tacrolimus and Heart-Failure

Heart transplantation remains the best therapeutic option for the treatment of end-stage heart failure. However, good survival rates can be obtained only if patients are closely monitored, particularly for their immunosuppressive regimens. Currently, a triple-drug regimen usually based on calcineurin-inhibitors (cyclosporin A or tacrolimus), anti-proliferative agents and steroids is used in most recipients. New agents such as the mTOR inhibitors, a more recently developed class of immunosuppressive drugs, can also be used in some patients. The aim of this article is to review currently used immunosuppressive regimens after heart transplantation, and to propose some individualized options depending on specific patient characteristics and recent pharmacological developments in the field.

Topics: Chronic Disease; Clinical Trials as Topic; Cyclosporine; Drug Therapy, Combination; Glucocorticoids; Graft Rejection; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Meta-Analysis as Topic; Monitoring, Immunologic; Mycophenolic Acid; Protein Kinases; Randomized Controlled Trials as Topic; Sirolimus; Survival Analysis; T-Lymphocytes; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Many novel immunosuppressive agents are under active clinical investigation. In addition, creative approaches are being developed for the use of established immunosuppressive agents, with the goal of minimizing immunosuppression as early as possible posttransplantation. The hope is that these approaches will minimize the toxicity of these agents without sacrificing efficacy. Evidence suggests that the nephrotoxicity of calcineurin inhibitors can be reduced using these approaches. The introduction of newer immunosuppressive agents, including the proliferation signal inhibitors, raises the possibility that some of the long-term scourges of cardiac transplantation, including cardiac allograft vasculopathy and malignancy, can be ameliorated. Finally, costimulatory pathway inhibitors and other new immunosuppressive agents offer hope that all these goals can be accomplished with very low long-term maintenance immunosuppression.

Topics: Abatacept; Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Calcineurin Inhibitors; Cyclosporine; Everolimus; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Janus Kinase 3; Kidney Failure, Chronic; Prognosis; Protein Kinases; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Pediatric heart transplantation is a surgical therapy for dilated cardiomyopathy and for complex congenital heart defects with low pulmonary artery resistance. However, it is still discussed as controversial because of uncertain long-term results. We report our experience with pediatric heart transplantation in a heterogeneous population.. Since 1988, 50 heart transplants were performed in 47 patients (30 with dilated cardiomyopathy, 17 with congenital heart disease). Mean age was 9.4 +/- 6.9 years (range, 4 days to 17.9 years). Twenty-three patients had a total of 36 previous operations. Clinical outcome was evaluated retrospectively.. Perioperative mortality was 6% due to primary graft failure. Late mortality (12%) was caused by acute rejection (n = 2), pneumonia (n = 2), intracranial hemorrhage (n = 1), and suicide (n = 1). Mean follow-up was 5.24 +/- 3.6 years. Actuarial 1, 5, and 10 year survival was 86%, 86%, and 80% and improved significantly after 1995 (92% [1 year]; 92% [5 years]). There was no significant difference between patients with dilated or congenital heart disease (1 year: 86% vs 82%; 5 years: 83% vs 74%; 10 years 83% vs 74%; p = 0.62). Three patients with therapy resistant acute or chronic rejection and assisted circulation underwent retransplantation and are alive. Freedom from acute rejection after 5 years was 40% with primary cyclosporine immunosuppression regime and 56% with tacrolimus. Since the introduction of mycophenolate mofetil, freedom from acute rejection increased to 62%. All survivors are at home and in good cardiac condition.. Pediatric heart transplantation is the treatment of choice for end-stage dilated cardiomyopathy as for congenital heart disease with excellent clinical midterm results. It is a valid alternative to reconstructive surgery in borderline patients. However, further follow-up is necessary to evaluate the long-term side effects of immunosuppressants.

