Haemodilution-induced changes in coagulation and effects of haemostatic components under flow conditions.

BACKGROUND: Blood flow patterns are important modifiers of platelet interactions with plasma coagulation factors. However, it is not feasible to evaluate rheological effects of haemodilution on coagulation using conventional coagulation testing. METHODS: We evaluated thrombus formation with a microchip-based flow-chamber system using whole blood from 12 healthy volunteers (with/without 40% dilution with saline), and 15 cardiac patients [before/after cardiopulmonary bypass (CPB)] in parallel with thromboelastometry. The in vitro additions of von Willebrand factor (vWF, 1.5 U ml(-1)), prothrombin complex concentrate (PCC, 0.3 U ml(-1)), fibrinogen (2 g litre(-1)), or combined PCC (0.3 U ml(-1)) and fibrinogen (1 g litre(-1)) were examined. Recalcified whole-blood samples were perfused over the microchip coated with collagen and tissue thromboplastin at flow rates of 10 and 3 µl min(-1). RESULTS: Dilution of whole blood led to delayed onset of thrombus formation (Ton), and thrombus growth (T80). Changes relative to baseline values were more extensive at 10 µl min(-1) (≥85% prolongation for Ton and T80) than at 3 µl min(-1) (≥40% prolongation for Ton and T80). Adding vWF accelerated thrombus formation only at 10 µl min(-1), while PCC increased thrombin generation in the thrombus at both flow rates. Fibrinogen increased mural thrombus formation at 3 µl min(-1). Decreased clot strength after dilution was restored by fibrinogen, but not by vWF or PCC on thromboelastometry. Additive effects of fibrinogen and PCC in post-CPB blood were demonstrated by both flow chamber and thromboelastometry. CONCLUSIONS: Blood flow affects thrombus formation after haemodilution and subsequent haemostatic component interventions, with differential effects at low and high flow.

Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism.

BACKGROUND: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. METHODS: Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. RESULTS: No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 x upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (> or = 1.5 x ULN), 32 (84%) were either TA7 homozygotes (n=18) or TA7 heterozygotes (n=14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3-32.2) compared with other genotypes. CONCLUSIONS: The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.

[HIV infection and associated factors of male sex workers among men who have sex with men].

Objective: This study aimed to discover the HIV infection and associated factors among male sex workers (MSW) who provide sexual services for men. Data from this study thus can be used to provide evidence for designing related intervention programs. Methods: In this observational study, MSW were recruited from May to July, 2019 in KTV venues in Wuxi, China. A questionnaire was used to collect information with blood sample collected and tested for HIV and syphilis. EpiData 3.0 and SPSS 17.0 software were used to clean up data and statistical analysis. Results: A number of 500 MSW were involved including 243 (48.6%) heterosexual and 257 (51.4%) homosexual MSW. The overall HIV prevalence was 5.4%(27/500) among all the MSW. there were significant differences between the HIV prevalence rates, the heterosexual MSW (3.3%, 8/243) and the homosexual MSW (7.4%, 19/257)(χ(2)=4.112, P=0.043). In the past 3 months, 28.0% (72/257) of the homosexual MSW mainly engaged in receptive anal sex which was higher than 11.5%(28/243) of the heterosexual MSW. Compared to 15.6% (40/257) of the homosexual MSW who engaged in heterosexual behavior, a higher proportion of 98.4% (239/243) was noticed among the heterosexual MSW. Higher percentage (44.9%, 109/243) appeared among the heterosexual MSW who had not been tested for HIV than the homosexual MSW (20.6%, 53/257). Results from logistic regression multivariate analysis showed that age ≥30 (aOR=7.54, 95%CI: 2.53-37.11), having unprotected anal sexual practice (aOR=3.76, 95%CI:1.15-12.23), having anal sex after drinking alcohol (aOR=10.91, 95%CI: 2.29-51.87) and syphilis tested positive (aOR=8.23, 95%CI:1.29-52.51) were risk factors associated with HIV infection among the heterosexual MSW. Having unprotected anal sexual behavior (aOR=2.94, 95%CI: 1.17-7.37), having group anal sex (aOR=4.08, 95%CI:1.05-15.81), without record on HIV testing (aOR=6.58, 95%CI: 2.01-18.06) and syphilis tested positive (aOR=4.55, 95%CI: 1.15-18.06) were risk factors associated with HIV among the homosexual MSW. Conclusions: High HIV prevalence was discovered among both heterosexual and homosexual MSW in Wuxi, China. Differences in sexual behaviors between these two groups should be considered when designing targeted HIV intervention programs for these populations.

