tacrolimus and Coronary-Artery-Disease

Drug-eluting stents (DES) with antiproliferative drugs attached via polymers on the stent surface have reduced in-stent restenosis and repeat revascularization compared with bare metal stent (BMS) across nearly all lesion and patient subsets. However, the small number of patients with in-stent restenosis after DES treatment still exists. Furthermore, concerns about long-term safety of DES are raised, particularly regarding the higher-than-expected late-event thrombosis. There is no doubt that the DES will continue to play a pivotal role in the treatment of coronary artery disease, yet future designs need to incorporate features that reduce thrombosis and promote endothelialization along with maintaining the efficacy. This review focuses on novel generation of DES, discussing new programs, including new antiproliferative agents, novel polymeric and non polymeric stents.

Topics: Absorbable Implants; Coronary Artery Disease; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Equipment Design; Everolimus; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Polymers; Prosthesis Design; Sirolimus; Tacrolimus

Topics: Animals; Antineoplastic Agents, Phytogenic; Coronary Artery Disease; Coronary Restenosis; Drug Delivery Systems; Humans; Immunosuppressive Agents; Paclitaxel; Stents; Tacrolimus

Stents represent a major step forward in the treatment of coronary artery disease since the introduction of balloon angioplasty. They have demonstrated the reduction of angiographic indexes of restenosis and rates of repeat revascularization. However, in-stent neointimal proliferation represents the persisting limitation and challenge. Local delivery using a stent platform for deposition of therapeutic drug concentration in the arterial wall has emerged as an effective strategy to reduce in-stent neointimal hyperplasia and restenosis. The purpose of this article is to describe the design characteristics of a new drug-eluting stent. Its unique features consist of integral Carbofilm thromboresistant coating combined with the capability to load the drug into and to release it from deep sculptures made on the external surface of the stent. The advantages of this design are the possibility to load higher amounts of drug, to selectively deliver it to the vessel wall without loss in the blood stream, and to improve the biocompatibility and thromboresistance of the stent. Preclinical studies, using tacrolimus as the biological agent, showed excellent vessel tissue response and mild inflammation scores. A significant reduction of intimal proliferation was observed in comparison with a control stent. The enrollment in a safety first-in-man evaluation has been successfully completed. A randomized, double-blind, multicenter study is expected to start at the completion of the "safety" evaluation.

Topics: Adult; Aged; Aged, 80 and over; Animals; Coated Materials, Biocompatible; Coronary Artery Disease; Coronary Restenosis; Drug Carriers; Equipment Design; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Rabbits; Stents; Tacrolimus

Cardiovascular disease is one of the major causes of morbidity and mortality following solid organ transplantation. Many of the current immunosuppressive drugs are associated with an increase of one or more risk factors for the development of atherosclerosis. This review compares the mechanism by which individual immunosuppressive agents may impact on these risk factors and the differential contribution of cyclosporine, tacrolimus, mycophenolate, azathioprine, and Rapamycin to these individual risk factors. Attention to the potential cardiovascular toxicities of individual immunosuppressive agents may help design strategies for maintenance of immunosuppression tailored to individual patients.

Topics: Adrenal Cortex Hormones; Animals; Cardiovascular System; Coronary Artery Disease; Cyclosporine; Diabetes Mellitus; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Sirolimus; Tacrolimus