Topics: Adolescent; Antiviral Agents; Bacterial Infections; Cardiomyopathy, Dilated; Child; Child, Preschool; Cyclosporine; Cytomegalovirus Infections; Extracorporeal Membrane Oxygenation; Female; Follow-Up Studies; Ganciclovir; Germany; Graft Rejection; Heart Defects, Congenital; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Life Tables; Lymphoma, Non-Hodgkin; Male; Mycophenolic Acid; Pneumonia, Pneumocystis; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Vascular Resistance; Virus Diseases

In the past 2 years, an emerging body of research has focused on a novel transcriptional pathway involved in the cardiac hypertrophic response. Ever since its introduction, the significance of the calcineurin-NFAT module has been subject of controversy. The aim of this review is to provide both an update on the current status of knowledge and discuss the remaining issues regarding the involvement of calcineurin in hypertrophic heart disease. To this end, the molecular biology of calcineurin and its direct downstream transcriptional effector NFAT are discussed in the context of the genetic studies that established the existence of this signaling paradigm in the heart. The pharmacological mode-of-action and specificity of the calcineurin inhibitors cyclosporine A (CsA) and FK506 is discussed, as well as their inherent limitations to study the biology of calcineurin. A critical interpretation is given on studies aimed at analyzing the role of calcineurin in cardiac hypertrophy using systemic immunosuppression. To eliminate the controversy surrounding CsA/FK506 usage, recent studies employed genetic inhibitory strategies for calcineurin, which confirm the pivotal role for this signal transduction pathway in the ventricular hypertrophy response. Finally, unresolved issues concerning the role of calcineurin in cardiac pathobiology are discussed based upon the information available, including its controversial role in cardiomyocyte viability, the reciprocal relationship between myocyte Ca(2+) homeostasis and calcineurin activity and the relative importance of calcineurin in relation to other hypertrophic signaling cascades.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Cyclosporine; Heart Failure; Humans; Signal Transduction; Tacrolimus

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in heart transplant (HTx). Our aim was to analyze the rate of CMV infection in HTx patients receiving treatment with cyclosporine (CsA) or tacrolimus (Tac). Ninety-five patients were randomized to receive either CsA (53.7%) or Tac (46.3%). We performed prophylaxis with valganciclovir in patients with the highest risk of CMV infection. We considered CMV infection as an increased viral load or the presence of CMV in histological samples. We analyzed baseline characteristics, CMV infection, and other complications. Event-free rates were calculated using the Kaplan-Meier method. There were no significant differences in baseline characteristics between both groups. CMV infection was detected in 31.6% of patients (in 66.7% due to asymptomatic replication). The group treated with Tac had a lower rate of CMV infection (15.9% vs. 45.1%, p = 0.002) and longer CMV infection-free survival time (1440 vs. 899 d, p = 0.001). No differences were observed in the complications analyzed in both groups. The independent risk factors for infection identified in the multivariate analysis were treatment with CsA and bacterial infections. This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.

Topics: Adult; Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Survival Rate; Tacrolimus; Valganciclovir

Cardiac remodeling is associated with plasma biomarkers of fibrinogenesis, inflammation, and oxidative stress, and upregulation of mitogenic, pro-fibrotic, and apoptotic signaling pathways. Our primary objective was to evaluate biomarker and subcellular myocardial changes in pediatric heart transplant recipients. Fifty-two-week prospective, randomized (tacrolimus, Tac, vs. cyclosporine, CsA), open-label, parallel group study. Serial myocardial biopsies were probed for mitogenic and pro-inflammatory proteins. Plasma biomarkers of oxidative stress (F2α isoprostanes, nitrotyrosine), and inflammation and oxidation (hsCRP and cystatin-C) were measured. Nine of 11 randomized patients completed the study (four Tac, five CsA). Mean levels of F2α isoprostanes, hsCRP, and cystatin-C were maximal at Week 2. Peak activation of all MAP kinases in myocardial tissue was maximal at Week 10; no association was seen with rejection. Cardiac Bax/Bcl-2 levels (index of apoptosis) correlated negatively with F2α isoprostanes at Week 2 (r = -0.88) and with hsCRP at Week 52 (r = -0.67). At Week 52, hsCRP levels correlated positively with molecular indices of cardiac cell growth. We found evidence of systemic and myocardial oxidative damage and inflammation early posttransplant, which may be related to the remodeling process. Further study is needed to better understand the cardiac and systemic repair processes following pediatric heart transplantation.

