Impact of bilateral superior venae cavae on outcome of staged Fontan procedure.

BACKGROUND: The presence of bilateral superior venae cavae may add complexity to the performance of a bidirectional Glenn procedure (BDG). Stagnation of blood flow between the two cavopulmonary anastomoses may increase the risk of thrombosis and impair central pulmonary artery growth. METHODS: Forty patients underwent BDG from January 2004 to April 2011. The cohort was divided into two groups: those receiving bilateral BDG (b-BDG, n = 13) and those receiving unilateral BDG (u-BDG, n = 27). Operative, angiographic, and follow-up data were analyzed retrospectively. RESULTS: None of the patients experienced thrombosis. There was no difference in actuarial survival rate (u-BDG vs b-BDG, 100% vs 92% at 5 years, p = 0.15). On follow-up angiography, no difference in central pulmonary artery index was noted (78.4 ± 45.5 vs 60.4 ± 32.1, p = 0.24). Central pulmonary artery stenosis was detected in 6 patients (4 with u-BDG and 2 with b-BDG), 4 of whom (2 from each group) underwent balloon pulmonary artery plasty before the Fontan procedure. There was no difference in freedom from reintervention for central pulmonary artery stenosis (93% vs 85% at 1 year, p = 0.59). The rate of Fontan completion was comparable between groups, with similar operative variables and satisfactory outcomes. CONCLUSIONS: Bilateral BDG did not increase the risks of thrombosis and central pulmonary artery hypoplasia and can be performed safely without altering the outcome of the Fontan procedure.

Repair of acute aortic dissection in an octogenarian with prior thoracoplasty.

Cardiovascular surgery is challenging in patients who have previously undergone thoracoplasty because of severe chest deformity and impaired pulmonary function. We report a case of an octogenarian with prior left thoracoplasty, who successfully underwent surgical repair of an acute aortic dissection through a standard median sternotomy. We suggest that prior thoracoplasty might not necessarily be an exclusion criterion for aortic surgery in cases with adequate pulmonary function.

Aortic valve replacement in a porcelain aorta using endo balloon occlusion.

Aortic valve surgery carries increased risks in patients with an extensively calcified aorta. We describe a technique in which we maintain systemic perfusion via bilateral axillary artery perfusion in conjunction with endoaortic balloon occlusion, and limit the circulatory arrest time.

Catastrophic hemorrhage due to aortic injury during resternotomy: what to do?

Aortic injury occurred during resternotomy in a 22-year-old woman who had undergone a Rastelli-type operation. Although extracorporeal circulation using the right femoral artery and vein was commenced immediately, hemostasis through the midline incision was impossible, and her circulation was hardly maintained. Thus, the parasternal approach was attempted, dividing the right first through fourth ribs and the head of the right clavicle. This approach enabled the assistant to give effective compression to the aortic injury site. Dissection of the adhesions around the ascending aorta was safely carried out, and the aortic laceration was closed without the help of circulatory arrest.

Application of cyclophosphamide-induced tolerance in alpha1,3-galactosyltransferase knockout mice presensitized with Gal alpha 1-3Gal beta-4-GlcNAc antigens.

PURPOSE: Hyperacute rejection (HAR) mediated by the natural antibody (nAb) against Gal alpha 1-3Gal beta-4-GlcNAc (alpha Gal) is the major obstacle in xenogeneic organ transplantation. Previously, we reported the acceptance of donor heart grafts in anti-alpha Gal nAb-producing galactosyltransferase knockout (GalT KO) mice after cyclophosphamide (CP)-induced tolerance conditioning. In the present study, we applied our tolerance induction conditioning in presensitized recipient mice. METHODS: GalT KO (alpha Gal(-/-), H-2(b/d)) recipient mice were presensitized with alpha Gal(+) rabbit red blood cells (RRBCs). Presensitized or nonsensitized recipient mice were treated with CP-induced tolerance conditioning, consisting of AKR (alpha Gal(+/+), H-2(k)) spleen cells (SC), CP, busulfan (BU), and AKR bone marrow cells (BMC). We assessed the survival of donor hearts and skin grafts and analyzed the production of anti-alpha Gal Abs by flow cytometry. RESULTS: Donor mixed chimerism was achieved in the presensitized GalT KO mice treated with CP-induced tolerance conditioning. In parallel with the disappearance of anti-alpha Gal Abs, permanent acceptance of donor heart grafts and skin grafts was observed in presensitized and GalT KO mice treated with CP-induced tolerance conditioning. CONCLUSIONS: Both B-cell and T-cell tolerance was achieved in the presence of a higher titer of anti-alpha Gal Abs after treatment with CP-induced tolerance conditioning.

