sirolimus and Cardiomyopathies

Rapamycin is a U.S. Food and Drug Administration-approved drug for the prevention of immunorejection following organ transplantation. Pharmacological studies suggest a potential new application of rapamycin in attenuating cardiomyopathy, but the potential for this application is not yet supported by genetic studies of genes in target of rapamycin (TOR) signaling in rodents. Recently, supporting genetic evidence was presented in zebrafish using two adult cardiomyopathy models. By characterizing a heterozygous zebrafish target of rapamycin (ztor) mutant, the therapeutic effect of long-term TOR signaling inhibition was demonstrated. Dose- and stage-dependent functions of TOR signaling provide an explanation for the seemingly contradictory results obtained in genetic studies of TOR components in rodents. The results from the zebrafish studies, together with the supporting preliminary clinical studies, suggested that TOR signaling inhibition should be further pursued as a novel therapeutic strategy for cardiomyopathy. Future directions for developing TOR-based therapy include assessing the long-term benefits of rapamycin as a candidate drug for heart failure patients, defining the dynamic activity of TOR, exploring the impacts of TOR signaling manipulation in different models of cardiomyopathies, and elucidating the downstream signaling branches that confer the therapeutic effects of TOR signaling inhibition.

Topics: Animals; Cardiomyopathies; Humans; Immunosuppressive Agents; Rodentia; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Zebrafish

Autophagy is a major cytoprotective pathway that eukaryotic cells use to degrade and recycle cytoplasmic contents. Recent evidence indicates that autophagy under baseline conditions represents an important homeostatic mechanism for the maintenance of normal cardiovascular function and morphology. By contrast, excessive induction of the autophagic process by environmental or intracellular stress has an important role in several types of cardiomyopathy by functioning as a death pathway. As a consequence, enhanced autophagy represents one of the mechanisms underlying the cardiomyocyte dropout responsible for the worsening of heart failure. Successful therapeutic approaches that regulate autophagy have been reported recently, suggesting that the autophagic machinery can be manipulated to treat heart failure or to prevent rupture of atherosclerotic plaques and sudden death.

Topics: Animals; Autophagy; Cardiomyopathies; Cardiovascular Diseases; Humans; Models, Biological; Signal Transduction; Sirolimus

Protein turnover represents the balance between protein synthesis and degradation. It can be controlled quantitatively, for instance by an activation of protein synthesis during cardiac hypertrophy or by activating protein degradation during ventricular unloading. It can also be regulated qualitatively by changing the steady state concentration of specific proteins and enzymes. The recent literature points to an emerging role for the mammalian target of rapamycin (mTOR) and for the ubiquitin-proteasome system (UPS) in this process, and both pathways interact in the regulation of cell growth and survival. We highlight the critical role played by such interaction in different cellular functions, including insulin signaling, stress response to hypoxia, adaptation to variations in workload, regulation of protein phosphatase activity, apoptosis and post-ischemic recovery. A deregulation of these pathways participates in the mechanisms of cardiac ischemia, hypertrophy and failure, and controlling their activity represents an opportunity for novel therapeutic avenues.

Topics: Animals; Cardiomyopathies; Cell Proliferation; Cell Survival; Humans; Myocytes, Cardiac; Neoplasms; Phosphorylation; Proteasome Endopeptidase Complex; Protein Biosynthesis; Proteins; Signal Transduction; Sirolimus; Ubiquitin

Left ventricular hypertrophy (LVH) and diastolic dysfunction occur after cardiac transplantation. We investigated sirolimus (SRL) as primary immunosuppression for the attenuation of LVH and diastolic dysfunction of the cardiac allograft.. Seventy cardiac transplant recipients were converted to SRL, 5.79+/-3.90 years after transplant, with complete calcineurin-inhibitor (CNI) withdrawal. Three consecutive echocardiographic studies, 1 year apart, were analyzed for changes in left ventricular (LV) mass and diastolic function during CNI and SRL treatment.. Changes in systolic (P=0.69) and diastolic blood pressures (BP) (P=0.32) did not differ between SRL and CNI treatment. LV mass and LV mass index increased (185.03+/-41.59-197.21+/-47.39 g, P=0.033 and 94.20+/-18.64-98.93+/-20.08 g/m; P=0.030) during CNI and decreased (197.21+/-47.39-187.59+/-48.88 g, P=0.025 and 98.93+/-20.08-94.06+/-20.31 g/m P=0.050) during SRL. The difference in Delta LV mass and Delta LV mass index was significant (P=0.011 and P=0.017, respectively) and was not associated with changes in BP. Left atrium volume index increased during CNI (46.73+/-16.3 5-54.20+/-18.47 cm/m, P=0.006) and decreased during SRL (54.20+/-18.47-49.75+/-18.40 cm/m, P=0.0036). The difference in left atrium (Delta LA) volume index was significant (P=0.002) and was not associated with changes in BP.. Withdrawal of CNI and replacement with SRL in cardiac transplant recipients results in a decrease in LV mass and improvement in diastolic function. SRL may be useful to attenuate LVH and improve cardiac allograft diastolic function.

