tacrolimus and Myocardial-Infarction

The current therapeutic strategy for the management of acute myocardial infarction (AMI) is to return blood flow into the occluded coronary artery of the heart, a process defined as reperfusion. However, reperfusion itself can increase mortality rates in AMI patients because of cardiac tissue damage and dysfunction, which is termed 'ischaemia/reperfusion (I/R) injury'. Mitochondria play an important role in myocardial I/R injury as disturbance of mitochondrial dynamics, especially excessive mitochondrial fission, is a predominant cause of cardiac dysfunction. Therefore, pharmacological intervention and therapeutic strategies which modulate the mitochondrial dynamics balance during I/R injury could exert great beneficial effects to the I/R heart. This review comprehensively summarizes and discusses the effects of mitochondrial fission inhibitors as well as mitochondrial fusion promoters on cardiac and mitochondrial function during myocardial I/R injury. The comparison of the effects of both compounds given at different time-points during the course of I/R injury (i.e. prior to ischaemia, during ischaemia and at the reperfusion period) are also summarized and discussed. Finally, this review also details important information which may contribute to clinical practices using these drugs to improve the quality of life in AMI patients.

Topics: Animals; Cardiotonic Agents; Cell Line; Disease Models, Animal; GTP Phosphohydrolases; Humans; Hydrazones; Mitochondria, Heart; Mitochondrial Dynamics; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Peptide Fragments; Quinazolinones; Tacrolimus; Ventricular Function, Left

The aim of this multicentre, non-randomised trial was to evaluate the safety and efficacy at 180+/-14 days of a pimecrolimus eluting coronary stent based on a cobalt-chromium platform and a poly-L-lactic acid (PLLA) bioresorbable polymer.. Sixty-one patients, with single de novo coronary lesions <14 mm in length and a reference vessel diameter of 3.0 to 3.5 mm, were enrolled in five centres (Germany and Belgium). Angiography and IVUS were performed at baseline, post-procedure and 180+/-14 days later. The primary endpoint was a composite of major adverse cardiac events (MACE) at 180+/-14 days and expected to be below 20%. Patients had single vessel disease in 59%, 2-vessel disease in 28% and 3-vessel disease in 13% of cases. MACE rate at 180+/-14 days was 18.0%. Binary in-stent restenosis was 32.7% due to in-stent late lumen loss of 1.11+/-0.65 mm by QCA. Stent thrombosis rate at 30+/-7 and 180+/-14 days was 1.6% and 3.3%, respectively. Overall TLR rate at 30+/-7, 180+/-14 days and 12+/-1 months was 1.6%, 27.9% and 32.8% respectively.. The primary endpoint was met at 180+/-14 days. However, the anti-restenotic effect of the pimecrolimus eluting stent did not reach levels similar to clinically established DES.

Topics: Aged; Angioplasty, Balloon, Coronary; Belgium; Cardiovascular Agents; Chromium Alloys; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Germany; Humans; Lactic Acid; Male; Middle Aged; Myocardial Infarction; Polyesters; Polymers; Prospective Studies; Prosthesis Design; Severity of Illness Index; Tacrolimus; Thrombosis; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Drug eluting stents (DES) have been shown to reduce restenosis compared with bare metal stents in bifurcated lesions. The aim of this study was to evaluate the long-term clinical outcomes of patients with bifurcated lesions treated by 3 different DES.. Consecutive patients with symptomatic coronary artery disease on one bifurcated lesion with SB>2.25 mm (on visual estimation) undergoing at the Department of Cardiology of the Catholic University of Rome, Italy were screened. Patients treated with Sirolimus-eluting stent (Cypher Select; SES Group), Tacrolimus-eluting stent (Taxus-Libertè; TA Group) and Zotarolimus-eluting stent (Endeavor Driver; ZOT Group) were enrolled in the study. Clinical and angiographic characteristics of all patients were prospectively recorded. Major adverse clinical events (MACE), including death, acute myocardial infarction (MI) or target lesion revascularization (TVR) by either percutaneous coronary intervention (PCI) or coronary surgery were recorded during the follow-up. Incidence of definite or probable stent thrombosis was calculated according to the ARC criteria.. Two hundred and forty-one consecutive patients were enrolled (89 Group CY, 98 Group TA and 54 Group EN). Length of follow-up was 235+/-60 days. Baseline clinical and angiographic characteristic were similar across the groups. The adopted technique for stent implantation was provisional stenting (73.4%), T-stenting technique (7%), crush (7%) and V-stenting (2.6%). The rate of patients finally treated with two stents was similar among groups. The cumulative rate of MACE (9% SES, 12% TA, 11% ZOT: P=0.7) and of TVR (2% SES, 9% TA, 7% ZOT) was similar among groups. No definite stent thrombosis was observed during follow-up, while 1 probable stent thrombosis was observed in TA group.. The clinical outcome of bifurcated lesions using DES and mainly a technique of single stent implantation is good. In the present observational study, clinical adverse events did not differ in patients with bifurcated lesions treated by Cypher, Taxus or Endeavor stent implantation.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug Therapy, Combination; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Prospective Studies; Risk Factors; Rome; Sirolimus; Tacrolimus; Treatment Outcome

