Combination therapy with sildenafil and bosentan reverts severe pulmonary hypertension and allows heart transplantation: case report.

INTRODUCTION: Severe pulmonary hypertension with no response to vasodilators on an acute hemodynamic study is a contraindication to cardiac transplantation. The development of oral pulmonary vasodilators improves the prognosis in these patients. We present the case of a patient whose admission to the waiting list for cardiac transplantation was possible after 6 months of combination therapy with Sildenafil and Bosentan. CASE REPORT: The patient was a 50-year-old man with severe dilated alcohol-induced cardiomyopathy. A pretransplantation study, including a right hemodynamic analysis, revealed irreversible pulmonary hypertension, with 59 mm Hg mean pulmonary artery pressure and 6.4 Wood IU pulmonary vascular resistance, with no response to acute vasodilators with nitric oxide or prostacyclin. Initially, heart transplantation was not possible and the patient started treatment with oral Sildenafil. After 6 months there was no improvement in echocardiographic or hemodynamic parameters, and combination therapy with Bosentan was started. With the combination therapy, the patient progressively improved clinically and hemodynamically, the pressures becoming normal at the sixth month, at which time he was included on the waiting list for a heart transplantation. Eight months later he received a graft with a good posttransplantation course, no right ventricular failure in the acute phase, and absence of pulmonary hypertension on echocardiogrphic and invasive studies. CONCLUSION: Combinations of an oral pulmonary vasodilator with diverse action mechanisms may represent an alternative for patients with irreversible pulmonary hypertension who do not respond to monotherapy.

Sirolimus experience in heart transplantation.

INTRODUCTION: Sirolimus is a potent, nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Recent data support the conversion in late renal failure secondary to calcineurin inhibitors (CNIs), with limited experience in de novo regimens in patients with predictive factors of postoperative renal impairment. OBJECTIVE: We evaluated our experience of sirolimus-based immunosuppression administered to 25 heart transplant recipients. METHODS: A retrospective analysis of 25 heart transplant recipients who received sirolimus included 17 conversions due to late CNI-related chronic renal dysfunction, six patients with a de novo regimen, and two patients who developed posttransplant pulmonary neoplasms. The conversion from CNI to sirolimus was started with 2 mg, with an average time after transplantation of 78 +/- 43 months and a mean baseline serum creatinine level of 2.1 +/- 0.45 mg/dL. The mean clinical follow-up was 17 +/- 9 months postconversion, and included echocardiography and laboratory studies. In the de novo group successive endomyocardial biopsies were performed during the first semester. RESULTS: Serum creatinine fell from 2.1 +/- 0.45 mg/dL to 1.8 +/- 0.51 mg/dL (P = .012). Mean sirolimus levels were 15 +/- 9 ng/mL (doses 2.2 +/- 0.4 mg). This improvement continued until 3 months (creatinine 1.5 +/- 0.35 P < .01)/sirolimus levels 11.7 +/- 5 ng/mL [1.9 +/- 0.7 mg]), with maintenance at 6 months (1.58 +/- 0.3 mg/dL/14 +/- 4 ng/mL [1.85 +/- 0.7 mg]) and 1-year postconversion (1.53 +/- 0.39 mg/dL; P = .019/10.7 +/- 2.5 ng/mL [1.5 +/- 0.7 mg]). De novo, after a mean follow-up of 13 months (range 3 to 35), sirolimus appeared to increase the incidence of a moderate histological grade of rejection without hemodynamic compromise. Side effects were common (63%), including peripheral edema, skin eruptions, and pericardial effusion. Only one patient discontinued treatment, due to intestinal intolerance. Four patients died during follow-up: two because of lung neoplasms and two because of progressive graft vessel disease. CONCLUSION: Sirolimus improved late CNI-related chronic renal dysfunction. Kidney function was preserved using a de novo CNI-free immunosuppressive regimen for recent cardiac transplant recipients.

Sirolimus improves renal function in cardiac transplantation.

