tacrolimus and Heart-Diseases

Topics: Child; Heart Diseases; Heart Transplantation; Humans; Pediatrics; Pharmacogenetics; Precision Medicine; Tacrolimus; TOR Serine-Threonine Kinases

Transplantation has evolved into an accepted treatment for end-stage heart or lung disease. Acute rejection, complications related to immunosuppressive protocols, and the development of chronic rejection continue to challenge the long-term success of heart and lung transplantations. Wide acceptance of tacrolimus as an important immunosuppressant in renal and hepatic transplantations has led subsequently to its investigation as primary immunosuppression in heart and lung transplant recipients, either combined with azathioprine or with the newer agents mycophenolate mofetil or rapamycin. Studies have shown that tacrolimus is an effective therapeutic alternative to cyclosporine for primary immunosuppression in heart or lung transplantation and demonstrates equivalent if not improved prophylaxis of acute rejection, and more recently demonstrates a potential influence on chronic rejection, particularly in lung transplant recipients. Of importance, the enhanced immunosuppressive activity of tacrolimus is achieved without increased risk of infection or malignancy. Differences in tolerability profiles and side effects between tacrolimus and cyclosporine may be used in selecting the optimal immunotherapy after thoracic transplantation. In particular, the lesser propensity of tacrolimus to cause hypertension and hyperlipidemia potentially offers decreased cardiovascular risk for heart and lung transplant recipients.

Topics: Cyclosporine; Graft Rejection; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Diseases; Lung Transplantation; Tacrolimus; Treatment Outcome

Credit for the first pediatric heart transplant is given to Kantrowitz and colleagues who, in 1967, transplanted the heart of an anencephalic infant into a 3-week-old with tricuspid atresia (1). Although the infant only survived a few hours after surgery, this pioneering procedure emphasized the technical feasibility of heart transplantation in childhood. Over the next decade, enthusiasm for heart transplantation declined in both adults and children, as it became apparent that the therapeutic armamentarium for controlling acute allograft rejection was inadequate for achieving graft and patient survival. Towards the end of the 1970s, several advances led to renewed interest in human heart transplantation. These included topical cooling of the donor heart to protect the myocardium from ischemia (and enabling distant procurement), the technique and interpretation of endomyocardial biopsy for the diagnosis of allograft rejection (2) and, most importantly, the introduction of cyclosporine into human clinical trials (3). Cyclosporine was the first oral agent specifically to inhibit T lymphocytes, the principal mediators of allograft rejection. The favorable impact on survival of adult heart transplant recipients was immediately apparent (4) and led to renewed interest in pediatric heart transplantation. The pediatric heart transplant program at the University of Pittsburgh commenced in 1982, drawing on the experience of the adult program which had begun two years earlier. It rapidly became apparent that children present unique problems for the transplant physician and surgeon. This review draws on many of the lessons learned in our program over the last 15 years and reviews some of the prospects for the future of pediatric thoracic organ transplantation.

Topics: Child; Contraindications; Graft Rejection; Heart Diseases; Heart Transplantation; Hospitals, University; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphoproliferative Disorders; Patient Selection; Pennsylvania; Postoperative Complications; Survival Analysis; Tacrolimus; Tissue Donors

Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research.. The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

Topics: Child; Drug Therapy, Combination; Everolimus; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Renal Insufficiency, Chronic; Tacrolimus

Following heart transplantation (HT), HMG CoA reductase inhibitors (statins) have been shown to reduce total and low-density lipoprotein (LDL) cholesterol, development of cardiac allograft vasculopathy (CAV), and mortality. Studies in HT patients have demonstrated the safety of low/moderate intensity statins; however, little data exist using high-intensity (HI) statins. The study aim was to evaluate the safety and efficacy of HI statins in HT recipients receiving tacrolimus.. This single-center, retrospective analysis included adult HT recipients from January 1, 2005, to December 31, 2015, who received HI statin therapy during posttransplant follow-up. The primary outcome, tolerability, was defined as the absence of myalgias, hepatotoxicity, rhabdomyolysis, or HI statin dose reduction/discontinuation. The secondary end point was the mean reduction in total and LDL cholesterol.. Among the 24 patients included, one experienced myalgias and therapy discontinuation (4%; P > 0.99). No other HI statin dose reduction/discontinuation occurred, and no instances of rhabdomyolysis or hepatotoxicity were observed. The average reduction in total and LDL cholesterol after conversion to HI statin was 35 mg/dL (P = 0.02) and 19 mg/dL (P = 0.10), respectively.. High-intensity statin therapy appears safe and efficacious in HT recipients receiving tacrolimus and is a reasonable option for the treatment of refractory hyperlipidemia.

