A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients.

OBJECTIVE: Inhaled nitric oxide has been shown to reduce pulmonary vascular resistance in patients undergoing cardiothoracic surgery, but it is limited by toxicity, the need for special monitoring, and cost. Inhaled prostacyclin also decreases pulmonary artery pressure, is relatively free of toxicity, requires no specific monitoring, and is less expensive. The objective of this study was to compare nitric oxide and prostacyclin in the treatment of pulmonary hypertension, refractory hypoxemia, and right ventricular dysfunction in thoracic transplant recipients in a prospective, randomized, crossover pilot trial. METHODS: Heart transplant and lung transplant recipients were randomized to nitric oxide or prostacyclin as initial treatment, followed by a crossover to the other agent after 6 hours. Pulmonary vasodilators were initiated in the operating room for pulmonary hypertension, refractory hypoxemia, or right ventricular dysfunction. Nitric oxide was administered at 20 ppm, and prostacyclin was administered at 20,000 ng/mL. Hemodynamic and oxygenation parameters were recorded before and after initiation of pulmonary vasodilator therapy. At 6 hours, the hemodynamic and oxygenation parameters were recorded again, just before discontinuing the initial agent. Crossover baseline parameters were measured 30 minutes after the initial agent had been stopped. The crossover agent was then started, and the hemodynamic and oxygenation parameters were measured again 30 minutes later. RESULTS: Heart transplant and lung transplant recipients (n = 25) were randomized by initial treatment (nitric oxide, n = 14; prostacyclin, n = 11). Nitric oxide and prostacyclin both reduced pulmonary artery pressure and central venous pressure, and improved cardiac index and mixed venous oxygen saturation on initiation of therapy. More importantly, at the 6-hour crossover trial, there were no significant differences between nitric oxide and prostacyclin in the reduction of pulmonary artery pressures or central venous pressure, or in improvement in cardiac index or mixed venous oxygen saturation. Nitric oxide and prostacyclin did not affect the oxygenation index or systemic blood pressure. There were no complications associated with nitric oxide or prostacyclin. CONCLUSION: In heart transplant and lung transplant recipients, nitric oxide and prostacyclin similarly reduce pulmonary artery pressures and central venous pressure, and improve cardiac index and mixed venous oxygen saturation. Inhaled prostacyclin may offer an alternative to nitric oxide in the treatment of pulmonary hypertension in thoracic transplantation.

Chemokine receptor blockade with a synthetic nonpeptide compound attenuates cardiac allograft vasculopathy.

BACKGROUND.: Recruitment of recipient mononuclear cells to the donor heart is a central event in the development of cardiac allograft vasculopathy (CAV). The role of individual chemokine receptors in this process is incompletely defined. TAK-779 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetra-hydro-2H-pyran-4-aminium chloride) is a synthetic nonpeptide antagonist of CCR5 and CXCR3. The purpose of this study is to determine if combined CCR5 and CXCR3 blockade by TAK-779 would attenuate CAV in an experimental model. METHODS.: We used a previously characterized murine model of CAV. Recipient mice were treated with TAK-779 or vehicle control. Donor hearts were harvested on day 24 posttransplantation and analyzed for intimal thickening and cellular infiltration. Recipient splenocytes were analyzed for proliferative response and interferon (IFN)-gamma production by enzyme-linked immunosorbent spot assay. The donor hearts were also examined for heme oxygenase-1 (HO-1) gene induction. RESULTS.: CCR5 and CXCR3 blockade by TAK-779 reduced the severity of intimal lesions (53+/-10% vs. 16+/-2%; P<0.05) and decreased the number of graft infiltrating CCR5 and CXCR3 CD4 and CD8 lymphocytes. Moreover, treatment with TAK-779 (a) decreased alloantigen-specific T-lymphocyte proliferation and number of IFN-gamma producing cells and (b) increased HO-1 gene transcript level in the allografts. CONCLUSIONS.: Antagonism of CCR5 and CXCR3 by TAK-779 is effective in controlling CAV. The beneficial effects of TAK-779 may be because of (a) reduction in CCR5 and CXCR3 T-lymphocyte subset infiltration into the graft, (b) attenuation of alloantigen-specific T-lymphocyte proliferative response and IFN-gamma production, and (c) induction of HO-1 gene. This compound may offer a novel approach in clinical management of CAV.