Long-term results of prospective randomized trials comparing triple immunosuppressive strategies combining tacrolimus (TAC) or cyclosporine A (CsA) with mycophenolate mofetil (MMF) and steroids after heart transplantation (HTX) are rarely published. Therefore, we collected long-term follow-up data of an intervention cohort 10 years after randomization.. Ten-year follow-up data of 60 patients included in a prospective, randomized trial between 1998 and 2000 were analyzed as intention-to-treat (TAC-MMF n=30; CsA-MMF n=30). Baseline characteristics were well balanced. Cardiac allograft vasculopathy (CAV) was graduated in accordance with the new ISHLT classification.. Survival at 1, 5, and 10 years was 96.7%, 80.0%, and 66.7% for TAC-MMF and 90.0%, 83.3%, and 80.0% for CsA-MMF (P=ns). Freedom from acute rejection (AR) was significantly higher in TAC-MMF versus CsA-MMF (65.5% vs. 21.7%, log-rank 8.3, P=0.004). Freedom from ISHLT≥CAV1 after 5 and 10 years was in TAC-MMF 64.0% and 45.8%, and in CsA-MMF 36.0% (log-rank 3.0, P=0.085) and 8.0% (log-rank 9.0, P=0.003). No difference in long-term results for freedom from coronary angioplasty or stenting, renal dysfunction, diabetes mellitus, CMV infection, or malignancy was detected.. Cross-over effects because of treatment switch may result in impairment of significance between the groups. The long-term analysis resulted in a significant difference in manifestation of CAV between the groups after 10 years. Less rejection in the TAC-group might have contributed to the lower incidence of CAV. Superior freedom from AR and CAV in the TAC-MMF group did not result in better long-term survival.

Topics: Adult; Chi-Square Distribution; Coronary Artery Disease; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Female; Germany; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Cardiac transplantation, a procedure nearly abandoned in the 1970s, has evolved into the standard of care for appropriate patients with end-stage heart failure. Much of this success has been due to improvements in immunosuppression, including the introduction of a triple-drug regimen. Retrospective reports suggested that single-drug immunosuppression with tacrolimus was feasible. As such, a prospective, randomized trial was conducted to test this approach.. One hundred fifty adult de novo heart transplant recipients were enrolled in a prospective, randomized, controlled, open-label trial comparing tacrolimus monotherapy (MONO) with tacrolimus and mycophenolate mofetil therapy (COMBO). Corticosteroids were used in the early postoperative period but discontinued in all patients over 8 to 9 weeks. The primary end point was the composite biopsy score at 6 months after transplant. Patients were followed for 1 to 5 years. The composite biopsy score was similar between groups at 6 and 12 months: 6-month MONO, 0.70 ± 0.44 (95% confidence interval, 0.60 to 0.80) versus COMBO, 0.65 ± 0.40 (95% confidence interval, 0.55 to 0.74; P=0.44). Allograft vasculopathy was assessed by angiography and intravascular ultrasound, with no significant differences noted. Three-year survival was also similar (92.4% MONO versus 97% COMBO; P=0.58, log-rank).. Addition of mycophenolate to single-agent immunosuppression did not provide an advantage over single-agent immunosuppression in terms of rejection, allograft vasculopathy, or 3-year survival. Corticosteroids, which have traditionally been a mainstay of therapy, were successfully discontinued in all patients. These conclusions are tempered by the limited statistical power associated with a sample size of only 150 patients. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00299221.

Topics: Adrenal Cortex Hormones; Adult; Aged; Biopsy; Coronary Angiography; Coronary Artery Disease; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome; Ultrasonography, Interventional; United States

