Cariporide (HOE-642) improves cardiac allograft preservation in a porcine model of orthotopic heart transplantation

BACKGROUND: Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury. METHODS: A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively. RESULTS: The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001). CONCLUSIONS: Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.     

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.     

A comparative study of experimental models for cardiac preservation through orthotopic transplantation

Various kinds of models for canine heart preservation were evaluated through orthotopic transplantation. Following warm ischemic (WIT) and preservation times (PT), donor hearts were orthotopically transplanted to recipients and observed for 2 hours. The study was divided into four groups. A heart-lung preparation (Group A) was preserved by coronary perfusion with diluted blood for an hour following 15-minute WIT in A-1 (n = 33), and 2 hours following 30-minute WIT in A-2 (n = 19). Following 30-minute WIT, the heart (Group B) was preserved for an hour by coronary perfusion with diluted blood in B-1 (n = 20), a modified Krebs solution in B-2 (n = 14), and a EL-solution in B-2 (n = 14). Following 30-minute WIT, the heart (Group C) was preserved for 2 hours by a Langendorff's model with coronary perfusion using perfluorochemical in C-1 (n = 5) and Hydroxyethyl starch in C-2 (n = 1). In Group D, electromechanical arrest of the heart and coronary vascular washout were performed in D-1 (n = 8) with K+ cardioplegia, D-2 (n = 8) with K+-verapamil cardioplegia, and D-3 (n = 5) with Collins M-verapamil cardioplegia. The heart was then removed and suspended in the same solution. The graft was preserved at 4 degrees C for 6 hours in D-1 and D-2, and 24 hours in D-3. Fourty-eight % in A-1 and 26% in A-2 were successfully transplanted.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heart and liver transplantation. Consistent survival after prolonged donor heart preservation.

Twelve dogs underwent orthotopic cardiac transplantation after donor heart preservation for 24 hr in a hypothermic hypertonic intracellular solution. Donors were divided into two groups: continuous oxygenated perfusion and nonperfusion. After 24 hr, transplantation was performed. All six perfused and four nonperfused donors hearts survived a 24-hr postoperative period. Survivors had normal cardiac output, right and left atrial pressures, and aortic pressures. After transplantation, all perfused hearts demonstrated mild left ventricular damage while nonperfused hearts had severe damage. Hypothermic hypertonic intracellular perfusion may allow improved protection for short-term myocardial preservation and survival after extended myocardial preservation.     

Myocardial energy metabolism in asphyxiated canine hearts preserved for 24 hours.

Myocardial energy metabolism in asphyxiated cadaver hearts preserved in UW solution (UWS; group 1, n = 6) or modified Collins' solution (MCS; group 2, n = 6) was compared with that in cardioplegic arrested hearts immersed in ice-cold MCS with (group 3, n = 6) or without myoprotective drugs (group 4, n = 5). All hearts were stored for 24 hr. The hearts in groups 1 and 2 were pretreated with prostacyclin, verapamil, and propranolol; asphyxiated for 10 min, reversed by coronary perfusion with warm blood cardioplegia (WBCP); perfused with ice-cold crystalloid cardioplegia for 2 hr; excised and immersed in cold storage solution for 22 hr; and perfused again with WBCP before reperfusion. ATP contents were measured in biopsy specimens by HPLC. Myocardial ATP level decreased significantly from 23.7 +/- 1.7 to 15.9 +/- 2.5 mumol/g dry wt. (P less than 0.0001) by asphyxia, but recovered to within normal limits by WBCP in group 1. The ATP level again decreased to 15.8 +/- 2.4 mumol/g dry wt. during 24-hr storage, but finally rose to 22.4 +/- 3.5 mumol/g dry wt. by terminal WBCP. The ATP metabolism in group 2 was similar to that in group 1. The ATP content in group 4 was significantly lower than that in other groups (P less than 0.01) after 24-hr preservation. The study shows that damage to cadaver hearts can be reversed and the hearts maintained satisfactorily viable for 24 hr.     

