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Biomedical subjects

Christopher G A McGregor

Publications and source records attributed to Christopher G A McGregor.

At least 19 recordsLinked to original sources
PubMed2007

Pulmonary arterial reactivity during induced infection of single lung allografts.

OBJECTIVE: Infection is a major cause of mortality in the first year following single lung transplantation and is a distinct risk factor for the development of obliterative bronchiolitis. However, little is known about changes in pulmonary vascular activity in the setting of infection, which might affect and limit function of the graft. Therefore, the aim of this study was to determine how acute infection altered pulmonary arterial reactivity in single lung allografts. Such information could help to develop better diagnostic and therapeutic targets to improve outcome when grafts become infected. METHODS: Following single lung transplantation, dogs were immunosuppressed with methylprednisolone acetate, cyclosporine and azathioprine. On postoperative day 5, infection was induced in one group of dogs by endobronchial inoculation of antibiotic resistant Eschericia coli (infection group, n=5); in the second group, the same amount of culture media without bacteria was flushed into the bronchus (control group, n=4). All animals were medicated under the same drug protocol. On postoperative day 8, lungs were removed, reviewed for histological assessment, pulmonary arteries were isolated, cut into rings and suspended for pharmacological characterization in organ chambers. RESULTS: With acute infections, contractions to phenylephrine and angiotensin-1, but not endothelin-1, were reduced in pulmonary arteries with but not without endothelium. Inhibition of nitric oxide synthase with N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA) restored these contractions. Endothelium-dependent relaxations to adenosine diphosphate and calcium ionophore, which stimulate release of endothelium-derived nitric oxide by a receptor and non-receptor mediated process, respectively, were not different between groups. Relaxations to nitric oxide also were not different between groups. CONCLUSION: These results suggest that acute infection selectively reduces contractions of pulmonary arteries in part through receptor-mediated release of nitric oxide from the endothelium. Inhibiting nitric oxide during episodes of acute infection may help to improve graft perfusion during episodes of acute infection.

Acute Disease↗
PubMed2006

Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival.

BACKGROUND: Cardiac xenograft function is lost due to delayed xenograft rejection (DXR) characterized by microvascular thrombosis and myocardial necrosis. The cause of DXR is unknown but may result from thrombosis induced by antibody-mediated activation of endothelial cells and/or by incompatibilities in thromboregulatory interactions. METHODS: To examine these issues, a series (Groups 1-6) of previous transgenic CD46 pig-to-baboon heterotopic cardiac transplants were reanalyzed for baseline immunosuppressive levels, graft survival and infectious complications with and without systemic anticoagulation. Groups 1-4 received low dose tacrolimus and sirolimus maintenance therapy, with splenectomy, anti-CD20 and daily alpha-Gal polymer. Group 1 recipients received no anticoagulation. Groups 2-4 were anticoagulated with aspirin and Plavix, Lovenox, or Coumadin, respectively. Group 5 was treated with Lovenox and high dose tacrolimus and sirolimus maintenance therapy. Group 6 recipients received no postoperative anticoagulation but the same immunosuppression as group 5. RESULTS: Median survival (15-22 days) within groups 1-4 was not significantly different. At rejection all tissues exhibited microvascular thrombosis, coagulative necrosis and similar levels of platelet and fibrin deposition. Groups 5 and 6 median survival (76 days) was significantly increased compared to groups 1-4. There was no significant difference in median survival between Lovenox treated recipients (68 days) and anticoagulant free recipients (96 days). Rejected tissues showed vascular antibody deposition, microvascular thrombosis, and myocyte necrosis. CONCLUSION: Significant prolongation in xenograft survival is achieved by improved immunosuppression. These results suggest that ongoing immune responses remain the major stimulus for DXR.

Animals↗
PubMed2006

Ex vivo hypothermic recirculatory adenoviral gene transfer to the transplanted pig heart.