Long-term efficacy and safety of tacrolimus-eluting stent (Janus) for treatment of coronary artery disease in percutaneous coronary interventions (PCI) "real world" is uncertain. The aim of this study was to evaluate the efficacy and safety of Janus stent for treating coronary heart disease in PCI daily practice, the safety of 4-month clopidogrel therapy after Janus stent implantation and the feasibility for treating patients with acute myocardial infarction (AMI) for first time.. From February 20, 2006 to August 26, 2006, a total of 200 patients were enrolled and randomly assigned to receive either Janus stent (n = 100) or bare metal stent (Tecnic Carbostent, n = 100). All patients were administered with clopidogrel for 4 months and aspirin for life long after stenting.. Baseline clinical and angiographic characteristics were comparable between the two groups. AMI was present in 37% of patients with Janus and 36% with Tecnic Carbostent. At an average of 246-day follow-up, major adverse cardiac events (MACE) was 6% with the Janus stent and 15% with the Tecnic Carbostent (P = 0.038). Primary events included 1 cardiac death, 1 myocardial infarction (MI) due to subacute stent thrombosis and 13 target lesion revascularizations (TLR) due to restenosis in patients with Tecnic Carbostent and 6 TLR due to restenosis in patients with Janus stent. Although all patients had discontinued clopidogrel for an average of 126 days, there was no additional thrombotic event in the two groups.. Janus stent is efficient in reducing MACE compared with Tecnic Carbostent at an average of 8-month follow-up. Discontinuation of clopidogrel at 4 months after PCI is safe for patients with Janus stent, including AMI patients. Long-term efficacy of Janus stent in reducing restenosis requires further study.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Disease; Drug Delivery Systems; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Tacrolimus

To investigate the effect of tacrolimus (FK506) on myocardial infarction, and to further explore its function mechanism.. C57BL/6J mice were randomly divided into three groups: the sham group, the control group and the FK506 group. Anterior descending branch ligation was conducted in the control and the FK506 groups, while sham operation was conducted in the sham group. Mice in the sham and the control groups were intragastrical administration with saline, while the FK506 group were with FK506. Heart function were detected by echocardiogram at 3rd day or 21st day after MI. Hearts were harvested at 3rd day or 21st day after MI for the detection of apoptosis, autophagy, mTOR and NF-κB pathway.. FK506 treatment increased survival rate and cardiac function in mice after MI. It decreased infarction area, inflammation reaction and apoptosis. To further study the mechanism of FK506 protection effect, we discovered it could increase autophagy via inhibit mTOR pathway.. FK506 protect heart function after MI as it improved myocardial cells autophagy process via inhibiting mTOR pathway.

Topics: Animals; Apoptosis; Autophagy; Cardiotonic Agents; Electrocardiography; Heart; Male; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; NF-kappa B; Phosphorylation; Survival Rate; Tacrolimus; TOR Serine-Threonine Kinases

This study investigates the therapeutic potential of intracoronary tacrolimus against acute myocardial infarction (AMI) in minipigs with serial cardiac magnetic resonance (CMR) and changes at histological and protein levels. Twelve minipigs subjected to permanent left anterior descending artery ligation were randomized as tac-treated group (n=6, with intracoronary tacrolimus treatment) and controls (n=6). CMR with cine and late gadolinium enhancement (LGE) studies were performed on postoperative days 2, 5, and 21. There were no significant differences in left ventricular function (LVF), contractility, and LGE between the two groups on day 2. On day 5, the tac-treated group showed a significantly higher ejection fraction, smaller infarct, and lower day-5/day-2 infarct ratio than controls. On day 21, the controls demonstrated further deterioration of LVF and infarct. Contrastingly, the tac-treated animals demonstrated preservation of LVF, contractility, significantly smaller infarct, and lower day-21/day-2 infarct ratios compared with those on day 5 and controls. The in vivo CMR results were correlated with in vitro findings on histology, immunostaining, and Western blotting which revealed significantly less fibrosis, higher vascularities, less CD68+ and CD40+ inflammatory cells, lower expressions of inflammatory (MMP-9, NF-κB, and TNF-α), and apoptotic (Bax, Caspase-3, c-PARP) biomarkers, respectively, in tac-treated AMI minipigs than controls.