The ecology and biodemography of Caenorhabditis elegans.

The nematode Caenorhabditis elegans is a well-known model organism for research on aging and life span, but very little is known about its ecology and natural history. The strain N2 is the standard wild-type C. elegans and arose from the progeny of a single hermaphrodite. Since N2 has passed through laboratory culture, the influence of inadvertent selection and genetic drift on C. elegans strains kept in culture is unclear. Because it seems that other wild-type strains have also been subject to lengthy laboratory culture, the life span and biodemography of wild-caught C. elegans is of interest. We recovered C. elegans from snails (Helix aspersa) in ca. 50% of the California locations where we made collections. In experiments with one of the wild-caught isolates, it differed in important demographic properties, mortality, fertility, fitness, and activity patterns, from the standard N2 strain, when both strains were evaluated in a common laboratory environment. The differences were not only statistically significant; they were also large enough to be biologically important. The differences are consistent with the hypothesis that N2 has adapted to laboratory conditions.

Influence of Lysobacter enzymogenes Strain C3 on Nematodes.

Chitinolytic microflora may contribute to biological control of plant-parasitic nematodes by causing decreased egg viability through degradation of egg shells. Here, the influence of Lysobacter enzymogenes strain C3 on Caenorhabditis elegans, Heterodera schachtii, Meloidogyne javanica, Pratylenchus penetrans, and Aphelenchoides fragariae is described. Exposure of C. elegans to L. enzymogenes strain C3 on agar resulted in almost complete elimination of egg production and death of 94% of hatched juveniles after 2 d. Hatch of H. schachtii eggs was about 50% on a lawn of L. enzymogenes strain C3 on agar as compared to 80% on a lawn of E. coli. Juveniles that hatched on a lawn of L. enzymogenes strain C3 on agar died due to disintegration of the cuticle and body contents. Meloidogyne javanica juveniles died after 4 d exposure to a 7-d-old chitin broth culture of L. enzymogenes strain C3. Immersion of A. fragariae, M. javanica, and P. penetrans juveniles and adults in a nutrient broth culture of L. enzymogenes strain C3 led to rapid death and disintegration of the nematodes. Upon exposure to L. enzymogenes strain C3 cultures in nutrient broth, H. schachtii juveniles were rapidly immobilized and then lysed after three days. The death and disintegration of the tested nematodes suggests that toxins and enzymes produced by this strain are active against a range of nematode species.

Revising the standard wisdom of C. elegans natural history: ecology of longevity.

Here, we consider that most of the research concerning Caenorhabditis elegans has been laboratory focused and that only limited research has directly considered the worm's biology relative to its natural history in the wild. We describe that, although the worm has traditionally been considered a soil nematode, we could not find it in soil but frequently recovered it from snails. Finally, we discuss how a better understanding of the natural history of C. elegans may enhance its usefulness as a model organism for studying aging and other phenomena.

Right ventricular failure--insights provided by a new model of chronic pulmonary hypertension.