Topics: Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Diseases; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Immunosuppressive Agents; Incidence; Male; Maximum Tolerated Dose; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Tacrolimus; United States

Renal failure is one of the primary medium- to long-term morbidities in heart transplant (HT) recipients. To a great extent, this renal deterioration is associated with calcineurin inhibitors, primarily cyclosporine A (CsA). It has been suggested that tacrolimus provides better renal function in these patients. We assessed the medium-term evolution of renal function depending on the calcineurin inhibitor used after HT.. We assessed 40 consecutive HT recipients over one year. Patients were randomized to receive CsA (n = 20) or tacrolimus (n = 20) in combination with mycophenolate mofetil (1 g/12 h) and deflazacort in decreasing dosages. We analyzed demographic variables before HT, creatinine values before and six months after HT and incidence of acute rejection.. No demographic, clinical, or analytical differences were observed were between the two groups before HT. Repeated measures analysis of variance of creatinine values showed no significant differences between the two groups (P = .98). Furthermore, no differences were observed in either the incidence of rejection (P = .02) or rejection-free survival (P = .14).. There seems to be no difference in efficacy profile and renal tolerability between CsA and tacrolimus therapy during the first months after HT.

Topics: Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Pregnenediones; Tacrolimus

Previous multicenter, randomized trials, lacking standardized post-transplant protocols, have compared tacrolimus (Tac) and cyclosporine (CyA, Sandimmune) and demonstrated similar outcomes with some different adverse effects. The microemulsion form of CyA (mCyA, Neoral) has replaced Sandimmune CyA as the more widely utilized CyA formulation. This is the first 5-year follow-up study of a large, single-center trial (n = 67) under a standardized post-transplant protocol comparing Tac and mCyA.. Sixty-seven heart transplant patients were randomized to Tac (n = 33) or mCyA (n = 34), both in combination with corticosteroids and azathioprine without cytolytic induction. Five-year end-points included survival, Grade > or = 3A or treated rejection, angiographic cardiac allograft vasculopathy (CAV; any lesion > or = 30% stenosis), renal dysfunction (creatinine > or = 2.0 mg/dl), use of two or more anti-hypertensive medications, percent diabetic and lipid levels.. Five-year survival, freedom from Grade > or = 3A or any treated rejection and angiographic CAV, mean cholesterol level and percent diabetic were similar between the two groups. The Tac group had a significantly lower 5-year mean triglyceride level (Tac 97 +/- 34 vs mCyA 175 +/- 103 mg/dl, p = 0.011) and average serum creatinine level (Tac 1.2 +/- 0.5 mg/dl vs mCyA 1.5 +/- 0.4 mg/dl, p = 0.044). There was a trend toward fewer patients requiring two or more anti-hypertensive drugs in the Tac group (Tac 33% vs mCyA 59%, p = 0.065).. Tac and mCyA appear to be comparable with regard to 5-year survival, freedom from rejection and CAV. However, compared with mCyA, Tac appears to reduce the adverse effect profile for hypertriglyceridemia and renal dysfunction and the need for hypertensive medications.

