sirolimus and Cardiomyopathy--Dilated

In this study, we examined whether cyclosporine was effective when combined with everolimus in clinical heart transplantation (HT).. From August 2004 to July 2007, 108 adult patients underwent primary HT. The main exclusion criteria were: donors > 60 years; cold ischemia times > 6 hours; recipients of multiorgan transplantation or a previous transplantation; and panel-reactive antibodies > or = 25%. The cyclosporine plus everolimus regimen (group CE, n = 32) was suggested first; upon refusal or if the recipient or donor was positive for hepatitis B surface antigen or PCR + hepatitis C infection, then patient was randomly assigned to success cyclosporine plus mycophenolate mofetil (MMF; group CM, n = 24) or tacrolimus plus MMF (group TM, n = 25). All patients underwent similar operative procedures and postoperative care with protocol endomyocardial biopsies.. No 30-day mortality was noted in any group. The efficacy failure rates were 3%, 25%, and 16% in groups CE, CM, and TM, respectively (P = .04 between groups CE and CM). The 1-year survivals were 96.7% +/- 18.1%, 89.7% +/- 29.8%, and 81.0% +/- 35.5% for groups CE, CM, and TM, respectively (P = .04 between groups CE and TM). The 3-year survival rates were 91.9% +/- 28.3%, 79.8% +/- 46.0%, and 81.0% +/- 35.5% in groups CE, CM, and TM, respectively.. The 3 immunosuppressive regimens offered good efficacy after HT. The cyclosporine plus everolimus regimen showed a significantly better result with less efficacy failure (compared with cyclosporine plus MMF: 3% vs 25%) and better 1-year survival compared with tacrolimus plus MMF: 96.7% vs 81.0%.

Topics: Adult; Cardiomyopathy, Dilated; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Myocardial Ischemia; Patient Selection; Sirolimus; Survival Analysis; Survivors; Tacrolimus; Tissue Donors; Treatment Outcome

Both the proliferation signal inhibitor everolimus (1.5 mg/day) and mycophenolate mofetil (MMF) (3 g/day) have shown superior efficacy versus azathioprine in de novo heart transplantation. The cost-effectiveness of everolimus and MMF versus azathioprine was assessed to 6 months posttransplantation.. The evaluation was performed from the German health insurance payer perspective. The composite efficacy endpoint in the everolimus trial was death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR) grade>or=3A, rejection with hemodynamic compromise, and loss to follow-up. The composite endpoint in the MMF trial included only death, retransplantation, and BPAR with hemodynamic compromise. To mimic the everolimus endpoint, an estimated number of patients with BPAR>or=3A was added to the MMF trial results, using two mapping scenarios.. The incremental 6-month cost versus azathioprine was euro2535 for everolimus and euro3007 for MMF. The absolute reduction in efficacy failure versus azathioprine was 10.4% for everolimus and 9.8% and 10.1% for MMF, respectively, using scenarios 1 and 2. The incremental cost per efficacy failure avoided (ie, the incremental cost versus azathioprine divided by the reduction in efficacy failure) was euro24,457 for everolimus, and euro30,628 and euro29,912 for MMF in scenarios 1 and 2.. This analysis, based on findings from two clinical trials, suggested that everolimus was more cost-effective than MMF versus azathioprine in the first 6 months after heart transplantation. Data from a head-to-head trial are required to confirm these results.

Topics: Acute Disease; Adult; Azathioprine; Belgium; Cardiomyopathy, Dilated; Coronary Disease; Cost of Illness; Double-Blind Method; Everolimus; Female; Graft Rejection; Heart Transplantation; Hemodynamics; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Survival Analysis; Treatment Failure

