords better myocardial protection by avoiding the damage that occurs during nonvented reperfusion.     

HOE-642联合尼可地尔对无心跳猪供心的保护作用

目的 探讨无心跳供者(NHBD)的心脏进行移植的可行性,以及HOE-642联合尼可地尔对这种供心的保护效果.方法 将健康雄性家猪随机分为实验组和对照组,实验组供者采取主动脉快速完全放血法制成NHBD模型,取其心脏,冷保存4 h后进行移植;对照组供者经主动脉适量放血(仍有心跳),造成热缺血,然后取其心脏,冷保存4 h后进行移植.实验组于供心热缺血前5 min静脉给予HOE-642(2 mg/kg);以含HOE-642和尼可地尔的4 ℃ Stanford液灌洗和保存供心;供心吻合前经主动脉根部以含HOE-642和尼可地尔的4 ℃ 4:1血心停搏液(高钾)灌注1次;供心吻合期间以含HOE-642和尼可地尔的4 ℃ 4:1血心停搏液(低钾)间断灌注;心脏吻合完毕主动脉开放后初始5 min时段内,静脉给予HOE-642(2 mg/kg).对照组的供心处理除不用HOE-642和尼可地尔外,其余同实验组.采集供心主动脉根部放血前、移植心脏吻合完毕主动脉开放后1 h(停机)以及主动脉开放后2 h(实验结束)3个时点的心脏血流动力学指标,测定移植心脏的心肌含水量,观察心肌的组织学变化.结果 两组在主动脉开放后心肌红润,心脏搏动有力,均成功脱机.两组各检测时点的左心室舒张末压、左心室峰发展压及左心室压力变化速率的差异均无统计学意义(P＞0.05);实验组和对照组心肌组织含水量分别为(78.6±5.7)%和(76.4±4.2)%,其差异无统计学意义(P＞0.05);光镜下见两组的心肌纤维结构清楚,排列紧密,间质未见炎症细胞浸润,也未见变性、坏死,无排斥反应征象,电镜下见心肌细胞超微结构完整.结论 NHBD的供心可用于移植,其效果与有心跳者相近;HOE-642和尼可地尔联用可能对该类供心具有一定的保护作用.     

Experimental study on myocardial preservation with perfluorochemical

The effect of perfluorochemical as cardioplegic solution was studied with isolated canine hearts. They were divided into two groups as follows each consisting of ten, and cardioplegia was made every 30 minutes during 3 hours of ischemia. Group I: The solution was oxygenated to PaO2 of 542 +/- 67 mmHg (mean +/- SD). Group II: The solution was deoxygenated to PaO2 of 55 +/- 12 mmHg. Both temperature were 20 degrees C. After 3 hours cardiac arrest, the hearts were fixed to the perfusion unit filled up with the diluted blood. Then hemodynamic and biochemical variables were measured every 30 minutes. There were some significant differences between the groups. Hemodynamic indices especially negative LV max dp/dt were recovered excellently in Group I but not so much in Group II. Negative LV max dp/dt, which was the distinction of the diastole, showed significant difference more than positive LV max dp/dt, which was the distinction of the systole. It was considered that under the same condition, negative LV max dp/dt reflected not only compliance but also preparatory ability of the left ventricle, and it could be one of the important indices evaluating cardiac function. As regarding metabolism, delivery of oxygen with cardioplegic solution was good for the aerobic metabolism also after reperfusion, and in these circumstances, catecholamine was available effectively to the hearts. The conclusion is as follows. It is important for myocardial preservation to suppress the anaerobic metabolism and to keep the circumstances in which catecholamine was available effectively. And oxygenated PFC is good to preserve myocardium and useful as cardioplegic solution.     