Topics: Adolescent; Biomarkers; Biopsy; Cell Proliferation; Child; Child, Preschool; Cyclosporine; Female; Heart Failure; Heart Transplantation; Humans; Infant; Inflammation; Male; Muscle Cells; Oxidative Stress; Oxygen; Postoperative Period; Prospective Studies; Signal Transduction; Tacrolimus; Treatment Outcome

We report a case of anti-MuSK antibody (Ab)-positive myasthenia gravis (MG) in a patient who developed recurrent right-sided congestive heart failure. The patient presented with right-sided congestive heart failure of unknown etiology, necessitating hospitalization on three occasions over a 6-month period. During the third episode of hospitalization, she developed disturbance of consciousness, and heart failure was attributed to carbon dioxide narcosis. We performed various investigations including an anti-MuSK Ab assay, which showed positive results, and she was diagnosed with MG based solely on anti-MuSK Ab positivity. Selective plasma exchange did not produce a satisfactory therapeutic effect, and she received additional intravenous immunoglobulin, plasmapheresis, and oral immunosuppressive therapy after which she was successfully weaned off the ventilator. This case report highlights the following points: (a) Recurrent right-sided congestive heart failure may be the first manifestation of anti-MuSK Ab-positive MG and, (b) detection of the anti-MuSK Ab alone is a convincing rationale to diagnose patients with MG.

Topics: Autoantibodies; Biomarkers; Female; Heart Failure; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Middle Aged; Myasthenia Gravis; Plasma Exchange; Prednisolone; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic; Recurrence; Respiration, Artificial; Tacrolimus; Treatment Outcome

Tacrolimus is an immunosuppressive agent well known to be capable of producing renal impairment. Acute renal failure with right heart failure caused by tacrolimus is rarely described. We report the findings of one such case in which tacrolimus caused acute renal failure with severe tricuspid regurgitation and right ventricular failure documented by echocardiography.

Topics: Acute Disease; Aged; Echocardiography, Doppler; Female; Heart Failure; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune-mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X-linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self-antigens and eliminating autoreactive B cells. This case report describes a 10-year-old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.

Topics: B-Lymphocytes; Child; Female; Forkhead Transcription Factors; Heart Failure; Heart Transplantation; Hepatitis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Intestinal Mucosa; Polyendocrinopathies, Autoimmune; Sirolimus; T-Lymphocytes; Tacrolimus; Thymectomy; Up-Regulation

Over the past decades donor and recipient characteristics and medical management of heart transplantations patients have changed markedly. We studied the impact of these changes on long-term clinical outcome.. Data of all consecutive heart transplant recipients in our center have been collected prospectively. Cohort A (n = 353 patients) was defined as the patients transplanted between 1984 and 1999, and was compared with cohort B (n = 227 patients) transplanted between 2000 and 2013.. Compared to cohort A, recipients in cohort B had older donors (mean age 29 vs. 43 years, donors aged > 50 year: 2% vs. 33%, respectively). One-year survival in cohort A vs. B was 89% vs. 86% and at 10 years 53% vs. 68%, respectively (p = 0.02). Cohort B patients were treated more often with tacrolimus based immunosuppression (77% vs. 22%; p < 0.001), and early statins post-heart transplantation (88% vs. 18%; p = 0.001), while renal function was better conserved at 5 and 10 years (p = 0.001 and 0.02). Multivariate analysis showed significant reduction in 10 years mortality with tacrolimus-based immunosuppression (HR: 0.27 and 95% CI 0.17-0.42), treatment of hypertension (HR: 0.5, 95% CI 0.36-0.72) and revascularization (HR: 0.28, 95% CI 0.15-0.52).. In spite of the use of much older donors, the long-term outcome after heart transplantation has improved considerably in the last decade, probably due to the introduction of newer treatment modalities.

Topics: Adult; Age Factors; Donor Selection; Female; Heart Failure; Heart Transplantation; Humans; Immunosuppression Therapy; Male; Middle Aged; Netherlands; Prospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Tissue Donors; Treatment Outcome

Topics: Cyclosporine; Female; Heart Failure; Heart Transplantation; Humans; Male; Muscle Cells; Oxidative Stress; Tacrolimus