BACKGROUND: To facilitate the application of adenoviral gene therapy in clinical heart transplantation, we developed an ex vivo hypothermic recirculatory adenoviral gene transfer method to the transplanted pig heart. METHODS: Experimental animals were assigned into three groups; controls, 1x10(8) plaque-forming units (pfu)/ml group and 1x10(9) pfu/ml group. During the 30 min gene transfer perfusion, 200 ml of University of Wisconsin solution containing the adenoviral vector was recirculated through the coronary vessels. The myocardial temperature was maintained below 4 degrees C and the perfusion pressure was adjusted at 50 mmHg. RESULTS: Cardiac myocyte transduction efficiencies in the 1x10(8) pfu/ml group were 0.04% and 0.07%, whereas transduction efficiencies in the 1x10(9) pfu/ml group were widely distributed from 0.45% to 22.62%. The gene transduction efficiency increased with the virus titer. Additionally, no difference in the transduction efficiency was observed between different segments of the left ventricle. The current gene transfer method at 1x10(9) pfu/ml of adenovirus titer enabled homogeneous gene transduction into the transplanted pig heart up to a maximum of 22.62%. CONCLUSIONS: This model can be applied to a large isolated heart and will greatly facilitate the investigation of gene therapy in large animal models of heart transplantation.

Adenoviridae↗
PubMed2006

Thoracic aorta false aneurysm: what surgical strategy should be recommended?

BACKGROUND: Thoracic aorta false aneurysms (TAFA) are a surgical challenge. The best technical approach remains uncertain. METHODS: Between 1981 and 2004, 57 patients underwent operation for TAFA (mean age 57 +/- 18 years; 43 [75%] were male). Symptoms included dyspnea 25 (44%), chest pain 22 (39%), and fever 18 (32%). Twelve (21%) were asymptomatic. Thirty-seven (65%) had undergone previous operation with a mean interval between operations of 80 +/- 90 months. Fifteen (26%) had a mycotic etiology. The TAFA involved the aortic root in 10 (18%), ascending aorta in 28 (49%), arch in 6 (11%), and descending aorta in 13 (32%). Twenty-one (37%) required femorofemoral cannulation and 28 (49%), circulatory arrest. Surgical techniques included graft replacement in 27 (47%), composite root in 10 (18%), patch repair in 10 (18%), and direct suture in 10 (18%). RESULTS: Operative mortality was 7% (4 patients). Four of 32 (13%) had massive hemorrhage during redo sternotomy, and all of these had planned extramediastinal cannulation (all survived). Follow-up was 100% for 349 patient-years. Actuarial survival was 77% +/- 6%, 63% +/- 8%, and freedom from recurrent TAFA was 87% +/- 5% and 83% +/- 7%, at 5 and 10 years, respectively. Univariate analysis identified TAFA greater than 55 mm, urgent operation, and NewYork Heart Association functional class III or IV as predictors of hemorrhage during redo sternotomy. Obesity and ejection fraction of 35% or less were predictors of operative death. CONCLUSIONS: Thoracic aorta false aneurysm symptoms may be minimal, and consequently a high degree of suspicion plus serial imaging is warranted. Extramediastinal cannulation, deep hypothermia, and circulatory arrest are required for large mediastinal TAFA. Despite serious risks, TAFA correction is possible with good long-term results.

Adult↗
PubMed2006

T-cell responses during pig-to-primate xenotransplantation.

UNLABELLED: Xenotransplantation using porcine organs may resolve a chronic shortage of donor organs for clinical transplantation if significant immunological barriers can be overcome. To determine the potential role of T lymphocytes in Xenograft (Xg) rejection, we transplanted transgenic hCD46 porcine hearts heterotopically into baboon recipients. METHODS: Recipients were treated to deplete anti-Gal antibody with a non-antigenic alpha-Gal polyethylene glycol polymer (TPC) (n = 2), TPC plus rituximab (anti-CD20) (n = 1) or were untreated (n = 1). None of the recipients received T-cell immunosuppression. RESULTS: All Xgs failed within 7 days and showed evidence of a mixed humoral and cellular rejection process. Cellular infiltration consisting primarily of CD4+ T cells and few CD8+ T cells. Proliferation and cytotoxicity assays showed sensitization of CD4+ and CD8+ T cells that reacted with porcine IFN-gamma (pIFN-gamma)-stimulated porcine aortic endothelial cells (PAEC). The CD4+ lymphocytes displayed greater cytotoxicity than CD8+ cells. An increased frequency of PAEC-specific interleukin (IL) 2 and IFN-gamma-secreting T cells was observed, suggesting a Th1 cytokine bias. An increase in the percentage of circulating CD4+CD28- cells was observed at the time of rejection and over 50% of the CD4+ cells recovered from residual pig tissue at necropsy lacked CD28 expression. CONCLUSIONS: These findings show that lymphocytes are efficiently stimulated by PAEC antigens and can mediate direct tissue destruction. These studies (1) provide an insight into the potential of cellular-mediated cardiac Xg rejection, (2) show for the first time the induction of cytotoxic pig-specific CD4+CD28- lymphocytes and (3) provide a rational basis for determining different modes of immunosuppression to treat Xg rejection.