This study was designed to examine the effects of both nitric oxide and milrinone on pulmonary hemodynamics and right ventricular function using a newly established model of monocrotaline pyrrole-induced chronic pulmonary hypertension. Sixteen mongrel dogs (23-25 kg) were used. All animals underwent percutanous pulmonary artery catheterization to measure right heart hemodynamics prior to and 8 weeks after a right atrial injection of either monocrotaline pyrrole (MCTP, n=8) or placebo (CTL, n=8). Eight weeks postinjection, all hearts were instrumented with a pulmonary artery flow probe and intracavitary micromanometers. Data were collected at baseline as well as following both nitric oxide and milrinone administration. There was no significant difference in the baseline hemodynamic measurements between the two groups. Eight weeks postinjection, significant increases in the pulmonary artery pressure and pulmonary vascular resistance were observed in MCTP compared with CTL. Both nitric oxide and milrinone resulted in significant improvements in pulmonary vascular resistance, pulmonary blood flow, and right ventricular contractility. In addition, nitric oxide caused a significant improvement in pulmonary artery pressure and transpulmonary efficiency, while milrinone led to a significant increase in right ventricular hydraulic power. This study demonstrates the well-known clinical effects of nitric oxide and milrinone in improving pulmonary hypertension, which were also associated with an increase in pulmonary blood flow, transpulmonary efficiency, and right ventricular hydraulic power in the setting of monocrotaline pyrrole-induced chronic pulmonary hypertension.

The effect of combined daunorubicin and triamcinolone acetonide treatment on a refined experimental model of proliferative vitreoretinopathy.

Prior studies have shown that intravitreal daunorubicin (9-15 nmol) and triamcinolone acetonide (2 mg) are effective individually in preventing retinal detachment in experimental proliferative vitreoretinopathy. This report compares the efficacy of the combination of daunorubicin (15 nmol) and triamcinolone acetonide (2 mg) with that of daunorubicin alone in a refined experimental model of proliferative vitreoretinopathy. The degree of retinal detachment in each treatment group was graded, with the unequivocal absence or presence of retinal detachment used as an indicator of treatment success or failure. Both treatments (daunorubicin alone and in combination with triamcinolone acetonide) effectively prevented retinal detachment. However, there was no significant difference in the rate of retinal detachment between the two treatment groups. These results indicate that combination therapy with daunorubicin/triamcinolone is no more effective at preventing retinal detachment than daunorubicin alone.

Aclacinomycin A in the treatment of experimental proliferative vitreoretinopathy. Efficacy and toxicity in the rabbit eye.

PURPOSE: Aclacinomycin A is an oligosaccharide anthracycline that, by contrast with daunomycin, lacks carcinogenicity. The authors evaluated the efficacy of aclacinomycin A in prevention of experimental proliferative vitreoretinopathy (PVR) and its toxicity on the rabbit retina. METHODS: Dutch-belted rabbit were used to create a model for traction retinal detachment. Seven to 10 days after vitreous gas compression, 25,000 homologous fibroblasts were injected into the vitreous cavity. Subsequently, the eyes received either sham injections or doses of 6, 30, or 60 nmol of aclacinomycin A, respectively. The fundus findings were documented on days 7, 14, and 28 after the fibroblast injection. The toxicity studies were conducted according to the same protocol as was used for the efficacy evaluation but without the fibroblast injection. Simultaneous electroretinograms were recorded on days 0, 3, 7, and 14 from the right eyes that were injected with 30 or 60 nmol of aclacinomycin A and the left eyes that were sham injected. Morphologic studies were conducted on the eyes enucleated on days 3, 7, and 14 after drug exposure. RESULTS: Intraocular administration of 30 nmol of aclacinomycin A on day 2 after fibroblast injection resulted in a detachment rate of 37.5% (controls, 100%; P < 0.01, by Fisher's exact test). Administration of 60 nmol of aclacinomycin A 3 days after fibroblast injection resulted in a detachment rate of 26.7% (controls, 100%; P < 0.0001). Six nanomoles of aclacinomycin A 3 days after fibroblast injection had no effect. No electroretinogram changes were present in eyes treated with 30 nmol of aclacinomycin A. Such recordings from eyes exposed to 60 nmol of aclacinomycin A demonstrated decreased a- and b-waves on day 3; these completely recovered by day 7. Morphologic studies of these eyes revealed no damage to the retina. CONCLUSIONS: These results suggest that aclacinomycin A should be considered an alternative to daunomycin for treatment of human PVR because, in addition to its lack of carcinogenicity, it shows good efficacy and causes less retinal toxicity.