The aim of this study was to compare, in a randomized multicenter trial, paclitaxel-eluting stents (CoStar, Conor Medsystems, Menlo Park, California) versus pimecrolimus-eluting stents (Corio, Conor Medsystems) versus stents with dual elution of both drugs (SymBio, Conor Medsystems) in native coronary arteries.. The CoStar cobalt-chromium reservoir-based stent platform, eluting paclitaxel in a controlled way via a bioresorbable polymer, reduces restenosis versus its respective bare-metal stent. The reservoir system allows the use of other drugs targeted to different mechanisms involved in the process of vascular restenosis and simultaneous loading of multiple, synergistic drugs.. Patients with single de novo lesions were asymmetrically randomized to 1 of the 3 types of stent (1:2:2). Six-month coronary angiography was planned in all. The primary analysis was a noninferiority test for the primary end point of 6-month angiographic in-stent late lumen loss of Corio versus CoStar and SymBio versus CoStar. Secondary end points included binary angiographic restenosis and major adverse clinical events (cardiac death, myocardial infarction, target vessel revascularization).. The trial was prematurely suspended after 246 patients were enrolled (planned enrollment: 375 patients): 49 patients received CoStar, 97 received SymBio, and 100 received Corio. In-stent late loss was significantly reduced with CoStar versus either SymBio or Corio (0.58 +/- 0.58 mm vs. 0.96 +/- 0.73 mm and 0.58 +/- 0.58 mm vs. 1.40 +/- 0.67 mm, p < 0.001 for both comparisons). Binary in-stent restenosis rates were, 7.1%, 20%, and 40.9%, respectively (p < 0.001 for both comparisons); 6-month major adverse cardiac event rates were, 2.0%, 14.4%, and 39.0%, respectively (p < 0.001 for both comparisons).. Stents eluting pimecrolimus or the dual combination of pimecrolimus and paclitaxel failed to show angiographic noninferiority when compared with paclitaxel-eluting stents. (A Randomized, Multi-Center Study of the Pimecrolimus-Eluting and Pimecrolimus/Paclitaxel-Eluting Coronary Stent Systems; NCT00322569).

Topics: Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Survival Analysis; Tacrolimus

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

Cardiovascular morbidity and mortality is high in patients following renal transplantation. The present analysis assessed major cardiovascular risk factors and estimated the risk of coronary artery disease in the largest present-day comparative trial of tacrolimus vs. microemulsified cyclosporine A. In this 6-month study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) or cyclosporine A (n = 271) concomitantly with azathioprine and corticosteroids. The primary endpoint was the incidence of and time to acute rejection. Blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose were measured at baseline, and at months 1, 3, and 6. Ten-year risk of coronary heart disease was estimated according to the Framingham risk algorithm. Tacrolimus resulted in significantly lower summary measures (time-weighted average) of serum cholesterol (p = 0.0004) and mean arterial blood pressure (p = 0.0156), but in a higher summary measure of blood glucose (p = 0.0028) than cyclosporine. The summary measure of serum triglycerides was not different between treatment groups (p = 0.368). The mean 10-year coronary artery disease risk estimate was significantly lowered in men (p = 0.0032) treated with tacrolimus, but was unchanged in women. Tacrolimus and cyclosporine A microemulsion exert a compound-specific impact on cardiovascular risk factors and appear to affect the predicted rate of cardiovascular morbidity in different manners.

Topics: Calcineurin Inhibitors; Coronary Artery Disease; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Prospective Studies; Risk Factors; Survival Analysis; Tacrolimus

A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcomes after kidney transplant. We hypothesized that a high intrapatient variability of tacrolimus exposure after heart transplant may be associated with cardiac allograft vasculopathy as a determinant of long-term survival of heart transplant recipients.. Eighty-six heart transplant recipients were included. Patients underwent coronary angiography at years 1 and 4 after transplant and were divided according to low and high intrapatient variability of tacrolimus exposure, with the median variability as cut-off. The primary outcome was the association between tacrolimus intrapatient variability and the progression of cardiac allograft vasculopathy score between years 1 and 4. Secondary outcome was this association with acute cellular rejection.. There was no significant difference in the proportion of patients with high tacrolimus intrapatient variability in the group that progressed to higher grades of cardiac allograft vasculopathy (n = 15) versus the group without progression (n = 71) at 4-year follow-up (60.0% vs 47.9%; P = .57). There was no significant difference in the proportion of patients with high tacrolimus intrapatient variability between the 58 patients with 1 or more acute cellular rejection episodes and the 28 patients without rejection (51.7% vs 46.4%; P = .82).. A high intrapatient variability in tacrolimus exposure does not appear to influence heart transplant outcomes, unlike its influence on kidney transplant function. A higher immunosuppression exposure after heart transplant, including the use of prednisone often in a combination of 3 immunosuppressive drugs, may protect against the effects of high intrapatient tacrolimus variability.