Animals↗
PubMed2006

An echocardiographic left ventricular wall area index for functional detection of myocardial injury in hemodynamically unloaded hearts.

Functional assessment of the left ventricle is affected by loading conditions. Detection of rejection-mediated myocardial injury in a heterotopic heart transplant model is a challenge for the echocardiographer because the heart is in an unloaded state. We examined the relationship of a novel left ventricular (LV) wall area index (LVWAI) and serum cardiac troponin T (cTnT) levels. The LVWAI, based on prior methods of determining LV mass, was defined as the difference between epicardial and endocardial areas divided by the epicardial area. The biphasic morphometric response of LVWAI reflected changes in the cTnT levels and allowed echocardiographic detection of myocardial injury in hemodynamically unloaded hearts.

Animals↗
PubMed2006

The effect of adjuvant perfusion techniques on the incidence of paraplegia after repair of traumatic thoracic aortic transections.

OBJECTIVE: To analyze the effect of adjuvant perfusion techniques of the distal aorta on the outcome of traumatic thoracic aortic transections. PATIENTS AND METHODS: From 1973 to 2004, 72 patients (mean age, 39 years) with thoracic aortic transections arrived alive at the emergency department. Nineteen patients arrived in extremis and underwent emergency operations, 42 patients were stable and underwent diagnostic evaluation before surgery (4 patients experienced aortic rupture during evaluation), and 11 patients presented more than 24 hours after the accident. Sixteen patients died before aortic repair could be performed. Operative repair was possible in 53 patients (46 stable and 7 in extremis). Interposition graft was performed in 47 patients, and primary repair was performed in 6 patients. Morbidity, mortality, and paraplegia rate were analyzed. RESULTS: Patients in extremis had a mortality rate of 84% (16 of 19), stable patients had a mortality rate of 11% (4 of 38), patients who experienced rupture during evaluation had a mortality rate of 100% (4 of 4), and patients who underwent delayed operation had a mortality rate of 0% (0 of 11). The paraplegia rate with and without adjuvant distal aortic perfusion techniques was 2% (1 of 41 patients) and 33% (4 of 12 patients), respectively (P=.007). Mortality and paraplegia rates were 4% and 4% for partial bypass (n=24), 42% and 33% for the clamp and sew technique (n=12), 0% and 0% for Gott shunt (n=10), and 29% and 0% for full cardiopulmonary bypass (n=7), respectively. CONCLUSIONS: Although thoracic aortic transections remain a highly lethal injury, hemodynamically stable patients have a low operative mortality. Spinal cord injury is decreased by the use of adjuvant perfusion techniques that maintain distal aortic perfusion during cross-clamping of the aorta.

Adult↗
PubMed2006

Effects of pulmonary thromboendarterectomy on right-sided echocardiographic parameters in patients with chronic thromboembolic pulmonary hypertension.

OBJECTIVE: To determine the echocardiographic changes in the heart at 3 months and 1 year after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). PATIENTS AND METHODS: Thirty-two adult patients who underwent PTE for CTEPH at the Mayo Clinic in Rochester, Minn, from 1997 to 2003 were included in the study. All underwent transthoracic echocardiography before surgery. Follow-up echocardiography was performed within 3 months of surgery in 28 patients and 1 year postoperatively in 17 patients. The results were compared with baseline data. RESULTS: Within 3 months after PTE, the right ventricular end-diastolic area decreased from 38.4 +/- 12.8 cm2 to 32.5 +/- 10.4 cm2 (mean difference, 5.8 +/- 10.4 cm2; P = .02). The right ventricular end-systolic area decreased from 30.4 +/- 12.1 cm2 to 24.1 +/- 8.6 cm2 (mean difference, 6.3 +/- 10.1 cm2; P = .008). The right ventricular systolic pressure decreased significantly from 92.6 +/- 22.0 mm Hg to 55.0 +/- 19.8 mm Hg (mean difference, 40.0 +/- 24.8 mm Hg; P < .001). Tricuspid regurgitation (TR) improved from a mean grade of 2.5 +/- 1.2 to 1.2 +/- 1.1 (mean difference, 1.5 +/- 1.0; P < .001). At 12 months, the right ventricular end-diastolic area, right ventricular end-systolic area, right ventricular systolic pressure, and TR also were significantly lower than baseline values. CONCLUSION: In patients with CTEPH who undergo PTE, echocardiographic measurements of right ventricular size, systolic pressure, and TR show significant improvement immediately after surgery, which is sustained for up to 1 year after surgery.

