sirolimus and Vascular-Diseases

We performed a systematic review and meta-analysis to analyze the efficacy and safety of sirolimus-eluting stents (SESs) in the treatment of below-the-knee (BTK) arterial disease.. An electronic literature search was conducted from inception to July 24, 2021. Retrospective, prospective, and randomized studies that had used SESs to treat BTK arterial disease and had reported the primary patency, technical success, target lesion revascularization, and/or mortality were included. Meta-analyses of the proportions were conducted to derive pooled summary statistics of the outcomes. Where Kaplan-Meier curves were provided for primary patency, a meta-analysis of the individual patient data was conducted via a graphic reconstruction tool to estimate primary patency at various follow-up points. For studies comparing SESs and bare metal stents (BMSs), a two-stage meta-analysis was performed to compare the 6-month primary patency of SESs vs BMSs.. Ten studies across 13 publications, including 995 patients, were retrieved for analysis. In the meta-analysis of proportions, across six studies (n = 339 patients), the pooled 6-month primary patency was 87.3% (95% confidence interval [CI], 81.6%-92.1%). Across seven studies (n = 283 patients), the pooled 6-month mortality was 5.4% (95% CI, 1.4%-11.2%). An individual patient data analysis of three studies (n = 282 patients) yielded a primary patency rate of 95.2% (95% CI, 92.7%-97.8%), 82.8% (95% CI, 78.3%-87.6%), 79.8% (95% CI, 75.0%-85.0%), and 79.8% (95% CI, 75.0%-85.0%) at 6, 12, 18, and 24 months, respectively. The 12-month target lesion revascularization rate across four studies (n = 324 patients) was 9.6% (95% CI, 6.4%-13.4%). In the two-stage meta-analysis of 6-month primary patency across three studies (n = 168 patients), the use of SESs was significantly favored over BMSs (risk ratio, 1.28; 95% CI, 1.12-1.46; P < .001).. The overall evidence suggests that the use of SESs appears to be safe and offers favorable outcomes for BTK arterial disease compared with BMSs.

Topics: Drug-Eluting Stents; Humans; Prospective Studies; Retrospective Studies; Sirolimus; Stents; Treatment Outcome; Vascular Diseases

Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension.

Topics: Apoptosis; Autophagy; Calcium Channels; Cell Proliferation; Humans; Hypertension, Pulmonary; Hypoxia; Intercellular Signaling Peptides and Proteins; Lung; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Muscle, Smooth, Vascular; Pulmonary Artery; Pulmonary Circulation; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Diseases

Prognosis after cardiac transplantation continues to improve with long-term outcomes limited by malignancy and coronary allograft vasculopathy (CAV). Everolimus may potentially reduce these late term complications, while maintaining the low cellular rejection rates seen with standard therapy.. Multiple studies have demonstrated the efficacy of everolimus in reducing acute rejection in heart transplant patients, progression and development of CAV, and the prevention and treatment of common malignancies, including skin cancer and Kaposi sarcoma. This review re-examines these studies with a focus on patient tolerability and safety.. Tolerability and safety of everolimus remain a concern with pneumonitis, effusions, mouth ulcers, edema and impaired wound healing associated with morbidity and mortality. Studies have repeatedly demonstrated renal function deterioration with concomitant everolimus and a standard dose calcineurin inhibitor (CNI). This impact can be partly reduced with CNI dose reduction without an increase in the rate of rejection.. If future studies confirm reduced CAV and malignancy rates, everolimus will become an important agent in de novo and maintenance immunotherapy in cardiac transplantation. Patient centered immunotherapy is preferred to protocol-based immunotherapy as it allows tailoring of immune therapy to each individual patient's rejection risk and side profile.

Topics: Animals; Disease Susceptibility; Dyslipidemias; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Lung Diseases; Mice; Multicenter Studies as Topic; Neoplasms; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases; Vascular Diseases; Wound Healing

Sirolimus (rapamycin), a macrolide antibiotic approved for use as an immunosuppressive agent in the prevention of organ rejection, is a cell proliferation inhibitor and regulator of the immune response which acts through inhibition of TOR (target of rapamycin), a kinase essential to cell cycle progression. Recent studies suggest that the TOR pathway is critical to overall cell function, and at a basic mechanistic level, may be a regulator and potential therapeutic target involved in many of the major (and minor) disorders seen in man today. Cardiovascular diseases including restenosis following percutaneous coronary intervention as well as the more widespread condition of atherosclerosis, share this common involvement of TOR. The present report addresses the current state of intervention in cardiovascular disorders with Sirolimus and similar inhibitors of TOR, including the rationale for this approach and the successes observed to date. Success of the first drug-eluting stent to locally treat restenosis in the clinic is discussed, as are preclinical studies addressing a role in overall atherosclerosis in animal models. In addition, due to the known toxicities when given systemically, an approach for targeted delivery to local areas of vascular disease is discussed.