Heart failure is a leading cause of morbidity and mortality in Western society. The cardiovascular transcription factor CHF1/Hey2 has been linked to experimental heart failure in mice, but the mechanisms by which it regulates myocardial function remain incompletely understood. The objective of this study was to determine how CHF1/Hey2 affects development of heart failure through examination of contractility in a myocardial knockout mouse model. We generated myocardial-specific knockout mice. At baseline, cardiac function was normal, but, after aortic banding, the conditional knockout mice demonstrated a greater increase in ventricular weight-to-body weight ratio compared with control mice (5.526 vs. 4.664 mg/g) and a significantly decreased ejection fraction (47.8 vs. 72.0% control). Isolated cardiac myocytes from these mice showed decreased calcium transients and fractional shortening after electrical stimulation. To determine the molecular basis for these alterations in excitation-contraction coupling, we first measured total sarcoplasmic reticulum calcium stores and calcium-dependent force generation in isolated muscle fibers, which were normal, suggesting a defect in calcium cycling. Analysis of gene expression demonstrated normal expression of most genes known to be involved in myocardial calcium cycling, with the exception of the ryanodine receptor binding protein FKBP12.6, which was expressed at increased levels in the conditional knockout hearts. Treatment of the isolated knockout myocytes with FK506, which inhibits the association of FKBP12.6 with the ryanodine receptor, restored contractile function. These findings demonstrate that conditional deletion of CHF1/Hey2 in the myocardium leads to abnormalities in calcium handling mediated by FKBP12.6 that predispose to pressure overload-induced heart failure.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Calcium; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Heart Conduction System; Heart Failure; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Repressor Proteins; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Stroke Volume; Tacrolimus; Tacrolimus Binding Proteins

Calmodulin (CaM) is well known to modulate the channel function of the cardiac ryanodine receptor (RyR2). However, the possible role of CaM on the aberrant Ca(2+) release in diseased hearts remains unclear. In this study, we investigated the state of RyR2-bound CaM and channel dysfunctions in pacing-induced failing hearts.. The characteristics of CaM binding to RyR2 and the role of CaM on the aberrant Ca(2+) release were assessed in normal and failing canine hearts. The affinity of CaM binding to RyR2 was lower in failing sarcoplasmic reticulum (SR) than in normal SR. Addition of FK506, which dissociates FKBP12.6 from RyR2, to normal SR reduced the CaM-binding affinity. Dantrolene restored a normal level of the CaM-binding affinity in either FK506-treated (normal) SR or failing SR, suggesting that the defective inter-domain interaction between the N-terminal domain and the central domain of RyR2 (the therapeutic target of dantrolene) is involved in the reduction of the CaM-binding affinity in failing hearts. In saponin-permeabilized cardiomyocytes, the frequency of spontaneous Ca(2+) sparks was much more increased in failing cardiomyocytes than in normal cardiomyocytes, whereas the addition of a high concentration of CaM attenuated the aberrant increase of Ca(2+) sparks.. The defective inter-domain interaction between N-terminal and central domains within RyR2 reduces the binding affinity of CaM to RyR2, thereby causing the spontaneous Ca(2+) release events in failing hearts. Correction of the defective CaM binding may be a new strategy to protect against the aberrant Ca(2+) release in heart failure.

Topics: Animals; Calcium Signaling; Calmodulin; Cardiac Pacing, Artificial; Dantrolene; Disease Models, Animal; Dogs; Excitation Contraction Coupling; Heart Failure; Microscopy, Confocal; Myocardium; Peptide Fragments; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Protein Structure, Tertiary; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Tacrolimus; Tacrolimus Binding Proteins

Simultaneous heart and kidney transplantation (SHKT) has become an accepted therapeutic option for patients with end-stage heart failure associated with end-stage renal disease. The immunosuppressive therapy is usually based upon a heart transplantation protocol using a calcineurin inhibitor (CNI). Sirolimus (SRL) is a potent nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Its use has recently been reported to show less nephrotoxicity among both heart and kidney transplants. However, the data for the SHKT are limited. We retrospectively examined the causes of 5 patients who received combined SRL-CNI immunosuppressive therapy with reduced CNI doses from 2003 to 2009. There was no mortality during follow-up. Two of the 3 patients who received a conversion regimen recovered renal function. One who suffered severe proteinuria after transplantation proceeded to hemodialysis at 3 years after conversion. Both of the patients who received the combined regimen de novo remained stable regarding their renal function. Cardiac function was stable in these patients; there was neither allograft rejection nor allograft coronary vasculopathy. We observed that patients without dyslipidemia or hyperuricemia before SHKT were less likely to develop these disorders under the combined regimen. Early medical intervention after close follow-up of lipid and uric acid values by dose adjustments resulted in a stable status of our patients.