Topics: Adult; Aged; Allografts; Biological Variation, Individual; Calcineurin Inhibitors; Coronary Angiography; Coronary Artery Disease; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

The transplant vasculopathy as a sign of chronic graft rejection affects both the epicardial and the intramyocardial arteries of the graft. This is at least partially mediated by NO synthases. The aim of this study was to assess possible protective effects of cyclosporine A (CsA), tacrolimus (FK506), and mycophenolate mofetil (MMF) on the expression of NO synthases in an experimental transplant rat model.. Heart transplantation was performed in 322 rats. These were randomly assigned to four equal groups (control, CsA, FK506, MMF). Recipients were monitored up to 60 days after transplantation, while transplanted hearts were recovered at certain time points for analysis. Expression and staining intensity for endothelial nitric oxide synthases (e-nos) and inducible nitric oxide synthases (i-nos) were analyzed in epicardial and intramyocardial vessels in each group.. All employed drugs led to a significant reduction of expression or staining intensity of i-nos and e-nos. MMF was most effective in reduction in expression of both NO synthases.. These results imply that all described drugs prevent endothelial impairment induced by toxicity of NO and thereby prevent transplant vasculopathy. MMF seems to be the most effective drug.

Topics: Allografts; Animals; Coronary Artery Disease; Coronary Vessels; Cyclosporine; Disease Models, Animal; Down-Regulation; Graft Rejection; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Mycophenolic Acid; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats, Inbred Lew; Tacrolimus; Time Factors

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

Topics: Aspirin; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Drug-Eluting Stents; Female; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Tacrolimus; Ticlopidine

A key determinant of long-term survival in heart transplant recipients is the development of coronary vasculopathy. Both coronary macrovascular and microvascular disease are prognostically important. However, the relationship between these in transplant patients and the determinants of microvascular disease are not known.. We reviewed the simultaneously obtained endomyocardial biopsies and intravascular ultrasound (IVUS) images of coronary arteries in 33 heart transplant recipients. Coronary microvascular disease was classified by light microscopy into four grades based on thickening of endothelial cell layer and stenotic versus nonstenotic medial wall thickening. Macrovascular disease was evaluated from IVUS studies and assigned into one of five grades based on the Stanford classification. Coronary microvascular and macrovascular diseases were compared.. Age at transplantation was 26 (18) years; 67% were men, and the average time to posttransplantation study was 4 years. Endomyocardial biopsy revealed more advanced grade C and D microvascular disease in 45% and 36% of the patients, respectively. However, IVUS analysis for macrovascular disease revealed mostly lesser changes with grade 1 in 12%, grade 2 in 61%, and grade 3 in 21%. There was no significant correlation between grades of microvascular and macrovascular disease (P=0.10). Microvascular disease correlated positively with donor age (P=0.06) and treatment with tacrolimus (0=0.02) and statins (P=0.05).. There is a poor relationship between coronary microvascular and macrovascular disease in patients with cardiac transplants, likely indicating divergent pathogenetic mechanisms. Microvascular disease increases with donor age. There is an intriguing positive relationship between microvascular disease and treatment with statins and tacrolimus.

Topics: Adolescent; Adult; Age Factors; Biopsy; Child; Child, Preschool; Coronary Artery Disease; Endocardium; Endothelium, Vascular; Female; Graft Rejection; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infant; Male; Microvessels; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Tunica Media; Ultrasonography, Interventional; Vascular Diseases; Young Adult

Topics: Adrenal Cortex Hormones; Biopsy; Coronary Artery Disease; Drug Therapy, Combination; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Randomized Controlled Trials as Topic; Research Design; Tacrolimus; Time Factors; Treatment Outcome

