Function In Cardiac Transplant Recipients Research Articles

Impact of mTOR Inhibitor Conversion Protocol on Renal Function in Cardiac Transplant Recipients

<h3>Purpose</h3> Renal insufficiency is common in heart transplant recipients and is associated with increased all-cause cardiovascular mortality. The use of mammalian target of rapamycin inhibitor (mTORi)-based immunosuppression may help mitigate the renal insufficiency associated with calcineurin inhibitors (CI), however complete CI withdrawal is associated with an increased risk of rejection. This study aims to evaluate the effect of mTORi-based immunosuppression with low dose tacrolimus on renal function in patients post-cardiac transplant. <h3>Methods</h3> This was a single-center retrospective study of adult heart transplant recipients who were initiated on an mTORi at least six months post-transplant. The primary outcome of this study was change in renal function from pre-conversion to 3-, 6-, and 12-months post-mTORi initiation. Patients served as their own controls from pre-to-post conversion. <h3>Results</h3> A total of 61 heart transplant patients met inclusion criteria. At baseline, all patients remained on concomitant tacrolimus which was continued in 84% of patients at one year. Renal function for all patients was significantly improved at 3 months (p = 0.001) and 6 months (p = 0.004) post conversion, although the largest impact was seen in those with a baseline eGFR < 35mL/min/1.73m2. Change in renal function over time also differed by goal tacrolimus level. For patients with FK level less than 4 ng/mL, there was a significant main effect of time on eGFR (p=0.0004). There were no significant differences in renal function for the goal tacrolimus ranges of 4-6 ng/mL or 6-8 ng/mL at any time point. There were no identified safety concerns and no difference in rejection. <h3>Conclusion</h3> Overall, conversion to mTORi-based immunosuppression with low dose CI was shown to be associated with improved renal function at 3- and 6-months post conversion. Renal recovery appeared to be greatest for patients with baseline eGFR <35 mL/min/1.73m2 and in those with an FK goal < 4 ng/mL. To our knowledge, this is one of the first studies to describe the impact of FK goal levels on renal function post-conversion to mTORi-based immunosuppression. These results suggest renal improvement may be feasible while maintaining low target levels of CI therapy.

Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73 m(2) were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. -1.4 mL/min/1.73 m(2) , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

56 Safety and Efficacy of Conversion to Sirolimus vs Continued Calcineurin Inhibitor Use in Cardiac Transplant Recipients with Renal Insufficiency

Evaluate the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus (SRL) vs continued CNI use on renal function in cardiac transplant recipients with mild to moderate renal insufficiency.

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.

18: Sirolimus as Primary Immunosuppressant Attenuates Left Ventricular Hypertrophy and Improves Diastolic Function in Cardiac Transplant Recipients

18: Sirolimus as Primary Immunosuppressant Attenuates Left Ventricular Hypertrophy and Improves Diastolic Function in Cardiac Transplant Recipients

357: Does basiliximab decrease acute rejection and improve renal function in cardiac transplant recipients at mid-term follow-up

357: Does basiliximab decrease acute rejection and improve renal function in cardiac transplant recipients at mid-term follow-up

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.

Pyridoxine improves endothelial function in cardiac transplant recipients

Background: Endothelial dysfunction is common in cardiac transplant recipients and predicts the development of transplant coronary artery disease. Hyperhomocysteinemia is associated with endothelial dysfunction in the general population, is common in transplant recipients, and has been associated with transplant coronary artery disease. Thus therapy that decreases homocysteine concentrations might also improve endothelial function and decrease the risk of transplant coronary artery disease. Folate and pyridoxine are important cofactors in distinct aspects of homocysteine metabolism. The purpose of this study was to determine whether folate or pyridoxine supplementation improves endothelial function in cardiac transplant recipients. Methods and Results: This was a double-blind, randomized, placebo-controlled trial. We assigned 31 transplant recipients to either pyridoxine ( n = 11:100 mg/day), folate ( n = 12:5 mg/day), or placebo ( n = 8) for 10 weeks. Fasting and post-methionine-load (methionine 100 mg/kg orally) homocysteine concentrations were determined. Brachial artery flow-mediated dilatation was used as a measure of endothelial function. At follow-up, we noted no significant changes in homocysteine concentrations in any of the groups. However, pyridoxine supplementation was associated with a significant improvement in endothelial function (2.8 ± 6.7 to 6.9 ± 6.3, p = 0.05). No significant changes were seen in patients treated with folate or placebo. Conclusions: Pyridoxine, but not folate supplementation, significantly improves endothelial function in cardiac transplant recipients.

Intermediate term results of total lymphoid irradiation for the treatment of non-specific graft dysfunction after heart transplantation.

A proportion of heart transplant recipients develop poor graft function in the absence of cellular infiltrate in endomyocardial biopsies or transplant associated coronary artery disease. The condition has a poor prognosis and its aetiology is poorly understood. We report encouraging intermediate term results with total lymphoid irradiation (TLI) in the management of this condition. Eleven adult cardiac transplant recipients who developed severe allograft dysfunction (NYHA class-4) at a median period of 4 months after orthotopic heart transplantation were successfully treated with TLI. Endomyocardial biopsies and coronary angiography were normal in each patient and biventricular failure developed in spite of immunosuppression with Cyclosporin-A, Azathioprine, oral Prednisolone, Cyclophosphamide and intravenous Methylprednisolone therapy. Total lymphoid irradiation was given with standard Mantle and inverted Y-fields over ten treatments to achieve a cumulative dose of 8 Gy. Each patient had a significant improvement in clinical response and in ventricular performance within 2 months of commencing TLI. Nine patients are currently well (four NHYA class-1, five NHYA class-2) at 4-48 (median 26) months following TLI. Two patients died; one from bacterial septicaemia and one as a consequence of chronic renal failure. Three patients developed opportunistic infection which was successfully treated with appropriate antimicrobial agents. An Ebstein-Barr virus associated lymphoproliferative disorder occurred in one patient and was successfully treated by reduction in immunosuppression and high dose Acyclovir. Two patients developed transient bone marrow suppression. The intermediate term results of TLI in the management of poor graft function in cardiac transplant recipients with normal endomyocardial biopsies and coronary angiography are encouraging. Although complications of opportunistic infection, bone marrow suppression and lymphoproliferative disorder occurred, treatment was successful in each case.