Effects of cyclosporin A on the activation of natural killer T cells induced by alpha-galactosylceramide.

BACKGROUND: Natural killer T (NKT) cells play crucial roles in preventing autoimmune diseases and inducing transplantation tolerance. We investigated whether cyclosporin A (CsA), which is generally used in clinical transplantation and autoimmune disease therapy, could modulate the NKT cell activation induced by alpha-galactosylceramide (alpha-GalCer) treatment. METHODS: C57BL/6 (B6) mice were given daily intraperitoneal injections of CsA (30 or 50 mg/kg) from day -1 and injected intravenously with alpha-GalCer (2 mug/mouse) on day 0. The kinetics of NK1.1CD3 or NK1.1Thy1.2 cells in the liver and spleen were analyzed by flow cytometry. Apoptosis of NK1.1CD3 cells, cytokine levels (interleukin [IL]-2, IL-4, IL-10 and interferon [IFN]-gamma) in the recipient serum and changes in dendritic cell activation in the spleen were analyzed. RESULTS: In B6 mice treated with alpha-GalCer, NK1.1CD3 cells rapidly decreased in both the liver and spleen, and repopulated to their normal levels by day four, while NK1.1Thy1.2 cells rapidly decreased, expanded by day four and reduced to their normal level by day 15. When B6 mice were treated with alpha-GalCer plus 30 or 50 mg/kg CsA, NK1.1CD3 or NK1.1 Thy1.2cells were similarly decreased and then expanded via extensive proliferation by day seven or four, respectively. When B6 mice were treated with alpha-GalCer, substantial amounts of IL-2, IL-4 and IFN-gamma were produced, and the surface markers of dendritic cells were upregulated. However, these cytokine productions and maturation of dendritic cells were profoundly suppressed after treatment with alpha-GalCer and CsA. Apoptosis of NK1.1CD3 cells was not affected in mice treated with alpha-GalCer or alpha-GalCer and CsA. CONCLUSIONS: CsA suppresses alpha-GalCer-induced cytokine productions and dendritic cell maturation of mouse NKT cells but does not decrease NK1.1CD3 cells on day one. The modulation of NKT-mediated immunoregulatory functions by CsA requires careful consideration in clinical transplantation and autoimmune disease therapy.

The immunoregulatory roles of natural killer T cells in cyclophosphamide-induced tolerance.

BACKGROUND: Recent studies have indicated that natural killer T (NKT) cells are essential for the establishment of transplantation tolerance. In the present study, we have elucidated the role of recipient and donor NKT cells in cyclophosphamide (CP)-induced tolerance. METHOD: DBA/2 (DBA; H-2) mice were used as donors and BALB/c (BALB; H-2) wild-type (WT) or Valpha14 NKT-knockout (KO, BALB/c background) mice were used as recipients. Recipients were treated with CP-induced tolerance regimen, which consists of donor spleen cells (SC) on day 0 and CP on day 2. In some experiments, NKT KO mice, which received NKT cells from either WT, inferon-gamma KO, or interleukin-4 KO mice, were treated with tolerant regimen. To deplete Ly49 inhibitory receptors on NKT cells in the recipient mice, anti-Ly49 monoclonal antibody cocktails were injected on day -1 when indicated. RESULTS: Donor skin graft was permanently accepted in recipient BALB WT mice with induction of donor mixed chimerism. On the contrary, donor DBA skin allografts were chronically rejected in NKT KO recipient. Lower levels of mixed chimerism were observed in NKT KO recipients comparing to the WT recipients. The production of interferon-gamma or interleukin-4 from NKT cells did not affect the induction of tolerance. Depletion of Ly49 positive NKT cells abrogated the induction of skin graft tolerance. CONCLUSION: Recipient NKT cells, but not donor NKT cells, were dominantly required for the induction of allograft tolerance. Our results indicated that the single cytokine produced by NKT cells did not mediate the regulatory function in the induction of allograft tolerance.