We tested whether transplant arteriosclerosis can be reduced by pre-treatment of the donor with immunosuppressive agents, using a rat allogeneic aorta transplantation model. Donor rats received no pre-treatment, or tacrolimus, methylprednisolone, rapamycin, or mycofenolate mofetil (MMF) 16 and 2h before explantation of the grafts. Eight weeks after transplantation, aorta allografts were harvested. Percent intima area/intima+media area (I/I+M), inflammatory cells and in situ MMP-2 and -9 activity were determined. In pre-transplantation biopsies, MMP-2 and -9 ratio, and mRNA levels for genes of interest were determined. In pre-transplantation biopsies we found no differences in MMP-2/9 ratio, and Bcl-2, Bax, TGF-beta, HO-1, p21, and HIF-1alpha mRNA expression between the groups. Aorta allografts, pre-treated with tacrolimus, showed significantly lower I/I+M ratio compared to untreated controls (p<0.01). Pre-treatment with methylprednisolone, rapamycin or MMF did not significantly reduce I/I+M ratio. In situ MMP-2/MMP-9 activity was significantly reduced in grafts treated with tacrolimus and rapamycin compared to controls (p<0.05). Immunohistochemistry revealed a high number of CD4+ cells and high CD4/CD8 ratio in grafts pre-treated with tacrolimus. Donor pre-treatment with tacrolimus significantly reduces transplant arteriosclerosis and is associated with reduced in situ MMP-2/MMP-9 activity and increased number of CD4+ cells.

Topics: Animals; Aorta; CD4 Lymphocyte Count; Coronary Artery Disease; Graft Rejection; Graft Survival; Immunosuppressive Agents; Inflammation; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Inbred BN; Rats, Wistar; Tacrolimus; Time Factors; Tissue Donors; Tunica Intima

To evaluate the degree of endothelialization of the nonapposed struts located at the ostia of side branches.. Endothelialization of coronary stents has got considerable relevance because of the phenomenon of late thrombosis. Bifurcation location and incomplete stent apposition have been linked to this complication.. Domestic pigs (n = 11; weight: 25 +/- 3 kg) were anesthetized and had one stent per coronary artery implanted: one stainless steel (Tecnic), one cobalt-chromium (Chrono), and one tacrolimus-eluting stent (Janus), all of them being Carbofilm-coated (Sorin). One, three, or seven days postprocedure, the pigs were sacrificed, the hearts explanted, and longitudinal sections examined by surface electron microscopy to quantify the percentage of the strut endothelialized over the branches and in the total surface.. Forty-four side branches (25 stents) that had stent struts over their origin were evaluated. Different patterns of endothelialization were observed, from the total absence to the complete endothelialization. There were no significant differences in relation to type of stent or to the artery treated. The predictors of higher percentage of endothelialization were the ratio of metal to branch diameter (P = 0.04) and better endothelialization in the rest of the stent (P = 0.0002), only this parameter maintaining significant correlation (P = 0.03) in multivariate analysis.. Carbofilm-coated stent struts located over the origin of side branches follow the pattern of endothelialization for the rest of the stent, even in the case of tacrolimus-eluting stent.

Topics: Analysis of Variance; Animals; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Endothelium; Humans; Immunosuppressive Agents; Risk Factors; Statistics as Topic; Swine; Tacrolimus; Thrombosis

Topics: Anti-Inflammatory Agents; Biocompatible Materials; Coronary Artery Disease; Drug-Eluting Stents; Humans; Polyglactin 910; Tacrolimus

To characterize in-stent restenosis after the implantation of sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES), tacrolimus-eluting stents (TES), and zotarolimus-eluting stents (ZES), 25 patients treated with drug-eluting stents (DES; 9 PES, 10 SES, 4 TES, and 2 ZES) and 19 with bare-metal stents (BMS) underwent directional coronary atherectomy for in-stent restenosis 4 to 36 months after implantation. Restenosis after DES implantation was more frequently focal and associated with smaller specimens compared to that after BMS implantation. Light and confocal microscopy were used. Histologic features were similar in DES and BMS. In-stent restenotic lesions were composed mainly of neointima containing proteoglycan-rich smooth muscle cells and fibrolipidic regions. Small inflammatory infiltrates were observed, mostly in patients with unstable angina; CD18- and/or CD3(+) cells were detected in patients with BMS and DES. Different smooth muscle cell phenotypes were observed: synthetic was more frequent with BMS and PES, intermediate with ZES, contractile or intermediate with SES, and contractile with TES. The mean proliferation index was low and comparable among stent types; cyclins B1 and D1 were expressed in all DES. In conclusion, intra-DES and intra-BMS restenotic tissue was composed mainly of smooth muscle cells with different phenotypes, proliferating at a low rate. The different smooth muscle cell phenotypes within the stent types might suggest different mechanisms of restenosis.