Topics: Adolescent; Antilymphocyte Serum; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Heart Failure; Heart Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Sirolimus; Tacrolimus; Young Adult

Anaemia is common following renal transplantation and is associated with the development of congestive heart failure (CHF). However the prevalence of anaemia in the first year following transplantation and the association between anaemia occurring early and the development of CHF have been understudied.. In this study, 132 incident patients undergoing tacrolimus and mycophenolate mofetil-based renal transplantation were studied for the prevalence of, and risk factors for, anaemia and CHF in the early period post transplantation.. Anaemia occurred in 94.5% and 53.1% of patients at 1 week and 12 months, respectively, and was associated with allograft dysfunction, hypoalbuminaemia, higher mycophenolic acid (MPA) levels, bacterial infection and hypoalbuminaemia. The association with hypoalbuminaemia may reflect the presence of chronic inflammation post-transplantation. Of patients displaying haemoglobin <11 g/dl, 41.1% and 29.4% were treated with erythropoiesis stimulating agents (ESAs) at 1 and 12 months respectively. CHF developed in 26 patients beyond 1 month post-transplantation, with echocardiographic left ventricular systolic function preserved in all but one. CHF was associated with anaemia and lower haemoglobin, allograft dysfunction, duration of dialysis and left ventricular hypertrophy on echocardiography prior to transplantation, suggesting the aetiology of CHF may involve the interplay of diastolic cardiac dysfunction, pre-load mismatch and after-load mismatch.. Modification of risk factors may improve anaemia management post transplantation. Reducing the prevalence of anaemia may in turn reduce the incidence of CHF-these observations support the need for clinical trials to determine how anaemia management may impact CHF incidence.

Topics: Adult; Anemia; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Hypoalbuminemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Proteins; Risk Factors; Tacrolimus; Time Factors

Heart transplant recipients treated with long-term calcineurin inhibitors (CNIs) experience significant nephrotoxicity and transplant vasculopathy. Signal proliferation inhibitors might prevent the development of transplant vasculopathy. In an open, prospective pilot study, 33 primary heart transplant recipients received tacrolimus (Tac) and sirolimus (rapamycin, Rapa) with steroids. To reduce both nephrotoxicity and transplant vasculopathy at the same time, both Tac and Rapa exposure was kept low (6 to 8 ng/ml). Steroids were withdrawn successfully from all patients within 6 months. Just one acute rejection occurred at 54 days post-transplant, resulting in 0.03 acute rejection episode per patient at 1-year (primary end-point) and 2-year follow-up. Transplant vasculopathy assessed by angiogram was absent at 2 years. Graft and patient survival were 100% at 1 and 2 years. Accordingly, the survival estimate for freedom from first acute rejection, transplant vasculopathy, graft loss or death was 0.97 at 1 and 2 years. The regimen was well tolerated with only 3 patients requiring a change of study medication. Mean serum creatinine increased during the first year but returned to baseline at 2 years.

Topics: Adrenal Cortex Hormones; Adult; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Postoperative Complications; Prospective Studies; Sirolimus; Tacrolimus; Time Factors

Topics: Adult; Heart Failure; Heart Transplantation; Humans; Israel; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus; Treatment Outcome