Efficacy and limitations of natural killer cell depletion in cyclophosphamide-induced tolerance.

PURPOSE: We previously developed a cyclophosphamide (CP)-induced tolerance protocol, consisting of an intravenous injection of 1 x 10(8) donor spleen cells (SC) given on day 0 and an intraperitoneal injection of 200 mg/kg CP given on day 2. In the present study, we modified this protocol with natural killer cell (NK) depletion in recipient mice, and evaluated the efficacy of tolerance induction. METHODS: We used B10.D2 (H-2d; IE+) and B10 (H-2b; IE-) mice as both donors and recipients. The recipient mice were treated with donor SC, CP, and donor bone marrow cells (BMCs) with or without NK depletion. RESULTS: A higher level of mixed chimerism was achieved in the NK-depleted recipients. Survival of both the skin and heart donor grafts was significantly prolonged in the NK-depleted recipients. Donor reactive Vbeta11+ T cells were found at the same level as in untreated control mice. Pretreatment with recipient NK cell depletion was effective in inducing higher levels of donor mixed chimerism; however, permanent engraftment of donor bone marrow was not achieved. CONCLUSION: Survival of donor grafts was remarkably prolonged in the NK cell-depleted group, but transplantation tolerance could not be induced. Our results suggest that NK cell depletion in CP-induced tolerance conditioning has some effect on the induction of donor-specific tolerance.

Regulatory roles of NKT cells in the induction and maintenance of cyclophosphamide-induced tolerance.

We have previously reported the sequential mechanisms of cyclophosphamide (CP)-induced tolerance. Permanent acceptance of donor skin graft is readily induced in the MHC-matched and minor Ag-mismatched recipients after treatment with donor spleen cells and CP. In the present study, we have elucidated the roles of NKT cells in CP-induced skin allograft tolerance. BALB/c AnNCrj (H-2(d), Lyt-1.2, and Mls-1(b)) wild-type (WT) mice or Valpha14 NKT knockout (KO) (BALB/c) mice were used as recipients, and DBA/2 NCrj (H-2(d), Lyt-1.1, and Mls-1(a)) mice were used as donors. Recipient mice were primed with 1 x 10(8) donor SC i.v. on day 0, followed by 200 mg/kg CP i.p. on day 2. Donor mixed chimerism and permanent acceptance of donor skin allografts were observed in the WT recipients. However, donor skin allografts were rejected in NKT KO recipient mice. In addition, the donor reactive Vbeta6(+) T cells were observed in the thymus of a NKT KO recipient. Reconstruction of NKT cells from WT mice restored the acceptance of donor skin allografts. In addition, donor grafts were partially accepted in the thymectomized NKT KO recipient mice. Furthermore, the tolerogen-specific suppressor cell was observed in thymectomized NKT KO recipient mice, suggesting the generation of regulatory T cells in the absence of NTK cells. Our results suggest that NKT cells are essential for CP-induced tolerance and may have a role in the establishment of mixed chimerism, resulting in clonal deletion of donor-reactive T cells in the recipient thymus.

Sequential analysis of anti-alpha Gal natural antibody-producing B cells in GalT knockout mice in cyclophosphamide-induced tolerance.