Topics: Aged; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Muscle, Smooth, Vascular; Paclitaxel; Sirolimus; Tacrolimus; Treatment Outcome

In this study we describe 3 single lung transplant recipients who developed unilateral pulmonary edema in the setting of cardiac and renal dysfunction. All 3 patients responded to diuresis with clinical and radiographic improvement. Unilateral cardiogenic pulmonary edema should be considered in the differential diagnosis of dyspnea and unilateral radiographic infiltrates in single lung transplant recipients.

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Disease; Echocardiography, Doppler; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Pulmonary Edema; Radiography, Thoracic; Sirolimus; Tacrolimus; Treatment Outcome; Tuberous Sclerosis

Topics: Carotid Artery Diseases; Clinical Trials as Topic; Coronary Artery Disease; Drug Delivery Systems; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Practice Patterns, Physicians'; Registries; Sirolimus; Stents; Tacrolimus; Time Factors

Pediatric heart transplantation is entering its third decade, allowing for the first time an analysis of a large group of true long-term survivors, specifically children who have survived > or =10 years post-transplantation.. Fifty-two patients < or =18 years, who had undergone heart transplantation at Stanford between August 1974 and June 1993 and survived > or =10 years, were retrospectively reviewed.. Forty (77%) patients are currently alive. Thirteen survived >15 years and 5 >20 years (the longest being 26 years). Actuarial survival was 79.4% at 14 years and 53.1% at 20 years. Cardiomyopathy was the reason for transplantation in 71% and congenital heart disease (CHD) in 29%. At last evaluation, 71% were on a cyclosporine-based regimen and 23% a tacrolimus-based regimen; 33% were steroid-free. Twenty-seven percent were totally free from treatable rejection, 44% developed serious infections, 69% were receiving anti-hypertensives, and 8% required renal transplantation. Neoplasms occurred in 23%, graft coronary artery disease (CAD) in 31%, and 15% required re-transplantation. Of the 12 deaths, CAD was the most common cause (n = 4), followed by non-specific late graft failure (n = 3), infection (n = 2), rejection (n = 1), non-lymphoid cancer (n = 1) and lymphoid cancer (n = 1). Physical rehabilitation and return to normal lifestyle has been nearly 100%.. Heart transplantation in pediatric patients is compatible with true long-term survival with a growing cohort of children approaching their second and third decades. The gradual constant-phase decrease in survival noted in earlier studies appears to be continuing. Rejection and infection are low but persistent risks after the first years. Graft CAD and non-specific late graft dysfunction are the leading causes of death after 10 years. Rehabilitation is excellent.

Topics: Actuarial Analysis; Adolescent; Bacterial Infections; Cardiomyopathies; Child; Child, Preschool; Coronary Artery Disease; Cyclosporine; Female; Graft Rejection; Heart Defects, Congenital; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Lymphoproliferative Disorders; Male; Reoperation; Retrospective Studies; Survival Analysis; Survivors; Tacrolimus

Topics: Angioplasty, Balloon, Coronary; Animals; Calcineurin Inhibitors; Carrier Proteins; Cell Cycle Proteins; Cell Division; Cell Movement; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation; Graft Occlusion, Vascular; Humans; Hyperplasia; Macromolecular Substances; Phosphotransferases (Alcohol Group Acceptor); Platelet Aggregation Inhibitors; Signal Transduction; Sirolimus; Stents; Tacrolimus; Tacrolimus Binding Protein 1A; Ticlopidine; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Tunica Media; Vascular Patency