In kidney and liver transplantation, sirolimus therapy has been shown to be comparable to cyclosporine in a head-to-head comparison, but it results in better preservation of renal reserve. In heart transplantation, information about the use of sirolimus is limited. We present the results of the progressive conversion from cyclosporine to sirolimus in a series of 8 heart transplant patients in whom renal dysfunction developed. The baseline creatinine level was 2.4 +/- 0.5 mg/dL, and plasma levels of cyclosporine were within the therapeutic range. After the introduction of sirolimus, the creatinine level fell within the first month to 1.76 +/- 0.2 mg/dL, or mean decrease of 0.6 +/- 0.25 mg/dL (P < .05). After 3 +/- 2.2 months the improvement continued (1.69 +/- 0.2 mg/dL). In 1 patient sirolimus was withdrawn during the first 24 hours, because of gastric intolerance. No patient developed an opportunist infection, allograft rejection, or important hematologic disorder. We conclude that sirolimus appears to be effective in heart transplant patients to improve renal function.

Comparative study of muromonab-CD3 (OKT3) versus daclizumab (Zenapax) in cardiac transplantation at our center.

Recent studies support the addition of new immunosuppressive drugs as cytolytic induction therapy in cardiac transplantation. We carried out a comparative study comprising 52 patients who had undergone cardiac transplantation at our center. Thirty patients received muromonab-CD3 (OKT3, Janssen-Cilag, The Netherlands) as the induction therapy, whereas 22 patients received Daclizumab (Zenapax, Hoffman-La Roche, Nutley, NJ, USA) instead. All patients received cyclosporine or tacrolimus, mycophenolate, and steroids. Over an average follow-up period of 23.21 +/- 18 months, we analyzed retrospectively the incidence of grade > or = 3A biopsy-confirmed acute rejection episodes, the presence of infectious processes at 1 and 6 months, the occurrence of significant secondary effects, and the necessity to modify the immunosuppressive therapy during the follow-up. The results suggest that daclizumab is linked to a decreased incidence of grade > or = 3A biopsy-confirmed acute rejection and to a reduced necessity to modify the immunosuppressive therapy during the medium-term follow-up.

Use of oral sildenafil in patients with irreversible pulmonary hypertension not eligible for heart transplantation.

Heart transplantation is contraindicated in patients with acute irreversible pulmonary hypertension (PH), but new drugs are opening up therapeutic possibilities. Sildenafil citrate is a nonselective pulmonary vasodilator that is being used in our hospital to treat several patients with PH and which has allowed the inclusion of 1 patient on the waiting list for heart transplantation. A 20-year-old man with Becker muscular dystrophy was diagnosed at the age of 19 years with dilated cardiomyopathy with severe pulmonary artery systolic pressure (PH = 60 mm Hg). A pretransplantation study, including a right hemodynamic analysis with an acute vasodilator test using intravenous epoprostenol, revealed the irreversible character of the PH. Inasmuch as the administration of dobutamine did not achieve an adequate reduction of PH, oral sildenafil was started (25 mg every 12 hours) as salvage therapy. An echocardiogram obtained 2 months after starting sildenafil therapy showed normal right cavities, previously dilated, as well as minimal protosystolic tricuspid regurgitation without PH. A new right hemodynamic study performed after 4 months showed a reduction in pulmonary vascular resistance, from 8 U to 3.5 U Woods. As a result, the patient has now been included on the waiting list for heart transplantation. The promising example of this patient confirms the necessity to carry out controlled trials to establish definitively the indications for the use of sildenafil in patients with irreversible PH.

Prevalence of sleep breathing disorders in outpatients on a heart transplant waiting list.

Sleep related periodic breathing with recurrent episodes of apnea and hypopnea is known to occur in patients with heart failure. We investigated the prevalence of sleep related breathing disorders (SRBD) in 14 outpatients on a heart transplant waiting list. All were younger than 60 years and had severe stable heart failure. Three patients (21%) exhibited 10 or more apneas and hypopneas per hour of sleep; these apneas and hypopneas were predominantly of the central type and occurred during Cheyne-Stokes respiration. There were no statistically significant differences between the apneic and non-apneic group in terms of age, left ventricular ejection fraction or pulmonary function tests. The group with SRBD had worse quality of life and less tolerance to exercise.