The broad-spectrum antineoplastic drug doxorubicin (DOX) has one of the most serious chronic side effects on the heart, dilated cardiomyopathy, but the precise molecular mechanisms underlying disease progression subsequent to long latency periods remain puzzling. Here, we established a model of DOX-induced dilated cardiomyopathy. In a cardiac cytology exploration, we found that differentially expressed genes in the KEGG signaling pathway enrichment provided a novel complex network of mTOR bridging autophagy and oxidative stress. Validation results showed that DOX caused intracellular reactive oxygen species accumulation in cardiomyocytes, disrupted mitochondria, led to imbalanced intracellular energy metabolism, and triggered cardiomyocyte apoptosis. Apoptosis showed a negative correlation with DOX-regulated cardiomyocyte autophagy. To evaluate whether the inhibition of mTOR could upregulate autophagy to protect cardiomyocytes, we used rapamycin to restore autophagy depressed by DOX. Rapamycin increased cardiomyocyte survival by easing the autophagic flux blocked by DOX. In addition, rapamycin reduced oxidative stress, prevented mitochondrial damage, and restored energy metabolic homeostasis in DOX-treated cardiomyocytes. In vivo, we used metformin (Met) which is an AMPK activator to protect cardiac tissue to alleviate DOX-induced dilated cardiomyopathy. In this study, Met significantly attenuated the oxidative stress response of myocardial tissue caused by DOX and activated cardiomyocyte autophagy to maintain cardiomyocyte energy metabolism and reduce cardiomyocyte apoptosis by downregulating mTOR activity. Overall, our study revealed the role of autophagy and apoptosis in DOX-induced dilated cardiomyopathy and demonstrated the potential role of regulation of the AMPK/mTOR axis in the treatment of DOX-induced dilated cardiomyopathy.

Topics: AMP-Activated Protein Kinases; Apoptosis; Autophagy; Cardiomyopathy, Dilated; Doxorubicin; Humans; Myocytes, Cardiac; Oxidative Stress; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Autophagy; Barth Syndrome; Cardiolipins; Cardiomyopathies; Cardiomyopathy, Dilated; Fibroblasts; Mechanistic Target of Rapamycin Complex 1; Mice; Mitophagy; Sirolimus; Ubiquitin-Protein Ligases

Autophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM).. We explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms.. Autophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82% vs 14.38 ± 1.24%, P < 0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48% vs 45.29 ± 6.68%, P < 0.01; 26.89 ± 4.04% vs 22.17 ± 2.82%, P < 0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice.. The study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.

Topics: Adaptor Proteins, Signal Transducing; Animals; Autophagosomes; Autophagy; Cardiomyopathy, Dilated; Cell Cycle Proteins; Disease Models, Animal; Fibrosis; Male; Mice, Inbred BALB C; Myocytes, Cardiac; Recovery of Function; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Ventricular Function, Left; Ventricular Remodeling

The objective of immunosuppressive drugs used in solid organ transplantation is to achieve acceptable rejection rates, minimize infections, and prolong graft and patient survival. Cardiovascular disease is a major cause of death in kidney transplant recipients. The drugs commonly used to prevent rejection (calcineurin inhibitors [CNIs] and steroids) contribute to cardiac disease seen in transplant patients by increasing the risk of hypertension and diabetes. Direct cardiac toxicity of chemotherapeutic drugs such as doxorubicin is well-known but potential direct effect of CNIs on myocardium is less explored and understood. Cardiac toxicity a rare but serious adverse effect of tacrolimus, has been observed in patients receiving solid organ transplants such as liver, bowel and kidney. In this report, we describe a case of new onset severe dilated cardiomyopathy after kidney transplantation. Reversal of heart failure occurred after tacrolimus discontinuation and the switch to a mammalian target of rapamycin (mTOR) inhibitor: sirolimus.

Topics: Cardiomyopathy, Dilated; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Sirolimus; Tacrolimus

The aim of this study was to determine promising treatment options for human inflammatory dilated cardiomyopathy using a computational drug-repositioning approach (repurposing established drug compounds for new therapeutic indications).. If the myocardial tissue is detected to be infiltrated with inflammatory cells, primarily of lymphocytes, and if the virus is confirmed using genetic examination (PCR) or immunostaining, the infection is suspected. However, there is no specific treatment (i. e., an antiviral drug) even if the virus is identified; therefore, we used Connectivity Map to identify compounds showing inverse drug-disease signatures, indicating activity against inflammatory dilated cardiomyopathy.. Potential drug-repositioning candidates for the treatment of inflammatory dilated cardiomyopathy were explored through a systematic comparison of the gene expression profiles induced by drugs using Gene Expression Omnibus and Connectivity Map databases.. Using a computational drug-repositioning approach based on the integration of publicly available gene expression signatures of drugs and diseases, sirolimus was suggested as a novel therapeutic option for inflammatory dilated cardiomyopathy.