Previously, we have shown that cyclophosphamide (CP)-induced tolerance, marked by permanent acceptance of donor skin graft and establishment of donor mixed chimerism, was readily induced with treatment with donor spleen cells (SC), CP, busulfan (BU) and donor bone marrow cells (BMC). Here, we investigated the mechanism of anti-donor natural antibody (nAb) producing B-cell tolerance in our CP-induced tolerance systems in alpha1,3-galactosyltransferase-deficient knockout mice (GalT KO; GalT-/-, H-2(b/d)). After induction of tolerance using donor AKR SC and BMC, survival of donor heart and skin grafts and production of anti-Galalpha1-3Galbeta1-4GlcNAc (anti-alphaGal) Ab in recipient GalT KO mice were analyzed. In addition, the production of anti-alphaGal Ab and the presence of Gal-BSA binding B cells in GalT KO mice were analyzed by flow cytometry (FCM) after treatments with rabbit red blood cells (RRBC) and CP. Permanent acceptance of donor skin and heart grafts and abrogation of anti-alphaGal Ab were achieved in GalT KO mice treated with donor SC + CP/BU + BMC. However, in the GalT KO mice treated with donor SC and CP, donor skin grafts were acutely rejected, even though anti-alphaGal Ab was undetectable. Similarly, anti-alphaGal Ab was undetectable in GalT KO mice treated with RRBC and CP. Our data strongly indicated the following mechanisms: the clonal destruction in the early stage and the clonal anergy or ignorance in the late stage after conventional conditioning with RRBC and CP. In conclusion, our drug-induced tolerance protocols are effective to induce tolerance in recipients that produce anti-donor nAb.

Case of isolated thoracic aortic aneurysm as a manifestation of undiscovered giant cell arteritis.

A 73-year-old woman was referred to our hospital to investigate dilatation of an aortic arch which had been detected by a chest roentgenogram and severe aortic valve regurgitation detected by echocardiography. On admission, a computed tomography scan of the chest showed a large fusiform ascending aortic aneurysm. She had not shown any symptoms such as headache or polymyalgia rheumatica and had no significant coronary atherosclerosis. She underwent aneurysmectomy and reconstruction of the ascending aorta using cardiopulmonary bypass without aortic valve replacement, and pathological examination of the aneurismal wall revealed giant cell arteritis (GCA). Preoperatively, she did not have any temporal pain, and no signs of inflammation were detected serologically. Postoperatively, aortic valve regurgitation improved and she did well. However, three months after the surgery, she died suddenly due to the rupture or dissection of aorta. In the Japanese population, GCA is reportedly a rare cause of aortic aneurysm. However, retrospective studies show that GCA affects the aorta and that thoracic aortic aneurysm is a possible complication of GCA. In cases of the thoracic aortic aneurysms with unknown etiology, there is a possibility that GCA is the cause of the aortic aneurysm.

Renal cancer treatment with low levels of mixed chimerism induced by nonmyeloablative regimen using cyclophosphamide in mice.

Recently, much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of metastatic renal cancer. Mature donor T cells cause graft-versus-host disease (GVHD) although they are also the main mediators of the beneficial graft-versus-tumor activity associated with this treatment. Hence, the segregation of the graft-versus-tumor activity from GVHD is an important challenge in managing the clinical course of treatment. We previously reported a series of studies regarding the allograft tolerance induced by allogeneic spleen cells (with bone marrow cells) and cyclophosphamide in mice. Here, we show a modified cyclophosphamide-induced tolerance system for the treatment of murine renal cell carcinoma, RENCA, by shifting the equal balance between graft-versus-host and host-versus-graft reactions toward graft-versus-host reaction with donor lymphocyte infusion. Our results clearly show the antitumor activity against RENCA with only low levels of mixed chimerism in the periphery and the in vivo and in vitro acquired immunity against RENCA even when mixed chimerism is almost undetectable. Because the withdrawal of mixed chimerism reduces the risk of GVHD, the antitumor activity is thus sequentially segregated from the initial GVHD in our model. We believe that this is the first unique model system of nonmyeloablative allogeneic hemopoietic cell transplantation to ever be reported for the treatment of renal cancer.

Surgical application for a prolapse of the anterior mitral leaflet by replacing artificial chordae with polytetrafluoroethylene grafts.