The effects of brain death on cardiopulmonary hemodynamics and pulmonary blood flow characteristics.

Deterioration of donor lung function contributes to the shortage of donor organs and early postoperative failure after transplantation. A decrease in donor pulmonary function is associated with opacification of lung fields on radiographs, rendering the lungs unsuitable for transplantation, which may be related to the effects of brain death (BD) on pulmonary hemodynamics. Twenty mongrel canines (25.5 +/- 0.7 kg) underwent 20 BD experiments using a previously validated BD organ donor model. An ultrasonic flowmeter was applied on the pulmonary artery and micromanometers were inserted into the right ventricle, pulmonary artery, and left atrium to measure, which allowed the hemodynamic assessment and impedance profile analysis of the pulmonary vasculature by Fourier transformation. Characteristic impedance (Zo) was compared with input resistance (RIN) and with calculated pulmonary vascular resistance (PVR), the conventional index. Right ventricular hydraulic power was analyzed and divided in its components oscillatory and steady power. The results are expressed as means and SEM (analysis of variance, paired two-tailed t tests). Cushing reflex, hemodynamic response, and diabetes insipidus were consistent findings following BD. PVR, Zo, and RIN decreased significantly (p < 0.05) from 367 +/- 40 dyne.s.cm-5, 226 +/- 13 dyne.s.cm-5, and 771 +/- 52 dyne.s.cm-5 to 261 +/- 25 dyne.s.cm-5, 159 +/- 10 dyne.s.cm-5, and 651 +/- 69 dyne.s.cm-5 6 h after BD. Pulmonary artery blood flow increased significantly from 1,499 +/- 107 mL/min to 2,064 +/- 209 mL/min (p < 0.05) after BD. Hydraulic power increased from 69 +/- 6 mW to 104 +/- 13 mW (p < 0.05) and the oscillatory power to steady power ratio of 33%/67% changed to 23%/77% following BD. Extravascular pulmonary water content increased significantly by 10% after BD. BD causes a significant change in pulmonary vascular hemodynamics. The decrease in impedance and right ventricular afterload may lead to significant pulmonary overflow injury and edema. The increase in steady power represents an important reserve of the right ventricle to sustain pulmonary blood flow following BD.

Nitric oxide improves pulmonary vascular impedance, transpulmonary efficiency, and left ventricular filling in chronic pulmonary hypertension.

OBJECTIVE: Chronic pulmonary hypertension is difficult to treat and despite the introduction of several therapeutic options, no single therapy is universally recommended. Nitric oxide has had some role clinically in improving pulmonary hemodynamics in this setting; however, basic investigation has not been performed in an appropriate large animal model of stable pulmonary hypertension. This study was designed to examine the effects of inhaled nitric oxide on pulmonary hemodynamics in the setting of a canine model of monocrotaline pyrrole-induced chronic pulmonary hypertension and used Fourier analysis for assessment of pulmonary vascular impedance. METHODS: Sixteen mongrel dogs (22 to 25 kg) were used. Animals underwent percutaneous pulmonary artery catheterization to measure-right-sided hemodynamics before and 6 weeks after a right atrial injection of either monocrotaline pyrrole (n = 8) or placebo (n = 8). Six weeks after the injection all hearts were instrumented with an ultrasonic flow probe, sonomicrometric dimension transducers, and micromanometers. Data were collected at baseline and after nitric oxide administration. Harmonic derivation of functional data was achieved with Fourier analysis. RESULTS: Six weeks after the injection, significant increases in pulmonary artery pressure and pulmonary vascular resistance were observed in the monocrotaline pyrrole group. Nitric oxide led to significant decreases in pulmonary vascular impedance. Significant improvements in pulmonary blood flow, transpulmonary efficiency, and left ventricular filling were also observed. CONCLUSIONS: This investigation demonstrates the well-known clinical effects of nitric oxide in improving pulmonary hypertension, which were also associated with an increase in pulmonary blood flow, transpulmonary efficiency, and left ventricular filling in the setting of monocrotaline pyrrole-induced pulmonary hypertension.