Topics: Humans; Immunosuppressive Agents; Sirolimus; Vascular Diseases

Topics: Animals; Aorta; Chronic Disease; Disease Models, Animal; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Muscle, Smooth, Vascular; Sirolimus; Vascular Diseases

The PRISON-IV trial showed inferior outcome in patients with chronic total occlusions (CTOs) treated with the ultrathin-struts (60 μm for stent diameter ≤3 mm, 81μm >3 mm) hybrid-sirolimus eluting stents (SES) compared with everolimus eluting stents (EES, 81 μm). The aim of this study is to investigate if the use of smaller stents (≤3 mm) was responsible for the inferior outcome reported in the trial.. In the PRISON-IV trial 330 patients with CTO lesion were randomized 1:1 to receive either hybrid-SES or EES. The hybrid-SES failed to reach the non-inferiority primary endpoint of in-segment late lumen loss (LLL) at 9-month angiographic follow-up. In this sub-analysis, we divided the population according to the different size of stents implanted in those receiving only stents with diameter ≤3 mm (Group-A, 178 patients), only stents >3 mm (Group-B, 59 patients), and those receiving stents of both sizes (Group-C, 93 patients).. The present analysis suggests that the inferior performance of the ultra-thin hybrid-SES in CTO-PCI is particularly pronounced when smaller stent (≤3 mm diameter) are adopted, if compared with EES.

Topics: Aged; Coronary Angiography; Coronary Occlusion; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Percutaneous Coronary Intervention; Prosthesis Design; Sirolimus; Stents; Tomography, Optical Coherence; Treatment Outcome; Vascular Diseases

Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age-dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age-dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age-dependent change in CYP3A activity. The increasing pattern over time of allometrically size-normalized sirolimus CL estimates vs. age was well described by a sigmoidal Emax model. This age-dependent increase was also observed within each individual patient over a 4-year study period. CYP3A-dependent sirolimus metabolite formation changed in a similar fashion. This study clearly demonstrates the rapid increase of sirolimus CL over time in neonates and infants, indicating the developmental change. This developmental pattern can be explained by a parallel increase in CYP3A metabolic activity.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Metabolic Clearance Rate; Sirolimus; Vascular Diseases; Young Adult

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Topics: Adult; Allografts; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Sirolimus; Transplant Recipients; Vascular Diseases

We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality.. Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002).. Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

Topics: Adult; Calcineurin; Coronary Angiography; Coronary Artery Disease; Enzyme Inhibitors; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Sirolimus; Survival Rate; Transplantation, Homologous; Treatment Outcome; Ultrasonography, Interventional; Vascular Diseases

In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

Topics: Adult; Aged; Case-Control Studies; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Vascular Diseases

Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown.. In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression.. No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor.. Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.

Topics: Aged; Azathioprine; C-Reactive Protein; Calcineurin Inhibitors; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Scandinavian and Nordic Countries; Sirolimus; Ultrasonography, Interventional; Vascular Cell Adhesion Molecule-1; Vascular Diseases; von Willebrand Factor

Topics: Humans; Immunosuppressive Agents; Sirolimus; Vascular Diseases; Vascular Malformations

The abnormal proliferation of vascular smooth muscle cells (VSMCs) is a key pathological characteristic of vascular proliferative diseases. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays an important role in regulating cell growth, motility, proliferation, and survival, as well as gene expression in response to hypoxia, growth factors, and nutrients. Increasing evidence shows that mTOR also regulates VSMC proliferation in vascular proliferative diseases and that mTOR inhibitors, such as rapamycin, effectively restrain VSMC proliferation. However, the molecular mechanisms linking mTOR to vascular proliferative diseases remain elusive. In our review, we summarize the key roles of the mTOR and the recent discoveries in vascular proliferative diseases, focusing on the therapeutic potential of mTOR inhibitors to target the mTOR signaling pathway for the treatment of vascular proliferative diseases. In this study, we discuss mTOR inhibitors as promising candidates to prevent VSMC-associated vascular proliferative diseases.