PURPOSE: There are an increasing number of reports concerning mitral valve repair by a reconstruction of the chordae tendinae using expanded polytetrafluoro-ethylene (PTFE) sutures. However, little information is available about extended application or results of this technique for an extended prolapse of the anterior mitral leaflets. METHODS: Between July 1991 and August 2003, 28 patients with moderate to severe mitral regurgitation as a result of a prolapse of anterior leaflets (age range, 15-73 years) underwent mitral valve repair by reconstruction of the artificial chordae with 4-CV expanded polytetrafluoroethylene sutures without a leaflet resection. Either Kay's suture technique or ring annuloplasty was also performed to correct annular dilatation in all patients. RESULTS: No operative death or late mortality was observed. The prolapsed segment, which was successfully repaired, was within 33% of the anterior mitral leaflet (AML) in 6 patients, from 33% to 50% in 5, from 50% to 99% in 11, and 100% in 6 patients. Before discharge, immediate postoperative echocardiography showed less than moderate mitral regurgitation in 28 of 28 patients. The follow-up, consisting of a clinical examination and serial echocardiograms, was complete in all cases and the mean follow-up period was 80.6 months (range, 12-146). There were two failures that required a reoperation because of a worsening mitral regurgitation and hemolytic anemia (elongation of anchored side of papillary muscle). The other two patients required mitral valve replacement due to a progressive regression of the left ventricular function, although the regurgitation worsened from a mild level to a moderate one. When the reoperated patients were excluded from the following data, the degree of mitral regurgitation, estimated by echocardiography performed at recent follow-up period, was none in 10 patients, trivial in 13 patients, and mild in 1 patient. In addition, the systolic and diastolic dimensions of the left ventricle decreased significantly (P < 0.01). CONCLUSIONS: The replacement of artificial chordae was not complicated and it seemed to help to preserve a good relationship among leaflet tissues, chordae, and papillary muscles. We therefore suggest that the extensive use of PTFE artificial chordae appears to be a promising procedure for the repair of all kinds of mitral lesions causing mitral regurgitation.

The regulatory functions of Ly-49A, Ly-49D and Ly-49G2 on NK cells in the recognition and rejection of the alloantigen in vivo.

Ly-49A is an inhibitory receptor that binds H-2Dd and H-2Dk. The downregulation of Ly-49A is thought to mediate NK self tolerance in vivo. In this study, we analyzed the regulation of Ly-49A, D and G2 on NK cells in an in vivo rejection model. After injection with 1 x 10(8) B10.D2 spleen cells (SC) into B 10 mice, we found Ly-49A downregulated within 3 h on NK cells of B10 mice, whereas expressions of Ly-49D and G2 were augmented. To investigate effects of different expression patterns of Ly-49 receptors on NK cells, Ly-49A, D or G2-depleted B10 mice were inoculated with B10.D2 SC. NK cells from SC of Ly-49A-depleted and B10.D2 SC-injected B10 mice showed enhanced cytotoxicity to Dd-positive targets in vitro. Furthermore, reduced numbers of B10.D2 SC were observed in Ly-49A or G2-depleted B10 mice, whereas increased numbers of B10.D2 SC were observed in Ly-49D-depleted B10 mice after inoculation with B10.D2 SC in vivo. These findings indicated that the downregulation of Ly-49A and the augmentation of Ly-49D expression may mediate NK cells to recognize and kill Dd antigen efficiently. In conclusion, each Ly-49 isoform may play independent roles in the regulation of activation or inhibition on NK cells.

Absent mRNA accumulation of Th1 or Th2 cytokines in heart allografts with chimerism-based drug-induced tolerance.