The role of phosphorylation of the ryanodine receptor at serine-2808 (RyRS2808) in congestive heart failure (CHF) is controversial, and effects of RyRS2808 phosphorylation on contraction are unclear. It has been reported that diastolic sarcomere length (SL) fluctuations accompany propagating contractile waves due to propagating SR Ca2+ release in trabeculae from rats with CHF. Here, we studied the influence of RyR destabilization by FK506 and isoproterenol on twitch force (Ftw) and SL fluctuations in right ventricular (RV) trabeculae. We measured phosphorylation of RyRS2808 in rats with myocardial infarction (MI) with or without beta-blockade and in rats during isoproterenol stimulation in order to assess the role of RyRS2808 phosphorylation in SL fluctuations in failing hearts.. Five groups of male Lewis Brown-Norway rats were studied 3 months after MI: i) Sham; ii) MI with CHF (cMI); iii) MI without CHF; iv) metoprolol-treated MI, with and without CHF. The root mean square (RMSSL) of SL fluctuations in RV trabeculae was calculated.. RMSSL increased strongly both following a short train of stimuli at 2.5 Hz and following catecholamine activation in trabeculae from MI with CHF, resulting in a decrease in Ftw in proportion to RMSSL. RyRS2808 phosphorylation was increased significantly in the left ventricle (LV; approximately 58%, P<0.05) but not in the RV (n.s.) in MI rats with CHF. FK506 tripled high frequency stimulation-induced RMSSL in nonfailing trabecula but did not further enhance RMSSL in failing trabecula. Isoproterenol increased RMSSL in nonfailing trabeculae only modestly despite a substantial increase in RyRS2808 phosphorylation in the RV (approximately 60%, P<0.05). Isoproterenol induced SL fluctuation without an increase in RV-RyRS2808 phosphorylation in failing trabeculae. Chronic beta-blockade decreased high frequency and catecholamine stimulation-induced RMSSL while RyRS2808 phosphorylation in the RV was indistinguishable from that in cMI.. Acute RyRS2808 phosphorylation by itself does not cause spontaneous contractile waves owing to RyR2 destabilization. Spontaneous contractile waves in CHF are not caused by RyRS2808 phosphorylation alone, suggesting that factors other than RyRS2808 phosphorylation affect RyR function.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Diastole; Echocardiography; Heart Failure; Isoproterenol; Male; Metoprolol; Models, Animal; Myocardial Contraction; Phosphorylation; Rats; Rats, Inbred BN; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Serine; Tacrolimus

Topics: Adult; Diagnosis, Differential; Eyelashes; Female; Follow-Up Studies; Graft Rejection; Hair Diseases; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Tacrolimus

Kaposi's sarcoma is a relatively rare but potentially fatal malignancy which affects immunosuppressed individuals. It has been found to occur especially in association with cyclosporine and tacrolimus use and with concurrent cytomegalovirus infection. When detected and treated early, it usually carries a good prognosis and responds well to measures increasing immunocompetence. We report a case of cutneous Kaposi's sarcoma occurring in a cardiac transplant patient treated with tacrolimus.

Topics: Biopsy; Diagnosis, Differential; Female; Follow-Up Studies; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Middle Aged; Risk Factors; Sarcoma, Kaposi; Tacrolimus; Tomography, X-Ray Computed

1 The calcineurin (CaN) enzyme-transcriptional pathway is critically involved in hypertrophy of heart muscle in some animal models. Currently there is no information concerning the regulation of CaN activation by endogenous agonists in human heart. 2 Human right ventricular trabeculae from explanted human (14 male/2 female) failing hearts were set up in a tissue bath and electrically paced at 1 Hz and incubated with or without 100 nM endothelin-1 (ET-1), 10 M, angiotensin-II (Ang II) or 20 nM human urotensin-II (hUII) for 30 min. Tissues from four patients were incubated with 200 nM tacrolimus (FK506) for 30 min and then incubated in the presence or absence of ET-1 for a further 30 min. 3 ET-1 increased contractile force in all 13 patients (P<0.001). Ang II and hUII increased contractile force in three out of eight and four out of 10 patients but overall nonsignificantly (P>0.1). FK506 had no effect on contractile force (P=0.12). 4 ET-1, Ang II and hUII increased calcineurin activity by 32, 71 and 15%, respectively, while FK506 reduced activity by 34%. ET-1 in the presence of FK506 did not restore calcineurin activity (P=0.1). 5 There was no relationship between basal CaN activity and expression levels in the right ventricle. Increased levels of free phosphate were detected in ventricular homogenates that were incubated with PKC(epsilon) compared to samples incubated without PKC(epsilon). 6 Endogenous cardiostimulants which activate G(alpha)q-coupled receptors increase the activity of calcineurin in human heart following acute (30 min) exposure. PKC may contribute to this effect by increasing levels of phosphorylated calcineurin substrate.