Topics: Adult; Aged; Calcineurin Inhibitors; Cardiomyopathies; Diastole; Echocardiography; Female; Follow-Up Studies; Heart Diseases; Heart Transplantation; Hemodynamics; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Systole; Transplantation, Homologous; Ventricular Dysfunction, Left; Ventricular Function, Left

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

Danon disease is a lethal X-linked genetic syndrome resulting from radical mutations in the LAMP2 gene. LAMP2 protein deficiency results in defective lysosomal function, autophagy arrest and a multisystem disorder primarily involving the heart, skeletal muscle and the central nervous system. Cardiomyopathy is the main cause of morbidity and mortality. To investigate the mechanisms of and develop therapies for cardiac Danon disease we engineered a mouse model carrying an exon 6 deletion human mutation in LAMP2, which recapitulates the human cardiac disease phenotype. Mice develop cardiac hypertrophy followed by left ventricular dilatation and systolic dysfunction, in association with progressive fibrosis, oxidative stress, accumulation of autophagosomes and activation of proteasome. Stimulation of autophagy in Danon mice (by exercise training, caloric restriction, and rapamycin) aggravate the disease phenotype, promoting dilated cardiomyopathy. Inhibiting autophagy (by high fat diet or hydroxychloroquine) is better tolerated by Danon mice compared to wild type but is not curative. Inhibiting proteasome by Velcade was found to be highly toxic to Danon mice, suggesting that proteasome is activated to compensate for defective autophagy. In conclusion, activation of autophagy should be avoided in Danon patients. Since Danon's is a lifelong disease, we suggest that lifestyle interventions to decrease cardiac stress may be useful to slow progression of Danon's cardiomyopathy. While Danon mice better tolerate high fat diet and sedentary lifestyle, the benefit regarding cardiomyopathy in humans needs to be balanced against other health consequences of such interventions.

Topics: Animals; Autophagy; Bortezomib; Cardiomegaly; Cardiomyopathies; Glycogen Storage Disease Type IIb; Humans; Hydroxychloroquine; Mice; Phenotype; Proteasome Endopeptidase Complex; Sirolimus

Topics: Cardiomyopathies; Ferroptosis; Humans; Sirolimus; TOR Serine-Threonine Kinases

Topics: Cardiomyopathies; Humans; Sepsis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cardiomyopathies; Cardiotonic Agents; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Echocardiography; Female; Insulin; Insulin Resistance; Longevity; Male; Mice; Mice, Inbred C57BL; Sirolimus; Weight Gain

To explore the role of mammalian target of rapamycin (mTOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic condition.. Male albino Wistar rats weighing 100-120 g were treated with tetrachloride carbon (CCl4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin (2 mg/kg per day). The QTc intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles were isolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-mTOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor (TNF)-α was measured. Western blot was used to measure levels of ventricular phosphorylated-mTOR protein.. Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight (P < 0.001). A significant prolongation in QTc intervals occurred in cirrhotic rats exposed to CCl4 (P < 0.001), while this prolongation was decreased with rapamycin treatment (P < 0.01). CCl4-induced cirrhosis caused a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-α. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated-mTOR expression in left ventricles. Phosphorylated-mTOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-mTOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment.. In this study, we demonstrated a potential role for cardiac mTOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-mTOR expression and myocardial localization in cirrhotic rats.

Topics: Action Potentials; Animals; Carbon Tetrachloride; Cardiomyopathies; Cardiotonic Agents; Chemical and Drug Induced Liver Injury; Heart Rate; Isoproterenol; Liver Cirrhosis, Experimental; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Phosphorylation; Protein Kinase Inhibitors; Rats, Wistar; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K-ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K-ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway.. Biosynthesis of MBG by cultured human JEG-3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 μmol/L of rapamycin inhibited production of MBG in human JEG-2 cells. Male Sprague-Dawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025±60 vs 377±53 pmol/L; P<0.01), systolic blood pressure (169±1 vs 111±1 mm Hg; P<0.01), and cardiac fibrosis compared to controls. Plasma MBG levels were significantly decreased in PNx-rapamycin animals compared to PNx (373±46 vs 1025±60 pmol/L; P<0.01), and cardiac fibrosis was substantially attenuated by rapamycin treatment.. Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG-mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy.