Topics: Cell Proliferation; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Diseases

An alteration in extracellular matrix (ECM) production by vascular smooth muscle cells is a crucial event in the pathogenesis of vascular diseases such as aging-related, atherosclerosis and allograft vasculopathy. The human target of rapamycin (TOR) is involved in the synthesis of ECM by vascular smooth muscle cells. TOR inhibitors reduce arterial stiffness, blood pressure, and left ventricle hypertrophy and decrease cardiovascular risk in kidney graft recipients and patients with coronary artery disease and heart allograft vasculopathy. Other drugs that modulate ECM production such as cilostazol and colchicine have also demonstrated a beneficial cardiovascular effect. Clinical studies have consistently shown that cilostazol confers cardiovascular protection in peripheral vascular disease, coronary artery disease, and cerebrovascular disease. In patients with type 2 diabetes, cilostazol prevents the progression of subclinical coronary atherosclerosis. Colchicine reduces arterial stiffness in patients with familial Mediterranean fever and patients with coronary artery disease. Pathophysiological mechanisms underlying the cardioprotective effect of these drugs may be related to interactions between the cytoskeleton, TOR signaling, and cyclic adenosine monophosphate (cAMP) synthesis that remain to be fully elucidated. Adult vascular smooth muscle cells exhibit a contractile phenotype and produce little ECM. Conditions that upregulate ECM synthesis induce a phenotypic switch toward a synthetic phenotype. TOR inhibition with rapamycin reduces ECM production by promoting the change to the contractile phenotype. Cilostazol increases the cytosolic level of cAMP, which in turn leads to a reduction in ECM synthesis. Colchicine is a microtubule-destabilizing agent that may enhance the synthesis of cAMP.

Topics: Cilostazol; Colchicine; Coronary Artery Disease; Cyclic AMP; Diabetes Mellitus, Type 2; Humans; Muscle, Smooth, Vascular; Sirolimus; Tetrazoles; Vascular Diseases

Venous malformations (VMs) are the most common vascular anomalies and have been associated with somatic variants in TEK. Current treatment of VM joint component might be challenging due to the size or location of some lesions or ineffective with recurrence of malformed veins. Targeted molecular therapies after identification of genetic defects might be an alternative.. We report a case with intraarticular bleeding due to VM with a TEK pathogenic somatic variant treated with rapamycin.. A 26-year-old female patient was evaluated for right calf pain secondary to venous malformation of the right inferior limb with an intraarticular component in the right knee. Hemarthrosis and degenerative chondropathy of the knee were evidenced at MRA. Molecular diagnosis evidenced a pathogenic somatic TEK variant. Rapamycin was introduced to stop bleeding, with good tolerance and efficacy.. The TEK receptor signals through the PI3K/AKT/mTOR pathway and TEK mutations have been linked to AKT activation. As rapamycin acts against angiogenesis and reduces phosphorylated-AKT levels, targeted molecular therapy should be discussed as first-line therapy in patients with proven molecular diagnosis and diffuse VM inaccessible to conventional treatment.

Topics: Adult; Female; Hemarthrosis; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sirolimus; Vascular Diseases; Vascular Malformations

Topics: Female; Humans; Klippel-Trenaunay-Weber Syndrome; Sirolimus; Vascular Diseases; Vascular Malformations

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Vascular inflammation is closely related to the pathogenesis of a diverse group of CVDs. Currently, it remains a great challenge to achieve site-specific delivery and controlled release of therapeutics at vascular inflammatory sites. Herein we hypothesize that active targeting nanoparticles (NPs) simultaneously responsive to low pH and high levels of reactive oxygen species (ROS) can serve as an effective nanoplatform for precision delivery of therapeutic cargoes to the sites of vascular inflammation, in view of acidosis and oxidative stress at inflamed sites. The pH/ROS dual-responsive NPs were constructed by combination of a pH-sensitive material (ACD) and an oxidation-responsive material (OCD) that can be facilely synthesized by chemical functionalization of β-cyclodextrin, a cyclic oligosaccharide. Simply by regulating the weight ratio of ACD and OCD, the pH/ROS responsive capacity can be easily modulated, affording NPs with varied hydrolysis profiles under inflammatory microenvironment. Using rapamycin (RAP) as a candidate drug, we first demonstrated in vitro therapeutic advantages of RAP-containing NPs with optimal dual-responsive capability, i.e. RAP/AOCD NP, and a non-responsive nanotherapy (RAP/PLGA NP) and two single-responsive nanotherapies (RAP/ACD NP and RAP/OCD NP) were used as controls. In an animal model of vascular inflammation in rats subjected to balloon injury in carotid arteries, AOCD NP could accumulate at the diseased site after intravenous (i.v.) injection. Consistently, i. v. treatment with RAP/AOCD NP more effectively inhibited neointimal hyperplasia in rats with induced arterial injuries, compared to RAP/PLGA NP, RAP/ACD NP, and RAP/OCD NP. By surface decoration of AOCD NP with a peptide (KLWVLPKGGGC) targeting type IV collagen (Col-IV), the obtained Col-IV targeting, dual-responsive nanocarrier TAOCD NP showed dramatically increased accumulation at injured carotid arteries. Furthermore, RAP/TAOCD NP exhibited significantly potentiated in vivo efficacy in comparison to the passive targeting nanotherapy RAP/AOCD NP. Importantly, in vitro cell culture experiments and in vivo animal studies in both mice and rats revealed good safety for AOCD NP and RAP/AOCD NP, even after long-term treatment via i. v. injection. Consequently, our results demonstrated that the newly developed Col-IV targeting, pH/ROS dual-responsive NPs may serve as an effe

