Heart transplant recipients are at increased risk of developing malignant neoplasms. Administration of the calcineurin inhibitors cyclosporine A (CSA) or tacrolimus (TAC) may contribute to this risk.
...We compared tumor incidence in heart transplant recipients receiving either CSA (n=25) or TAC (n=120) as maintenance immunosuppressive therapy. Exclusion criteria were therapy with mammalian target of rapamycin-inhibitors, death within the first postoperative year, re-transplantation, and age less than 18 years.
The 2 study groups were comparable with respect to sex, primary and concomitant diagnoses, and mean follow-up (60.7 ± 19.3 months in the CSA group vs. 59.8 ± 18.1 months in the TAC group; P=0.81). The CSA group was, however, significantly older compared with the TAC group (58.8 ± 11.4 years vs. 49.1 ± 13.0 years, P=0.001), as was the donor age of the CSA group (43.2 ± 11.2 years vs. 37.0 ± 11.7 years, P=0.02). In the CSA group, 5 patients (20%) developed malignant neoplasms compared with 10 patients (8.3%) in the TAC group (P=0.14). Covariate-adjusted 5-year tumor-free survival was comparable between groups (relative risk for the CSA group =1.162 95% CI: 0.378-3.572; P=0.794). Moreover, covariate-adjusted 5-year overall survival did not differ between the 2 groups (relative risk for the CSA group =1.95 95% CI: 0.53-7.19; P=0.36). The incidence of infection, acute rejection, graft vasculopathy, renal failure, and neurological complications was also comparable between the 2 groups.
Our data indicate that tumor incidence does not significantly differ in patients receiving CSA or TAC as maintenance therapy.
Clopidogrel reduces post‐transplant obliterative bronchiolitis Preidl, Raimund H. M.; Eckl, Sebastian; Ramsperger‐Gleixner, Martina ...
Transplant international,
October 2013, 2013-Oct, 2013-10-00, 20131001, Letnik:
26, Številka:
10
Journal Article
Recenzirano
Summary
Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by ...clopidogrel has an influence on the formation of obliterative bronchiolitis, the histopathological correlate to bronchiolitis obliterans syndrome, present in the majority of patients suffering from CLAD. C57Bl/6(H2b) donor tracheas were orthotopically transplanted into CBA.J(H2k). Mice received different doses of clopidogrel alone or in combination with tacrolimus or everolimus. Grafts were analyzed by histology and immunofluorescence method on postoperative days 15, 30 or 60. Cytokines were analyzed by real‐time polymerase chain reaction on postoperative day 21 and alloantibodies by FACS. Mice treated with 20 mg/kg/day clopidogrel for 30 days showed reduced obliteration 34.40 ± 3.76% (20 mg/kg/day clopidogrel) vs. 49.92 ± 2.11% (control), n = 5, P < 0.05. Platelet inhibition resulted in significant lower infiltration of T cells and macrophages, and we also found significantly lower expression of IL‐12, IL‐4, IL‐6, TNF‐α, TGF‐β, PDGFβ, MCP1, P‐/E‐selectin, ICAM1 and CD40L after treatment with clopidogrel. Combination of 1 mg/kg/day clopidogrel and 0.05 mg/kg/day everolimus or 12 mg/kg/day tacrolimus revealed a synergistic effect. Humoral immunity as manifested by donor‐specific alloantibody secretion was also impaired after treatment with clopidogrel. Here, we can show that platelet inhibition by clopidogrel as a single treatment and in combination with tacrolimus or everolimus reduced the development of fibrosis and obliteration in tracheal allografts.
Cytomegalovirus infection after heart transplantation is considered as risk factor for the development of transplant arteriosclerosis. Therefore, the aim of this study was to investigate the effect ...of murine cytomegalovirus (MCMV) as a single risk factor on transplant arteriosclerosis in an experimental aortic allograft model.
Major histocompatibility complex class I-mismatched aortas of C.B10-H2(b)/LilMcdJ donor were transplanted into BALB/c recipients, which were either mock-infected or infected with MCMV (strain Smith) on day 7 and harvested 37 days after transplantation. In one experimental group animals received a daily dose of everolimus to increase the viral load of recipients. Grafts were analyzed by histology, morphometry, and immunofluorescence. Intragraft cytokine mRNA production was analyzed by real-time polymerase chain reaction (PCR), and persistence of cytomegalovirus infection was confirmed by TaqMan PCR.