PURPOSE: We recently described using cyclophosphamide (CP) plus busulfan (BU) to create drug-induced skin and heart allograft tolerance capable of regularly overcoming fully H-2 mismatched barriers in mice. The present study investigates the intragraft mRNA expressions of Th1 and Th2 cytokines. METHODS: This method consists of the intravenous (i.v.) injection of 1 x 10(8) allogeneic spleen cells on day 0, the intraperitoneal injection of 200 mg/kg CP and 30 mg/kg BU on day 2, and the i.v. injection of 1 x 10(7) T cell-depleted allogeneic bone marrow cells from the same strain of mice on day 3. Heart grafting (HG) was performed on day 28. Chimerism in the peripheral blood was monitored by flow cytometric (FCM) analysis. The frequency of certain V(beta) families was determined by FCM to assess deletion of donor-reactive T cells. Th1 (interleukin [IL]-2, interferon [IFN]-gamma) and Th2 (IL-4, IL-10) cytokine expression in the heart grafts was analyzed with reverse transcription-polymerase chain reaction. RESULTS: In a fully MHC mismatched combination of B10.D2 (H-2d, IE+) --> B10 (H-2b, IE-), B10.D2 heart grafts were accepted permanently in a donor-specific manner, mixed chimerism was observed, and IE-reactive V(beta)11+ T cells were specifically reduced in the periphery from the recipient B10 mice. In the donor B10.D2 heart grafts, there was no accumulation of Th1 (IL-2, IFN-gamma) or Th2 (IL-4, IL-10) cytokines. CONCLUSIONS: These results show that the drug-induced tolerance we established can regularly induce long-lasting heart allograft tolerance without intragraft mRNA accumulation of Th1 or Th2.

Requirement of a higher degree of chimerism for skin allograft tolerance in cyclophosphamide-induced tolerance.

By using a cyclophosphamide (CP)-induced tolerance system, we previously raised the possibility that the degree of chimerism might determine the induction of heart and skin allograft tolerance. When C3H (H-2k; Thy1.2, Mls-1b) mice were intravenously primed with 1 x 10(8) spleen cells (SCs) from H-2 matched AKR (H-2k; Thy1.1, Mls-1a) mice and then treated intraperitoneally with 200 mg/kg CP, the survival of AKR skin grafts was permanently prolonged in a tolerogen-specific fashion. After this treatment, a minimal degree of mixed chimerism and the clonal destruction of Mls-1a-reactive CD4+Vbeta6+ T cells in the periphery were observed. When AKR SCs and 100 mg/kg CP were used for conditioning, the survival of the AKR skin grafts was mildly prolonged. The clonal destruction of CD4+Vbeta6+ T cells in the periphery was induced and a minimal degree of mixed chimerism was detectable. The degree of mixed chimerism induced with AKR SCs and 200 mg/kg CP was significantly higher than that with AKR SCs and 100 mg/kg CP during the observation. On the other hand, neither skin allograft prolongation nor permanent mixed chimerism could be induced when C3H mice were treated with AKR SCs and 50 mg/kg CP. In order to increase the degree of mixed chimerism, we injected 1 x 10(8) tolerant AKR SCs on day 3 into the recipient C3H mice that had been treated with AKR SCs on day 0 and with 100 mg/kg CP on day 2. The reason that we used tolerant SCs was that untreated AKR SCs caused graft-versus-host disease in most of the recipients. Tolerant AKR SCs were harvested from AKR mice that had been treated with C3H SCs and 200 mg/kg CP 2 weeks earlier, and did not contain regulatory cells. By adoptive transfer, the degree of chimerism was stably and significantly increased in all recipients, and AKR skin graft tolerance was induced in half of the recipients. T-cell-depleted bone marrow cells (BMCs) from untreated AKR mice induced skin allograft tolerance in 83% of recipients. Thus, the present study strongly confirmed the hypothesis that a higher degree of chimerism is required for the induction of skin allograft tolerance in CP-induced tolerance.

Extensive use of polytetrafluoroethylene artificial grafts for prolapse of posterior mitral leaflet.