Topics: Animals; Apoptosis; Biomarkers; Cardiac Imaging Techniques; Cardiovascular Agents; Heart Ventricles; Immunohistochemistry; Inflammation; Magnetic Resonance Imaging, Cine; Male; Myocardial Infarction; Swine; Swine, Miniature; Tacrolimus; Ventricular Function, Left

The inflammatory responses play a major role in the pathogenesis of acute myocardial infarction (MI). Early inhibition of inflammation may improve post MI cardiac function. The aim of this study was to investigate the effects of tacrolimus on cardiac function, hemodynamic parameters as well as histopathologic and electrocardiographic changes in isoproterenol-induced myocardial infarction.. Male Wistar rats were randomly divided into six groups of control, isoproterenol alone, tacrolimus alone, and isoproterenol plus tacrolimus (0.5, 1 and 2 mg/kg). Isoproterenol (100 mg/kg) was injected subcutaneously for two consecutive days to induce myocardial infarction, and simultaneously tacrolimus was administered orally twice a day for three days.. Administration of isoproterenol resulted in myocardial edema and necrosis as well as a marked reduction in the left ventricular systolic pressure (LVSP), left ventricular contractility (LVdP/dtmax) and relaxation (LVdP/dtmin) along with a severe elevation in left ventricular end-diastolic pressure (LVEDP). Isoproterenol also elevated the ST-segment and suppressed the R-amplitude and R-R interval on ECG. It was found that all doses of tacrolimus could amend the ECG pattern and ameliorated the isoproterenol induced disturbances in cardiac function. Acute and short term treatment with tacrolimus at dose of 2 mg/kg significantly (P < 0.001) improved LVdP/dtmax from 2712 ± 82 in myocardial infarcted rats to 4592 ± 149 mmHg/sec. Similarly, tacrolimus lowered LVEDP from 17.6 ± 0.68 in MI group to the value of 5.6 ± 0.22 mmHg (P < 0.001). Furthermore, tacrolimus was found to reduce malondialdehyde concentration in serum and myocardium by 50-70% (P < 0.001).

Topics: Administration, Cutaneous; Animals; Disease Models, Animal; Drug Administration Schedule; Electrocardiography; Isoproterenol; Male; Malondialdehyde; Myocardial Infarction; Oxidative Stress; Rats; Rats, Wistar; Tacrolimus; Ventricular Function, Left

This study investigated the association between innate immune reaction and myocardial damage after acute myocardial infarction (AMI) and anti-inflammatory role of tacrolimus in reducing infarct size. Male mini-pigs (n=18) were equally categorized into sham control (SC), untreated AMI (by ligation of left anterior descending coronary artery), and AMI-Tacrolimus (AMI-Tac) (0.5 mg intra-coronary injection 30 minutes post-AMI). Cardiac magnetic resonance imaging (MRI) was performed at post-AMI days 2, 5 and 21 before sacrificing the animals.. By post-AMI day 21, left ventricular ejection fraction (LVEF) was lowest in untreated AMI animals, significantly higher in SC than in AMI-Tac group (all p<0.003). Infarct areas at basal, middle, and apical levels, numbers of CD14+ and iNOS+ cells in infarct area (IA) and peri-IA, and protein expression of CD14, CD68, and Ly6g from circulating inflammatory cells showed an opposite pattern compared with that of LVEF in all groups (all p<0.005). Protein expressions of MCP-1, MIP-1, TNF-α, NF-κB, iNOS, and IL-12 in IA and peri-IA exhibited an identical pattern compared to that of CD14, CD68, and Ly6g from circulating inflammatory cells (all p<0.01). Expressions of myocardial damage biomarkers in IA and peri-IA [γ-H2AX, β-myosin heavy chain (MHC), Smad3, TGF-β] were highest in AMI and higher in AMI-Tac than in SC, whereas expressions of myocardial integrity biomarkers (connexin43, mitochondrial cytochrome-C, α-MHC, BMP-2, Smad1/5) were opposite to those of damage biomarkers (all p<0.001).. Innate immune responses were markedly augmented and LVEF was significantly reduced after AMI but were remarkably improved after tacrolimus treatment.

Topics: Animals; Blotting, Western; Immunity, Innate; Immunohistochemistry; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Myocardial Infarction; Swine; Swine, Miniature; Tacrolimus; Ventricular Function, Left

This study tested the hypothesis that tacrolimus therapy limited left ventricular (LV) infarct and remodeling by suppressing the inflammatory response, oxidative stress and regulating the mitogen-activated protein kinase (MAPK) and Akt signaling pathways in an acute myocardial infarction (AMI) mini-pig model by ligating the left anterior descending coronary artery (LAD).. Twelve male mini-pigs were equally randomized into AMI treated by saline (3.0 mL) (AMI(S)), and AMI treated by tacrolimus (0.5 mg) (AMI(T)). Thirty minutes after the procedure, intra-LAD injections were performed just beyond the ligation.. Inflammatory biomarkers at transcription or protein levels [matrix metalloproteinase (MMP9), plasminogen activator inhitor-1, tumor necrotic factor (TNF-α), nuclear factor (NF)-κB] and the cellular level (CD40+ cells) were markedly higher in AMI(S) than in AMI(T) animals (all p<0.001). Fibrosis biomarkers at the protein level (α-smooth muscle actin, transforming growth factor-β) and Sirius-red staining were notably higher in AMI(S) than in AMI(T) animals (all p<0.03). Antioxidant biomarkers at protein or transcription levels (heme oxygenase-1, quinone oxidoreductase-1, glutathione reductase, glutathione peroxidase) were significantly higher in AMI(S) than in AMI(T) animals (all p<0.01). Protein expressions of ERK1, p38 MAPK and Akt were markedly increased in AMI(S) compared to AMI(T) animals (all p<0.001). Significantly aggravated LV infarction and remodeling were noted in AMI(S) compared to AMI(T) animals, whereas LV ejection fraction was markedly decreased in AMI(S) compared to AMI(T) animals (all p<0.001).. Intra-coronary administration of tacrolimus attenuated inflammation and MAPK signaling, limited infarct size, and preserved LV function.