Topics: Animals; Drug Delivery Systems; Hydrogen-Ion Concentration; Inflammation; Mice; Nanomedicine; Nanoparticles; Oxidative Stress; Rats; Reactive Oxygen Species; Sirolimus; Vascular Diseases

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects.

Topics: Alzheimer Disease; Animals; Apolipoprotein E4; Blood-Brain Barrier; Cerebrovascular Circulation; Glucose Metabolism Disorders; Learning Disabilities; Metabolic Diseases; Mice; Mice, Transgenic; Neuroimaging; Secondary Prevention; Sirolimus; Vascular Diseases

: Spontaneous coronary artery dissection (SCAD) is a rare and poorly understood cause of acute coronary syndrome in relatively young patients. Nowadays, the optimal treatment of SCAD is uncertain. A conservative approach seems to be preferable, but in particular conditions, an invasive strategy is necessary. The poor rate of procedural success, the high risk of procedural complications and the uncertain long and mid-term results make the interventional treatment of SCAD a challenge. We report a case of a young male patient presenting with SCAD successfully treated with a sirolimus-eluting self-expanding coronary stent. To our knowledge, the use of self-expanding coronary stent for SCAD has never been described yet and we discuss about the rationale of a possible larger use in clinical practice.

Topics: Cardiovascular Agents; Coronary Angiography; Coronary Vessel Anomalies; Drug-Eluting Stents; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Prosthesis Design; Sirolimus; ST Elevation Myocardial Infarction; Tomography, Optical Coherence; Treatment Outcome; Vascular Diseases

Topics: Aged; Cardiotonic Agents; Coronary Vessel Anomalies; Drug-Eluting Stents; Female; Humans; Imaging, Three-Dimensional; Sirolimus; Tomography, Optical Coherence; Vascular Diseases

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a recently described glucose transporter 1-negative multifocal vascular disorder with significant morbidity and mortality. However, data are lacking on the clinical spectrum, long-term prognosis, and treatment of MLT. It is often confused with multifocal infantile hemangioma, but the conditions must be differentiated for appropriate assessment and therapeutic management. Treatments for MLT have been disappointing, and the treatments classically used for infantile hemangioma are often ineffective. We report 3 newborn cases featuring various clinical and biological phenotypes of MLT: 1 patient had severe brain involvement and died early; another had no thrombocytopenia; and the third had nearly no skin involvement. Histologically, all were negative for glucose transporter 1 and positive for the lymphatic marker lymphatic vessel endothelial hyaluronan receptor 1 or D2-40 (∼38-kDa O-linked transmembrane sialoglycoprotein podoplanin). Two cases with severe gastrointestinal bleeding were treated with sirolimus 0.1 mg/k per day, which was efficient after the first month of treatment. MLT clinically presents in various forms, and when complicated by widespread or severe extracutaneous involvement, initial aggressive therapeutic intervention is justified. The pathogenesis of MLT remains unclear, but lymphatic differentiation is widely acknowledged. Because of its antiangiogenic properties, including anti-lymphangiogenesis, sirolimus offers an adequate and targeted therapeutic approach for MLT.