Pulmonary vascular impedance and recipient chronic pulmonary hypertension following cardiac transplantation.

STUDY OBJECTIVES: Recipient chronic pulmonary hypertension (CPH), secondary to long-standing congestive heart failure, represents a significant risk factor for right ventricular (RV) dysfunction following orthotopic cardiac transplantation (TX). This study was designed to characterize the changes occurring in pulmonary hemodynamics, pre-TX and post-TX, using Fourier analysis, a canine model of bicaval TX, and monocrotaline pyrrole (MCTP)-induced recipient CPH. DESIGN: Prospective, controlled study. SETTING: Experimental laboratory. PARTICIPANTS: Twenty adult male mongrel dogs (23 to 26 kg). INTERVENTIONS: Recipients underwent pulmonary artery injection of 3 mg/kg MCTP 4 months pre-TX. On the day of TX, donor hearts were instrumented with an ultrasonic flow probe and micromanometers. Harmonic derivation of functional data was achieved with Fourier analysis. MEASUREMENTS AND RESULTS: At the time of TX, significant increases were observed in the mean pulmonary artery pressure and pulmonary vascular resistance of recipient animals in comparison to donors, which were further significantly increased following the termination of cardiopulmonary bypass. Significant increases were also observed in the input resistance, characteristic impedance, and RV hydraulic power post-TX compared to pre-TX, and occurred in association with a significant decrease in the transpulmonary efficiency. CONCLUSIONS: In the setting of MCTP-induced recipient CPH donor hearts were exposed to significant alterations in cardiopulmonary hemodynamics following bicaval TX. Pulmonary blood flow is maintained by a significantly higher energy expenditure by the RV, but at a lower level of efficiency. This experimental model may provide a useful means by which to evaluate therapeutic options to better manage cardiopulmonary hemodynamics in order to prevent RV failure following TX in the setting of recipient CPH.

Physiologic effects of extracellular superoxide dismutase transgene overexpression on myocardial function after ischemia and reperfusion injury.

OBJECTIVE: Myocardial injury after ischemia and reperfusion may be mediated, in part, by oxygen-derived free radicals. In this study the protective effects of extracellular superoxide dismutase overexpression were directly assessed in the hearts of transgenic mice, after ischemia and reperfusion injury, using an isolated work-performing murine heart preparation and computerized analysis of functional data. METHODS: A blinded study was performed to compare cardiac function in the hearts of both transgenic mice with a 3.5-fold overexpression of myocardial extracellular superoxide dismutase (n = 6, 22 to 26 gm) and littermate controls (n = 8, 22 to 26 gm). Preload-dependent cardiac output, contractility, heart rate, stroke work, and stroke volume were evaluated in the two groups before and after a 6-minute period of normothermic ischemia. RESULTS: No differences were found between extracellular superoxide dismutase hearts and control hearts in any parameter of myocardial function before ischemia. After ischemia, decreases in cardiac output occurred in both groups; however, this decrease was larger in control mice compared with extracellular superoxide dismutase mice. A higher percentage of recovery was also observed in the contractility, heart rate, stroke work, and stroke volume of extracellular superoxide dismutase hearts compared with control hearts. CONCLUSION: After global normothermic ischemia and subsequent reperfusion, decreases in cardiac function occurred in both extracellular superoxide dismutase and control mice; however, a higher percentage of recovery was observed in the extracellular superoxide dismutase overexpressed hearts. These data suggest that extracellular superoxide dismutase transgene overexpression significantly improves preservation of myocardial function after ischemia and reperfusion injury.

Brain death alters cardiopulmonary hemodynamics and impairs right ventricular power reserve against an elevation of pulmonary vascular resistance.