Topics: Animals; Biomarkers; Blotting, Western; Disease Models, Animal; Echocardiography; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Mitogen-Activated Protein Kinases; Myocardial Infarction; Oxidative Stress; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Swine; Swine, Miniature; Tacrolimus

The Multicentre registry with Antiplatelet TReatment two-sIX months (MATRIX) evaluated safety and efficacy at 12-month follow-up of Janus Flex stenting with 2- or 6-month dual antiplatelet therapy (DAT) period.. There are no data of Janus Flex stent (Carbostent and Implantable Devices-CID, Saluggia, Italy), a polymer-free, tacrolimus-eluting coronary stent, followed by short-term DAT, in daily practice.. Patients were prospectively enrolled at 12 high-volume procedures centres. After stenting, four sites prescribed 2-month DAT, eight sites 6-month DAT. Major adverse cardiac events (MACE) and stent thrombosis (ST) rate was evaluated at 12-month follow-up, for entire population, as well as for 2- and 6-month DAT groups, distinctly. MACE included cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR).. From March 2007 to June 2008, 572 patients (mean age 64.91 ± 11 years, 77.45% males) were enrolled. After successful stenting, 12-month follow-up showed a 12.74% MACE occurrence (cardiac death 0.98%; MI 3.13%; TLR 8.62%), with good Janus Flex safety profile confirmed by only two (0.39%) ST. After adjustment for potential confounding, no significant differences were noted at 12-month follow-up among 2- or 6-month DAT groups (MACE-8.99% versus 12.47%, P = 0.16; cardiac death-0.54% versus 1.14%, P = 0.52; MI-2.38% versus 2.71%, P = 0.83; TLR-5.66% versus 10.60%, P = 0.20; ST-0% versus 0.55%, P = 0.99). At multivariable analysis, DAT time duration was not an independent risk factor for adverse events (adjusted HR 0.47, 95% confidence interval 0.16-1.35, P = 0.16).. Janus Flex coronary stenting, followed by short DAT, is safe and feasible, without differences between 2- and 6-month DAT groups. A randomized trial confirming these encouraging data is needed.

Topics: Aged; Aspirin; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Drug Administration Schedule; Drug Therapy, Combination; Drug-Eluting Stents; Female; Hospitals, High-Volume; Humans; Italy; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Prosthesis Design; Registries; Risk Assessment; Risk Factors; Tacrolimus; Ticlopidine; Time Factors; Treatment Outcome

We investigated protective effect of FK506 on rat hearts subjected to ischemia/reperfusion (I/R) injury by regulating CaN and ASK1. Wistar rats were divided into four groups: Ischemia/reperfusion group (I/R), FK506 + Ischemia/reperfusion group (FK506-I/R), sham group, and FK506 + sham group (FK506-sham). Ischemia/reperfusion was achieved by occluding left coronary artery for 30 min and subsequently reperfusing for 120 min. FK506 was administered 15 min before ischemia. Rats in sham group and FK506-sham group were operated only by placing a ligature around the coronary artery, and the blood supply was not blocked. I/R group showed a rapid increase in TUNEL-positive cells and high risks of histopathological changes in damaged cardiac tissues. FK506 reduced the infarct size and inhibited the activation of CaN enzyme in FK506-I/R group. Increase in Bcl-2/Bax ratio in FK506-IR group indicated that FK506 protected myocardium from apoptosis induced by IR. The activity of CaN and ASK1 protein level decreased significantly after I/R injury in FK506-treated I/R heart. FK506 suppresses the activation of CaN and ASK1 through CaN-mediated apoptosis pathway, and ASK1 negatively regulates CaN activity. Suppression of CaN and ASK1 signaling circuitry are involved in protective effect of FK506 on rat myocardium I/R injury.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Calcineurin; Cytoprotection; In Situ Nick-End Labeling; MAP Kinase Kinase Kinase 5; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Signal Transduction; Tacrolimus; Time Factors

Topics: Adult; CD4 Lymphocyte Count; Graft Rejection; Heart Transplantation; HIV Infections; HIV-1; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Male; Myocardial Infarction; Myocardial Ischemia; Tacrolimus