Topics: Cardiomyopathy, Dilated; Computational Biology; Datasets as Topic; Drug Repositioning; Gene Expression Profiling; Humans; Myocardium; Sirolimus; Tissue Array Analysis

Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a substantial percentage of DCMs remains unknown, and no gene-specific therapy is available. On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ancestry, we discovered rare, functional RAF1 mutations in 3 of the cohorts (South Indian, North Indian and Japanese). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in these three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but in AKT that was hyperactivated in a BRAF-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders.

Topics: Adult; Age of Onset; Aged; Amino Acid Sequence; Animals; Cardiomyopathy, Dilated; Case-Control Studies; Cohort Studies; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblasts; HEK293 Cells; Humans; India; Japan; Male; Mice; Middle Aged; Molecular Sequence Data; Mutation; Phenotype; Prevalence; Proto-Oncogene Proteins c-raf; Sequence Homology, Amino Acid; Sirolimus; Zebrafish

Previous studies reported that autophagy is activated in human dilated cardiomyopathy (DCM). It is still unknown whether modulating autophagy can improve cardiac function of the failing heart.. We immunized rats with porcine cardiac myosin to set up a model of DCM. Rapamycin, a kind of mTOR inhibitor upregulating autophagy, was given to rats weeks after the immunization at low (1 mg/kg · day i.p.), intermediate (2 mg/kg · day i.p.) and high dose (4 mg/kg · day i.p.) for 2 weeks.. Compared to the control group (ejection fraction, EF = 81.3 ± 3.8%), the average EF decreased in both the DCM group (EF = 56.1 ± 3.3%) and the high-dose rapamycin group (EF = 55.9 ± 3.6%), but recovered in the low-/intermediate-dose rapamycin groups (EF = 64.9 ± 4.6/69.4 ± 4.4%). Phosphorylation of p70s6k and 4E-BP1 decreased and the expression of LC3BI/II increased in all rapamycin groups. Autophagic vacuoles were easily found in these groups. However, body weight was significantly reduced in the rapamycin groups. Furthermore, mortality was increased in the high-dose rapamycin group.. Rapamycin could improve cardiac function of early-stage DCM, but the effect of rapamycin turned out to be biphasic and the effective range appeared narrow.

Topics: Analysis of Variance; Animals; Autoimmune Diseases; Autophagy; Cardiomyopathy, Dilated; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Rats; Rats, Inbred Lew; Sirolimus; Stroke Volume; TOR Serine-Threonine Kinases; Weight Loss

The objective of the present study was to investigate whether mTOR is involved in cardiac fibrosis evident in dilated cardiomyopathy, and whether rapamycin provides therapeutic potential for cardiac fibrosis.. Forty-five rats were divided into three groups. Fifteen rats in the Adriamycin group underwent 8 weeks of Adriamycin treatment (2.5 mg/kg, twice per week; i.v.) to induce cardiac fibrosis and dilated cardiomyopathy. Fifteen rats in the rapamycin group received rapamycin (2 mg/kg, per day, orally) and i.v. Adriamycin simultaneously for 8 weeks. Fifteen untreated rats served as controls. Cardiac morphology and function were quantified using echocardiography. mTOR and p70S6K1 mRNA expression were assessed using reverse transcription-PCR.. Collagen volume fraction (CVF) was significantly elevated in the adriamycin group (3.36 ± 0.75) compared with controls (1.51 ± 0.31), whereas mTOR and p70S6K mRNA expression were significantly increased in the adriamycin group (0.68 ± 0.03 and 0.69 ± 0.03) compared with controls (0.38 ± 0.03 and 0.34 ± 0.02). The Adriamycin group was associated with cardiac dilation and decreased contractile function. The rapamycin group showed significantly decreased CVF (1.87 ± 0.45), accompanied with a significant decrease in mTOR and p70S6K mRNA expression (0.42 ± 0.05 and 0.45 ± 0.04) relative to the Adriamycin group. In addition, treatment with rapamycin recovered impairments in cardiac morphology and function.. The mTOR/p70S6K pathway plays an important role in adriamycin-induced cardiac fibrosis resulting from dilated cardiomyopathy. Rapamycin is a potential therapeutic treatment that can be used to attenuate cardiac fibrosis and improve cardiac function.