Adult↗
PubMed2005

Elevated donor troponin levels are associated with a lower frequency of allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is considered a major cause of morbidity and mortality in transplant recipients and may reflect immune-mediated endothelial injury in response to the donor heart. Elevated troponin levels in the donor serum might provide a marker for this phenomenon; therefore, we evaluated the relationship of donor troponin levels to the development of CAV. METHODS: A retrospective analysis of troponin levels was undertaken from cardiac donor patients, and transplant recipients were monitored for the development of vasculopathy by angiography (N = 171). RESULTS: Angiographically significant CAV developed in 6% of transplantation patients and troponin levels were inversely related to the severity of CAV. CONCLUSIONS: Elevated donor troponin levels are not associated with the development of CAV but rather with a significantly reduced long-term risk of developing CAV, suggesting a possible protective effect of donor released protein.

Adult↗
PubMed2005

Cyclosporine decreases vascular progenitor cell numbers after cardiac transplantation and attenuates progenitor cell growth in vitro.

OBJECTIVE: Recent experimental evidence suggests that the neointimal proliferation seen in cardiac allograft vasculopathy may in part derive from recipient progenitor cells. The effect of cyclosporine on these circulating progenitors in the setting of cardiac transplantation is currently unknown. METHODS: Three surgical series were performed: sham operation alone, sham operation with immunosuppression, and heterotopic porcine cardiac transplantation with immunosuppression. The sham operation involved laparotomy and consecutive clamping of the abdominal aorta and inferior vena cava. Post-operative immunosuppression consisted of cyclosporine at therapeutic levels (100-300 ng/ml) and 0.5 mg/kg methylprednisolone. Endothelial outgrowth colony numbers (EOC(CFU)) and smooth muscle outgrowth colony numbers (SOC(CFU)) were quantified weekly for 4 weeks post-operatively. A series of in vitro experiments were performed to determine the effect of cyclosporine on the differentiation, migration, and proliferation of EOCs and SOCs. RESULTS: In the sham alone series there were no changes to either EOC(CFU) or SOC(CFU). In the sham with immunosuppression and the transplant series, both EOC(CFU) and SOC(CFU) fell in the first 2 weeks (p < 0.05) compared with baseline (EOC(CFU), 3.4 +/- 0.6; SOC(CFU), 11.1 +/- 2.8). EOC(CFU) recovered at 4 weeks to above baseline levels in the sham immunosuppression group only (15.2 +/- 3.9; p = 0.01). SOC(CFU) showed no recovery in the immunosuppression groups. Cyclosporine, even at a low dose, prevented differentiation, inhibited proliferation, and attenuated migration of both EOCs and SOCs. CONCLUSION: Immunosuppression in the setting of cardiac transplantation causes a profound reduction in circulating progenitor cells capable of differentiating into endothelial and smooth muscle cells. This effect can in part be explained by the inhibitory effects of cyclosporine on progenitor growth and differentiation seen in this study.

Animals↗
PubMed2005

Successful use of Thoratec biventricular support in a small child awaiting cardiac transplantation.

The use of paracorporeal mechanical biventricular support devices either as a bridge to transplantation or while awaiting recovery of the failing heart has been well described in the literature. The majority of these reports detail conditions specific to the adult population. We describe use of the Thoratec ventricular assist device (Thoratec Corp, Pleasanton, CA) in the smallest known cardiomyopathy patient to date to be successfully supported with an emergent biventricular device before subsequent cardiac transplantation. The operative technique, pump settings, and modifications utilized to optimize peripheral perfusion are detailed.

Cardiomyopathies↗
PubMed2005

Surgical treatment of cardiac papillary fibroelastoma: a single center experience with eighty-eight patients.