Autologous mesenchymal stem cell transplantation has been shown to improve myocardial function in ischaemic cardiomyopathy. We studied one hypothetical mechanism, neo-angiogenesis, using allogeneic mesenchymal stem cell transplantation in an ischaemic swine model.. Allogeneic mesenchymal stem cells were injected in the peri-infarct area (1×10(6) cells kg(-1)) 2 weeks after myocardial infarction. Myocardial infarction alone (n=3) served as a control group. In the myocardial infarction-mesenchymal stem cells group (n=6), tacrolimus was given from day 0 to day 12. Capillary density and inflammatory/rejection processes (anti-factor VIII and anti-CD3/CD68 monoclonal antibodies, respectively) were compared between groups.. In scarred myocardium, capillary density was similar between both ischaemic groups: 15.4 (±15.3) and 14.7 (±15.2) vessel/field in myocardial infarction-mesenchymal stem cells and myocardial infarction-alone groups (non-significant). In viable myocardium adjacent to the infarction, capillary density was significantly increased in the myocardial infarction-mesenchymal stem cells group than in the myocardial infarction-alone group (p=0.002). The number of infiltrating CD3+ cells was equivalent in both myocardial infarction-alone and myocardial infarction-mesenchymal stem cells groups (CD3+: 8.6% vs 9.3%, non-significant). However, CD68+ cell infiltration was more prominent after mesenchymal stem cell transplantation (4.7% vs 2% in myocardial infarction alone, p<0.01).. Allogeneic mesenchymal stem cell transplantation enhances angiogenesis after myocardial infarction. This effect is limited to the viable myocardium. Using a concomitant 12-day course of tacrolimus, no mesenchymal stem cell-specific cellular immune response was demonstrated.

Topics: Animals; Capillaries; Cells, Cultured; Coronary Circulation; Disease Models, Animal; Immunity, Innate; Immunocompetence; Immunophenotyping; Immunosuppressive Agents; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Swine; Swine, Miniature; Tacrolimus

We sought to evaluate the safety and performance of the Janus Tacrolimus-Eluting stent (TES) in an unselected population of patients, without application of restrictive clinical or angiographic criteria.. Continued attention to the safety, efficacy, and deliverability of first-generation drug eluting stents has led to the development of new antiproliferative agents with alternative stent platforms and different drug carrier vehicles.. The TEST (Tacrolimus Eluting STent) registry is a prospective, nonrandomized single-center registry in which 140 consecutive patients who underwent single- or multi-vessel percutaneous coronary intervention between February 2005 and August 2005 were enrolled.. The composite rate of major adverse cardiac events (MACE) at 22 months clinical follow-up was 40.9%. The rate of mortality, myocardial infarction, and target lesion revascularization (TLR) were 5.5%, 11%, and 31.5%, respectively. Angiographic follow-up at 8 months was achieved in 74% of patients; binary restenosis occurred in 39.4% of lesions. Most restenosis lesions (94.6%) had a diffuse pattern, while focal restenosis was observed in 5.4% of cases. Definite or probable stent thrombosis was observed in 2.4% of patients.. The present prospective, nonrandomized, TEST registry indicated high MACE and restenosis rates, and thereby rather discouraging long-term outcomes with use of the Janus TES in an unselected "real world" population of patients who underwent single- or multi-vessel percutaneous coronary intervention.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Prosthesis Design; Registries; Risk Assessment; Tacrolimus; Time Factors; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Humans; Myocardial Infarction; Prosthesis Design; Risk Assessment; Tacrolimus; Time Factors; Treatment Outcome

Opening of the mitochondrial permeability transition pore (MPTP) has been shown to contribute to myocardial ischemia/reperfusion injury. We sought to demonstrate that the myocardial protective effect of inhibiting MPTP opening with cyclosporine A (CsA) results in stabilization of mitochondrial morphology and is independent of CsA-induced calcineurin inhibition.. Thirty-seven rabbits were divided into three groups: control (n = 15), CsA (MPTP and calcineurin inhibitor, n = 12), or FK506 (calcineurin inhibitor, n = 10). Each group received a 1-hour infusion of either a saline vehicle, 25 mg/kg CsA or 1 mg/kg FK506. All animals underwent 30 minutes of regional ischemia and 3 hours of reperfusion. Myocardial infarct size was determined using Evans blue dye and triphenyltetrazolium chloride. In situ oligo ligation was used to assess apoptotic cell death. Transmission electron microscopy was used to quantitatively evaluate morphologic differences in the mitochondria between groups.. Infarct size in the CsA group (39% +/- 3%) was significantly reduced compared with the control group (60% +/- 2%, p < 0.001) and FK506 group (55% +/- 3%, p = 0.001). Apoptotic cell death was also attenuated in the CsA group (1.2% +/- 0.5%) compared with the control group (4.3% +/- 0.8%, p = 0.01) and FK506 group (4.1% +/- 0.9%, p = 0.05). Transmission electron microscopy revealed a preservation of normal mitochondrial morphology and a reduction in the percentage of disrupted mitochondria in the CsA group (20% +/- 7%) compared with the control group (53% +/- 12%) and FK506 group (47% +/- 9%).. Cyclosporine A-induced MPTP inhibition preserves mitochondrial morphology after myocardial ischemia/reperfusion and limits myocyte necrosis and apoptosis. These effects are independent of calcineurin inhibition.