Topics: Animals; Cardiomyopathy, Dilated; Doxorubicin; Echocardiography; Endomyocardial Fibrosis; Gene Expression Regulation; Heart Ventricles; Immunosuppressive Agents; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

A-type lamins, generated from the LMNA gene by differential splicing, are type V intermediate filament proteins that polymerize to form part of the nuclear lamina, and are of considerable medical interest because missense mutations in LMNA give rise to a wide range of dystrophic and progeroid syndromes. Among these are dilated cardiomyopathy and two forms of muscular dystrophy (limb-girdle and Emery-Dreifuss), which are modeled in lmna (-/-) mice and mice engineered to express human disease mutations. Our recent study demonstrates that cardiac and skeletal muscle pathology in lmna (-/-) mice can be attributed to elevated MTORC1 signaling leading to impairment of autophagic flux. An accompanying paper from another laboratory shows similar impairments in mice engineered to express the LMNA H222P associated with dilated cardiomyopathy in humans and also in left ventricular tissue from human subjects. MTORC1 inhibition with rapalogs restores autophagic flux and improves cardiac function in both mouse models, and extends survival in the lmna (-/-) mice. These findings elaborate a potential treatment option for dilated cardiomyopathy and muscular dystrophy associated with LMNA mutation and supplement growing evidence linking impaired autophagy to human disease.

Topics: Animals; Autophagy; Cardiomyopathy, Dilated; Disease Models, Animal; Humans; Lamin Type A; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes; Muscular Dystrophy, Animal; Proteins; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

Recent studies suggest that patients on mammalian target of rapamycin (mTOR) inhibitors experience a reduction in cutaneous carcinogenesis by an estimated 50% or more compared with calcineurin inhibitors. While randomized trials are running, organ transplant recipients are frequently switched from calcineurin inhibitors to mTOR inhibitors when cutaneous carcinogenesis increases.. To slow carcinogenesis in our patient, a heart transplant recipient with a neuropathic diabetic foot syndrome who had developed cutaneous carcinogenesis at a rate of more than 20 squamous cell carcinomas (SCC) annually.. The patient's immunosuppression was switched from the calcineurin inhibitor ciclosporin to the mTOR inhibitor everolimus.. Carcinogenesis slowed to six SCC annually; however, he developed recalcitrant diabetic foot ulcers which were purely neuropathic and nonangiopathic, and a limb-threatening fistulating necrotic erysipelas of the right leg. Both sites responded poorly to antibiotic therapy, offloading and debridement. This skin fistula became chronic and some toes were at risk for minor amputation. In view of the propensity for mTOR inhibitors to impair would healing, immunosuppression was switched back to ciclosporin. All wounds healed rapidly, but skin carcinogenesis rose to former levels.. This case impressively illustrates the clinical dilemma for mTOR inhibitor use where benefit in carcinogenesis is counterbalanced by impairment in wound healing. Changes in immunosuppressive regimens should thus be made on an individual basis with careful consideration of the relative risks.

Topics: Aged; Calcineurin Inhibitors; Cardiomyopathy, Dilated; Cell Transformation, Neoplastic; Diabetic Foot; Drug Substitution; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Sirolimus; Skin Neoplasms; Toes; TOR Serine-Threonine Kinases; Wound Healing

A 60-year-old man with severe heart failure underwent an orthotopic heart transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, mycophenolate mofetil (MMF), and a glucocorticoid. Six months after the transplantation, coronary angiography (CAG) and intravascular ultrasound sonography (IVUS) showed rapidly progressive cardiac allograft vasculopathy (CAV) along with acute cellular rejection. Methylprednisone pulse therapy resulted in the resolution of acute rejection. MMF was exchanged for everolimus (EVL) and 6 months after EVL therapy, CAG and IVUS revealed the regression of CAV. EVL can improve established CAV as well as prevent the progression of CAV.