Coronary allograft vasculopathy (CAV) is the major factor limiting the long-term survival after cardiac transplantation. Intravascular ultrasound (IVUS) markedly improved our knowledge about in vivo morphology of CAV by precise determination of vessel morphology. In vivo studies with IVUS demonstrated that transplant vasculopathy may present with a very heterogeneous morphology suggesting a dual etiology of transplant coronary artery disease. The high incidence of donor-transmitted atherosclerosis and its role in further progression of CAV could be demonstrated by the use of IVUS. Beside intimal hyperplasia, adaptive remodeling processes of vessel and lumen geometry may have physiologic and prognostic importance. IVUS is so far the only method that allows the evaluation of compensatory enlargement and shrinkage of coronary vessels in CAV. IVUS investigations allow the assessment of CAV progression in early angiographically not visible stages. The influence of different medical treatment regimens on CAV progression can be quantified. Further studies showed that IVUS parameters may have prognostic impact on subsequent clinical events and angiographic progression of CAV. However, besides all the diagnostic information provided by IVUS, the main application of this method is currently in the field of clinical research.

Topics: Clinical Trials as Topic; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Cyclosporine; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Multicenter Studies as Topic; Practice Guidelines as Topic; Prognosis; Prospective Studies; Research; Risk Factors; Tacrolimus; Time Factors; Ultrasonography, Interventional

Topics: Animals; CDC2-CDC28 Kinases; Coronary Artery Disease; Coronary Vessels; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Endothelins; Genetic Therapy; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Oligonucleotides, Antisense; Postoperative Complications; Protein Serine-Threonine Kinases; Tacrolimus; Transfection

Graft arteriopathy limits the long-term survival of allograft recipients. Cardiac allografts in mice develop graft coronary arteriopathy similar to that observed in clinical chronic rejection in human beings. We found that antiintercellular adhesion molecule-1 (ICAM-1) and antilymphocyte function-associated antigen-1 (LFA-1) monoclonal antibodies (mAbs) induce immunologic tolerance to mice with cardiac allografts.. To evaluate the effects of short-term administration of anti-ICAM-1 plus anti-LFA-1 mAbs in preventing graft arteriopathy, we treated C3H/He mice that received cardiac allografts from BALB/c mice with anti-ICAM-1 plus anti-LFA-1 mAbs for the first 5 days after transplantation. For control studies, FK506 was administered daily to other allograft recipients. Allografts were harvested on day 60. Immunohistochemical analysis was used to detect the expression of ICAM-1 and vascular cell adhesion molecule (VCAM)-1, and in situ reverse transcriptase polymerase chain reaction was performed to detect platelet-derived growth factor (PDGF)-B mRNA expression in the graft arteries.. Allografts from mice that received FK506 treatment daily showed significant neointimal thickening with increased expression of ICAM-1, VCAM-1, and PDGF-B mRNA, whereas there was almost no intimal thickening and ICAM-1, VCAM-1, and PDGF-B mRNA expression in the mice that received anti-ICAM-1 plus anti-LFA-1 mAbs.. Short-term blockade of ICAM-1 and LFA-1 adhesion not only induces immunologic tolerance to cardiac allografts but also prevents graft arteriopathy.

Topics: Animals; Antibodies, Monoclonal; Coronary Artery Disease; Graft Rejection; Heart Transplantation; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Platelet-Derived Growth Factor; Postoperative Complications; RNA, Messenger; Tacrolimus; Transplantation, Heterotopic

Topics: Animals; Coronary Artery Disease; Coronary Vessels; Graft Rejection; Graft Survival; Heart Transplantation; Histocompatibility Testing; Major Histocompatibility Complex; Male; Minor Histocompatibility Antigens; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Rats, Inbred WKY; Tacrolimus