Lazaroid (U74389G)-supplemented cardioplegia: results of a double-blind, randomized, controlled trial in a porcine model of orthotopic heart transplantation.

BACKGROUND: U74389G (16-desmethyl tirilazad), a 21-aminosteroid or "lazaroid," inhibits lipid peroxidation, which is an important element of ischemia-reperfusion injury. The aim of this study was to determine whether the addition of U74389G to the cardioplegic preservation solution could improve early cardiac allograft function. METHODS: A porcine model of donor brain death and orthotopic cardiac transplantation was used. Hearts were arrested and preserved for 6 hours in an aspartate-enriched extracellular cardioplegia that had been supplemented with either U74389G and its carrier (n = 7) or the carrier alone (n = 9). Epicardial sonomicrometry and transmyocardial micromanometry were used to obtain pressure-volume loops before and after transplantation. Left ventricular wall volume was measured by volume displacement. RESULTS: A higher proportion of U74389G-treated hearts were weaned successfully from cardiopulmonary bypass, but this difference did not achieve statistical significance (86% [6 of 7] vs 56% [5 of 9]; p = 0.308). In the hearts that were weaned successfully, preservation of left ventricular contractility, as judged by the pre-load recruitable stroke work relationship, was significantly better in the U74389G-treated hearts (p = 0.0271). In contrast, left ventricular compliance, as judged by the end-diastolic pressure-volume relationship, was significantly better preserved in the control group (p < 0.0001). U74389G-treated hearts developed less myocardial edema, as judged by the post-transplant left ventricular wall volume/baseline steady-state epicardial end-diastolic volume ratio (64 +/- 9% vs 76 +/- 11%; p = 0.045). CONCLUSIONS: The benefit obtained from U74389G-supplemented cardioplegic preservation solution was marginal for hearts stored for 6 hours. After longer ischemic times, the benefit may be clearer.     

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, an 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 micrograms/kg + 25 micrograms/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 orthotopically transplanted after a mean myocardial ischemic time of 4 hours. RESULTS: All 12 recipients 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.     

The effect of graft perfusion with warm blood cardioplegia for cadaver heart transplantation

This study was designed to verify the effect of reperfusion of donor hearts in a perfusion apparatus after 60 min of global ischemia prior to heart transplantation. Thirteen dogs were exsanguinated from the femoral artery and cardiac arrest was achieved. The hearts were left in situ at room temperature (25°C)for 60 min. In group A (n=7), the hearts were excised and reperfused 60 min after cardiac arrest in the perfusion apparatus with substrate-enriched warm blood cardioplegia (WBCP) containing a hydroxyl radical scavenger, EPC, followed by 45 min of blood perfusion, Next, the hearts were preserved in cold (4°C) University of Wisconsin (UW) solution. In group B (n=6), the hearts were perfused with cold (4°C) St. Thomas' solution 60 min after cardiac arrest and preserved in cold UW solution. Thereafter, all hearts in both groups were transplanted orthotopically to recipient dogs. In group A, 6 of 7 dogs were weaned from cardiopulmonary bypass (CPB). In group B, only 2 of 6 dogs were weaned from CPB. Moreover, 3 of the 6 hearts in group B did not start beating after transplantation (stone heart). This study suggested reperfusion of the donor heart in the perfusion apparatus with WBCP to be a beneficial preconditioning method when utilizing 60-min arrested hearts for transplantation. This study was supported in part by Senju Pharmaceutical Co. Ltd., Osaka, Japan     

A comparative study of Celsior and University of Wisconsin solutions based on 12-hr preservation followed by transplantation in canine models