Right ventricular (RV) failure, which is a leading cause of early morbidity and mortality following cardiac transplantation, is attributed to the inability of the donor RV to acutely compensate for the recipient's elevated pulmonary vascular resistance (PVR). Furthermore, the effect of donor brain death (BD) on RV function is unclear. The purpose of this study was to investigate the effects of donor BD on RV function in the setting of elevated PVR. The interactions of the RV and its afterload, the pulmonary vasculature, and left atrial pressure were assessed by measurements of pulmonary vascular energetics and their oscillatory nature using proximal ultrasonic pulmonary artery (PA) flow probe and micromanometers in the proximal and distal PA in 20 mongrel dogs (25.8 +/- 0.4 kg, five control animals). A band was placed around the distal PA (PA-systolic gradient > 15 mm Hg). BD was induced by rising intracranial pressure and was validated neuropathologically. Data were collected at 0, 2, 4, and 6 h after BD in both banded and control animals. Fourier analysis was used to calculate RV oscillatory power, mean power, and total power (TP). Comparison of changes due to banding were made to baseline measurements using multivariate analysis and paired Student's t test (p < 0.05). A significant twofold to fourfold increase in pulmonary impedance and PVR occurred with an acute rise in PA gradient. Control animals tolerated acute increases in PVR without significant changes in TP. There was a significant increase of RV TP from 73 (+/-11) to 98 (+/-10) mW at baseline after the acute rise in PVR and impedance. After BD, the response to increased PVR and impedance was abolished significantly compared with baseline and control animals, suggesting a significant loss of compensatory TP to sustain pulmonary vascular blood flow. The data indicate that BD is detrimental to RV mechanical function.

Total respiratory support from swine lungs in primate recipients.

UNLABELLED: The use of nonhuman lung donors, such as swine, has the potential to provide an unlimited supply of organs. However, hyperacute rejection has prevented pulmonary xenotransplantation. OBJECTIVE: Our aim was to test the hypothesis that immunodepletion by pretransplantation swine lung perfusion will prevent hyperacute swine-to-primate pulmonary xenograft rejection and allow for a functional swine pulmonary xenograft. METHODS: Seven baboons underwent left pneumonectomy followed by orthotopic transplantation of the swine left lung. Four baboons received immunodepletion by perfusion with swine lungs before transplantation, and three received no treatment before transplantation. RESULTS: After transplantation, pulmonary xenografts from immunodepleted baboons had a low pulmonary vascular resistance and a high pulmonary blood flow compared with control animals, which had a high pulmonary vascular resistance and a low pulmonary blood flow. After 60 minutes of reperfusion, three of four immunodepleted animals also tolerated complete occlusion of the right pulmonary artery, with the baboon relying completely on the swine pulmonary xenograft for respiratory function for 11 hours. Pathologic analysis of peripheral lung biopsy specimens taken from control lungs displayed alveolar disruption and hemorrhage within small vessels, whereas swine lungs transplanted into immunodepleted baboons displayed little histologic evidence of injury. Furthermore, pulmonary xenografts transplanted into immunodepleted baboons demonstrated excellent respiratory function and adequate hemodynamics during occlusion of the right pulmonary artery. CONCLUSION: Hyperacute pulmonary xenograft rejection can be prevented by pretransplantation swine lung perfusion. Swine pulmonary xenografts can provide complete respiratory support in primates when rejection is prevented.

Swine lungs expressing human complement-regulatory proteins are protected against acute pulmonary dysfunction in a human plasma perfusion model.