Topics: Animals; Blood Pressure; Bufanolides; Cardiomyopathies; Cells, Cultured; Enzyme Inhibitors; Fibroblasts; Fibrosis; Heart; Humans; Immunosuppressive Agents; Male; Myocardium; Nephrectomy; Rats; Rats, Sprague-Dawley; Sirolimus; Sodium-Potassium-Exchanging ATPase; Uremia

Cardiomyocyte death is one major factor in the development of heart dysfunction, thus, understanding its mechanism may help with the prevention and treatment of this disease. Previously, we reported that anti-β1-adrenergic receptor autoantibodies (β1-AABs) decreased myocardial autophagy, but the role of these in cardiac function and cardiomyocyte death is unclear. We report that rapamycin, an mTOR inhibitor, restored cardiac function in a passively β1-AAB-immunized rat model with decreased cardiac function and myocardial autophagic flux. Next, after upregulating or inhibiting autophagy with Beclin-1 overexpression/rapamycin or RNA interference (RNAi)-mediated expression of Beclin-1/3-methyladenine, β1-AAB-induced autophagy was an initial protective stress response before apoptosis. Then, decreased autophagy contributed to cardiomyocyte death followed by decreases in cardiac function. In conclusion, proper regulation of autophagy may be important for treating patients with β1-AAB-positive heart dysfunction.

Topics: Adenine; Adrenergic beta-1 Receptor Antagonists; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autoantibodies; Autophagy; Beclin-1; Cardiomyopathies; Cell Line; Gene Expression Regulation; Humans; Immunization, Passive; Male; Myocytes, Cardiac; Rats; Rats, Wistar; Receptors, Adrenergic, beta-1; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Ventricular Dysfunction, Left; Ventricular Pressure

Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late-life cardiovascular function with a reversal or attenuation of age-related changes in the heart. RNA-seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late-life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age-related inflammation.

Topics: Aging; Animals; Cardiomyopathies; Disease Susceptibility; Echocardiography; Female; Immunosuppressive Agents; Longevity; Mice; Mice, Inbred C57BL; Signal Transduction; Sirolimus; Survival Analysis

Recent evidence has depicted a role of macrophage migration inhibitory factor (MIF) in cardiac homeostasis under pathological conditions. This study was designed to evaluate the role of MIF in doxorubicin-induced cardiomyopathy and the underlying mechanism involved with a focus on autophagy.. Wild-type (WT) and MIF knockout (MIF(-/-)) mice were given saline or doxorubicin (20 mg/kg cumulative, i.p.). A cohort of WT and MIF(-/-) mice was given rapamycin (6 mg/kg, i.p.) with or without bafilomycin A1 (BafA1, 3 μmol/kg per day, i.p.) for 1 week prior to doxorubicin challenge. To consolidate a role for MIF in the maintenance of cardiac homeostasis following doxorubicin challenge, recombinant mouse MIF (rmMIF) was given to MIF(-/-) mice challenged with or without doxorubicin. Echocardiographic, cardiomyocyte function, and intracellular Ca(2+) handling were evaluated. Autophagy and apoptosis were examined. Mitochondrial morphology and function were examined using transmission electron microscopy, JC-1 staining, MitoSOX Red fluorescence, and mitochondrial respiration complex assay. DHE staining was used to evaluate reactive oxygen species (ROS) generation. MIF knockout exacerbated doxorubicin-induced mortality and cardiomyopathy (compromised fractional shortening, cardiomyocyte and mitochondrial function, apoptosis, and ROS generation). These detrimental effects of doxorubicin were accompanied by defective autophagolysosome formation, the effect of which was exacerbated by MIF knockout. Rapamycin pretreatment rescued doxorubicin-induced cardiomyopathy in WT and MIF(-/-) mice. Blocking autophagolysosome formation using BafA1 negated the cardioprotective effect of rapamycin and rmMIF.. Our data suggest that MIF serves as an indispensable cardioprotective factor against doxorubicin-induced cardiomyopathy with an underlying mechanism through facilitating autophagolysosome formation.