Topics: Female; Humans; Infant, Newborn; Male; Sirolimus; Thrombocytopenia; Vascular Diseases

The aim of the study was to assess temporal changes in plaque size and components after heart transplantation (HTx), and to evaluate the differences in treatment effects on plaque progression between sirolimus and calcineurin inhibitors (CNIs).. The study comprised 146 HTx recipients who were converted from CNIs to sirolimus as primary immunosuppressant (sirolimus group, n = 61) and those who were maintained on CNIs (CNI group, n = 85). A retrospective compositional analysis of serial virtual histology-intravascular ultrasound was performed.. During a median follow-up of 2.8 years, there was a significant difference in plaque volume in favor of sirolimus between groups (p = 0.004). When subjects were sub-classified according to the time interval between HTx and study inclusion, those in the early group (≤2 years after HTx) had a greater increase in plaque volume (p = 0.006), characterized by a higher progression rate of fibrous plaque volume (p = 0.01). The treatment difference between groups in plaque volume was identified in the early group in favor of sirolimus with attenuating effects on the progression of fibrous plaque component (both p = 0.03 for interaction). By contrast, there were significant differences in necrotic core and dense calcium volume (both p < 0.05 for interaction) in favor of CNIs in the late group (≥6 years after HTx).. Compared with continued CNI therapy, sirolimus attenuated plaque progression in recipients with early conversion, but contributed to increases in necrotic core and dense calcium volume in those with late conversion. Our study supports the hypothesis that early initiation of sirolimus offers greater benefits in the treatment of CAV.

Topics: Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Plaque, Atherosclerotic; Retrospective Studies; Sirolimus; Time Factors; Transplantation, Homologous; Vascular Diseases

Bleomycin (BLM), one of the most common sclerosants, is often used to treat venous malformations (VMs). The present study was designed to investigate whether endothelial mesenchymal transition (EndoMT) contributes to the therapeutic effects of BLM.. Endothelial and mesenchymal markers of HUVECs were measured by immunofluorescence, real-time quantitative PCR and Western blot analysis. Cell migration and tube formation assays were performed to evaluate endothelial cell function. Slug small-interfering RNA and specific inhibitors [Z-VAD-FMK for pan caspases, rapamycin for mammalian target of rapamycin (mTOR)] were used to investigate the mechanism.. Long term (48 h or longer) treatment with BLM (0.1 mU·mL(-1) ) induced EndoMT in HUVECs, as manifested by a reduction in the expression of vascular endothelial-cadherin and an up-regulation in the expression of α-smooth muscle actin and fibroblast specific protein-1, as well as activation of the transcription factor Slug. The size and protein content of the transformed cells were increased. BLM also enhanced the migration of HUVECs but diminished their tube formation. By employing rapamycin, we demonstrated that activation of the mTOR pathway is involved in BLM-induced EndoMT in HUVECs.. Our results show that a Slug-dependent EndoMT process is involved in BLM-induced therapeutic effects on endothelial cells and, more importantly, indicate the potential role of this process in the sclerotherapy of VMs.

Topics: Bleomycin; Cell Movement; Cell Transdifferentiation; Human Umbilical Vein Endothelial Cells; Humans; Proto-Oncogene Proteins c-akt; Sclerosing Solutions; Sclerotherapy; Sirolimus; Snail Family Transcription Factors; TOR Serine-Threonine Kinases; Transcription Factors; Vascular Diseases; Veins

Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology.. Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT-PCR) were assessed.. Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells.. Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling.

Topics: Animals; Cell Proliferation; Cells, Cultured; Cyclosporine; Disease Models, Animal; Immunosuppressive Agents; In Vitro Techniques; Kidney Transplantation; Male; Podocytes; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sirolimus; Transplantation, Homologous; Vascular Diseases; Vascular Endothelial Growth Factor A

Topics: Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Sirolimus; Vascular Diseases

Connective tissue growth factor (CTGF) has been reported to be upregulated in experimental models of chronic cardiac allograft rejection. We investigated the contribution of CTGF to the development of cardiac allograft vasculopathy (CAV), a surrogate marker for chronic rejection.. This prospective study included 72 adult heart allograft recipients. Genotyping of the rs6918698 polymorphism was performed by sequence-specific primer polymerase chain reaction (PCR). CTGF protein levels were measured in serum. CTGF messenger RNA (mRNA) from myocardial biopsy specimens was quantified by quantitative real-time PCR.. Recipient genotype was associated with the development of CAV (p = 0.014) and the carriers of the C allele (CC and CG genotype) were high-risk recipients for the development of CAV (odds ratio, 3.30; 95% confidence interval, 1.12-9.74; p = 0.044). Serum CTGF protein levels could not be associated with the presence of the C allele but were significantly lower in the patients that had developed CAV (p = 0.038). This was attributed to the addition of everolimus to their immunosuppression scheme. Myocardial relative CTGF mRNA expression was estimated to be approximately twice as much in the CAV patients than in the patients without CAV (p = 0.013).. The important role of CTGF during the development of CAV in heart transplantation was supported by the association of CAV with the recipient CTGF-945 CC/CG genotypes. The CAV patients, who were all receiving everolimus treatment, displayed elevated myocardial CTGF mRNA transcription levels, while everolimus has been observed to reduce serum CTGF protein levels.