Sustained improvements in cardiac geometry and function following kidney-pancreas transplantation

Kidney-pancreas (KP) transplantation has been shown to improve left ventricular (LV) geometry and function 6-24 months after the procedure, yet whether these improvements are sustained in long-term survivors has not been demonstrated. This study examined whether early improvements in LV geometry and function were sustained 3-5 years after KP transplantation. Left ventricular function and geometry were prospectively evaluated prior to, and at 1, 2, and 3-5 years posttransplant using two-dimensional, M-mode, echocardiography with Doppler interrogation in the parasternal and apical views. The sample included 21 KP and a comparison group of 12 diabetic kidney-alone (KA) recipients. Long-term (3-5 years) data were obtained for KP recipients only. Although KA recipients had a longer duration of dialysis and worse diastolic function pretransplant, the groups were similar on other baseline measures. KA recipients experienced minimal improvements while KP recipients had significant improvements in cardiac function and geometry, both in terms of mean values and the percentage of KP recipients who experienced normalization posttransplant (p < 0.05). KP recipient improvements were also sustained at 3-5 years posttransplant on three of five measures, with 75% of long-term KP recipients achieving normal LV mass posttransplant compared with 31% pretransplant. Data indicate that significant impairments in cardiac geometry and function occur in diabetic KA and KP recipients. Though both groups experienced early improvements posttransplant, KP recipients achieved more dramatic and clinically significant improvements at 1, 2, and 3-5 years posttransplant. Additional studies are needed to examine the relevance of these findings with regard to the cardiac morbidity and mortality of these patients.     

Heterotopic transplantation as a model to study functional recovery of unloaded failing hearts

OBJECTIVES: Recent studies have demonstrated cardiac improvement in patients supported with a ventricular assist device, suggesting that reverse remodeling and myocardial recovery are possible. We developed an animal model of cardiac unloading by adapting a heterotopic transplantation technique and used it to examine the pattern of functional recovery in the left ventricle of the failing heart. METHODS: Heart failure was induced in adult New Zealand rabbits by coronary artery ligation with subsequent myocardial infarction. Animals undergoing sham operation served as a control group. After 4 weeks or 3 months, failing hearts were transplanted into the necks of recipient rabbits. A left ventricular latex balloon connected to subcutaneous tubing allowed repeated physiologic analysis on days 1 and after transplantation and then every 5 days until day 30. RESULTS: Contractility (left ventricular dP/dt(max)) and relaxation (left ventricular dP/dt(min)) were significantly lower in transplanted postinfarction hearts as compared to control hearts immediately after transplantation. Both left ventricular dP/dt(max) and left ventricular dP/dt(min) responses to increased preload and to beta-adrenergic stimulation progressively improved to a significantly higher level after 30 days of left ventricular unloading for the hearts that were transplanted 4 weeks after myocardial infarction. However, this functional improvement was not detected in failing hearts transplanted 3 months after infarction. CONCLUSIONS: This model of cardiac unloading appears at least partially to mimic conditions of ventricular assist devices. If performed early in the development of heart failure, it permits improvement of contractile dysfunction and restoration of cardiac responsiveness to mechanical and beta-adrenergic stimulation. Therefore this model may constitute a novel alternative in the study of reverse remodeling in unloaded failing hearts.     

Dose dependent effects of cardiac beta2 adrenoceptor gene therapy

BACKGROUND: Adenoviral-mediated gene transfer during cardiopulmonary bypass (CPB) achieves efficient myocardial transgene expression. The optimal vector dose required to produce not only increased beta adrenoceptor (betaAR) density but, more importantly, enhanced left ventricular (LV) function is unknown. In addition, it is unclear if absent extracardiac expression in preliminary studies represented cardiac specific, as opposed to selective gene delivery, as a consequence of low vector doses. MATERIALS AND METHODS: Adenoviral vector encoding the human beta(2) adrenoceptor (Adeno-beta(2)AR) was delivered to cardioplegic arrested hearts of neonatal piglets during CPB in three doses ranging from 5 x 10(11) total viral particles (tvp) to 2 x 10(12) tvp. Control animals received adenoviral vector encoding beta galactosidase (Adeno-betagal) or PBS (PBS). LV and liver betaAR density and in vivo LV function were assessed 5 days later. RESULTS: Elevated LV betaAR density was present after delivery of Adeno-beta(2)AR at all doses. Piglets which received 5 x 10(11) tvp and 1 x 10(12) tvp Adeno-beta(2)AR demonstrated enhanced LV dP/dt(max) but in those receiving 2 x 10(12) tvp LV dP/dt(max) was unchanged. Moreover, at this higher dose of adenoviral vector the detrimental effects of cardiac inflammation and extracardiac gene overexpression became apparent. CONCLUSIONS: Although the highest increase in cardiac betaAR density occurred after high-dose Adeno-beta(2)AR, LV dP/dt(max) was not enhanced. Moreover, significant extracardiac gene expression was present at this dose, emphasizing the need for careful dose response studies in gene therapy. However, cardiac selective beta(2)AR overexpression does occur following adenoviral vector delivery during CPB and cardioplegic arrest resulting in enhanced LV dP/dt(max).     