Topics: Adult; Antihypertensive Agents; Coronary Stenosis; Cyclosporine; Emulsions; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Methylprednisolone; New York; Racial Groups; Survival Analysis; Tacrolimus

Generic immunosuppressants may offer economic advantages, but their use is still controversial. At our center, 55 heart transplant patients were switched from CellCept(®) to Myfenax Teva(®) (MT) (n = 51, 18% female, 8.1 ± 6.6 yr post-transplantation) and/or Prograf(®) to Tacrolimus Sandoz(®) (TS) (n = 17, 41% female, 6.6 ± 5.8 yr post-transplantation).. We conducted an acute monitoring and a retrospective follow-up with regard to safety and efficacy. Acute cellular rejections (ACRs) on endomyocardial biopsies (EMBs) four wk after the MT switch were specifically compared to a matched retrospective control group.. Tacrolimus C0 levels (TS switch) as well as hemoglobin, leukocytes, and thrombocytes (MT switch) did not change (p = NS) during the three wk after each respective switch (8.7 ± 2.9 vs. 8.4 ± 1.9 μg/L, 129.1 ± 12.6 vs. 130.1 ± 12.8 g/L, 6.3 vs. 6.2 × 10(9) /L, and 217.4 ± 56.6 vs. 219.3 ± 61.8 × 10(9) /L, respectively). 0% of the EMBs in the MT switch vs. 3% of the EMBs in the control group showed ACR>grade 1R (p = NS). After six months, survival was 96% (MT switch) and 100% (TS switch), and the frequency of severe ACR was low. Safety parameters measured at the next annual follow-up were also stable following each switch.. Switching to MT and/or TS several years after heart transplantation appeared safe in the short-term perspective, showing no detectable changes in tacrolimus C0 levels, safety or efficacy, during an average follow-up of six months.

Topics: Adolescent; Adult; Aged; Child; Drugs, Generic; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Safety Management; Survival Rate; Tacrolimus; Young Adult

Chronic kidney disease is directly associated with cardiovascular complications. Heart remodelling, including fibrosis, hypertrophy, and decreased vascularization, is frequently present in renal diseases. Our objective was to investigate the impact of calcineurin inhibitors (CNI) on cardiac remodelling and function in a rat model of renal disease.. Male Sprague Dawley rats were divided into six groups: sham-operated rats, 5/6 nephrectomized rats (Nx) treated with vehicle, CNI (cyclosporine A 5.0 or 7.5, or tacrolimus 0.5 mg/kg/day) or hydralazine (20 mg/kg twice a day) for 14 days, starting on the day of surgery. Creatinine clearance was significantly lower and blood pressure significantly higher in Nx rats when compared with controls. Morphological and echocardiographic analyses revealed increased left ventricular hypertrophy and decreased number of capillaries in Nx rats. Treatment with CNI affected neither the renal function nor the blood pressure, but prevented the development of cardiac hypertrophy and improved vascularization. In addition, regional blood volume improved as confirmed by contrast agent-based echocardiography. Hydralazine treatment did not avoid heart remodelling in this model. Gene expression analysis verified a decrease in hypertrophic genes in the heart of CNI-treated rats, while pro-angiogenic and stem cell-related genes were upregulated. Moreover, mobilization of stem/progenitor cells was increased through manipulation of the CD26/SDF-1 system.. We conclude from our studies that CNI-treatment significantly prevented cardiac remodelling and improved heart function in Nx rats without affecting renal function and blood pressure. This sheds new light on possible therapeutic strategies for renal patients at high cardiovascular risk.

Topics: Animals; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Heart Diseases; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney Diseases; Male; Nephrectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Tacrolimus; Ventricular Remodeling

Cardiovascular disease is an important cause of morbidity and death in kidney transplant recipients. This study examines the Framingham risk score's ability to predict cardiac and stroke events. Because cyclosporine and tacrolimus have different cardiovascular risk profiles, these agents were also examined.. A prospective cohort evaluation of 540 patients were followed for a median of 4.7 yr in an outpatient kidney transplant clinic. Baseline Framingham risk scores were calculated and all cardiovascular outcomes were collected.. Rates per 100 patient-years were 1.79 for cardiac and 0.78 for stroke events. The ratio of observed-to-predicted cardiac events was 1.64-fold higher [95% confidence interval (CI) 1.19 to 2.94] for the cohort, 2.74-fold higher (95% CI 1.70 to 4.24) in patients age 45 to 60 with prior cardiac disease or diabetes mellitus, but not higher in other age subgroups. Stroke was not increased above predicted. Risk scores for cardiac (c = 0.65, P = 0.003) and stroke (c = 0.71, P = 0.004) events were modest predictors. 10-yr event scores for cardiac (9.3 versus 13.5%, P < 0.001) and stroke (7.1 versus 10.0%, P = 0.002) were lower for tacrolimus compared with cyclosporine-treated patients. However observed cardiac events were higher in tacrolimus recipients (2.50, 95% CI 1.09 to 5.90) in an adjusted Cox model.. Although risk scores are only modest predictors, patients with the highest event rates are easily identified. Treating high-risk patients with cardioprotective medications should remain a priority.