Topics: Adolescent; Adult; Biomarkers; Biopsy; Connective Tissue Growth Factor; Everolimus; Female; Follow-Up Studies; Genotype; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardium; Polymorphism, Genetic; Prospective Studies; RNA; Sirolimus; Transplantation, Homologous; Vascular Diseases; Young Adult

A common situation presented in any clinical facility is a woman with swelling and redness of the breast. Diagnosis upon suspicion is often mastitis or inflammatory breast cancer, which are popular and well-known diseases of the breast. However, there is one main differential diagnosis which has to be taken into consideration: lymphedema of the breast. Twenty patients with internal diseases presented in our Breast Care Unit over a 4-year period with breast-affecting lymphedema. The patients suffered from cardiac failure, nephrotic syndrome, liver failure, lymphadenopathy, and central vein occlusion. Additionally, we identified 5 patients with a history of organ transplantation and under immunosupressive medication with sirolimus or everolimus. These mTor inhibitors are known to have unwanted side effects such as unilateral or bilateral upper/lower extremity peripheral edema or facial/eyelid edema, but as we know, isolated lymphedema of the breast represents a previously unreported complication.

Topics: Adult; Aged; Aged, 80 and over; Breast; Diagnosis, Differential; Everolimus; Female; Heart Failure; Humans; Immunosuppressive Agents; Liver Failure; Lymphatic Diseases; Lymphedema; Middle Aged; Nephrotic Syndrome; Sirolimus; Tissue Transplantation; TOR Serine-Threonine Kinases; Vascular Diseases

We present a case of a 43-year-old woman who presented with a non-ST elevation myocardial infarction. During her first cardiac catheterisation, she was diagnosed with a chronic total occlusion of the right coronary artery and a flow limiting dissection of her middle left anterior descending artery. The dissection of the left anterior descending artery was stented with two overlapping everolimus-eluting stents. There were no complications from this percutaneous coronary intervention. On the following day, the patient continued to have persistent chest pain and returned to the catheterisation laboratory. It was then found that the patient had a total occlusion of the right coronary artery secondary to dissection. This was also stented with three everolimus-eluting stents with excellent clinical and angiographic results. It is important to consider spontaneous multivessel coronary dissections which can be treated successfully with percutaneous coronary intervention.

Topics: Adult; Chest Pain; Coronary Occlusion; Coronary Vessel Anomalies; Drug-Eluting Stents; Everolimus; Female; Humans; Immunosuppressive Agents; Myocardial Infarction; Sirolimus; Vascular Diseases

Topics: Aged, 80 and over; Constriction, Pathologic; Coronary Angiography; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Mammary Arteries; Postoperative Complications; Saphenous Vein; Sirolimus; Tomography, X-Ray Computed; Vascular Diseases; Vascular Grafting

Pulmonary vein (PV) stenosis (PVS) is a complication of radiofrequency PV isolation (PVI). Reported restenosis rates after balloon dilatation and bare-metal stent implantation are high. Drug-eluting stent implantation (DES) has not been reported in the setting of PVS.. Patients suspected of having PVS after PVI based on clinical symptoms and transesophageal echocardiography (TEE) follow-up (FU) were referred for PV DES. One or more branches of the affected PV as documented by angiography were stented (paclitaxel or zotarolimus DES). Follow-up consisted of repeat PV angiography and TEE. Over a period of 2 years, five patients were treated with a total of eight DES. A paclitaxel DES was used in seven of eight implants. Mean FU was 12 ± 14 months during which all patients remained asymptomatic. Transesophageal echocardiography Doppler maximal flow velocity (V(max)) of the affected PVs rose from 58 ± 6 cm/s pre-PVI to 207 ± 20 cm/s pre-DES (+358%, P < 0.0001). After DES, V(max) decreased acutely with 86 ± 15 cm/s (-58%, P < 0.01). During FU, V(max) remained stable in three patients and increased moderately in one. Angiography at 3 months confirmed absence of restenosis in the first three patients and moderate (40%) restenosis in one patient. In one patient, an increase of V(max) back to pre-DES values correlated with a 65% peri-stent stenosis, treated with a redo DES. In total, after seven primary DES only one (asymptomatic) proximal margin restenosis required re-stenting.. Initial experience with DES for PV stenosis suggests an excellent stent patency rate. Transesophageal echocardiography Doppler measurements provide a viable way of monitoring stent patency.