Combined CXCR3/CCR5 blockade attenuates acute and chronic rejection.

Chemokine-chemokine receptor interactions orchestrate mononuclear cells recruitment to the allograft, leading to acute and chronic rejection. Despite biologic redundancy, several experimental studies have demonstrated the importance of CXCR3 and CCR5 in acute rejection of allografts. In these studies, deficiency or blockade of CXCR3 or CCR5 led to prolongation of allograft survival, yet allografts were ultimately lost to acute rejection. Given the above findings and the specificity of mononuclear cells bearing CXCR3 and CCR5, we hypothesized that combined blockade of CXCR3 and CCR5 will lead to indefinite (>100 days) graft survival in a full MHC-mismatched murine cardiac allograft model. The donor hearts in the control group were rejected in 6 +/- 1 days after transplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival >15-fold vs the control group; all allografts survived for >100 days. More importantly, the donor hearts did not display any intimal lesions characteristic of chronic rejection. Further analysis of the donor hearts in the CXCR3/CCR5 blockade group demonstrated graft infiltration with CD4(+)CD25(+) T cells expressing the Foxp3 gene. Depletion of CD25(+) cells in the combined CXCR3 and CCR5 blockade group resulted in acute rejection of the allografts in 22 +/- 2 days. Combined CXCR3 and CCR5 blockade also reduced alloantigen-specific T lymphocyte proliferation. Combined CXCR3 and CCR5 blockade is effective in preventing acute and chronic rejection in a robust murine model. This effect is mediated, in part, by CD25(+) regulatory T cell recruitment and control of T lymphocyte proliferation.

Lung transplantation in older patients?

OBJECTIVE: Age 65 years and older is generally considered a contraindication to lung transplantation. Our group has offered lung transplantation to select patients 65 years of age and older who lack other comorbid conditions. We sought to define the short- and medium-term outcome of lung transplantation in patients aged 65 years and older. METHODS: We reviewed the records of our lung transplant recipients from March 2000 to September 2006. During this interval, 50 patients were 65 years or older at the time of transplantation. Fifty patients younger than 65 years were matched to the older cohort by means of propensity analysis. The demographics and perioperative and postoperative characteristics and survival of the 2 groups were compared. RESULTS: Older patients were more likely to receive single-lung transplantation (older group: 76% vs younger group: 16%, P < .05) and nonstandard donor lungs (older group: 46% vs younger group: 28%, P = .06). The composite in-hospital morbidity rate was similar in the older and younger groups. There was no significant difference in the early oxygenation parameters, incidence of acute cellular rejection, or incidence of bronchiolitis obliterans syndrome between the 2 groups. The early survival of the older patients was 95.7% compared with 95.9% in the younger cohort (P = .73). The 1-year survival of the 2 groups was also similar (older group: 79.7% vs younger group: 91.2%, P = .16). The 3-year survival of the older and younger recipients was 73.6% and 74.2%, respectively (P = .64). There were 8 deaths in the older recipient group during the 1-month to 1-year posttransplantation interval, predominantly because of infections. CONCLUSIONS: Lung transplantation can be performed in patients older than 65 years with acceptable clinical outcomes. The "increased" mortality of older patients between 1 month and 1 year after transplantation, predominantly from infectious causes, might be due to immunosenescence of older patients. This finding warrants adjustments in the immunosuppression protocol of older patients undergoing lung transplantation. The effect of offering lung transplantation to older patients on donor lung availability deserves further investigation.