Mild hypothermia impairs left ventricular diastolic but not systolic function.

Hypothermia is a component of myocardial protection during cardiopulmonary bypass (CPB) and cardioplegic arrest (CA). Patients in the early post CPB period often show mild hypothermia and cardiac dysfunction. We sought to investigate the impact of hypothermia on left ventricular (LV) function. Anesthetized dogs (n = 12) were instrumented with myocardial ultrasonic crystals and LV micromanometer. Systolic function was measured by preload recruitable stroke work (PRSW). Diastolic function was measured by -dP/dt(max) and tau. In six dogs (Norm group), body temperature was maintained at baseline levels. In another six dogs (Hypo group), body temperature dropped gradually over the time course of the experiment. The body temperature in the Hypo group decreased from 37.0 +/- 0.3 degrees C to 35.2 +/- 1.0 degrees C. -dP/dt(max) decreased and tau increased significantly with hypothermia but were stable in the Norm group. Both tau and -dP/dt(max) showed a linear relationship to the body temperature (r =.91 and r = .93, respectively). PRSW did not change and cardiac output decreased with hypothermia. Thus, even mild hypothermia impairs LV diastolic but not systolic function. Cardiac output is temperature sensitive and therefore rewarming of patients post-CPB has priority.     

A free radical scavenger, edaravone, prevents ischemia-reperfusion injury in liver grafts from non-heart-beating donors

BACKGROUND: Due to the increase in liver transplantation, the donor shortage has become a serious problem, requiring marginal, non-heart-beating donors (NHBDs). The aims of this study were to evaluate the cytoprotective effect of edaravone, a free radical scavenger, on warm ischemia-reperfusion (I/R) injury of liver grafts from NHBDs. METHODS: Rat livers were harvested from heart-beating donors (HB group) or from NHBDs undergoing cardiac arrest for 30 minutes led by thoracotomy (NHB group), and reperfused for 60 minutes with Krebs-Henseleit bicarbonate buffer after cold preservation for 6 hours. In another group (ED group), warm ischemic livers from NHBDs were reperfused with buffer containing edaravone (1 mg/L) after cold preservation. RESULTS: In the ED group, portal flow volume, bile production, and energy charge were significantly ameliorated. Lipid peroxidation, elevation of hepatic enzymes, and release of tumor necrosis factor-alpha and interleukin-1 beta were significantly alleviated, compared with the NHB group. CONCLUSIONS: These results suggested that edaravone has suppressive effects on warm I/R injury in liver grafts from NHBDs.     