BACKGROUND: Cardiac papillary fibroelastoma is a rare benign tumor that can cause thromboembolism. We have found no large surgical series describing its treatment and outcome. METHODS: A retrospective review of all patients treated surgically for this tumor from 1985 to 2002. RESULTS: There were 88 patients with a mean age of 62 +/- 16 years. Sixty-two (71%) were male. Cardiac papillary fibroelastoma was a primary indication for surgery in 47 (group 1, 53%) and an incidental finding in 41 (group 2, 47%). The common clinical symptoms were neurologic (group 1) and cardiac (group 2). Cardiac valves were predominantly involved (77%); the aortic valve was the most affected (52%). Other common sites were the left ventricular outflow tract (18%) and anterior mitral leaflet (11%). All heart valves were involved in one patient. Seventy-three patients (83%) had shave excision and 8 (9%) excision with valve repair. Of 5 (6%) valve replacements, 2 were for concurrent degenerative valve disease. Concomitant procedures included repair or replacement of another valve (32%), CABG (28%), and septal myectomy (19%). Surgical mortality occurred in 1 patient (2.1%) in group 1 who had concomitant lung resection for bronchiolitis obliterans. There was no tumor recurrence, and no tumor-related late morbidity or mortality at a mean follow-up of 3 years. CONCLUSIONS: Cardiac papillary fibroelastoma has a propensity to affect the anatomically contiguous structures of the aortic valve, left ventricular outflow tract, and anterior mitral leaflet. Surgical treatment by simple shave excision is low risk and can achieve good results.

Adult↗
PubMed2005

Rejection severity directly correlates with myocyte apoptosis in pig-to-baboon cardiac xenotransplantation.

BACKGROUND: The process by which cardiac myocytes die during xenograft rejection is incompletely understood. The presence of cardiac myocyte apoptosis in discordant xenotransplant models has been noted, yet no investigators have examined whether a relationship between myocyte apoptosis and rejection severity exists. Thus, we chose to further investigate this observation. METHODS: Eight explanted pig-to-baboon cardiac grafts with varying severities of rejection, as determined by hematoxylin and eosin histology, were examined for apoptosis by transmission electron microscopy (TEM) and TUNEL (terminal deoxynucleotide transferase-mediated digoxigenin-dUTP nick-end labeling) immunohistochemistry. In addition, Western blot analysis for the cleavage of the apoptosis regulatory proteins pro-caspase 8 and 3 was performed. RESULTS: Transmission electron microscopy revealed that a severely rejected graft displayed widespread condensation of nuclear chromatin, which is a characteristic morphologic feature of apoptosis. TUNEL staining verified this observation and allowed for the quantification of myocyte apoptosis in each graft. Subsequent linear regression analysis of the extent of myocyte apoptosis and rejection severity revealed a direct correlation (R(2)=0.757, p=0.005). In addition, Western blot analysis demonstrated that myocyte apoptosis involves the cleavage of pro-caspase 8 and 3. CONCLUSIONS: Myocyte death in rejecting pig-to-baboon cardiac xenografts occurs through an apoptotic pathway and directly correlates with the severity of graft rejection. Further studies aimed at elucidating the apoptotic stimulus are therefore warranted. Moreover, our data suggest that antiapoptotic strategies may be of benefit in the treatment of xenograft rejection.

Animals↗
PubMed2005

Operative risk of reoperative aortic valve replacement.

OBJECTIVE: The contemporary risk of reoperative aortic valve replacement is ill-defined. We therefore compared the recent early results of reoperative and primary aortic valve replacement in our institution. METHODS: Between January 1993 and January 2001, a total of 162 patients underwent reoperative aortic valve replacement with or without coronary artery bypass grafting, and 2290 underwent primary aortic valve replacement with or without coronary artery bypass grafting. The reoperative and primary groups were similar with regard to gender (37% female in both), preoperative New York Heart Association functional class (2.8 +/- 1 vs 2.8 +/- 1), and ejection fraction (58% +/- 15% vs 57% +/- 15%). Patients undergoing reoperative aortic valve replacement were younger than those undergoing primary aortic valve replacement (64 +/- 15 years vs 70 +/- 13 years, P < .001). Previous prostheses were xenografts in 77 patients (48%), homografts and autografts in 25 (15%), and mechanical prostheses in 60 (37%). Mean time to reoperation was 9.7 +/- 6.8 years. RESULTS: Early mortality for reoperative aortic valve replacement (8/162, 5%) was not statistically different from that for primary aortic valve replacement (71/2290, 3%, P = .20). Endocarditis was more common in the reoperative group (22% vs 3%, P < .001); when endocarditis was excluded from the analysis, early mortality was 3% in both groups. Multivariate predictors for early mortality were prosthetic valve endocarditis ( P < .001, odds ratio 9.8), advanced preoperative functional class ( P < .001, odds ratio 2.0), peripheral vascular disease ( P = .008, odds ratio 2.0), preserved left ventricular ejection fraction ( P = .004, odds ratio 0.98), and male gender ( P = .009, odds ratio 0.49). After adjustment for these factors, there was no difference in early mortality between the groups ( P = .095). CONCLUSION: The risk of reoperative aortic valve replacement is similar to that for primary aortic valve replacement. These data support the expanded use of bioprosthetic valves in younger patients.