After infection with MCMV, there was significantly more intimal proliferation when compared with uninfected controls (intimal proliferation 83.5%+/-9.6% MCMV vs. 43.9%+/-5.1% MCMV), indicating that MCMV plays a role in the development of transplant arteriosclerosis. Even after treatment with everolimus, MCMV infection pronounced significantly more intimal proliferation (intimal proliferation 52.5%+/-7.3% MCMV vs. 20.2%+/-1.7% MCMV). Intragraft mRNA expression showed significantly higher production of CD62E, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 after infection with MCMV. Cellular infiltration revealed significantly more CD4, CD8, and dendritic cells. We could also confirm the presence of MCMV for the duration of the experimental protocol by PCR within the spleen, liver, salivary glands, lung, and the aortic transplant.
These data suggest that MCMV infection plays an important role in the development of transplant arteriosclerosis.
Abstract
Aims
We sought to evaluate the outcomes of transcatheter mitral valve replacement (TMVR) for patients with degenerated bioprostheses valve-in-valve (ViV), failed annuloplasty rings ...valve-in-ring (ViR), and severe mitral annular calcification valve-in-mitral annular calcification (ViMAC).
Methods and results
From the TMVR multicentre registry, procedural and clinical outcomes of ViV, ViR, and ViMAC were compared according to Mitral Valve Academic Research Consortium (MVARC) criteria. A total of 521 patients with mean Society of Thoracic Surgeons score of 9.0 ± 7.0% underwent TMVR (322 patients with ViV, 141 with ViR, and 58 with ViMAC). Trans-septal access and the Sapien valves were used in 39.5% and 90.0%, respectively. Overall technical success was excellent at 87.1%. However, left ventricular outflow tract obstruction occurred more frequently after ViMAC compared with ViR and ViV (39.7% vs. 5.0% vs. 2.2%; P < 0.001), whereas second valve implantation was more frequent in ViR compared with ViMAC and ViV (12.1% vs. 5.2% vs. 2.5%; P < 0.001). Accordingly, technical success rate was higher after ViV compared with ViR and ViMAC (94.4% vs. 80.9% vs. 62.1%; P < 0.001). Compared with ViMAC and ViV groups, ViR group had more frequent post-procedural mitral regurgitation ≥moderate (18.4% vs. 13.8% vs. 5.6%; P < 0.001) and subsequent paravalvular leak closure (7.8% vs. 0.0% vs. 2.2%; P = 0.006). All-cause mortality was higher after ViMAC compared with ViR and ViV at 30 days (34.5% vs. 9.9% vs. 6.2%; log-rank P < 0.001) and 1 year (62.8% vs. 30.6% vs. 14.0%; log-rank P < 0.001). On multivariable analysis, patients with failed annuloplasty rings and severe MAC were at increased risk of mortality after TMVR ViR vs. ViV, hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.27–3.12; P = 0.003; ViMAC vs. ViV, HR 5.29, 95% CI 3.29–8.51; P < 0.001.
Conclusion
The TMVR provided excellent outcomes for patients with degenerated bioprostheses despite high surgical risk. However, ViR and ViMAC were associated with higher rates of adverse events and mid-term mortality compared with ViV.
Transcatheter aortic valve-in-valve implantation represents one interesting therapeutic option for high-risk surgical patients with degenerated bioprostheses. The procedure is less invasive and can ...be performed without thoracotomy and general anesthesia, if the femoral approach is used. Until recently, failing small bioprostheses could only be treated percutaneously by underexpanding the CoreValve (Medtronic, Inc) or Edwards Sapien valve (Edwards Lifesciences). Underexpansion of these valves might compromise the hemodynamic performance and potentially limit its durability. Herein, we report our initial experience with the 23 mm CoreValve Evolut in 4 patients with degenerated 21 mm Mitroflow valves. The CoreValve prosthesis was successfully implanted in all 4 patients, with no major complications and no mortality at 3-month follow-up exam. However, 2 of the 4 patients developed mildly elevated transvalvular gradients. Therefore, despite our promising results, caution is necessary when considering patients with small degenerated bioprostheses for a valve-in-valve procedure.