Effect of creatine monohydrate on cardiac function in a rat model of endotoxemia

BACKGROUND: Reports have attributed cardiac failure during acute models of endotoxemia to a lack of high-energy phosphates. This study was undertaken to investigate whether creatine (Cr) administered during perfusion could enhance myocardial protection and improve recovery of cardiac function in a rat model of endotoxemia. METHODS: Acute endotoxemia was induced in rats by a bolus injection of Escherichia coli endotoxin (LPS: 4 mg/kg, ip) while control rats were injected with an equal volume of 0.9% normal saline. To assess the adequacy of energy metabolism, freeze-clamped hearts were obtained from animals to study the concentrations of endogenous ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), and intracellular pH by (31)P-cryomagnetic resonance spectroscopy. In a separate experiment, isolated hearts were perfused via a Langendorff column with Krebs-Henseleit buffer containing different concentrations of creatine monohydrate (1, 3, or 10 mM). Cardiac performance was evaluated via a paced (300 bpm) isovolumetric balloon preparation. Measurements of cardiac function including left ventricular developed pressure (LVDP), the maximum rates of ventricular pressure rise (LV +dP/dt) and fall (LV -dP/dt), and coronary flow were made for both LPS and saline-treated animals. RESULTS: High-energy phosphate ratios of PCr/ATP and PCr/P(i) in hearts declined significantly at 4 h after endotoxin treatment. As anticipated, LVDP and LV +dP/dt(max) at a given preload and heart rate were significantly (P < 0.05) lower at 4 h when measured at the same time point. The functional recovery of these parameters was not improved by the addition of creatine monohydrate to the perfusion buffer. Creatine produced a significant (P < 0.05) negative inotropic effect in hearts from saline-treated animals. The LVDP was reduced by 30% at the lowest concentration and by 50% at the highest concentration of creatine monohydrate. Furthermore, creatine significantly (P < 0.05) reduced LV -dP/dt(max) in both saline and LPS-treated rats. These data demonstrate that exogenous creatine does not contribute to myocardial preservation in endotoxemia. CONCLUSIONS: Energy stores in the rat heart decline early in endotoxemia accompanied by reduced myocardial performance, suggesting that the ability of the heart to perform mechanical work is impaired. Cardiac dysfunction in an acute model of endotoxemia was not improved with exogenous creatine during perfusion. Creatine's effects were primarily lusitropic by delaying the onset of myocardial relaxation in all hearts. The deleterious effects of exogenous creatine monohydrate in normal hearts should be examined in future experimental studies.     

Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy

Diabetic cardiomyopathy is characterized by reduced cardiac contractility due to direct changes in heart muscle function independent of vascular disease. An important contributor to contractile dysfunction in the diabetic state is an impaired sarcoplasmic reticulum (SR) function, leading to disturbed intracellular calcium handling. We investigated whether overexpression of the SR calcium pump (SERCA2a) in transgenic mice could reduce the impact of diabetes on the development of cardiomyopathy. Diabetes was induced by streptozotocin injection (200 mg/kg), and left ventricular (LV) function was analyzed in isolated hearts 3 weeks later. In diabetic hearts systolic LV pressure was decreased by 15% and maximum speed of relaxation (-dP/dt) by 34%. Functional changes were also assessed in isolated papillary muscles. Active force was reduced by 61% and maximum speed of relaxation by 65% in the diabetic state. The contractile impairment was accompanied by a 30% decrease in SERCA2a protein in diabetic mice. We investigated whether increased SERCA2a expression in transgenic SERCA2a-overexpressing mice could compensate for the diabetes-induced decrease in cardiac function. Under normal conditions, SERCA2a overexpressors show improved contractile performance relative to wild-type (WT) mice (-dP/dt: 3,169 vs. 2,559 mmHg/s, respectively). Measurement of LV function in hearts from diabetic SERCA2a mice revealed systolic and diastolic functions that were similar to WT control mice and markedly improved relative to diabetic WT mice (-dP/dt: 2,534 vs. 1,690 mmHg/s in diabetic SERCA2a vs. diabetic WT mice, respectively). Similarly, the contractile behavior of isolated papillary muscles from diabetic SERCA2a mice was not different from that of control mice. SERCA2a protein expression was higher (60%) in diabetic SERCA2a mice than WT diabetic mice. These results indicate that overexpression of SERCA2a can protect diabetic hearts from severe contractile dysfunction, presumably by improving the calcium sequestration of the SR.     

Effects of adding P38 mitogen-activated protein-kinase inhibitor to celsior solution in canine heart transplantation from non-heart-beating donors

BACKGROUND: The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in ischemia-reperfusion injury. This study evaluated the effects of p38 MAPK inhibition using FR167653, a novel p38 MAPK inhibitor, as an additive to Celsior solution in canine heart transplantation from non-heart-beating donors (NHBDs). METHODS: Donor hearts were left in situ for 20 minutes after cardiac arrest, which was induced by rapid exsanguination. Twelve donor-recipient pairs of mongrel dogs were divided into two groups: the control and FR167653 (FR) groups (n=6 each). In both groups, the grafts were subjected to coronary flushing and immersed in Celsior solution for 4 hours with or without FR167653. Orthotopic heart transplantation was then performed. Cardiac output (CO), left ventricular pressure (LVP), and end-systolic maximal elastance (Emax) were measured 2 hours after weaning from cardiopulmonary bypass (CPB), and the hearts were then harvested for histopathologic study. The activation of p38 MAPK was evaluated in another 20 mongrel dogs. RESULTS: In the FR group, CO, LVP recovery rate, and Emax were significantly (P<0.05) higher 2 hours after weaning from CPB, histopathologic damage was attenuated, and the activation of p38 MAPK was significantly (P<0.05) inhibited 10 minutes after reperfusion compared with the control group. CONCLUSIONS: The addition of FR167653 to Celsior solution improved heart-graft viability, probably by way of the inhibition of p38 MAPK activation, which may attenuate ischemia-reperfusion injury in heart transplantation from NHBDs.     

