Stable Cardiac Transplant Recipients Research Articles

064 Sirolimus as primary immunosuppression is associated with improved renal function and survival compared with calcineurin inhibitors in stable cardiac transplant recipients

<h3>Purpose</h3> Although transition to sirolimus (SRL) as primary immunosuppression has been associated with an improvement in glomerular filtration rate (GFR), long term follow up has not been reported. The aim of this study was to evaluate GFR in SRL treated patients and to compare with patients remained on CNIs during 5 years follow-up (FU). <h3>Methods and Materials</h3> The study population consisted of 85 cardiac transplant recipients with impaired renal function and/or cardiac allograft vasculopathy in whom CNIs were substituted with sirolimus (SRL group) and 86 cardiac transplant recipients maintained on CNI based immunosuppression (CNI group). Secondary immunosuppressants were not changed. GFR was measured by corrected iothalamate clearance. <h3>Results</h3> Mean follow up was 5.3 (IQR 3.7, 6.1) years. GFR increased from 53.522.4 to 59.524.7 mL/min (p=0.03) 4 years after SRL initiation while in the CNI group, GFR declined from 57.021.8 to 53.120.6 mL/min (p=0.03) in the same period of FU. In multivariate logistic regression analysis, treatment with CNI (p=0.04), lower GFR at study entry (p=0.03), and ischaemic aetiology of cardiomyopathy prior to transplantation (p=0.04), were all associated with long term worsening of GFR. In the SRL group, improvement in GFR was significant in patients with GFR 40 mL/min prior to conversion but not in patients with GFR&lt;40 mL/min. At the end of FU, 3 (4%) vs 6 (7%) (p=0.018), 3 (4%) vs 11 (13%) (p=0.33), and 7 (8%) vs 23 (28%) (p=0.001), in the SRL group vs the CNI group had kidney transplant, required haemodialysis, and died respectively. <h3>Conclusions</h3> Substitution of CNIs with SRL in stable cardiac transplant recipients was associated with improved renal function, particularly in patients with GFR 40 mL/min prior to conversion, and survival. These results suggest that the initial improvement seen with substituting SRL for CNIs is sustained over a longer FU period and this strategy has the potential to improve long-term outcome in cardiac transplantation.

52: Sirolimus as Primary Immunosupression Is Associated with Improved Renal Function and Survival Compared with Calcineurin Inhibitors in Stable Cardiac Transplant Recipients

Although transition to sirolimus (SRL) as primary immunosuppression has been associated with an improvement in glomerular filtration rate (GFR), long term follow up (FU) has not been reported. The aim of this study was to evaluate GFR in SRL treated patients and to compare with patients remained on CNIs during 5 years FU.

Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart. Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting. The mean dose of valsartan was 114 +/- 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group. Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

Sirolimus as primary immunosuppression is associated with improved coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients

The aim of this study was to evaluate coronary vasomotor function in cardiac transplant recipients maintained on sirolimus (SRL)- or cyclosporin (CyA)-based immunosuppression. Endothelium-independent response to intracoronary nitroglycerin and adenosine and endothelium-dependent response to intracoronary acetylcholine (Ach) were assessed in 15 SRL- and 21 CyA- treated subjects with angiographically normal coronary arteries. Baseline mean blood pressure was lower in the SRL group (85.6 +/- 10.3 vs. 105.2 +/- 8.7 mmHg, P = 0.002). There was no difference between the groups in coronary flow reserve after adenosine administration in multivariable analysis (P = 0.34). Nitroglycerin administration resulted in increase in coronary artery diameter in the SRL compared with the CyA groups (2.79 +/- 0.54 vs. 2.57 +/- 0.61, P = 0.0036). In 13 SRL-treated subjects without evidence of cardiac allograft vasculopathy (CAV), Ach administration resulted in less epicardial vasoconstriction compared with CyA-treated subjects (2.7 +/- 17.7 vs. -15.6 +/- 17.2%, P = 0.005). Two SRL-treated subjects with three-dimensional intravascular ultrasound evidence of CAV developed coronary spasm in response to Ach 10(-4). Microvascular endothelial function did not differ between the groups. Sirolimus immunosuppression is associated with less pronounced coronary epicardial endothelial dysfunction compared with CyA immunosuppression. Improvement of coronary vasomotor function with SRL may be an important mechanism for the prevention of CAV.