Topics: Analysis of Variance; Animals; Calcineurin; Cyclosporine; Disease Models, Animal; Immunohistochemistry; Ischemic Preconditioning, Myocardial; Male; Mitochondria, Muscle; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Probability; Rabbits; Random Allocation; Sensitivity and Specificity; Tacrolimus

The long-term effectiveness of drug-eluting stents (DES) in unselected diabetics in routine practice is currently unclear.. To evaluate the long-term effectiveness of bare metal stents and DES in a real-world setting of diabetic patients, we analyzed 2-year follow-up data from all diabetic patients with de novo lesions enrolled in a prospective Web-based multicenter registry (Registro Regionale Angioplastiche dell'Emilia-Romagna; study period, 2002 to 2004) comprising all 13 hospitals performing percutaneous coronary interventions in the Emilia-Romagna region of Italy. Among the 1648 eligible patients treated with either bare metal stents alone (n=1089) or DES alone (n=559), 27% were insulin dependent and 83% had multivessel coronary disease. At 2 years, use of DES was associated with lower crude incidence of major adverse cardiac advents (all-cause mortality, nonfatal myocardial infarction, and target vessel revascularization) compared with bare metal stents (22.5% versus 28.1%; P=0.01). After propensity score adjustment, only target vessel revascularization appeared significantly lower in the DES group (11.6% versus 15.0%; hazard ratio, 0.66; 95% confidence interval, 0.46 to 0.96; P=0.041). Two-year angiographic stent thrombosis occurred in 1.5% DES patients and 0.7% of the bare-metal-stents patients (P=0.18). At Cox regression analysis, predictors of 2-year major adverse cardiac advents were left ventricular ejection fraction <35%, Charlson comorbidity index, insulin-dependent diabetes, and total lesion length.. In this large, real-world, diabetic population, the use of DES was associated with a moderate reduction in the 2-year risk of target vessel revascularization, a benefit that was limited to non-insulin-dependent diabetic patients. Larger long-term studies are needed to clarify the long-term effectiveness and safety of such devices in diabetic patients.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Combined Modality Therapy; Comorbidity; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Diabetes Mellitus; Diabetic Angiopathies; Female; Humans; Insulin; Italy; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Registries; Risk Factors; Sirolimus; Stents; Tacrolimus; Treatment Outcome

To date, only two drug-eluting stents (DES) have been extensively tested in both randomized controlled clinical trials and large 'real world' registries: sirolimus-DES (Cypher stent, Cordis, Miami Lakes, Florida, USA) and paclitaxel-DES (Taxus stent, Boston Scientific, Natick, Massachusetts, USA). Recently, a new polymer-free tacrolimus-eluting Carbofilm-coated stent, the Janus stent (Sorin Biomedica, Saluggia, Italy), has entered the market but only few clinical data testing its safety and efficacy in selected patients are available. Thus, we performed a prospective registry of consecutive, unselected patients receiving this new DES.. A total of 118 patients scheduled for percutaneous coronary intervention (PCI) with DES were enrolled in two separate centers. End-points were: (i) immediate angiographic failure; (ii) major adverse coronary events (MACE) defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI) and target lesion revascularization (TLR); (iii) clinically driven TLR; (iv) and stent thrombosis at 6-month follow-up.. A total of 192 Janus stents were successfully implanted during elective (36%) or urgent PCIs (64%), including patients with ST elevation MI (16%). Twenty-four percent of patients were diabetics and 27% underwent multivessel PCI. Target lesions were B2-C type in 54%, in-stent restenosis in 8%, and located in degenerated venous grafts in 9%. Angiographic failure was observed in five of the 147 (3.4%) lesions treated. Total MACE rate at 6-month follow-up was 22% and clinically-driven TLR was carried out in 14% of patients. Stent thrombosis occurred in 4% of cases.. This registry of the new tacrolimus-eluting Carbofilm-coated Janus stent showed an incidence of MACE, TLR and stent thrombosis higher than that reported in previous similar studies on DES. Whether this risk is due to this specific device or to the unselected (i.e. high-risk) population warrants further research.

Topics: Coronary Disease; Coronary Thrombosis; Drug-Eluting Stents; Equipment Failure; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Prospective Studies; Registries; Tacrolimus; Treatment Outcome

Although amlodipine, a long-acting L-type calcium channel blocker, reportedly prevents left ventricular remodeling and dysfunction after myocardial infarction, the mechanism responsible is not yet well understood. Myocardial infarction was induced in mice by ligating the left coronary artery. Treatment of mice with amlodipine (10 mg x kg(-1) x day(-1)), beginning on the third day postinfarction, significantly improved survival and attenuated left ventricular dilatation and dysfunction 4 wk postinfarction compared with treatment with saline or hydralazine. Although infarct sizes did not differ among the groups, the infarcted wall thickness was greater and the infarct segment length was smaller in the amlodipine-treated group, and cellular components, including vessels and myofibroblasts, were abundant within the infarcted area. Ten days postinfarction (the subacute stage), the proliferation of granulation tissue cells in the infarcted area was similar among the groups, but the incidence of apoptosis was significantly lower in the amlodipine-treated group, where Bad, a proapoptotic Bcl-2 family protein, was significantly phosphorylated (inactivated). Calcineurin, which dephosphorylates (activates) Bad, was upregulated in infarcted hearts, but its levels were significantly reduced by amlodipine treatment. In vitro, Fas stimulation augmented calcineurin activity and induced apoptosis among infarct tissue-derived myofibroblasts; both of those effects were strongly inhibited by amlodipine, two other calcium channel blockers (verapamil or nifedipine), and two calcineurin inhibitors (cyclosporin A or FK-506). Amlodipine inhibits Fas-mediated granulation tissue cell apoptosis in infarcted hearts, possibly by attenuating the activities of calcineurin and Bad. These findings may provide new insight into the mechanism by which calcium channel blockers attenuate postinfarction cardiac remodeling and dysfunction.