Topics: Animals; Apoptosis; Autophagy; Calcium Signaling; Cardiomyopathies; Cytoprotection; Disease Models, Animal; Doxorubicin; Electron Transport Chain Complex Proteins; Intramolecular Oxidoreductases; Lysosomes; Macrolides; Macrophage Migration-Inhibitory Factors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Reactive Oxygen Species; Sirolimus; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Topics: Animals; Cardiomyopathies; Mutation; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Zebrafish

Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways, but the specific mechanisms are poorly understood. We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and demonstrate that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for treatment of LMNA cardiomyopathy with rapalogs and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation.

Topics: Animals; Autophagy; Cardiomyopathies; Lamin Type A; Mutation; Rats; Sirolimus

Sirolimus is a well-known, potent immunosuppressant that is widely used in solid-organ transplantation, but it is not without potential side effects. A rare but devastating adverse effect is sirolimus-associated pulmonary toxicity. We report a case of sirolimus-induced diffuse alveolar hemorrhage confirmed by bronchoscopic findings (after other possible etiologies were ruled out) and by clinical and radiographic resolution of the pulmonary signs and symptoms a few days after sirolimus administration was stopped. This case and the existing literature on this topic suggest that sirolimus-induced pulmonary toxicity should be suspected in any patient taking immunosuppressants and who develops unexplained pulmonary symptoms.

Topics: Cardiomyopathies; Diagnosis, Differential; Heart Transplantation; Hemorrhage; Humans; Immunosuppressive Agents; Male; Middle Aged; Pulmonary Alveoli; Sirolimus

Topics: Angioplasty, Balloon, Coronary; Cardiomyopathies; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Bypass; Humans; Myocardial Ischemia; Paclitaxel; Patient Selection; Prosthesis Design; Radiography; Severity of Illness Index; Sirolimus; Stents; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

We compared the outcome of drug eluting stent (DES) implantation (Sirolimus or Paclitaxel) in patients with ischemic cardiomyopathy and severe left ventricular (LV) dysfunction with the outcome of a similar group of patients undergoing coronary artery by-pass grafting (CABG).. Revascularization provides long-term benefits in patients with severe LV dysfunction. However the modality to achieve it is still unsettled in this high risk group of patients.. Two-hundred-twenty patients (20% women) with severe LV dysfunction (LV Ejection Fraction

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiomyopathies; Cardiovascular Agents; Cardiovascular Diseases; Coronary Angiography; Coronary Artery Bypass; Female; Follow-Up Studies; Humans; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Ischemia; Paclitaxel; Prosthesis Design; Research Design; Retrospective Studies; Severity of Illness Index; Sirolimus; Stents; Time Factors; Treatment Outcome; United States; Ventricular Dysfunction, Left

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

Mammalian target of rapamycin (mTOR) inhibitors are relatively new drugs in the field of cardiac transplantation (HT), hence the need for further study of their secondary effects. We described the nature and incidence of secondary effects of these drugs in a group of HT recipients.. We studied 23 HT recipients aged 52 +/- 9 years (Male: 91%, body mass index: 27 +/- 3.7, ischemic cardiopathy: 52%, dilated cardiomyopathy: 39%) who were started on an mTOR inhibitor (everolimus: 65%, sirolimus: 35%) as part of their treatment. We have described the secondary effects detected during a follow-up period of 10.7 +/- 6 months.. The reasons for starting the drug were renal impairment (65%), tumors (26%), and others (8%). During follow-up, 17% of patients required a dose reduction and 12% required drug withdrawal: edemas: 4%, recurrent infection: 4%, and hemolytic-uremic syndrome: 4%. Drug-attributable edemas presented in 26% of patients. Thirty nine percent suffered an infection that required hospital admission, 89% of which were lung and all bacterial two patients died due to the infection). The mean time to first infection was 5 +/- 6 months. In patients who had a treatment change due to tumors, 50% experienced improvement. We did not detect alterations in cholesterol, triglycerides, creatinine, or leukocytes. There was a nonsignificant trend toward decreased hemoglobin and platelet levels (P = .07 and P = .056, respectively).. Lung infection was the principal complication among our patients treated with mTOR inhibitors. A large percentage required dose reduction (17%) and even drug withdrawal (12%) due to secondary effects.