BACKGROUND: Celsior is a recently developed extracellular-type preservation solution that is effective in organ preservation. This experimental study was designed to compare the effects of Celsior and University of Wisconsin (UW) solutions in myocardial protection, using 12-hour preservation followed by orthotopic transplantation. METHODS: Fourteen pairs of adult mongrel dogs were divided into 2 groups. In the UW group (n = 7), UW solution at 4 degrees C was used for coronary vascular washout and storage following cardiac arrest with glucose-insulin-potassium (GIK) solution. In the Celsior group (n = 7), Celsior solution was used to produce cardiac arrest, for coronary vascular washout, and for storage. After 12-hour cold preservation, orthotopic transplantation was performed under cardiopulmonary bypass (CPB). The rate of recovery (%) of cardiac function of donor hearts was compared 1 and 2 hours after weaning from CPB, and then the transplanted hearts were harvested for histological study. RESULTS: Hemodynamic parameters including cardiac output, left ventricular pressure (LVP), and the maximum rates of positive and negative increase of LVP after transplantation were significantly (p < 0.05) higher in the Celsior group than in the UW group 2 hours after weaning from CPB. The transmission electron microscopic study found that degeneration of the mitochondria in the Celsior group was less extensive than in the UW group. CONCLUSION: Celsior solution enhanced the cardiac function of hearts preserved for 12 hours prior to transplantation compared to UW solution. Our results indicate that Celsior solution is equivalent or superior to UW solution for cardiac preservation.     

Myocardial viability twenty-four hours after orthotopic heart transplantation from non-heart-beating donors

OBJECTIVES: Using a new preservation strategy, we investigated the performance of hearts from non-heart-beating donors during an observation period of 24 hours after orthotopic heart transplantation in a pig model. METHODS: In the control group (n = 6) beating donor hearts were harvested with Bretschneider's HTK solution and transplanted orthotopically without reperfusion modifications. In the non-heart-beating donor group (n = 6) hearts were perfused with leukocyte-depleted blood cardioplegia after 30 minutes of normothermic ischemia. Blood cardioplegia was supplemented with a sodium-hydrogen exchange inhibitor and adenosine. After transplantation, a second controlled reperfusion with blood cardioplegia was performed. RESULTS: Preload recruitable stroke work of the left ventricle 24 hours after transplantation in the control versus non-heart-beating donor group was 108% +/- 24% versus 103% +/- 18% of baseline values. Myocardial blood flow of the left and right ventricle was increased to 146% +/- 32% and 176% +/- 51% in the control group versus 176% +/- 29% and 194% +/- 27% in the non-heart-beating donor group. Myocardial oxygen consumption was 11.2 +/- 2.1 versus 12.8 +/- 2.2 mL/100 g per minute at baseline and 11.6 +/- 2.6 versus 13.2 +/- 3.1 mL/100 g per minute after 24 hours (not significant). Histologic examination with Luxol fast blue staining revealed that 2.6% +/- 4.8% of myocytes in the control group versus 1.8% +/- 1.9% in the non-heart-beating donor group were damaged irreversibly. CONCLUSIONS: Recovery of donor hearts from non-heart-beating donors is comparable with recovery of organs harvested from heart-beating donors if the above-mentioned preservation technique is used. These results could encourage the use of marginal donor hearts and help to expand the limited donor pool.     

Prolonged preservation of the blood-perfused canine heart with glycolysis-promoting solution.

BACKGROUND: Prolonged ischemia and inadequate myocardial preservation remain significant perioperative risk factors in cardiac transplantation. Long-term preservation techniques that have been effective in small rodent hearts have not been as effective in larger animal models or in clinical studies. We developed a cardioplegia solution formulated to promote high-energy phosphate production from glycolysis and determined its efficacy in a blood perfused canine heart model subjected to 24 hours of ischemia. METHODS: Hearts harvested from adult dogs (n = 6 per group) were flushed with a histidine-buffered cardioplegia solution containing glucose or University of Wisconsin solution. The hearts were maintained at 4 degrees C for 24 hours then reperfused with autologous blood. After reperfusion, left ventricular pressures were measured with an intracavitary balloon at varying balloon volumes and compared with control nonischemic hearts. Predicted stroke volume and ejection fraction were calculated at an end-systolic pressure of 70 mm Hg and end-diastolic pressure of 15 mm Hg. RESULTS: Developed pressure was better preserved in the hearts that received histidine-buffered solution (93+/-9 versus 38+/-7 mm Hg, p<0.05), along with a higher end-diastolic volume at 15 mm Hg (31+/-3 versus 22+/-2 mL histidine-buffered versus University of Wisconsin solutions, respectively, p<0.05). Stroke volume and ejection fraction were also higher in the histidine group (17+/-2.5 versus 2.3+/-1.2 mL and 50%+/-3.5% versus 9% +/-4.5%, respectively) in the presence of dobutamine. CONCLUSIONS: The highly buffered glycolysis-promoting cardioplegia solution provided effective preservation of the blood perfused canine heart with superior recovery of pump performance after 24 hours of hypothermic ischemia compared with University of Wisconsin solution in this model.     