UNLABELLED: Pulmonary transplantation is currently limited by the number of suitable cadaver donor lungs. For this reason, pulmonary xenotransplantation is currently being investigated. OBJECTIVE: Our goal was to assess the role of complement in pulmonary xenograft dysfunction. METHODS: The pulmonary function of swine expressing human decay accelerating factor and human CD59 (n = 6) was compared with that of the lungs from nontransgenic (control) swine (n = 6) during perfusion with human plasma. RESULTS: After 2 hours of perfusion, the pulmonary vascular resistance was 1624 +/- 408 dynes.sec.cm-5 in control lungs and 908 +/- 68 dynes.sec.cm-5 in transgenic lungs (p < 0.05). Control lungs had a venous oxygen tension of 271 +/- 23 mm Hg with a ratio of venous oxygen tension to inspired oxygen fraction of 452 +/- 38 at 2 hours of perfusion; transgenic lungs had a venous oxygen tension of 398 +/- 11 mm Hg and a ratio of venous oxygen tension to inspired oxygen fraction of 663 +/- 18 (p < 0.05). Control lungs showed a decrease of 79.8% +/- 3.7% in static pulmonary compliance by 2 hours, versus a 12.0% +/- 8.1% decrease by the transgenic lungs (p < 0.05). The control lungs also developed 561.7 +/- 196.2 ml of airway edema over 2 hours, in contrast to 6.5 +/- 1.7 ml in transgenic lungs (p < 0.05). CONCLUSION: Lungs from swine expressing human decay accelerating factor and human CD59 functioned better than nontransgenic swine lungs when perfused with human plasma. These results suggest that complement activation is involved in producing acute pulmonary xenograft dysfunction and demonstrate that lungs from swine expressing human decay accelerating factor and human CD59 are protected against pulmonary injury when perfused with human plasma.

The role of antibodies in dysfunction of pig-to-baboon pulmonary transplants.

OBJECTIVE: Pulmonary transplantation has become the preferred treatment for end-stage lung disease, but application of the procedure is limited because of a paucity of donors. One way to solve donor limitations is to use animal organs as a donor source or xenotransplantation. The current barrier to pulmonary xenotransplantation is the rapid failure of the pulmonary xenograft. Although antibodies are known to play a role in heart and kidney xenograft rejection, their involvement in lung dysfunction is less defined. This project was designed to define the role of antibodies in pulmonary graft rejection in a pig-to-baboon model. METHODS: Orthotopic transgenic swine left lung transplants were performed in baboons depleted of antibodies by one of three techniques before transplantation: (1) ex vivo swine kidney perfusion, (2) total immunoglobulin-depleting column perfusion, and (3) ex vivo swine lung perfusion. Results were compared with those of transgenic swine lung transplants in unmodified baboons. RESULTS: All three techniques of antibody removal resulted in depletion of xenoreactive antibodies. Only pretransplantation lung perfusion improved pulmonary xenograft function compared with lung transplantation in unmodified baboons. CONCLUSIONS: The pathogenesis of pulmonary injury in a swine-to-primate transplant model is different from that in renal and cardiac xenografts. Depletion of antibodies alone does not have a beneficial effect and may actually be detrimental.

The combined effects of brain death and cardiac graft preservation on cardiopulmonary hemodynamics and function before and after subsequent heart transplantation.

BACKGROUND: The combined effects of brain death and graft preservation on right and left ventricular function and on pulmonary hemodynamics after subsequent heart transplantation have not been previously studied. METHODS: Fifty-seven dogs (25.5 +/- 0.3 kg) were divided into three groups and underwent a total of 20 brain death experiments and 16 orthotopic complete atrioventricular transplantations with the use of a validated brain death organ donor model, hypothermic heart preservation, and right and left ventricular functional analysis (preload-independent recruitable stroke work, Fourier analysis). In the first group, changes in cardiopulmonary function were assessed over a period of 6 to 7 hours after brain death. In the second group, the hearts were procured from a donor with brain death and immediately transplanted whereas in the third group cardiac graft preservation for a period of 4 hours followed harvest from a donor with brain death before heart transplantation and assessment of heart transplant function. RESULTS: After brain death alone, a significant increase in right and left ventricular end-diastolic pressures and a decrease in systemic and pulmonary resistance and pulmonary impedance occurred. Furthermore, right and left ventricular function decreased significantly by 35% and 19%, respectively, and subsequent transplantation did not cause further cardiac dysfunction. Preservation in combination with brain death led to further significant decreases in right ventricular function after subsequent transplantation compared with brain death alone, necessitating the use of dopamine to wean four animals from cardiopulmonary bypass. CONCLUSION: Brain death causes a significant loss of right and left ventricular function. These injuries are greater in the right ventricle and may contribute to early right ventricular failure after transplantation. Brain death and cardiac graft preservation have significantly additive deleterious effects on right ventricular function after transplantation.