Abstract One promising approach for the induction of transplant tolerance is the pre-treatment of transplant recipients with donor MHC-alloantigen. Our study focuses on the oral delivery of ...MHC-antigen encoding genes via chitosan-DNA nanoparticles to modulate the alloimmune response in order to reduce the development of transplant arteriosclerosis, the hallmark feature of chronic rejection after heart transplantation. Therefore, we performed fully allogeneic mouse abdominal aortic transplants using C57BL/6 (H2b ) mice as donors and CBA.J (H2k ) mice as recipients. Aortic grafts were analyzed by histology and morphometry on day 30 after transplantation, levels of circulating alloantibodies were detected by FACS analysis. Pre-treatment of recipient mice with chitosan-DNA nanoparticles encoding for Kb , one of the MHC-I molecules of the donor, resulted in a significant reduction of intimal proliferation compared to untreated controls. When Ovalbumin was fed instead of Kb encoding nanoparticles (Kb -NP) or Balb/c (H2d ) grafts were used instead of C57BL/6 (H2b ) grafts as antigen controls, both groups showed no reduction of intimal thickness indicating an antigen-specific mechanism. In addition, analysis of peripheral blood of the transplanted mice showed significant suppression of alloantibody formation in the Kb -NP fed group compared to all other allogeneic transplanted groups suggesting modulation of the humoral immune response. These results demonstrate the potential of chitosan-DNA nanoparticles to induce Kb -specific tolerance and to reduce the development of transplant arteriosclerosis.
Summary
Our group has shown that platelet inhibition with clopidogrel, an antagonist of the P2Y12 adenosine diphosphate receptor on platelets, reduced the formation of transplant arteriosclerosis. ...The aim of this study was to investigate whether a combination of cyclosporin or everolimus with clopidogrel has a beneficial effect on the development of transplant arteriosclerosis. Fully MHC mismatched C57Bl/6 (H2b) donor aortas were transplanted into CBA.J (H2k) recipients and mice received either clopidogrel alone (1 mg/kg/day) or in combination with cyclosporin (2 mg/kg/day) or everolimus (0.05 mg/kg/day). Grafts were analysed by histology and morphometry on day 30 after transplantation. In mice treated with clopidogrel alone, transplant arteriosclerosis was significantly reduced intima proliferation 56 ± 11% vs. 81 ± 7% (control)/n = 7. Daily application of everolimus reduced the development of transplant arteriosclerosis compared with untreated controls intima proliferation of 29 ± 9% vs. 81 ± 7% (control)/n = 7. Strikingly, combination of clopidogrel and everolimus almost abolished the formation of transplant arteriosclerosis intima proliferation: 11 ± 8% vs. 81 ± 7% (control)/n = 7. By contrast, combination of cyclosporin and clopidogrel compared with clopidogrel alone showed no additive effect. These results demonstrate that combination of platelet‐ and mammalian target of Rapamycin‐inhibition can dramatically reduce the development of transplant arteriosclerosis.
Clopidogrel reduces the development of transplant arteriosclerosis Abele, Silke; Weyand, Michael; Wollin, Martina ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
05/2006, Letnik:
131, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Transplant arteriosclerosis, the hallmark feature of chronic rejection, is still the major limiting factor for the long-term success of heart transplantation. Platelets have been implicated to play a ...role in the pathogenesis of this disease. Therefore the aim of this study was to investigate whether platelet inhibition alone has a positive effect on the development of transplant arteriosclerosis.
Fully major histocompatibility complex–mismatched C57BL/6 (H2
b) donor aortas were transplanted into CBA (H2
k) recipients, and mice received different doses (1, 10, and 20 mg/kg) of clopidogrel or control saline as a daily intraperitoneal injection for 30 days. Blood was analyzed on days 2, 7, 14, and 30 by using a platelet aggregation test (adenosine diphosphate) for effectiveness of the treatment. Grafts were analyzed by means of histology and morphometry on day 30 after transplantation.
When mice were treated daily with 1 mg/kg clopidogrel in the absence of any other immunosuppression, transplant arteriosclerosis was significantly reduced compared with that seen in saline-treated control animals (intimal proliferation of 66% ± 9% 1 mg/kg clopidogrel vs 77% ± 5% control, n = 7,
P ≤ .03). Daily application of 10 mg/kg and 20 mg/kg clopidogrel also significantly reduced the development of transplant arteriosclerosis compared with that seen in control animals (intimal proliferation of 61% ± 11% 10 mg/kg clopidogrel vs 54% ± 10% 20 mg/kg clopidogrel vs 77% ± 5% control, n = 8,
P ≤ .003). There was, however, no additional beneficial effect when compared with mice treated with 1 mg/kg clopidogrel (
P = .06). Isografts did not show any signs of vascular lesions on day 30 after transplantation.
These results demonstrate that monotherapy with clopidogrel can effectively reduce the formation of transplant arteriosclerosis in a murine aortic allograft model.
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