Myocardial depression after elective ischemic arrest. Subcellular biochemistry and prevention.

The hemodynamic and cardiac biochemical effects of global ischemic arrest during cardiopulmonary bypass (CPB) were studied in 54 animals and compared to seven animals without ischemic arrest. Ischemic arrest alone reduced the first derivative of left ventricular force of contraction (LV dF/dt) to 52 percent of control 10 minutes after resuming function and to 64 percent after 1 hour of reperfusion. Cardiac output was depressed to 52 percent of control after 10 minutes of reperfusion, and to 74 percent of control after 60 minutes of reperfusion. In six animals, moderate hypothermia (26 degrees C.) resulted in no protection of cardiac function from ischemic arrest, whereas profound hypothermia to 18 degrees C. resulted in values of LV dF/dt and cardiac output nearly equivalent to the CPB control group (no arrest). A continuous infusion of a hyperkalemic hypothermic solution slightly improved the degree of protection over hypothermia alone. The sarcoplasmic reticulum (SR) isolated from hearts which had undergone 60 minutes of ischemic arrest bound significantly less calcium when the isolation was done after 10 minutes of reperfusion as well as when it was done after 60 minutes of reperfusion. The time to spontaneous release of calcium from the SR also was significantly longer. Moderate hypothermia did not result in improved SR function, whereas deep hypothermia induced by local cooling or by hypothermic potassium infusion retained SR function at normal levels. Oxidative phosphorylation of mitochondria isolated after 60 minutes of reperfusion was also depressed. The mitochondrial respiration rate after normothermic ischemic arrest was 155 natoms of oxygen per minutes versus 237 natoms for the hypothermic hyperkalemic group. Respiratory control index was 5.5 for the normothermic group versus 9.4 for the hypothermic group. It is concluded that hypothermia, whether effected by surface cooling or by hypothermic potassium infusion, allowed full recovery of hemodynamic and biochemical functions within 1 hour of reperfusion.     

Orthotopic transplantation of pig hearts harvested after 30 min of normothermic ischemia: controlled reperfusion with blood cardioplegia containing the Na-H-exchange inhibitor HOE 642

Objectives: The aim of our study was to develop a surgical technique for a successful transplantation of hearts harvested after 30 min of normothermic ischemia without donor pretreatment. Successful transplantation of ischemic compromised hearts could help to expand the severely limited donor pool. We used the pig model because this species is very susceptible to myocardial ischemia. Na⁺-H⁺-exchange (NHE) inhibitors have shown excellent protective properties in several in vitro and in vivo models of myocardial ischemia and reperfusion. Methods: In group I (n=12) hearts were harvested after 30 min of normothermic ischemia following cardiac arrest induced by exsanguination. Hearts were perfused with warm blood cardioplegia and transplanted orthotopically. In group II (n=9) controlled reperfusion with cold leucocyte-depleted blood cardioplegia was performed after 30 min of normothermic ischemia. In group III (n=8) the same procedure was performed as in group II but blood cardioplegia contained 1 mmol/l HOE 642. Results: In group I massive myocardial oedema was observed and none of the animals could be weaned from cardiopulmonary bypass (CPB). In contrast, all animals in groups II and III could be weaned from CPB with low dose inotropic support. In groups II and III the contractility of the hearts, expressed as maximal left and right ventricular stroke work index was significantly impaired after transplantation as compared with the preoperative value. Supplementation of blood cardioplegia with HOE 642 resulted in a significantly better recovery of the LVSWImax (Group II vs. III). Conclusions: Successful transplantation of pig hearts is possible after 30 min of normothermic ischemia without donor pretreatment if a controlled reperfusion with cold leucocyte-depleted blood cardioplegia is performed. HOE 642 given during reperfusion only improves posttransplant left ventricular function.     