BACKGROUND: There are an increasing number of reports concerning mitral valve repair by means of reconstruction of the chordae tendinae with expanded polytetrafluoroethylene (e-PTFE) sutures. However little information is available about extended application or results of this technique for extended prolapse of posterior mitral leaflets. METHODS: Between March 1994 and December 2000, 22 patients with moderate-to-severe mitral regurgitation (MR) as the result of a prolapse of posterior leaflets (age range, 39-73 years) underwent mitral valve repair by means of reconstruction of artificial chordae with 4-CV e-PTFE sutures without leaflet resection. Either Kay's suture or ring annuloplasty was also performed to correct annular dilatation in all patients. RESULTS: No operative death or late mortality was observed. Before discharge immediate postoperative echocardiography indicated less than moderate MR in 20 out of 22 patients. The follow-up was complete in all cases by clinical examination and serial echocardiograms and the median follow-up period was 87 months (range 24-108). There were two failures that required reoperation because of unsuccessful repair and worsening MR (elongation of the anchored side of the papillary muscle). When the reoperated patients were excluded from the follow-up data, the degree of MR, estimated by echocardiography that was performed at a recent follow-up period, was nonexistent in 6 patients, trivial in 10 patients, and mild in 4 patients. The systolic and diastolic dimensions of the left ventricle decreased significantly (p < 0.01). CONCLUSIONS: Replacement of the artificial chordae was not complicated and seemed to preserve favorable relationships among leaflet tissues, chordae, and papillary muscles. We therefore suggest that the extensive use of PTFE artificial chordae seems to be a promising procedure regarding the repair of many kinds of mitral lesions causing MR.

Mechanical cardiac support system for patients with postcardiotomy cardiogenic shock: analysis of risk factors for survival.

OBJECTIVE: Mechanical cardiac support system (MCSS) has been used for adult patients in postcardiotomy cardiogenic shock and has been shown to provide excellent oxygenation and hemodynamic support. However, MCSS has a number of disadvantages that include high incidence rate of complications (e.g. stroke, bleeding) and limited duration of sufficient support. The objective of this study is to identify perioperative and postoperative factors for survival in patients having MCSS. METHODS: From January 1991 to April 2001, MCSS has been applied to 22 adult patients in postcardiotomy cardiogenic shock. These patients' charts were retrospectively reviewed. RESULTS: Of 22 patients, 9 patients (41%) were successfully weaned, and 6 (27%) were hospital survivors. The duration of assist ranged from 21 to 211 hours (median 66 hours). In 7 (78%) out of 9 patients who could be weaned from MCSS, MCSS were required for less than 3 days. Major complications were reexploration for bleeding (18%), leg ischemia (45%), renal dysfunction (77%), liver dysfunction (59%), infection (31.8%), hypoxia due to lung dysfunction (36%) and cerebral dysfunction (41%). pH, base excess, HCO3-, urine output, transfused platelets at first 24 hours of MCSS and preoperative body surface area were significant predictors for survival. CONCLUSION: The indices of insufficient hemodynamic support such as progression of acidosis or poor urine output are significant predictors for early death. Early conversion from MCSS to long-term assist device, such as left ventricular assist device, should be considered when these factors are associated with poor cardiac recovery.

Heart allograft tolerance without development of posttransplant cardiac allograft vasculopathy in chimerism-based, drug-induced tolerance.

BACKGROUND: Recently, we have described a drug (cyclophosphamide [CP] plus busulfan [BU])-induced skin allograft tolerance in mice that can regularly overcome fully H-2-mismatched barriers. Using this method, we have investigated whether or not this regimen can prolong the survival of heart allografts and inhibit the development of posttransplant cardiac allograft vasculopathy (CAV). METHODS: The components of the method are intravenous administration of 1 x 108 allogeneic spleen cells on day 0, intraperitoneal injection of 200 mg/kg of CP and 30 mg/kg of BU on day 2, and intravenous injection of T cell-depleted 1 x 107 allogeneic bone marrow cells from the same strain of mice on day 3. Heart grafting was performed on day 28. Chimerism in peripheral blood was followed by flow cytometric analysis, and histological analysis was performed at various times after grafting. RESULTS: In a fully major histocompatability complex (MHC)-mismatched combination of B10.D2 (H-2d, IE+)-->B10 (H-2b, IE-), stable, multilineage-mixed chimerism was observed permanently. B10.D2 heart grafts were accepted permanently in a donor-specific manner, and posttransplant CAV did not develop. CONCLUSIONS: These results demonstrated that the drug-induced tolerance recently established by us can regularly induce a long-lasting heart allograft tolerance without development of CAV.