Glycine application and right heart function in a porcine heart transplantation model

Glycine reduces ischemia-reperfusion injury after experimental liver transplantation. We hypothesized that glycine might also protect right heart function in an isovolumic cardiac transplantation model. In six domestic donor pigs 150 ml of a 300 mmol L-glycine solution were administered intravenously. The hearts were then arrested with histidine-tryptophan-ketoglutarate solution. Animals without prior glycine infusion served as controls (n = 6). After 4 h of ischemia, hearts were transplanted into recipients. An isovolumic model was used in which the right ventricular (RV) volume was controlled in vivo using an intracavitary high-compliance balloon. After 1 and 2 h of reperfusion the RV balloon volume was gradually increased and the developed pressures were recorded (P(developed) = P(systolic) - P(diastolic)). Right ventricular failure was defined as a decrease in developed intracavitary pressure. Glycine hearts could be loaded with a significantly increased volume after 1 h (glycine: 53 +/- 13.7 ml vs. control: 32 +/- 11.7 ml; P = 0.015) and after 2 h (67 +/- 18.6 ml vs. 43 +/- 8.2 ml; P = 0.018). Maximal RV developed pressures were not significantly different between groups. Postischemic RV end-diastolic compliance was significantly higher in glycine-treated animals (P = 0.04). Glycine protects early postischemic RV compliance, but has no important influence on maximal developed pressures.     

Right heart function during prosthetic left ventricular assistance in a porcine model of congestive heart failure.

A left ventricular assist device was used to produce a 90% reduction in peak systolic left ventricular pressure in pigs with congestive heart failure, and the resultant effects on right ventricular function were determined. Initially, eight farm pigs underwent rapid ventricular pacing at 230 beats/min for 7 days to produce congestive heart failure. When compared with an independent series of normal pigs, cardiac output in the paced animals was 33.3% less (2.2 +/- 0.2 versus 3.3 +/- 0.5 L/min; p less than 0.05), left ventricular end-diastolic pressure was elevated (13.8 +/- 3.5 versus 6.6 +/- 1.8 mm Hg; p less than 0.05), and the slope of the right ventricular global stroke work curve was significantly depressed (0.004 +/- 0.001 versus 0.033 +/- 0.003 joules/mm Hg; p less than 0.05). Next, the left ventricular assist device was connected between left ventricular apex and ascending aorta and left ventricular pressure was reduced from 92.0 +/- 3.8 to 10.5 +/- 2.2 mm Hg, while systemic arterial pressure was maintained constant. This led to a further impairment in cardiac output (-14%), mean arterial pressure (-15%), and the slope of the right ventricular global stroke work curve (-50%). Under each condition, right ventricular preload recruitable stroke work and end-systolic pressure-dimension relationships were studied in three different regions on the right ventricle during both steady-state and transient inferior vena caval occlusion. In the right ventricular septal-free wall dimension, left ventricular pressure unloading resulted in a 47.5% +/- 5.4% (p less than 0.05) reduction in the slope and 20.1% +/- 4.8% (p less than 0.05) increase in the dimension intercept of the preload recruitable stroke work relationship. There was also a 44.6% +/- 4.8% (p less than 0.05) reduction in the slope and 15.6% +/- 2.8% (p less than 0.05) increase in the dimension intercept of the end-systolic pressure-dimension relation. These slope changes plus reductions in cardiac output and in global stroke work, which are indicative of impaired right ventricular function during left ventricular pressure unloading in the congestive heart failure pigs, are not seen in normal hearts, whereas the intercept changes associated with leftward septal shift are present in both. These results suggest that anatomic ventricular interactions have a more significant role in heart failure than in the normal heart in determining overall right ventricular function during left ventricular assist device support.     

Autologous porcine heart cell transplantation improved heart function after a myocardial infarction

OBJECTIVE: Fetal cardiomyocyte transplantation improved heart function after cardiac injury. However, cellular allografts were rejected despite cyclosporine (INN: ciclosporin) therapy. We therefore evaluated autologous heart cell transplantation in an adult swine model of a myocardial infarction. METHODS: In 16 adult swine a myocardial infarction was created by occlusion of the distal left anterior descending coronary artery by an intraluminal coil. Four weeks after infarction, technetium 99m-sestamibi single photon emission tomography showed minimal perfusion and viability in the infarcted region. Porcine heart cells were isolated and cultured from the interventricular septum at the time of infarction and grown in vitro for 4 weeks. Through a left thoracotomy, either cells (N = 8) or culture medium (N = 8) was injected into the infarct zone. RESULTS: Four weeks after cell transplantation, technetium 99m-sestamibi single photon emission tomography demonstrated greater wall motion scores in the pigs receiving transplantation than in control animals (P =.01). Pigs receiving transplantation were more likely to have an improvement in perfusion scores (P =.03). Preload recruitable stroke work (P =.009) and end-systolic elastance (P =. 02) were greater in the pigs receiving transplantation than in control animals. Scar areas were not different, but scar thickness was greater (P =.02) in pigs receiving transplantation. Cells labeled with bromodeoxyuridine in vitro could be identified in the infarct zone 4 weeks after transplantation. Swine receiving transplantation gained more weight than control animals (P =.02). CONCLUSION: Autologous porcine heart cell transplantation improved regional perfusion and global ventricular function after a myocardial infarction.     