Lymphocyte activation and correlation with IMPDH activity under therapy with mycophenolate mofetil

Background In an attempt to monitor the pharmacodynamics of mycophenolate mofetil (MMF) we investigated the association of inosine monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells with the expression of lymphocyte activation markers in stable cardiac transplant recipients treated with MMF. Methods Twenty-four study patients were switched from azathioprine to MMF 7.2 ± 4.1 years after heart transplantation. Results While the MPA trough level remained unchanged, the mean activity of IMPDH declined from 890 to 462 pmol/10 6PBMC/h three months after onset of MMF therapy, was almost completely inhibited at six months and partially restored to 160 pmol/10 6PBMC/h 12 months after switch to MMF ( p < .0001). We detected also significant changes in a number of activated lymphocyte subsets: CD4 +/25 +, CD8 +/38 +, CD19 +/69 +, CD3 +/16 +/56 +, natural killer (NK) cells, and monocytes. Moreover, the IMPDH activity profile correlated positively with the number of CD8 +/38 + T cells (correlation coefficient (CC) + 0.53), and inversely with NK cells (CC − 0.52) and CD19 +/69 + cells (CC − 0.61). Conclusions We revealed a close association of IMPDH baseline activity in mononuclear cells with the expression of lymphocyte activation markers in stable heart transplant patients after introduction of MMF therapy. This supports the assumption of a rather immunomodulatory than immunosuppressive effect of MMF.

Replacement of Calcineurin-Inhibitors With Sirolimus as Primary Immunosuppression in Stable Cardiac Transplant Recipients

Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR < or =50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. In the SRL group, GFR increased from 47.0+/-18.0 to 61.2+/-22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5+/-12.7 to 53.9+/-19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2+/-15.8 to 83.5+/-27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5+/-14.0 mL/min to 36.4+/-12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299+/-622 mg/day to 517+/-795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637+/-806 vs. 514+/-744 mg/day, P=0.39). Uric acid decreased from 7.6+/-2.4 to 6.2+/-1.9 mg/dL (P=0.0007) in the SRL group. Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.

218: Replacement of calcineurin-inhibitors with sirolimus to preserve renal function in stable cardiac transplant recipients

Purpose: We have previously demonstrated the feasibility of replacement of calcineurin inhibitors (CNI) with sirolimus (SRL) resulting in improved renal function. We extend these initial observations to a larger cohort of patients over a longer period of time.

Low Levels of High-Density Lipoprotein Cholesterol Are Associated With Vascular Remodeling in Cardiac Transplant Recipients

Background Early atherosclerosis may be associated with compensatory vessel enlargement, termed positive remodeling. Enlarged brachial artery diameter has been reported in patients with risk factors for atherosclerosis and in individuals with coronary atherosclerosis, indicating that brachial artery enlargement is a marker for the presence of atherosclerotic changes. Cardiac transplant recipients often have abnormal lipid levels, but the effect of specific lipid abnormalities on vascular remodeling in this population has not been evaluated. This study examined the relationship between lipid levels and brachial artery diameter in cardiac transplant recipients. Methods Thirty-five stable cardiac transplant recipients underwent high-resolution brachial artery ultrasound to evaluate resting brachial artery diameter. Levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were determined and the presence of other cardiac risk factors was assessed. Results Brachial artery diameter was larger (4.3 ± 0.1 mm) in subjects with low levels of HDL-C (<40 mg/dL, n = 11) compared to subjects with high HDL-C (≥40 mg/dL, n = 24), who had a mean brachial artery diameter of 3.7 ± 0.1 mm ( P = .006). Neither high LDL-C (≥100 mg/dL) nor high triglycerides (≥200 mg/dL) were associated with differences in brachial artery diameter. Multivariate analysis demonstrated that the relationship between low HDL-C and increased brachial artery diameter was independent of body surface area or statin use. Conclusions Low levels of HDL-C are an independent predictor of brachial artery enlargement in stable cardiac transplant recipients. These findings suggest that suboptimal HDL-C levels may be associated with the development of vascular remodeling and atherosclerosis in this population.