Topics: Amlodipine; Animals; Apoptosis; bcl-Associated Death Protein; Calcineurin; Calcineurin Inhibitors; Calcium; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Coronary Vessels; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; fas Receptor; Granulation Tissue; Hydralazine; Ligation; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Phosphorylation; Research Design; Tacrolimus; Time Factors; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

The aim of this study was to examine possible interactions of ERK and calcineurin in cardioprotection afforded by delta-opioid receptor stimulation. Infarction was induced in rat hearts by 20-min coronary occlusion and reperfusion. Tissue ERK level and calcienurin activity were determined by immunoblotting and an assay using a phosphopeptide substrate, respectively. Administration of a delta-opioid receptor agonist, D-Ala2-D-Leu5-enkephalin (DADLE, 1 mg/kg), before ischemia increased the phospho-ERK levels during ischemia and reduced infarct size (as percentage of risk area, %IS/AR) from 47.7 +/- 2.3% to 23.2 +/- 2.5%. This protection was abolished by 10 mg/kg of natrindole hydrochloride (NTI), a delta-opioid receptor antagonist. PD98059, a MEK1/2 inhibitor, abolished both ERK1/2 activation and infarct size limitation by DADLE. Calcineurin inhibitors, cyclosporine-A (5 mg/kg) and FK506 (3.5 mg/kg), reduced %IS/AR (27.4 +/- 4.4% and 29.9 +/- 3.4%, respectively). The protective effects of these calcineurin inhibitors were inhibited by PD98059, and the combination of DADLE with cyclosporine-A or FK506 did not afford further cardioprotection. DADLE significantly suppressed myocardial calcineurin activity, and this effect was inhibited by NTI. Suppression of calcineurin activity by FK506 was associated with modest activation of ERK1/2. These results suggest that suppression of calcineurin and activation of ERK1/2 are interacting mechanisms involved in cardioprotection by delta-opioid receptor activation.

Topics: Animals; Blood Pressure; Calcineurin Inhibitors; Enkephalin, Leucine-2-Alanine; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Heart; Heart Rate; Male; Myocardial Infarction; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Tacrolimus

Cardiovascular disease is the main cause of death after renal transplantation. There are few trials evaluating the efficacy of prevention strategies in renal transplant patients on major adverse cardiac events (MACE) and cardiovascular mortality. However, there is general agreement that active prevention strategies can significantly decrease cardiovascular mortality after renal transplantation. Here, we present the case of a 52-year-old male patient who received a first kidney transplant in 1993. He showed a small fixed perfusion defect on thallium scintigraphy before transplant. He was admitted at 13 months due to an antero-lateral myocardial infarction that was complicated with ventricular fibrillation. Despite anti-coagulation with acenocumarol, treatment with statins and angiotensin II receptor blocking agents and an excellent preservation of renal function, the patient presented with a second episode of myocardial infarction at 9 years post-transplant. This case report is discussed in order to highlight the way in which attitudes have been modified in the past decade in order to systematically pursue an early diagnosis of pre-existing coronary artery disease, aggressively treat MACE and actively decrease cardiovascular risk in transplant patients, using all available efficacious treatments as well as individualizing immunosuppression to prolong not only graft but also patient survival.

Topics: Acenocoumarol; Amiodarone; Angioplasty; Calcineurin Inhibitors; Carbazoles; Carvedilol; Cyclosporine; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Immunosuppressive Agents; Indoles; Kidney Transplantation; Male; Middle Aged; Myocardial Infarction; Nitroglycerin; Postoperative Complications; Pravastatin; Prednisone; Propanolamines; Risk Factors; Tacrolimus; Treatment Outcome