Topics: Adult; Cardiomyopathies; Creatinine; Dose-Response Relationship, Drug; Edema; Everolimus; Female; Follow-Up Studies; Heart Transplantation; Hemoglobins; Humans; Immunosuppressive Agents; Leukocyte Count; Lipids; Male; Middle Aged; Platelet Count; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

We examined the efficacy of drug-eluting stent (DES) implantation (Sirolimus or Paclitaxel) in patients with ischemic cardiomyopathy and severe left ventricular (LV) dysfunction and compared the outcome with a similar group of patients undergoing bare metal stent (BMS) implantation.. Patients with severe LV dysfunction are a high risk group. DES may improve the long term outcomes compared with BMS.. One hundred and ninety one patients (23% women) with severe LV dysfunction (LV ejection fraction < or =35%) underwent coronary stent implantation between May 2002 and May 2005 and were available for follow-up. One hundred and twenty eight patients received DES (Sirolimus in 72 and Paclitaxel in 54) and 63 patients had BMS. Patients with acute S-T elevation myocardial infarction (STEMI) were excluded. The primary endpoint was cardiovascular mortality. A composite endpoint of major adverse cardiac events (MACE) including cardiovascular mortality, myocardial infarction (MI), and target vessel revascularization (TVR) was the secondary endpoint.. Mean follow-up was 420 +/- 271 days. No differences were noted in age (69 +/- 10 years vs. 70 +/- 10 years, P = NS), number of vessel disease (2.3 +/- 0.7 vs. 2.2 +/- 0.8, P = NS), history of congestive heart failure (47% vs. 46%, P = NS), MI (60% vs. 61%, P = NS), or number of treated vessels (1.3 +/- 0.5 vs. 1.3 +/- 0.6, P = NS) for the DES and BMS group, respectively. Diabetes was more common among DES patients (45% vs. 25%, P = 0.01). The left ventricular ejection fraction (LVEF) was similar between the two groups (28% +/- 6% vs. 26% +/- 8%, P = NS for the DES and BMS, respectively). During the follow-up, there were a total of 25 deaths of which two were cancer related (2 in DES group). There were 23 cardiac deaths, 8/126 (6%) which occurred in the DES group and 15/63 (24%) in the BMS group (P = 0.05 by log-rank test). MACE rate was 10% for the DES group and 41% for the BMS group (P = 0.003). NYHA class improved in both groups (from 2.5 +/- 0.8 to 1.7 +/- 0.8 in DES and from 2 +/- 0.8 to 1.4 +/- 0.7 in the BMS, P = NS).. Compared with bare-metal stents, DES implantation reduces mortality and MACE in high risk patients with severe left ventricular dysfunction.

Topics: Aged; Aged, 80 and over; Blood Vessel Prosthesis Implantation; Cardiomyopathies; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Angiography; Female; Follow-Up Studies; Heart Failure; Humans; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Paclitaxel; Prosthesis Design; Research Design; Severity of Illness Index; Sirolimus; Stents; Stroke Volume; Survival Rate; Treatment Outcome; United States; Ventricular Dysfunction, Left

Mechanical unloading of the heart results in atrophic remodeling. In skeletal muscle, atrophy is associated with inactivation of the mammalian target of rapamycin (mTOR) pathway and upregulation of critical components of the ubiquitin proteosome proteolytic (UPP) pathway. The hypothesis is that mechanical unloading of the mammalian heart has differential effects on pathways of protein synthesis and degradation.. In a model of atrophic remodeling induced by heterotopic transplantation of the rat heart, we measured gene transcription, protein expression, polyubiquitin content, and regulators of the mTOR pathway at 2, 4, 7, and 28 days. In atrophic hearts, there was an increase in polyubiquitin content that peaked at 7 days and decreased by 28 days. Furthermore, gene and protein expression of UbcH2, a ubiquitin conjugating enzyme, was also increased early in the course of unloading. Transcript levels of TNF-alpha, a known regulator of UbcH2-dependent ubiquitin conjugating activity, were upregulated early and transiently in the atrophying rat heart. Unexpectedly, p70S6K and 4EBP1, downstream components of mTOR, were activated in atrophic rat heart. This activation was independent of Akt, a known upstream regulator of mTOR. Rapamycin treatment of the unloaded rat hearts inhibited the activation of p70S6K and 4EBP1 and subsequently augmented atrophy in these hearts compared with vehicle-treated, unloaded hearts.. Atrophy of the heart, secondary to mechanical unloading, is associated with early activation of the UPP. The simultaneous activation of the mTOR pathway suggests active remodeling, involving both protein synthesis and degradation.

Topics: Animals; Atrophy; Cardiomyopathies; Disease Models, Animal; Male; Organ Size; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Proteins; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterotopic; Tumor Necrosis Factor-alpha; Ubiquitin-Conjugating Enzymes; Ventricular Remodeling