Safe orthotopic transplantation of hearts harvested 24 hours after brain death and preserved for 24 hours

Objectives. The aim of this study was to demonstrate safe orthotopic transplantation of porcine donor hearts harvested 24?hours after brain death and preserved for 24?hours before transplantation. Design. Circulatory normalization of brain dead (decapitated) pigs was obtained using a new pharmacological regimen (n?=?10). The donor hearts were perfused at 8?°C in cycles of 15?min perfusion followed by 60?min without perfusion. The perfusate consisted of an albumin-containing hyperoncotic cardioplegic nutrition solution with hormones and erythrocytes. Orthotopic transplantation was done in 10 recipient pigs after 24?hours’ preservation. Transplanted pigs were monitored for 24?hours, then an adrenaline stress test was done. Results. All transplanted pigs were stable throughout the 24-hour observation period with mean aortic pressure around 80?mmHg and normal urine production. Mean right and left atrial pressures were in the range of 3–6 and 5–10?mmHg, respectively. Blood gases at 24?hours did not differ from baseline values. The adrenaline test showed a dose dependent response, with aortic pressure increasing from 98/70 to 220/150?mmHg and heart rate from 110 to 185 beats/min. Conclusion. Orthotopic transplantation of porcine hearts harvested 24?hours after brain death and preserved for 24?hours can be done safely.     

Experimental heart transplantation in dogs--preservation of isolated hearts for 36 hours by retrograde coronary sinus microperfusion

In this study, the method of preserving isolated canine hearts for transplantation was established. The newly-developed method is named retrograde coronary sinus microperfusion technique. Canine hearts were arrested and cooled to 4 degrees C by means of normograde coronary perfusion with Collins' solution containing 10% fluorocarbon (FC) in order to avoid myocardial damage during warm ischemic time. Then, the hearts, immersed in Collins' solution, were retrogradely perfused through a coronary sinus at a rate of 60 ml/hr or 30 ml/hr with above-mentioned solution. After preservation for 36 hours, heterotopic heart transplantation was performed in an abdominal cavity of a recipient dog. The 36 hour-preserved hearts restored their cardiac beat after reperfusion with recipient blood. Histological observation did not show any abnormal findings in these preserved hearts. In order to evaluate the cardiac functions of preserved hearts for 24 to 36 hours, left ventricular end-systolic pressure-volume ratio (Emax) and end-diastolic pressure-volume relation were measured. Both were well restored in 24 hour-preserved hearts. The 36 hour-preserved hearts resulted in Emax within a satisfactory range, while end-diastolic pressure was elevated in all cases. This was markedly impaired with infusion of isoproterenol. These results strongly suggested that transplantation using 24 hour-preserved hearts could be performed well. On the other hand, the 36 hour-preserved hearts were considered to function satisfactorily under careful management after grafting. The retrograde coronary sinus microperfusion method developed here was found to be useful for a distant heart procurement.     