Topics: Antineoplastic Agents; Biopsy; Cardiomyopathy, Dilated; Coronary Angiography; Everolimus; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardium; Sirolimus; Time Factors; Ultrasonography, Interventional

The side effects of proliferation signal inhibitors (PSIs) have been characterized as a class. However, it would be convenient to assess them according to the molecule.. To assess prospectively the tolerance of PSIs among heart transplant (HT) patients.. We studied 56 HT patients who sequentially received PSIs to either withdraw (77%) or reduce the dosage of a calcineurin inhibitor; 42 received everolimus (EVE) and 14 sirolimus (SRL). We analyzed the demographic variables, side effects, and need to withdraw the drug during a median follow-up period of 365 days.. No differences between groups were observed upon analysis of the clinical and demographic variables when the treatment was changed owing to renal dysfunction (67%) or tumor (32%). No difference between groups was observed over the follow-up period (P = .28). Infection was the most common side effect, 28.6%: EVE, 14.3% versus SRL, 71.4% (P < .0001). Edema occurred in 26.8% of patients: EVE, 14.3% versus SRL, 64.3% (P = .001); diarrhea in 5.4% of patients: EVE, 2.4% versus SRL, 14.3% (P = .15). Treatment was withdrawn in 23.2% of the patients due to intolerance: EVE, 11.9% versus SRL, 57.1% (P < .0001). EVE showed significantly better survival without edema or infections or used for drug withdrawal upon Kaplan-Meier analysis, (P = .01; P = .0005; P = .0097). Only SRL use was shown to be an independent predictor of side effects.. Edema and infections are the main problems caused by PSIs. EVE may display a better tolerance profile than SRL.

Topics: Adult; Calcineurin Inhibitors; Cardiomyopathy, Dilated; Coronary Disease; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Tolerance; Edema; Everolimus; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Regression Analysis; Retrospective Studies; Sirolimus

Neurotoxicity is a common adverse effect of cyclosporine (CsA) in transplant recipients. Although most patients develop mild toxic manifestations, leukoencephalopathy with seizures, visual complications, psychiatric symptoms and motor and speech disorders may occur. Whether everolimus exacerbates the neurotoxicity of CsA is not known. We describe a patient who developed severe neurologic complications, consistent with CsA-induced neurotoxicity, developing 7.5 years after cardiac transplantation, 3 months after everolimus was added to the immunosuppressive regimen.

Topics: Brain Diseases; Cardiomyopathy, Dilated; Cyclosporine; Everolimus; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Sirolimus; Ventricular Dysfunction, Right

Renal function deterioration is one of the main problems facing heart transplant recipients. The mammalian target of rapamycin (mTOR) inhibitors, in combination with or replacing calcineurin inhibitors, may help preserve renal function. The aim of this study was to evaluate the progression of renal function after switching the immunosuppressive regimen.. We studied 23 heart transplant recipients (5.5 +/- 4.5 years since transplantation). An mTOR inhibitor was introduced to replace cyclosporine (everolimus, 65%; sirolimus, 35%). Patient clinical characteristics and renal function were studied after switching. The statistical analysis used Student t test for paired data.. The reason for the transplantation was ischemic cardiopathy (52%), dilated myocardiopathy (39%), or other causes (9%). Mean age at time of transplantation was 52 +/- 9 years. Comorbidities were as follows hypertension (43%), insulin-dependent diabetes (22%), hypercholesterolemia (39%), and ex-smokers (70%). The reason for the switch was increased creatinine (65%), appearance of tumors (26%), or others (8%). Previous creatinine level was 1.89 +/- 0.6 mg/dL with clearance of 61.7 +/- 23 mL/min and at the end of follow-up (mean follow-up, 11 +/- 6 months) creatinine level was 2.0 +/- 1.45 mg/dL with clearance of 68.3 +/- 35 mL/min, namely, no significant difference (P = .49 and P = .57, respectively). In the subgroup of patients who switched treatment due to renal dysfunction, initial creatinine level was 2.38 +/- 0.4 mg/dL with clearance of 42.3 +/- 10 mL/min and at the end of follow-up it was 2.28 +/- 0.2 mg/dL and 43.6 +/- 11 mL/min, respectively (P = .68 for creatinine and clearance).. The introduction of mTOR inhibitors to the immunosuppressant regimen may be useful to delay renal functional deterioration caused by calcineurin inhibitors.

