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Background: In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i., Methods: In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences., Results: Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07)., Conclusion: In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Pharmacokinetic modeling supports trough monitoring of everolimus, but prospective data comparing this approach versus mycophenolate mofetil (MMF) in de novo cardiac transplant recipients are currently unavailable., Methods: In a 12-month multicenter open-label study, cardiac transplant patients received everolimus (trough level 3-8 ng/mL) with reduced cyclosporine A (CsA) or MMF (3 g/day) with standard CsA, both with corticosteroids+/-induction therapy., Results: In total, 176 patients were randomized (everolimus 92, MMF 84). Mean creatinine clearance was 72.5+/-27.9 and 76.8+/-32.1 mL/min at baseline, 65.4+/-24.7 and 72.2+/-26.2 mL/min at month 6, and 68.7+/-27.7 and 71.8+/-29.8 mL/min at month 12 with everolimus and MMF, respectively. The primary endpoint was not met since calculated CrCl at month 6 posttransplant was 6.9 mL/min lower with everolimus, exceeding the predefined margin of 6 mL/min. However, by month 12 the between-group difference had narrowed versus baseline (3.1 mL/min). All efficacy endpoints were noninferior for everolimus versus MMF. The 12-month incidence of biopsy-proven acute rejection International Heart and Lung Transplantation grade more than or equal to 3A was 21 of 92 (22.8%) with everolimus and 25 of 84 (29.8%) with MMF. Adverse events were consistent with class effects including less-frequent cytomegalovirus infection with everolimus (4 [4.4%]) than MMF (14 [16.9%], P=0.01)., Conclusion: Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation.

Our results suggest that bezafibrate may be useful in the treatment of high Lp(a) levels in heart transplant patients.

We analyzed the presence of T-cell subsets (CD4/CD8) and the activation markers CD25 and CD69 in the cellular infiltrates of endomyocardium biopsies taken from transplanted human hearts. The results indicate that CD25 was present within specimens mainly infiltrated by CD4+ cells. In contrast, CD69 was found in infiltrated biopsies by CD8+ cells, as determined by single immunofluorescence. Double immunoenzymatic staining was used to investigate the cellular distribution of the activation markers studied in some representative cases. Thus, CD25 was found on both CD4+ and CD8+ cells while CD69 molecule was selectively expressed on CD8+ T-cell subset. These results suggest that CD69 is a surface molecule relevant to the CD8+ cell-mediated graft rejection events of allografted human hearts.

The effects of an acute increase in preload, afterload, and inotropic state on several indices of left ventricular contractility were studied in 20 anesthetized intact dogs. The behaviour of the exponential rate of fiber shortening (ERFS), a newly described index, which is based on the instantaneous fiber length--time relationship through ejection, was compared with other classical ejection and isovolumic indices of left ventricular contractility. Acute volume overload by dextran 40 infusion produced a significant increase in preload as reflected by a 103% (p less than 0.01) increase in left ventricular end-diastolic pressure and a 121% (p less than 0.001) increase in end-diastolic circumferential wall stress. There was also a smaller but significant increase (p less than 0.05) of heart rate (30%) and of peak systolic circumferential wall stress (24%). None of the left ventricular contractility indices showed any significant change. Acute pressure overload, produced mechanically by an aortic balloon, increased the afterload significantly as reflected by a 33% (p less than 0.05) rise of end-systolic circumferential wall stress and a 43% (p less than 0.001) increase in systemic resistance. Stroke volume decreased significantly by 23% (p less than 0.05). All ejection indices, including ERFS, were significantly diminished by 30-37%; all isovolumic indices showed no significant changes. Positive inotropic intervention was induced by dopamine infusion, which caused a significant 28% (p less than 0.05) increase in cardiac output. End-diastolic and end-systolic circumferential wall stress were significantly diminished. All indices of left ventricular contractility increased significantly and ERFS showed the quantitatively greatest change.(ABSTRACT TRUNCATED AT 250 WORDS)

Seven patients, mean age 8 +/- 3.6 years, with clinical and hemodynamic diagnoses of discrete subaortic stenosis were treated by percutaneous transluminal balloon dilatation (PTBD) of the membrane during cardiac catheterization. One patient had an associated aortic coarctation that was first dilated. After PTBD left ventricular (LV) systolic pressure decreased significantly, from 181 +/- 25 to 139 +/- 11 mm Hg (p less than 0.005); peak gradient diminished from 65 +/- 18 to 12 +/- 9 mm Hg (p less than 0.001). Mild aortic regurgitation was present in 6 patients during basal conditions. After PTBD, the same degree of regurgitation was observed in all but 1 patient, in whom it disappeared. There were no major complications. Clinical observations after PTBD were consistent with hemodynamic findings. Precordial thrill always disappeared and the peak murmur became earlier in systole. In 2 patients the discrete subaortic stenosis was clearly visualized at 2-dimensional echocardiography as a fixed subvalvular structure throughout the cardiac cycle. After dilatation this was only identifiable at its implantation base; during contraction there was no fixed structure at the LV outflow tract. Four patients were hemodynamically reevaluated 6.7 +/- 1.7 months later and were found to have LV pressure relief and a degree of aortic regurgitation similar to those observed immediately after PTBD.