Energy state of the myocardium during long-term cold storage and subsequent reperfusion

Long-term preservation of dog hearts was performed over 24 h using Bretschneider-HTK cardioplegia and cold storage. Preservation was assessed in terms of conservation of myocardial tissue levels of high-energy phosphates (HEP) and functional outcome after cardiac transplantation. Serial left ventricular biopsies were taken and analysed for ATP, ADP, AMP, adenosine, inosine, hypoxanthine, xanthine and creatine phosphate. Myocardial structure was studied by electron microscopical examination of a similar biopsy specimen. Cardiac performance was measured before and after cardiac transplantation. Several techniques of cardioplegic arrest were studied: single dose cardioplegia, multidose cardioplegia and continuous perfusion with the cardioplegic solution. In all groups, the hearts were stored at 0.5 degree C for 24 h. In the group of single dose Bretschneider-HTK cardioplegia, myocardial ATP content after 24 h of cold storage was only 25% of control. The total sum of nucleotides at that time interval was however 65% of the control value. Reperfusion of these hearts using a support dog (whole blood reperfusion) did not result in any recovery of ATP. Creatinine phosphate however showed an overshoot. Accumulated nucleosides were washed out. The hearts showed electrical activity but were severely arrhythmic. Contractility was poor. In the group of multidose Bretschneider-HTK cardioplegia, HEP preservation was better than after single dose cardioplegia. ATP content was about 50% of control. The total sum of nucleotides was 85% of control. Ultrastructural assessment of the myocytes revealed only slight ischaemic damage to the mitochondria. Reperfusion on cardiopulmonary bypass after cardiac transplantation did not show any restoration of ATP, but a steady catabolism of HEP. The nucleosides adenosine and inosine were not washed out upon reperfusion. After cardiac transplantation, none of these hearts could be weaned from cardiopulmonary bypass due to irreversible low cardiac output. Histological examination demonstrated irreversible myocardial tissue damage. In the group of continuous cold Bretschneider cardioplegia, HEP content was completely preserved throughout the 24 h of perfusion. Ultrastructure of the myocytes was normal. Reperfusion of the transplanted hearts showed a mild breakdown of ATP to 70% of control values accompanied by a slight accumulation of nucleosides. Haemodynamic recovery however was perfect and none of the hearts needed positive inotropic support. Myocytes after reperfusion had a normal subcellular appearance.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

A simple and reliable method to assess heart viability after hypothermic procurement

Hearts from brain dead pigs (n = 18) were submitted to 0 (group I), 10 (group II), or 20 (group III) minutes of in situ warm ischemia (animal exsanguination). After harvesting, cold cardioplegia solution was perfused in retrograde fashion and initial coronary flow (ICF) measured. After left ventricular energetic indices were measured using NMR spectroscopy, the hearts were transplanted orthotopically. Follow-up was performed over 120 minutes after cardiopulmonary bypass. We observed a progressive decrease in ICF with increased warm ischemia times: 50 +/- 3.4 mL/min per 100 g of tissue in the group I, 36 +/- 7 and 30 +/- 3.5 in groups II and III, respectively (P < .05 and P < .01 versus group I). The ICF strongly correlated with the energetic index (r = 0.76, P < .001) and with posttransplant function of the transplanted heart. These data showed that measurement of initial coronary flow after cardioplegia was a reliable test to evaluate cardiac graft viability before transplantation.     

Morphology of canine hearts after 24 hours' preservation and orthotopic transplantation.

Ten dogs underwent orthotopic cardiac transplantation after preservation of the donor heart for 24 hours in an oxygenated hypothermic, hypertonic, intracellular solution, either with (five dogs) or without (five dogs) continuous, oxygenated, low-pressure perfusion. Eight dogs survived for 24 hours after transplantation, at which time they were put to death. The two nonsurvivors were among the five with nonperfused hearts. Examination of all 10 donor hearts showed differences between the two groups: Four of five nonperfused hearts showed severe transmural myocardial coagulation necrosis but only small foci of contraction band necrosis (myofibrillar degeneration). The perfused hearts, however, showed more extensive subendocardial areas of contraction-band necrosis, but only minimal and focal coagulation necrosis, indicating less severe hypoxic damage. These results indicate that oxygenated perfusion with a hypothermic, hypertonic, intracellular solution may permit improved transplant survival after extended cardiac preservation.     

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.     