Topics: Adult; Angiotensin II; Blotting, Western; Calcineurin; Endothelin-1; Female; Heart Failure; Heart Ventricles; Humans; In Vitro Techniques; Male; Middle Aged; Myocardial Contraction; Peptides; Phosphates; Protein Kinase C; Tacrolimus; Urotensins

We investigated the inward rectifier potassium current (I(K1)), which can be blocked by intracellular Ca(2+), in heart failure (HF).. We used the whole-cell patch-clamp technique to record I(K1) from single rat ventricular myocytes in voltage-clamp conditions. Fluorescence measurements of diastolic Ca(2+) were performed with Indo-1 AM. HF was examined 8 weeks after myocardial infarction (coronary artery ligation).. I(K1) was reduced and diastolic Ca(2+) was increased in HF cells. The reduction of I(K1) was attenuated when EGTA was elevated from 0.5 to 10 mM in the patch pipette and prevented with high BAPTA (20 mM). Ryanodine (100 nM) and FK506 (10 microM), both of which promote spontaneous SR Ca(2+) release from ryanodine receptor (RyR2) during diastole, reproduced the effect of HF on I(K1) in normal cells but had no effect in HF cells. The effects of ryanodine and FK506 were not additive and were prevented by BAPTA. Rapamycin (10 microM), which removes FKBP binding proteins from RyR2 with no effect on calcineurin, mimicked the effect of FK506 on I(K1). Cyclosporine A (10 microM), which inhibits calcineurin via cyclophilins, had no effect. In both HF cells and normal cells treated by FK506, the protein kinase C (PKC) inhibitor staurosporine totally restored the inward component of I(K1), but only partially restored its outward component at potentials corresponding to the late repolarizing phase of the action potential (-80 to -40 mV).. I(K1) is reduced by elevated diastolic Ca(2+)in HF, which involves in parallel PKC-dependent and PKC-independent mechanisms. This regulation provides a novel paradigm for Ca(2+)-dependent modulation of membrane potential in HF. Since enhanced RyR2-mediated Ca(2+)release also reduces I(K1), this paradigm might be relevant for arrhythmias related to acquired or inherited RyR2 dysfunction.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Depression, Chemical; Egtazic Acid; Heart Failure; Immunosuppressive Agents; Male; Myocardial Infarction; Myocardium; Patch-Clamp Techniques; Potassium Channels, Inwardly Rectifying; Protein Kinase C; Rats; Rats, Wistar; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sirolimus; Staurosporine; Tacrolimus

Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca(2+) release and [(3)H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca(2+) release was smaller than in normal SR (consistent with a decreased rate of Ca(2+) release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.

Topics: Animals; Binding, Competitive; Calcium; Calcium Channel Blockers; Cardiac Pacing, Artificial; Cardiotonic Agents; Coumarins; Disease Models, Animal; Dogs; Fluorescent Dyes; Heart Failure; Hemodynamics; Immunosuppressive Agents; Ion Channel Gating; Polylysine; Protein Conformation; Radioligand Assay; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Tacrolimus; Tacrolimus Binding Proteins; Thiazepines

The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury.. Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts.. During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.

Topics: Animals; Calcium; Cyclic AMP-Dependent Protein Kinases; Dogs; Heart Failure; Hemodynamics; Ion Transport; Models, Cardiovascular; Myocardium; Phosphorylation; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Tacrolimus; Tacrolimus Binding Proteins; Thiazepines; Ventricular Remodeling

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 10(5) nuclei, compared with 1.5 myocytes per 10(5) nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.

Topics: Animals; Apoptosis; Caspase 8; Caspase 9; Caspases; Dimerization; Disease Models, Animal; Disease Progression; Enzyme Activation; Enzyme Activators; Heart Failure; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Organ Specificity; Recombinant Fusion Proteins; Tacrolimus; Tacrolimus Binding Proteins; Transgenes

In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca2+ leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether beta-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function.. SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of rapid right ventricular pacing with or without propranolol [P(+) or P(-)]). End-diastolic and end-systolic diameters both increased less in P(+) than P(-), associated with a smaller decrease in fractional shortening in P(+). In SR from P(-), a prominent Ca2+ leak was observed, and FK506 (which dissociates FKBP12.6 from RyR) did not induce an additional Ca2+ leak. However, there was no appreciable Ca2+ leak in SR from P(+), although FK506 induced a Ca2+ leak as in normal SRs. In SR from P(+), an FK506-induced conformational change in RyR, which was virtually absent in SR from P(-), was observed as in normal SRs. Both the stoichiometry of FKBP12.6 versus RyR, assessed by [3H]FK506 and [3H]ryanodine binding assays, and the protein expression of FKBP12.6, assessed by Western blot analysis, were restored by propranolol toward the levels seen in normal SRs.. Low-dose propranolol corrects the defective interaction of FKBP12.6 with RyR (restoration of RyR conformational change and prevention of Ca2+ leak from RyR), apparently resulting in an attenuation of intracellular Ca2+ overload and hence preventing the development of left ventricular remodeling in heart failure.