Lung function at one month of age as a risk factor for infant respiratory symptoms in a high risk population

BACKGROUND: Abnormal premorbid lung function is a risk factor for subsequent wheezing in children with one or no atopic parent. This study was undertaken to establish whether early lung function in high risk infants (both parents atopic) was a risk factor for respiratory symptoms in infancy and to examine the influence of maternal asthma, smoking, and allergen exposure during pregnancy on any association. METHODS: Infants were recruited from the NAC Manchester Asthma and Allergy Study cohort at birth. Partial forced expiratory flow volume technique under sedation was carried out to determine maximal flow at FRC (V'maxFRC). Children were followed prospectively and parents completed a standard respiratory questionnaire at one year of age. RESULTS: Sixty nine term infants (34 boys; 88% mothers non-smokers; no household pets) underwent respiratory function testing. Size adjusted V'maxFRC was significantly lower in infants who had recurrent wheeze during the first year of life (mean 1.3 ml/s/cm, 95% CI 0.99 to 1.60) than in those who did not (mean 2.03 ml/s/cm, 95% CI 1.71 to 2.36; p=0.01). V'maxFRC was also significantly lower in infants who had recurrent cough symptoms. In multivariate regression analysis, when adjusted for age at test, sex, maternal asthma, smoking and maternal mattress Der 1 levels, a lower size adjusted V'maxFRC score remained strongly associated with wheezing (OR 0.37, 95% CI 0.18 to 0.77, p=0.007). Maternal smoking also remained an independent risk factor (OR 29.85, 95% CI 2.46 to 362.5, p=0.008). CONCLUSION: Significantly diminished lung function was present in high risk infants who subsequently wheezed and coughed. This was independent of maternal exposure to mite allergen, asthma, and smoking during pregnancy.     

Improved right heart function after myocardial preservation with 2,3-butanedione 2-monoxime in a porcine model of allogenic heart transplantation.

BACKGROUND: Right heart dysfunction is a major cause for early morbidity and mortality after heart transplantation. Experiments were designed to evaluate the influence of the calcium-desensitizing drug 2,3-butanedione 2-monoxime (BDM) on right heart function in a porcine model of heart transplantation. METHODS: Donor hearts of domestic pigs were arrested with BDM in Krebs solution (n = 7) and with BDM in Bretschneider's histidine-tryptophan-ketoglutarate (HTK) solution (n = 6). There were 2 control groups: University of Wisconsin (UW, n = 6) and HTK (n = 6). An isovolumic model was used in which the right ventricular volume was precisely controlled in vivo with an intracavitary high-compliance balloon. After 4 hours of ischemia, hearts were transplanted into recipients. After 1 and 2 hours of reperfusion, the right ventricular balloon volume was increased in 10-mL increments until right ventricular failure occurred and the developed pressures were recorded. RESULTS: Maximal right ventricular developed pressures were significantly different after 2 hours of reperfusion (UW: 35 +/- 13 mm Hg; HTK: 47 +/- 8 mm Hg; Krebs+BDM: 49 +/- 9 mm Hg; HTK+BDM: 50 +/- 6 mm Hg; P =.04). Hearts subjected to BDM could be loaded with a significantly increased volume after 1 hour and after 2 hours (UW: 57 +/- 10 mL vs HTK: 43 +/- 8 mL vs Krebs+BDM: 70 +/- 10 mL vs HTK+BDM: 67 +/- 15 mL; P =.002). Postischemic right ventricular enddiastolic compliance was significantly increased in groups treated with BDM after 1 hour (P =.02) and after 2 hours (P =.039). CONCLUSIONS: The drug BDM significantly improves right ventricular function in a heart transplantation model. The increase in volume load and developed right ventricular pressure achieved by BDM application would translate into a decreased risk of right ventricular failure after clinical transplantation.     

Synthetic liver function is detectable in transgenic porcine livers perfused with human blood

In addition to immune barriers, molecular incompatibilities between species are predicted to limit pig liver survival in primate xenotransplantation models. Assessment and measurement of synthetic function of genetically modified porcine livers after ex vivo perfusion with human blood have not previously been described. Eight porcine livers from α1,3‐galactosyl transferase knockout and human membrane cofactor (GalTKO.hCD46), six livers from GalTKO.hCD46 and N‐glycolylneuraminic acid knockout (GalTKO.hCD46.Neu5GcKO), and six livers from GalTKO.hCD46 with humanized decay‐accelerating factor (hCD55), endothelial protein C receptor (hEPCR), tissue factor pathway inhibitor (hTFPI), and integrin‐associated protein (hCD47) (GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47) pigs were perfused with human blood under physiologic conditions. Timed blood samples were tested for liver enzymes and for pig‐specific albumin production via Western blot. Porcine albumin levels increased with time in all experiments. By densitometry, GalTKO.hCD46.Neu5GcKO livers had the highest albumin levels, measured both as total produced, and when controlled for perfusion duration, compared to GalTKO.hCD46 (P = .068) and GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47 livers (P = .04). Porcine livers perfused with human blood demonstrated the synthetic ability to produce albumin in all cases. GalTKO.hCD46.Neu5GcKO pig livers demonstrated the most robust albumin production. This suggests that the Neu5GcKO phenotype provides a protective effect on the graft due to decreased human antibody recognition and graft injury.     