Topics: Adult; Aged; Atrial Fibrillation; Catheter Ablation; Constriction, Pathologic; Drug-Eluting Stents; Echocardiography, Transesophageal; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Paclitaxel; Pulmonary Veins; Retrospective Studies; Secondary Prevention; Sirolimus; Treatment Outcome; Vascular Diseases

Topics: Azathioprine; Calcineurin Inhibitors; Cell Proliferation; Disease Progression; Drug Therapy, Combination; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Muscle, Smooth, Vascular; Mycophenolic Acid; Risk Factors; Sirolimus; Vascular Diseases

Topics: Cardiac Catheterization; Constriction, Pathologic; Drug-Eluting Stents; Equipment Failure; Everolimus; Follow-Up Studies; Heart Transplantation; Humans; Incidence; Recurrence; Sirolimus; Transplantation, Homologous; Ultrasonography, Interventional; Vascular Diseases

Proliferation Signal inhibitors (PSI), sirolimus and everolimus, possess immunosuppressive and antiproliferative properties that have a substantial impact in organ transplantation. Their antiproliferative and pro-apoptotic action on vascular smooth muscle cells and endothelial cells, with positive effects on vascular remodeling, intimal proliferation, and atheroma plaques, has been demonstrated in many experimental studies in cell culture and on animal vascular, cardiac, and renal models. In humans, the PSI show a major advantage in heart transplantation, since they contribute satisfactory immunosuppression while preventing coronary vasculopathy related to intimal proliferation of smooth muscle cells, a factor that limits the long-term success of the graft. Intravascular ultrasound explorations, which measure intima thickness, showed that PIS treatment can inhibit intracoronary intimal proliferation after heart transplantation and thus reduce the morbidity and mortality at the medium term in transplantation patients. In kidney transplantation, even though their impact is less clear for the moment because of the multifactorial aspect of chronic graft dysfunction, the PSI nevertheless contribute undeniable benefits in terms of improving renal function and reducing the histological lesions of chronic allograft nephropathy.

Topics: Animals; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Vascular Diseases

Cardiac allograft vasculopathy (CAV) is a major cause of death after heart transplantation (HT). The reduced bioavailability of endothelium-derived nitric oxide may play a role in endothelial vasodilator dysfunction and thus in the structural changes characterizing CAV. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. It was hypothesized that ADMA concentrations may influence CAV progression during the first postoperative year.. Thirty-two consecutive HT recipients underwent intravascular ultrasound evaluation at month 1 and year 1 after HT. Immunosuppression included mycophenolate mofetil (MMF, n=16) and sirolimus (n=16). Change in intimal volume greater than the median and vascular remodeling were major outcome measures.. Plasma ADMA levels were associated with subsequent development of intimal hyperplasia (risk ratio [95% confidence interval] =2.72 [1.06-6.94]; P=0.038), and plasma ADMA levels greater than 0.70 micromol/L most accurately identified patients who would have developed intimal hyperplasia. However, ADMA levels did not correlate with negative coronary remodeling. Treatment with sirolimus, as compared with MMF, was associated with significantly lower ADMA levels (0.65+/-0.12 vs. 0.77+/-0.10 micromol/L; P<0.01) and less intimal hyperplasia (risk ratio [95% confidence interval] = 0.08 [0.01-0.56]; P=0.01).. Elevated plasma ADMA is associated with coronary intimal hyperplasia, supporting the importance of nitric oxide synthase inhibition in CAV pathogenesis. Treatment with sirolimus (rather than MMF) is associated with lower ADMA levels and reduced risk of accelerated CAV.

Topics: Adult; Aged; Arginine; Biomarkers; Heart Transplantation; Humans; Hyperplasia; Immunosuppressive Agents; Longitudinal Studies; Middle Aged; Sirolimus; Transplantation, Homologous; Tunica Intima; Ultrasonography; Vascular Diseases

The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimus-induced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.