Topics: Adrenergic beta-Antagonists; Animals; Calcium; Cardiac Pacing, Artificial; Diastole; Disease Models, Animal; Dogs; Heart Failure; Heart Ventricles; Hemodynamics; In Vitro Techniques; Myocardium; Phosphorylation; Propranolol; Protein Binding; Protein Conformation; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Systole; Tacrolimus; Tacrolimus Binding Proteins; Ventricular Remodeling

Little information is available as to the Ca(2+) release function of the sarcoplasmic reticulum (SR) in heart failure. We assessed whether the alteration in this function in heart failure is related to a change in the role of FK binding protein (FKBP), which is tightly coupled with the cardiac ryanodine receptor (RyR) and recently identified as a modulatory protein acting to stabilize the gating function of RyR.. SR vesicles were isolated from dog LV muscles [normal (N), n=6; heart failure induced by 3-weeks pacing (HF), n=6]. The time course of the SR Ca(2+) release was continuously monitored using a stopped-flow apparatus, and [3H]ryanodine-binding and [3H]dihydro-FK506-binding assays were also performed.. FK506, which specifically binds to FKBP12.6 and dissociates it from RyR, decreased the polylysine-induced enhancement of [3H]ryanodine-binding by 38% in N (P<0.05) but it had no effect in HF. In HF, the rate constant for the polylysine-induced Ca(2+) release from the SR was 61% smaller than in N. FK506 decreased the rate constant for the polylysine-induced Ca(2+) release by 67% in N (P<0.05) but had no effect in HF. The [3H]dihydro-FK506-binding assay revealed that the number (B(max)) of FKBPs was decreased by 83% in HF (P<0.05), while the K(d) value was unchanged. FK506 did not significantly change SR Ca(2+.)-ATPase activity in either N or HF.. In HF, the number of FKBPs showed a tremendous decrease; this may underlie the RyR-channel instability and the impairment of the Ca(2+) release function of RyR seen in the failing heart.

Topics: Analysis of Variance; Animals; Calcium; Cardiac Pacing, Artificial; Dogs; Female; Heart Failure; Male; Polylysine; Protein Binding; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Tacrolimus; Tacrolimus Binding Proteins

There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role.. Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg x kg(-1) x d(-1)) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure.. Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Calcineurin Inhibitors; Disease Models, Animal; Drug Administration Schedule; Echocardiography; Fibrosis; Gene Expression; Heart Failure; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Male; Myocardium; Organ Size; Rats; Rats, Inbred Dahl; RNA, Messenger; Sodium Chloride; Tacrolimus

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Cardiomegaly; Cells, Cultured; Cyclosporine; DNA-Binding Proteins; Enzyme Inhibitors; GATA4 Transcription Factor; Heart Failure; Humans; Mice; Myocardium; NFATC Transcription Factors; Nuclear Proteins; Signal Transduction; Tacrolimus; Transcription Factors

Topics: Adolescent; Arrhythmia, Sinus; Bone Marrow Transplantation; Digoxin; Heart Arrest; Heart Failure; Humans; Immunosuppressive Agents; Male; Tacrolimus

Reported side-effects of tacrolimus, a potent immunosuppressive agent, have not included cardiotoxicity. We describe 5 consecutive paediatric transplant recipients (3 small bowel with or without liver and 2 liver) who received tacrolimus. 2 developed congestive heart failure and hypertrophic obstructive cardiomyopathy which resolved after changing to cyclosporin. In the other 3 patients the cardiomyopathy regressed or improved with a lower dose of tacrolimus or after stopping the drug.

Topics: Blood Pressure; Cardiomyopathy, Hypertrophic; Child, Preschool; Colon; Echocardiography; Female; Heart Failure; Humans; Infant; Liver Transplantation; Male; Postoperative Complications; Tacrolimus