Topics: Adult; Age Factors; Aged; Ambulatory Care Facilities; Cardiovascular Agents; Cyclosporine; Diabetes Complications; Disease-Free Survival; Female; Health Status Indicators; Heart Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Tacrolimus; Time Factors

The use of C2 levels for therapeutic drug monitoring (TDM) of cyclosporine microemulsion (CsA) has been clinically validated. Routine TDM of tacrolimus and mycophenolate mofetil (MMF) is based on trough (C0) levels and side effects, respectively. The purpose of the present study was to determine the best single time points to assess the area-under-the-curve (AUC(0-12 hours)) in long-term heart transplant patients being treated with MMF in combination with CsA or tacrolimus.. We studied the AUC(0-12 hours) in long-term (>1 year), adult heart transplant patients being treated with CsA and MMF (14 patients) and with tacrolimus and MMF (9 patients).. C2 is the best surrogate (r2 = 0.87) of CsA AUC(0-12 hours). Tacrolimus C1 (r2 = 0.78), C2 (r2 = 0.83), C3 (r2 = 0.89) and C4 (r2 = 0.92) correlate better than C0 (r2 = 0.51) with the AUC(0-12 hours). When MMF is combined with CsA, there is poor correlation (r2) of MPA at all measured time points (C0 = 0.49, C2 = 0.09, C3 = 0.23, C4 = 0.44, and C6 = 0.60). When MMF is combined with tacrolimus, MPA C2 (r2 = 0.72), C4 (r2 = 0.86), C6 (r2 = 0.85), and C8 (r2 = 0.93) are better surrogates of the AUC(0-12 hours) compared with C0 (r2 = 0.69).. Our results suggest that in long-term heart transplant patients, the calcineurin inhibitor used in combination with MMF affects the correlation between MPA single time points and the AUC(0-12 hours). Future studies should determine the clinical benefit of TDM of tacrolimus and MPA with C2 or C4 compared with C0 and determine the therapeutic ranges. As for CsA-treated patients, CsA TDM should be performed with C2, and the TDM of MMF may be clinically irrelevant.

Topics: Adult; Aged; Area Under Curve; Calcineurin Inhibitors; Cardiomyopathies; Cyclosporine; Drug Interactions; Drug Monitoring; Enzyme Inhibitors; Heart Diseases; Heart Neoplasms; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

Mice expressing an error-prone mitochondrial DNA polymerase rapidly accumulate random mutations in mitochondrial DNA. Expression of the transgene in the heart leads to dilated cardiomyopathy accompanied by a wave of apoptosis in cardiomyocytes, and a vigorous and persistent protective response, including upregulation of the anti-apoptotic protein, Bcl-2. To investigate the role of the mitochondrial permeability transition pore in the development of disease, we treated mice with cyclosporin A (CsA), an inhibitor of pore opening. Drug treatment prevented cardiac dilatation, transgene-specific apoptosis, and upregulation of Bcl-2. It also rescued hearts from the profound decrease in connexin 43, which characterizes the dilatated heart. Treatment with FK506, which like CsA inhibits cytoplasmic calcineurin but not the mitochondrial pore, did not affect disease development, suggesting that the relevant target of CsA was the mitochondrial pore. These data implicate breakdowns in the mitochondrial permeability barrier in pathogenesis of elevated frequencies of mtDNA mutations.

Topics: Animals; Cell Death; Connexin 43; Cyclosporine; Dilatation, Pathologic; DNA-Directed DNA Polymerase; DNA, Mitochondrial; Enzyme Inhibitors; Heart Diseases; Immunosuppressive Agents; Mice; Mice, Transgenic; Mitochondria; Mutation; Myocardium; Tacrolimus

Topics: Adolescent; Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Time Factors