Prognostic significance of coronary flow reserve on left ventricular ejection fraction in cardiac transplant recipients.

Cardiac allograft vasculopathy is a common phenomenon in epicardial and microvascular vessels. Intramyocardial vessel disease may lead to small, stellate infarcts. The present study tested the impact of microvascular vasomotor function on changes in left ventricular systolic function in the long-term follow-up after cardiac transplantation. Seventeen consecutive cardiac transplant patients, 40+/-21 months after cardiac transplantation, without angiographically visible cardiac allograft vasculopathy and without episodes of acute rejection were included in the study. Coronary microvascular reactivity was assessed by the endothelium-dependent stimulus acetylcholine (50 microg i.c.) and by the endothelium-independent stimulus dipyridamole (0.56 mg/kg i.v.) utilizing an Doppler catheter. Radionuclide ventriculography was performed at the time of coronary flow measurement and repeated 2 years later to correlate changes in left ventricular ejection fraction with the coronary flow reserve measurement 2 years previously. There was a statistically significant correlation between endothelium- independent coronary flow reserve to dipyridamole and changes in ejection fraction at rest (r=0.59; P < 0.01) and during exercise (r=0.48; P < 0.05). Twenty-four months later, patients with a coronary flow reserve to dipyridamole < 2.5 showed a significant decline in ejection fraction during exercise (-7 +/- 5%) compared to patients with a coronary flow reserve > 2.5 (1.1+/-5%; P=0.003). Coronary flow reserve to acetylcholine was not correlated with a reduced ejection fraction during exercise. Endothelium-independent microvascular dysfunction has prognostic importance for deterioration of left ventricular function in cardiac transplant recipients without angiographically visible coronary artery stenoses. These results reinforce the concept that microvascular and epicardial vessel disease after transplantation are two distinct entities with different functional consequences.

Cardiac microvascular vasomotor response as a prognostic marker of left ventricular function in cardiac transplant recipients

T HE long-term survival of patients after heart transplantation is limited by the development of cardiac allograft vasculopathy (CAV).’ The lumina of the smaller intramyocardial branches are often occluded before those of the larger epicardial arteries and this results in small, multiple, stellate infarcts.’ To assess the degree to which transplant vascular sclerosis affects the resistance vessels, coronary blood flow measurement is useful. Several studies in transplant recipients suggest that resistance vessel function is altered at an early stage of the coronary disease process. 3,4 The left ventricular systolic function is relatively well preserved in patients without significant acute rejection5 but the importance of microvascular vasomotor (dys)function in the development of reduced left ventricular function has not been investigated. Therefore, it was the purpose of the present study to assess the relationship of coronary blood flow reserve (CFR) and subsequent changes in left ventricular systolic function to establish the clinical utility of coronary flow measurement to identify a distinct subset of patients in whom closer monitoring and aggressive risk factor modification may be indicated.

Renal function in cardiac transplant recipients: retrospective analysis of 133 consecutive patients in a single center

Renal function in cardiac transplant recipients: retrospective analysis of 133 consecutive patients in a single center

Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.

Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of L-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis. Acetylcholine (10(-6), 10(-5), 10(-4) mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of L-arginine (10 mg.kg-1.min-1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n = 14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of L-arginine (10(-4) mol/L, -6.8% versus -2.8%; P < .01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with L-arginine (at a dose of 10(-4) mol/L, + 121% versus 176%; before versus after L-arginine, P < .002). The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. L-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by L-arginine is more likely in vessels with normal wall morphology.

Coronary endothelial function in cardiac transplant recipients with accelerated coronary disease.

Previous studies with the endothelium-dependent vasodilator substance P have shown a preserved vasodilator response in cardiac transplant recipients with angiographically normal coronary arteries. Although endothelial dysfunction is known to occur in cardiac transplant recipients with accelerated coronary disease, the degree to which the endothelium is affected is not known precisely. The aim of the present study was to examine endothelial function in accelerated coronary disease following cardiac transplantation. Thirteen cardiac transplant recipients with epicardial coronary disease underwent substance P infusion. The response to incremental doses of substance P was measured in smooth segments of affected coronary arteries. Substance P was infused over 2 min with a starting dose of 1.4 pmol/min and a maximum of 22.4 pmol/min, reached by doubling the dose in steps, followed by an infusion of 2 mg isosorbide dinitrate over 2 min. Substance P caused less vasodilation at lower concentrations, with a significantly higher dose required to achieve half maximal dilation compared with cardiac transplant recipients with no coronary disease. The mean maximal dilatation achieved with substance P was 22.98 +/- 4.62% compared to 21.95 +/- 4.9% with isosorbide dinitrate; the latter value was not significantly different from the maximal dilation achieved in cardiac transplant recipients without coronary disease. In cardiac transplant recipients with accelerated coronary disease the functional vasodilatory ability of the coronary endothelium is impaired in segments of apparently unaffected epicardial arteries, which may lead to an increase in the resting vasoconstrictor tone and have important functional and therapeutic implications.