355: Canadian pilot study to determine safe and effective dosing of cyclosporine and everolimus in stable cardiac transplant recipients: Twelve-week interim analysis

355: Canadian pilot study to determine safe and effective dosing of cyclosporine and everolimus in stable cardiac transplant recipients: Twelve-week interim analysis

Sirolimus in Cardiac Transplantation: Use as a Primary Immunosuppressant in Calcineurin Inhibitor–induced Nephrotoxicity

Calcineurin inhibitor (CNI) immunosuppressants are a major cause of renal dysfunction in cardiac transplant recipients, leading to increased morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of CNI withdrawal and substitution with sirolimus as the primary immunosuppressant, and assess the effect on renal function in cardiac transplant recipients with CNI-induced renal impairment. Thirty-four stable cardiac transplant recipients (range 1 to 14 years post-transplant) with CNI-induced nephrotoxicity (iothalamate clearance 25 to 50 ml/min) or cardiac allograft vasculopathy (CAV) were enrolled. Twelve patients (Group A) were prospectively enrolled for renal dysfunction. The remaining patients (n = 22, Group B) were converted to sirolimus on clinical grounds because of poor renal function or the presence of CAV. CNI was withdrawn gradually over 12 weeks. Sirolimus was started at 1 mg/day with titration over 2 weeks to achieve levels of 10 to 15 ng/ml. Echocardiograms and cardiac biopsies were performed to determine rejection. Adjunct immunosuppression was left unchanged. Follow-up iothalamate clearance was performed. A further 24 patients (Group C) were retrospective controls, stable (range 2 to 10 years post-transplant), and maintained on a standard CNI-based immunosuppressant regimen. Iothalamate clearance (C(i)) improved significantly (Group A baseline: 36.08 +/- 2.4 ml/min to 48.67 +/- 4.1 ml/min, p = 0.004; Group B baseline: 48.14 +/- 3.2 ml/min to 55.77 +/- 4.2 ml/min, p < 0.001) without exacerbating rejection or compromising cardiac function. By contrast, in controls, Group C, the baseline renal clearance declined from 40.04 +/- 1.86 ml/min to 34.63 +/- 1.6 ml/min over the course of 1 year (p < 0.01). Substitution of CNIs with sirolimus in cardiac transplant recipients is safe and effective and leads to an improvement in renal function, without compromise in cardiac function and rejection.

Atrial resynchronisation after heart transplant in childhood

Objectives: Exercise capacity is known to be reduced in clinically stable cardiac transplant recipients, there is a substantial attenuation in the peak heart rate response to a maximal exercise effort due to the lack of direct sympathetic innervation of the donor SA node. Recipient SA node can still respond to this stimulation and we hypothesised that resynchronisation of both atria could improve exercise tolerance in these patients.

Regular use of margarine-containing stanol/sterol esters reduces total and low-density lipoprotein (LDL) cholesterol and allows reduction of statin therapy after cardiac transplantation: preliminary observations

Seventeen stable cardiac transplant recipients, of whom 16 were on statin therapy, used margarine with stanol/sterol esters. Total cholesterol in the treatment group was lowered from 211 mg/dl (range 168 to 244) to 177 mg/dl (136 to 241) (17% reduction, p = 0.003) and low-density lipoprotein (LDL) cholesterol was reduced from 125 mg/dl (73 to 161) to 98 mg/dl (57 to 146) (22% reduction, p = 0.0006). LDL cholesterol reached the pre-defined cut-off level of 115 mg/dl in 12 of 17 patients and statin dosages were reduced. In 8 of 12 patients, LDL cholesterol remained at <115 mg/dl 6 weeks after statin reduction.

Usefulness of B-type natriuretic peptide levels in predicting hemodynamic perturbations after heart transplantation despite preserved left ventricular systolic function

The aim of this prospective study was to evaluate the association of peripheral B-type natriuretic peptide (BNP) levels with clinical symptoms and central hemodynamic and echocardiographic measures in cardiac transplantation. BNP reflects ventricular wall stress and correlates with severity of heart failure. No previous investigation has comprehensively assessed the rapid bedside BNP assay for predicting hemodynamic measures of cardiac allograft function in heart transplantation. We evaluated BNP levels using a rapid point-of-care assay in 87 stable cardiac transplant recipients who had 237 consecutive measurements along with endomyocardial biopsy, right-sided cardiac catheterization, and echocardiography. Using median tendencies, 2 groups were identified: the low BNP group (n = 116, BNP <150 pg/ml) and the high BNP group (n = 121, BNP ≥150 pg/ml). The high BNP group had increased right atrial pressures, higher pulmonary artery systolic pressures, pulmonary capillary wedge pressures, and lower cardiac index. Besides hemodynamic variables, the presence of right ventricular dysfunction (p = 0.05) and significant tricuspid regurgitation (p = 0.003) were associated with higher BNP levels. Independent predictors of BNP levels on multivariate analysis included elevated pulmonary capillary wedge pressure, lower cardiac index, and symptoms of dyspnea and fatigue. This initial investigation establishes the accuracy of a point-of-care BNP assay in predicting cardiopulmonary hemodynamic aberrations despite preserved left ventricular systolic function in heart transplant recipients. Rapid bedside BNP analysis may provide a noninvasive surrogate method for the comprehensive assessment of cardiac allograft function and hemodynamics in heart transplantation.