Hemodynamic and inotropic effects of milrinone after heart transplantation in the setting of recipient pulmonary hypertension.

BACKGROUND: Right ventricular failure remains an important cause of early morbidity and death after heart transplantation and is commonly related to preexistent recipient chronic pulmonary hypertension, which occurs as a result of long-standing congestive heart failure. In this study, the hemodynamic and inotropic effects of milrinone were assessed after bicaval heart transplantation in the setting of monocrotaline pyrrole-induced recipient chronic pulmonary hypertension. METHODS: Twenty dogs were used for 10 successfully completed transplantation experiments. Recipient animals underwent right atrial injection of 3 mg/kg monocrotaline pyrrole 4 months before transplantation. Hemodynamic and functional data were taken 1 hour after termination of cardiopulmonary bypass and after milrinone infusion. Myocardial function was assessed with load-insensitive means (preload-recruitable stroke work) and pulmonary vascular impedance was calculated with Fourier analysis. RESULTS: At the time of transplantation, before cardiopulmonary bypass, pulmonary hemodynamic indexes in recipient animals were significantly increased when compared with donors and were further significantly increased after cardiopulmonary bypass. Two animals died after transplantation as a result of acute right ventricular failure. In surviving animals milrinone infusion led to significant increases in right ventricular function, which occurred in association with significant improvements in pulmonary vascular impedance and transpulmonary efficiency. CONCLUSIONS: In the setting of monocrotaline pyrrole-induced recipient pulmonary hypertension, milrinone was associated with significant improvements in pulmonary vascular impedance, right ventricular function, and transpulmonary efficiency. These data suggest that milrinone is an effective means to improve right ventricular dysfunction and pulmonary vascular efficiency after bicaval heart transplantation in the setting of recipient chronic pulmonary hypertension.

An adult canine model of chronic pulmonary hypertension for cardiopulmonary transplantation.

BACKGROUND: This study establishes a chemically-induced canine model of chronic pulmonary hypertension (CPH) using monocrotaline pyrrole (MCTP) and then characterizes this model in terms of hemodynamic, morphologic, and cardiac functional changes. METHODS: Thirty-three adult mongrel dogs (22 to 25 kg) were used. All animals underwent pulmonary artery catheterization to measure central venous pressure, mean right ventricular pressure (mRVP), mean pulmonary artery pressure (mPAP), and pulmonary capillary wedge pressure before and 6 weeks after a right atrial injection of either 60 mg/kg monocrotaline (group A, n = 8), 5 mg/kg MCTP (group B, n = 4), 3 mg/kg MCTP (group C, n = 13) or placebo (control, n = 8). Six weeks after injection, hearts in control and group C dogs were instrumented with flow probes, dimension transducers, and micromanometers to measure dynamic ventricular pressures and volumes. RESULTS: No significant differences in baseline hemodynamic indexes were observed between groups. All animals in group B and five in group C died after MCTP injection as a result of pulmonary edema. No significant increase in any hemodynamic parameters occurred in group A or in control dogs 6 weeks after injection. In group C, significant increases in central venous pressure, mRVP, and mPAP were observed 6 weeks after injection. Significant increases in right ventricular (RV) function and the weight ratio of the RV to left ventricle were observed in group C when compared with controls. CONCLUSIONS: A chemically-induced canine model of CPH has been created. Significant increases in mRVP, mPAP, and pulmonary capillary wedge pressure were observed 6 weeks after MCTP injection. RV function adapts to the increased afterload in the short term without evidence of failure. A stable model of pulmonary hypertension is provided as a potential means to evaluate posttransplantation RV dysfunction in the setting of CPH.