Hypertonic saline dextran resuscitation of thermal injury.

Burn treatment requires large volumes of crystalloid, which may exacerbate burn-induced cardiopulmonary dysfunction. Small-volume hypertonic saline dextran (HSD) resuscitation has been used for effective treatment of several types of shock. In this study isolated coronary perfused guinea pig hearts were used to determine if HSD improved left ventricular contractile response to burn injuries. Parameters measured included left ventricular pressure (LVP) and maximal rate of LVP rise (+dP/dt max) and fall (-dP/dt max) at a constant preload. Third-degree scald burns comprising 45% of total body surface area (burn groups, N = 75), or 0% for controls (group 1, N = 25) were produced using a template device. In group 2, 25 burned guinea pigs were not fluid resuscitated and served as untreated burns; 20 burns were resuscitated with 4 mL lactated Ringer's (LR) solution/kg/% burn for 24 hours (group 3); additional burn groups were treated with an initial bolus of HSD (4 mL/kg, 2400 mOsm, sodium chloride, 6% dextran 70) followed by either 1, 2, or 4 mL LR/kg/% burn over 24 hours (groups 4, 5, and 6, respectively). Untreated burn injury significantly impaired cardiac function, as indicated by a fall in LVP (from 88 +/- 3 to 68 +/- 4 mmHg; p = 0.01) and +/- dP/dt max (from 1352 +/- 50 to 1261 +/- 90 and from 1150 +/- 35 to 993 +/- 59; p = 0.01, respectively) and a downward shift of LV function curves from those obtained from control hearts. Compared to untreated burns, hearts from burned animals treated with LR alone showed no significant improvement in cardiac function. However hearts from burned animals treated with HSD + 1 mL LR/kg/% burn had significantly higher LVP (79 +/- 4 vs. 68 +/- 4 mmHg, p = 0.01) and +/- dP/dt max (+dP/dt: 1387 +/- 60 vs. 1261 +/- 90 mmHg/sc, p = 0.01; -dP/dt: 1079 +/- 50 vs. 993 +/- 59 mmHg/sc, p = 0.01) than hearts from untreated burned animals and generated left ventricular function curves comparable to those calculated for hearts from control animals. Mortality 24 hours after burn was 29% for untreated burns was 0% for control animals, as well as for groups treated with the Parkland formula or HSD plus 1 or 2 mL/kg/% burn lactated Ringer's. The only deaths after treatment occurred in those animals given HSD plus 4 mL/kg/% burn, Parkland formula (17% mortality).(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of lidocaine on myocardial contractility and baroreflex control of heart rate in conscious dogs

The effects of intravenous lidocaine (30 and 60 micrograms X kg-1 X min-1 during 30 min) at steady-state plasma levels (1.9 +/- 0.2 and 3.5 +/- 0.2 micrograms/ml, respectively) were investigated in conscious dogs, previously instrumented for measurements of arterial and left ventricular (LV) pressures, isometric myocardial contractility indexes (LV peak rate of tension development [dP/dt] and LV [dP/dt]/DP40), and heart rate. In addition, before and at the end of lidocaine infusions, arterial baroreflex responses were tested by bolus injections of nitroglycerin and phenylephrine. Whereas LV peak dP/dt and LV (dP/dt)/DP40 were significantly decreased after the low dosage of lidocaine, these indexes returned to control values after the 10th min of infusion of the high dosage. Moreover, eight out of 14 dogs exhibited continuous tremors, tachycardia, hypertension, and increase in contractility after the 10th min of lidocaine infusion (60 micrograms X kg-1 X min-1), although their lidocaine plasma levels (3.7 +/- 0.2 micrograms/ml) did not differ from those of the whole group. When these dogs were pretreated by combined alpha- and beta-adrenoceptor blocking drugs, none of them had tremors, and there was a constant depressant effect on cardiac chronotropism and inotropism. A specific enhancement of baroreflex sensitivity after phenylephrine injection was observed at the high lidocaine dosage. It is concluded that a central stimulation of both components of the autonomic nervous system modulates the direct effects of therapeutic plasma levels of lidocaine on cardiac chronotropism and inotropism in conscious dogs.