Activation-induced T cell death, and aberrant T cell activation via TNFR1 and CD95-CD95 ligand pathway in stable cardiac transplant recipients.

Specific blockade by antibodies (Abs) utilized in induction therapy may cause activation-induced cell death (AICD) in lymphocytes of transplant recipients, preactivated via CD95 and tumour necrosis factor-alpha receptor type 1 (TNFR1), and reduce allograft rejection frequency. Amongst 618 heart transplant (HTX) patients receiving antithymocytes globulin (ATG) therapy, 14 recipients with IVUS-verified freedom of transplant vasculopathy were studied. The control group contained 14 patients awaiting transplantation, classified by the New York Hearth Association heart failure as class IV. From 618 HTX patients 89% were free of rejection grade ISHLT > or =2-3 within 3-month post transplantation and 86% after one year. The death inducing receptors (DIR) such as CD95, CD95L and soluble TNFR1 were significantly increased in HTX recipients versus controls, as demonstrated by FACS, immunoblotting or ELISA (P < 0.001). The presence of increased DIR and in vivo apoptosis in HTX recipients, indicated by annexin-V binding, was further confirmed by the presence of high concentration of histones in the sera of patients. ATG, anti-IL-2R and OKT-3 Abs inhibited cell proliferation in a dose-dependent manner. The induction of apoptosis and/or necrosis was demonstrated in cells cultured with these Abs by annexin-V and 7-aminoactinomycin staining, respectively. Our findings demonstrate that T cells from HTX recipients express high level of CD95, CD95L and soluble TNFR1, and undergo apoptosis and AICD. These cells recognizing donor alloantigens may be selectively eliminated in vivo, and should be responsible for the observed immunological unresponsiveness, indicated by low rejection rates in our patient cohort treated by conventional triple therapy.

Increased death inducing receptors in vivo and activation-induced T-cell death by anti-thymocyte antibody treatment of stable cardiac transplant recipients

Introduction: Specific and unspecific triggering of the immunesystem triggers the CD95 and TNF receptor pathway. We aimed to identify if alloantigen activates T cells to upregulate the apoptosis trigger CD95 and if shedding of sTNF R1 takes place. Moreover, we sought to investigate if drugs which are capable of reducing rejection frequency in heart transplantation are triggering activation induced cell death (AICD) in T-cells.

Renal hemodynamic effects of l-arginine and sodium nitroprusside in heart transplant recipients

Long-term treatment with cyclosporine A (CsA) induces vasoconstriction in the kidney and causes renal impairment. An altered L-arginine (L-Arg)/nitric oxide (NO) pathway may play a key role in CsA nephrotoxicity. We studied the effect of L-Arg (dosage, 17 mg/kg/min over 30 min), the precursor of NO synthesis, and sodium nitroprusside (SNP; dosage, 1.0 microgram/kg/min over 30 min) on renal hemodynamics in a double-blind, placebo-controlled, randomized, three-way cross-over study comprising 12 stable cardiac transplant recipients on long-term CsA treatment, 10 patients with chronic nephropathy not receiving CsA, and 13 healthy controls. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by paraaminohippurate (PAH) and the inulin clearance method, respectively. In healthy subjects, L-Arg induced an increase in RPF (P = 0.009) and GFR (P = 0.001). By contrast, L-Arg did not induce renal hemodynamic effects in heart transplant patients or patients with chronic nephropathy. SNP reduced RPF (P = 0.050) and GFR (P = 0.005) in patients with chronic nephropathy but did not affect renal hemodynamics in heart transplant recipients or in healthy subjects. These data indicate that L-Arg cannot be used to reverse CsA-induced renal vasoconstriction in heart transplant recipients under long-term CsA treatment, although these patients have a normal renal response to SNP.