Gas exchange function one month after transplantation of lungs topically cooled for 2 hours in the non-heart-beating cadaver after failed resuscitation.

BACKGROUND: If lungs from subjects dying of heart attacks could be used for transplantation, the lung donor shortage could be radically reduced. The aim of this study was to investigate, in an experimental survival model, the results of lung transplantation using lungs from non-heart-beating donors. METHODS: The left lung, topically cooled to 25 degrees C for 2 hours in situ after 5 minutes of circulatory arrest and 26 minutes of unsuccessful cardiopulmonary resuscitation, was transplanted into a syngeneic rat. Five weeks after the transplantation, right pneumonectomy was performed and blood gases measured every 10 minutes for 1 hour. Comparison were made with two control groups, one where fresh donor lungs were transplanted and another where only right pneumonectomy was done. RESULTS: All animals survived and were in good condition at the end of the observation period. There was no statistically significant difference in arterial oxygen or carbon dioxide tension between the groups. The bronchial anastomoses showed normal healing in all cases. CONCLUSION: Lungs from non-heart-beating donors topically cooled in situ to 25 degrees C for 2 hours before being harvested showed excellent gas exchange and bronchial healing 5 weeks after transplantation.     

Congenital heart disease in the first month of life.

During the years 1963--73, 276 children with congenital heart disease were admitted to this hospital during their first month of life. Ventricular septal defect was the most common cardiac anomaly and this lesion, together with transposition of the great arteries, comprised 35% of all cardiovascular malformations. Extracardiac malformations were found in 86 patients. The cumulative survival rate for all patients was 66% in the first month of life and 33% in the first year. Forty-three patients were operated upon, but it is estimated from necropsy reports and available clinical data that another 74 patients, who died without operation, would have been suitable candidates for total corrective surgery.     

The function of transgenic human DAF-expressing porcine livers during hemoperfusion with human blood

Abstract  Extracorporal pig liver perfusion could bridge the deadly problem of acute human liver failure. However, preformed natural antibodies and complement activation (CA) are the predominant mechanisms of hyperacute xenoge-neic rejection. The blockade of both pathways of CA in the xenograft, using transgenic livers expressing human decay accelerating factor on the endothelial surface results in prolonged graft survival and lower release of mediators.     

Morphological assessment of sucrose preservation for porcine heart valves.

Porcine aortic valves stored in various concentrations of sucrose (50-80%) for up to 52 weeks were examined both histologically and by electron microscopy. The valves were compared with porcine aortic valves stored in a nutrient and antibiotic medium for 12 weeks. Overall preservation was better in those porcine valves stored in sucrose solution than in nutrient and antibiotic medium, the best preservation being in 50% sucrose. Despite wide separation of collagen at that concentration seen on electron microscopy (not noted histologically), tissue preservation was good after storage in sucrose solutions at concentrations up to 80%, at which clumping of collagen and distortion of fibroblasts occurred. It is suggested that sucrose solution is acceptable for the long-term preservation of biological valves.     

Celsior solution provides superior post-ischemic right ventricular function as compared with UW solution in a porcine heart transplantation model.

BACKGROUND: Use of the new cardioprotective Celsior solution has been suggested for organ preservation in cardiac transplantation, but selective data for right ventricular function, of special interest in the clinical setting, have not been evaluated. METHODS: Celsior solution was compared with the clinical standard University of Wisconsin solution (UW) in a porcine allogenic heart transplantation model with accurate isovolumic measurement of right ventricular (RV) function. RESULTS: Maximum RV developed pressures were significantly different between Celsior and UW groups (51.1 +/- 9.6 mm Hg vs 42.2 +/- 15.4 mm Hg after 1 hour, respectively, and 55.6 +/- 7.8 mm Hg vs 45.1 +/- 16.2 mm Hg after 2 hours, respectively; p = 0.02, 2-way analysis of variance). CONCLUSIONS: Celsior significantly improves post-ischemic right ventricular function when compared with UW solution in an experimental heart transplantation model.     

Experience with extracorporeal membrane oxygenation in children more than one month old.

Extracorporeal membrane oxygenation (ECMO) has been used at the Royal Children's Hospital, Melbourne, in the treatment of children with life-threatening respiratory or cardiac failure since May 1988. The main indications for its use are, first, the disease is thought to be reversible, second, the child will survive with an acceptable quality of life and, third, the child has an 80% chance of dying without ECMO. Seven of eighteen children receiving ECMO have survived to leave hospital, and all are functionally normal: these results are similar to international results. It would appear that ECMO is a useful therapy for some children with otherwise fatal cardiorespiratory failure.