Effects of supplemental L-arginine during warm blood cardioplegia.

OBJECTIVES: Effects of supplemental L-arginine, nitric oxide precursor, during warm blood cardioplegia were assessed in the blood perfused isolated rat heart. METHODS: The isolated hearts were perfused with blood at 37 degrees C from a support rat. After 20 minutes of aerobic perfusion, the hearts were arrested for 60 minutes with warm blood cardioplegia given at 20-minute intervals. This was followed by 60 minutes of reperfusion. The hearts were divided into the following three groups according to the supplemental drugs added to the cardioplegic solution. The control group (n = 10) received standard warm blood cardioplegia. The L-ARG group (n = 10) received warm blood cardioplegia supplemented with L-arginine (3 mmol/l). The L-NAME group (n = 10) received warm blood cardioplegia supplemented with L-arginine (3 mmol/l) and L-nitro-arginine methyl ester, a competitive inhibitor of nitric oxide synthase (1 mmol/l). After 60 minutes of cardioplegic arrest, cardiac function, myocardial metabolism and myocardial release of circulating adhesion molecules were measured during reperfusion. RESULTS: Left ventricular end-diastolic pressure was significantly lower (p<0.05) in the L-ARG group than in the control group and the L-NAME group during reperfusion. Isovolumic left ventricular developed pressure, dp/dt and coronary blood flow were significantly greater (p< 0.05) in the L-ARG group during reperfusion. The L-ARG group resulted in early recovery of lactate metabolism during reperfusion. Myocardial release of circulating intercellular adhesion molecule-1 (ICAM-1) and E-selectin were significantly less (p<0.05) in the L-ARG group at 15 minutes of reperfusion. CONCLUSIONS: The results suggest that augmented nitric oxide by adding L-arginine to warm blood cardioplegia can preserve left ventricular function and ameliorate endothelial inflammation. The technique can be a novel cardioprotective strategy in patients undergoing cardiac surgery.     

依达拉奉联合供心复跳后不停跳保存技术提高缺氧诱导的无心跳猪供心移植效果

目的 观察依达拉奉联合供心复跳后不停跳保存和移植技术提高缺氧诱导的无心跳猪供心的移植效果.方法 杂种家猪36只,取12只用于供血,用随机数字表法将其余24只分为实验组和对照组,每组供、受者各6对.(1)实验组:供心经缺氧诱导停跳后,继续热缺血25 min,阻断主动脉,用含依达拉奉氧合冷血经主动脉根部灌注.供心被切取后在离体灌注装置上进行氧合温血持续灌注复苏,并于复灌初期5 min时再次使用依达拉奉,心脏在体外持续跳动保存2h.(2)对照组:全程不用依达拉奉,其他操作与实验组完全相同.两组供心保存结束后,进行心脏移植,移植过程中保持供心持续跳动.在停呼吸机前(供心缺氧前)、主动脉开放后60和20 min等时点检测供心血流动力学指标,心肌酶,心肌组织含水量,以及对心肌组织进行电镜观察.结果 两组供者均成功脱离体外循环机.(1)供心缺氧前,两组间血流动力学指标的差异无统计学意义;主动脉开放后60和120min时,实验组显著优于对照组(P＜0.05).(2)主动脉开放后120 min时,两组间各心肌酶水平均较供心缺氧前明显上升,但两组间差异无统计学意义(P＞0.05).(3)对照组心肌组织含水量显著高于实验组(P＜0.05).(4)经电镜观察,对照组心肌细胞Z带欠清晰,线粒体轻度肿胀,部分嵴溶解,内质网肿胀,糖原颗粒减少;实验组心肌细胞线粒体嵴无断裂,内质网清晰可见,未见明显破坏.结论 将热缺血时限控制在25 min内,缺氧诱导的无心跳供者供心可用于移植;供心经离体氧合温血持续灌注,在不停跳下进行保存和移植的方法可行,心肌保护效果满意;依达拉奉可进一步提高缺氧诱导的无心跳供者供心的保护效果.