Age Factors↗
PubMed2005

Cardiac xenotransplantation: recent preclinical progress with 3-month median survival.

OBJECTIVES: Transplantation is limited by a lack of human organ donors. Organs derived from animals, most likely the pig, represent a potential solution to this problem. For the heart, 90-day median graft survival of life-supporting pig hearts transplanted to nonhuman primates has been considered a reasonable standard for entry into the clinical arena. Overcoming the immune barrier to successful cardiac xenotransplantation is most appropriately first explored with the non-life-supporting heterotopic model. METHODS: We performed a series of 7 heterotopic heart transplantations from CD46 transgenic pigs to baboons using a combination of therapeutic agents largely targeted at controlling the synthesis of anti-pig antibodies. Rituximab (anti-CD20) and Thymoglobulin (rabbit antithymocyte globulin [ATG]; SangStat Medical Corp, Fremont, Calif) were used as induction therapy. Baseline immunosuppression consisted of splenectomy, tacrolimus, sirolimus, steroids, and TPC (an anti-Gal antibody therapeutic). Rejection events were not treated. RESULTS: By using Kaplan-Meier analysis, median graft survival was 96 days (range, 15-137 days; 95% confidence interval, 38-99 days). Only 2 grafts were lost as a result of rejection, as defined by cessation of graft palpation. There was no evidence of a consumptive coagulopathy, infectious complications were treatable, and no posttransplantation lymphoproliferative disorders occurred. No cellular infiltration was observed. CONCLUSIONS: This study reports the longest median survival to date (96 days) of pig hearts transplanted heterotopically into baboons. Duplication of these results in the orthotopic life-supporting position could bring cardiac xenotransplantation to the threshold of clinical application.

Animals↗
PubMed2005

Prevention, detection, and management of early bacterial and fungal infections in a preclinical cardiac xenotransplantation model that achieves prolonged survival.

BACKGROUND: We analyzed bacterial and fungal infectious complications in a cohort of 16 consecutive experiments with the longest surviving cardiac xenografts to date. METHODS: Transgenic, porcine-to-baboon, heterotopic (abdomen) cardiac xenotransplantation was performed in 16 consecutive experiments, using rapamycin, tacrolimus, corticosteroids, anti-CD20 monoclonal antibody, and an alpha-Gal-PEG polymer, as immunosuppression. Prophylactic anti-microbials included i.v. trimethoprim/sulfamethoxazole, oral ganciclovir/valganciclovir, and oral itraconazole. An episode of bacterial infection was defined as a positive blood and/or wound culture with: leukocytosis, fever >101.5 degrees F, and/or clinical deterioration. RESULTS: Mean graft survival was 71 +/- 29 days; the longest was 113 days. There were 23 episodes of bacterial infection; 14 resolved with treatment. The mean time to the first episode of infection was 44 +/- 21 days (n=12). Eight of 16 deaths were due to infection: two bacterial-only, two cytomegalovirus (CMV) only, four both bacterial and CMV, and none fungal. The frequency of infection was 1, 2.8, and 1.8 episodes/100 survival days, respectively, for animals whose grafts survived for 30 to 59, 60 to 89, and >90 days. CMV infection (reviewed in detail in a separate communications) was due to baboon CMV, and was associated with low serum levels of ganciclovir. CONCLUSION: In a cardiac xenograft model that achieved prolonged (>3 months) survival, bacteremia was common, but usually reversible, and fungal infection was prevented with prophylaxis. The level of immunosuppression required to achieve clinically meaningful xenograft survival is associated with a level of bacterial and fungal infectious complications that is manageable and similar to the early clinical experiences in human transplantation. Further research will determine if the viral infectious complications observed in these experiments can be reduced by optimizing blood levels of anti-viral prophylaxis and monitoring viral polymerase chain reaction levels.

Animals↗
PubMed2005

Warfarin or low-molecular-weight heparin therapy does not prolong pig-to-primate cardiac xenograft function.

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low-molecular-weight heparin (LMWH) anti-coagulation on xenograft function using a heterotopic pig-to-primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti-coagulant drugs. The median duration of xenograft function was 20 days (range 3-62 days), 18 days (range 5-109 days) and 15 days (range 4-53 days) in Groups 1 to 3 respectively. Anti-coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti-factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti-coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti-coagulant strategies to achieve long-term xenograft function cannot be excluded.

Animals↗