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

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the pathogenesis of either human and experimental myocardial ischaemia. Tacrolimus, formerly known as FK506, has been previously shown to display cardioprotective effects on experimental ischaemia/reperfusion-induced myocardial damage. This study investigated whether cardioprotection induced by tacrolimus in myocardial ischaemia-reperfusion (MI/R) injury might be due to inhibition of the nuclear factor kappa B (NF- kappaB) that in turn causes reduced cardiac ICAM-1 expression and blunted polymorphonuclear leukocyte accumulation. Anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity, serum creatine kinase (CK) activity, cardiac mRNA for ICAM-1 reverse-transcriptase polymerase chain reaction, the inhibitory protein of NF- kappaB I kappaB alpha (Western blot analysis) in the myocardium-at-risk, and left ventricle d P/d t(max)were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CK activity and myeloperoxidase activity (MPO, a marker of leukocyte accumulation) both in the area at risk and in the necrotic area, and reduced the left ventricle dP/d t(max). Furthermore, inhibitory protein I kappaB alpha levels decreased, and cardiac mRNA for ICAM-1 increased, after 0.5 and 5 h of reperfusion, respectively. Administration of tacrolimus (25, 50 and 100microg/kg as an i.v. infusion 5 min after reperfusion) lowered myocardial necrosis and myeloperoxidase activity in the area at risk and in necrotic area, decreased serum CK activity, increased left ventricle dP/d t(max), reduced the loss the of inhibitory protein I kappaB alpha and blunted the message for ICAM-1. The present data suggest that tacrolimus blocks the early activation of the transcription factor NF- kappaB, suppresses ICAM-1 gene activation, reduces leukocyte accumulation and protects against myocardial ischaemia-reperfusion injury.

Topics: Animals; Creatine Kinase; Gene Expression Regulation; Hemodynamics; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophils; NF-kappa B; Peroxidase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tacrolimus; Transcriptional Activation

The role of the immunosuppressant cyclosporine A as a preconditioning-mimetic in the rabbit heart was examined.. Cyclosporine A, a potent protein 2B or calcium/calmodulin-dependent phosphatase (PP) inhibitor, was administered isolated rabbit hearts starting either 15 min prior to or 10 or 20 min after the onset of a 30 min period of regional ischemia and continuing until the onset of reperfusion. The effect of pretreatment with a second PP2B antagonist, FK-506, was also examined. In an additional protocol L-NAME was perfused for 50 min starting 5 min before the 45-min infusion of cyclosporine A. After 2 h of reperfusion infarct size was measured with triphenyltetrazolium chloride. In a second study left ventricular biopsies of isolated rabbit hearts were obtained to measure the effect of cyclosporine A on dephosphorylation of [32P] phosphorylase kinase by calcium/calmodulin-dependent phosphatases.. Pretreatment with cyclosporine A resulted in only 10.0%, infarction of the risk zone, significantly less than that in untreated control hearts (28.7%, p < 0.001) but comparable to the extent of infarction in ischemically preconditioned hearts (10.0% p < 0.001 vs. control). Equivalent protection was also observed in hearts with treatment delayed for 10 min following the onset of ischemia (10.4% infarction, p < 0.001 vs. control). However, protection waned when cyclosporine A was administered only during the last 10 min of the 30-min ischemic period (25.5% infarction, p = n.s. vs. control). Pretreatment with FK-506 also resulted in myocardial salvage (10.4% infarction, p < 0.001 vs. control). When hearts were exposed to a co-infusion of L-NAME and cyclosporine A, protection was still evident (18.1% infarction, p < 0.05 vs. L-NAME), although not as robust as that seen with the PP2B blocker alone. In hearts pretreated with cyclosporine A dephosphorylation of [32P] phosphorylase kinase by calcium/calmodulin-dependent phosphatases was inhibited by 67%.. Cyclosporine A and FK-506, potent PP2B inhibitors, can protect the ischemic rabbit heart, and at least cyclosporine A continues to be effective when infusion is delayed until after the onset of ischemia. The mechanism of this protection may be related to inhibition of phosphatases and prolongation of the phosphorylation state of ischemic cells.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cyclosporine; Enzyme Inhibitors; Female; Immunosuppressive Agents; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Perfusion; Rabbits; Tacrolimus

Topics: Animals; Calcineurin Inhibitors; Cyclosporine; Drug Evaluation, Preclinical; Enzyme Inhibitors; In Vitro Techniques; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Tacrolimus

The orthotopic liver transplantation (OLT) program of the University of Liège was initiated in 1986. Between 1986 and December 1998, 150 adult OLT have been performed in our institution, including 18 liver retransplantations, 1 combined heart and liver transplantation and 3 combined liver and kidney transplantations. The aim of this study was to report the last 3 years of our experience. From January 1996 to November 1998, we performed 50 OLT on 49 patients. Three were retransplantations and two were combined liver and kidney transplantations. Fourty-three patients were transplanted for chronic liver disease and 6 for acute or subacute hepatopathy. Mean waiting time on the list was 4 weeks. Immunosuppression was based on triple therapy (cyclosporin A/tacrolimus, steroids, azathioprine), with steroid and azathioprine withdrawal in most of the patients after 3 months. In the chronic liver disease group, operative (< 30 days) survival was 95% (peroperative myocardial infarction in 2 patients). In the acute liver disease group, postoperative survival was 66%. No perioperative death occurred in 1997 and 1998. Actuarial one year survival was 87%. In our experience, OLT has become a safe procedure.

Topics: Actuarial Analysis; Acute Disease; Adrenal Cortex Hormones; Adult; Azathioprine; Belgium; Chronic Disease; Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Liver Transplantation; Myocardial Infarction; Postoperative Complications; Reoperation; Survival Rate; Tacrolimus; Time Factors; Waiting Lists