Topics: Adult; Cardiomyopathies; Cardiomyopathy, Dilated; Everolimus; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Function Tests; Male; Middle Aged; Protein Kinases; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

Myosin-induced autoimmune myocarditis in rats is a model of human dilated cardiomyopathy. Rapamycin is a potent immunosuppressant and specifically inactivates the mammalian target of rapamycin (mTOR). To examine the role of mTOR in autoimmune myocarditis, we administered rapamycin to rats immunized with cardiac myosin. Phosphorylation of p70 ribosomal S6 kinase 1 (S6K1), a target of mTOR, was increased by 6.9 fold in the heart tissue of myosin immunized rats. Rapamycin (2 mg/kg/day) completely suppressed S6K1 and S6 phosphorylation. The amount of interleukin-1beta, interferon-gamma, interleukin-2, or tumor necrosis factor-alpha mRNA in the heart tissue was markedly increased in myosin-immunized rats, and rapamycin significantly attenuated the cytokine gene expressions. Rapamycin improved the survival of the rats and preserved cardiac function. The plasma level of brain natriuretic peptide increased by 4.7 fold in myosin-immunized rats, and rapamycin attenuated the increase in plasma brain natriuretic peptide. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.81 +/- 0.06 fold compared with vehicle-treated unimmunized rats, and rapamycin suppressed the increase in heart weight. Rapamycin decreased the cellular infiltration and fibrosis of the myocardium. The amount of phosphorylated S6 was increased in the infiltrating mononuclear cells in vehicle-treated myosin-immunized rats. Rapamycin significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis.

Topics: Animals; Autoimmunity; Cardiomyopathy, Dilated; Disease Models, Animal; Female; Gene Expression Regulation; Immunosuppressive Agents; Interferon-gamma; Interleukin-1; Interleukin-2; Myocarditis; Myosins; Natriuretic Peptide, Brain; Rats; Rats, Inbred Lew; Sirolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

We reported the late thrombosis of a drug-eluting coronary stent related to discontinuation of antiplatelet therapy for venous surgery of the right leg more than half and a year after its implantation. After this acute myocardial infarction, a cardiac assistance device has to be used as a bridge to transplantation because of end stage ischaemic cardiopathy. Antiplatelet therapy management must be revisited for eluting stents, which can clot lately after its implantation.

Topics: Acute Disease; Antineoplastic Agents, Phytogenic; Cardiomyopathy, Dilated; Heart Transplantation; Heart-Assist Devices; Humans; Leg; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Stents; Thrombosis; Vascular Surgical Procedures

Sirolimus is a potent immunosuppressive agent used with increasing frequency in solid organ transplantation (SOT). However, it has been associated with rare but devastating pulmonary toxicity. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 64-yr-old heart transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among SOT recipients in an effort to better understand the pathophysiology, risk factors, and outcomes of this rare but serious complication. A total of 64 cases have been reported since January 2000 including the present case. These consisted of 52 kidney, four lung, three liver, three heart, one heart-lung and one islet cell transplants. In most cases, patients presented with a constellation of symptoms consisting of fever, dyspnea, fatigue, cough, and occasionally hemoptysis. Although the risk factors for this association have not been clearly established, high dose, late exposure to the drug and male gender have been noticed among most. In almost all of the reported cases, sirolimus was added later in the course of immunosuppressive therapy, usually in an effort to attenuate the nephrotoxic effects of a previous regimen containing a calcineurin inhibitor. There were three deaths (4.8%) among 62 patients with known status at follow up; all deaths were among heart transplant recipients. Most patients (95%) resolved their clinical and radiographic findings with discontinuation or dose-reduction of the drug. Sirolimus-induced pulmonary toxicity is a rare but serious entity that should be considered in the differential diagnosis of a transplant recipient presenting with respiratory compromise. Dose-reduction or discontinuation of the drug can be life saving.

Topics: Bronchoscopy; Cardiomyopathy, Dilated; Disease Progression; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Sirolimus; Tomography, X-Ray Computed

Topics: Aged; Azathioprine; Cardiomyopathy, Dilated; Drug Therapy, Combination; Everolimus; Fever; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Sirolimus