Topics: Adult; Biopsy; Calcineurin Inhibitors; Down-Regulation; Endothelium, Vascular; Female; Graft Rejection; Humans; Image Cytometry; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Renal Circulation; Sirolimus; Thrombosis; Vascular Diseases; Vascular Endothelial Growth Factor A

Rapamycin inhibits extracellular matrix (ECM) accumulation (fibrosis) and vascular remodeling in experimental models of chronic allograft dysfunction (CAD) by poorly understood mechanisms. The aim of this study was to assess the effect of rapamycin on the expression of fibrosis-associated genes and correlate this with observed changes in ECM remodeling in an experimental of model allograft vasculopathy.. Vascular remodeling and ECM accumulation (picrosirius red) were measured by computerized histomorphometry of F344-to-Lewis rat aortic allograft sections harvested at serial timepoints. Expression of fibrosis associated genes was studied by means of semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR).. Rapamycin (0.5 mg/kg/day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodeling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intragraft gelatinase, collagen III and tissue inhibitor of metalloproteinase 1 (TIMP 1) mRNA levels. At a lower dosage (0.25 mg/kg/day), rapamycin inhibited intimal hyperplasia and medial ECM accumulation, but there was a lesser effect on vascular remodeling. Lower dose allografts were also seen to have a more severe inflammatory infiltrate and larger amounts of intragraft matrix metalloproteinase 9 (MMP 9) mRNA than those treated with the higher dose.. These data suggest that, in addition to the tissue response to injury, the alloimmune injury itself may contribute directly to the vascular remodeling that occurs in allograft vasculopathy. Rapamycin at higher but not lower doses inhibited both of these pathologic processes.

Topics: Animals; Aorta; Fibrosis; Gene Expression; Immunosuppressive Agents; Models, Animal; Organ Transplantation; Rats; Rats, Inbred Lew; Sirolimus; Vascular Diseases

Immunosuppressive drugs common in clinical transplantation are known to have untoward effects on the vascular system. The effects of some drugs, notably cyclosporin A (CyA), have been studied on the vascular system, while those of others have not. In the vascular system, endothelial cells are the predominant cell type exposed to intravascular concentrations of immunosuppressive drugs. We therefore studied the effects of drugs common in clinical transplantation on endothelial cells in a capillary tube assay. The endothelial cells in the capillary tubes are morphologically more similar to those in the microvasculature than endothelial cells in monolayers. We studied the kinetics and extent of capillary tube formation and prostacyclin (PGI2) and endothelin-1 (ET-1) release from the in vitro capillaries to determine the morphological and biochemical effects of five immunosuppressive agents on endothelial function. We found a significant difference in the morphological and biochemical effects of the two common calcineurin inhibitors, CyA and tacrolimus (FK506) on capillary morphology in vitro. The former had a pronounced injurious effect on the morphology of the in vitro capillaries, while the latter did not. CyA also significantly increased ET-1 release by the capillaries, but FK506 did not. Mycophenolate mofetil (MMF) was the only other agent that had a moderately injurious effect on the morphology of the in vitro capillaries. Sirolimus (rapamycin) and dexamethasone, similar to FK506, had no effect on the capillary morphology. All these agents, except dexamethasone, increased PGI2 release. Our data suggest that CyA adversely affects the morphology of the microvasculature and that this is mediated, at least partly, by an increased ET-1 release by endothelial cells exposed to CyA. These findings describe a novel effect of CyA and MMF on endothelial cells that could be relevant to understanding the mechanisms of immunosuppressive drug-mediated endothelial injury in clinical transplantation.

Topics: Cell Survival; Cyclosporine; Dexamethasone; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Immunosuppressive Agents; In Vitro Techniques; Mycophenolic Acid; Sirolimus; Tacrolimus; Vascular Diseases

A rare but well-documented serious adverse reaction to the administration of the calcineurin inhibitors tacrolimus and cyclosporine in renal transplant recipients is the development of medication-induced thrombotic microangiopathy. The recently introduced immunosuppressive medication sirolimus has a very similar molecular structure to tacrolimus and also binds to the same intracellular proteins. Despite these similarities with tacrolimus, sirolimus has a different side-effect profile and reportedly lacks documented specific renal toxicity. This is a case report of the isolated administration of sirolimus without a concomitant calcineurin inhibitor being associated with the development of renal transplant biopsy-proven thrombotic microangiopathy. The patient is a 47-year-old African-American woman whose primary cause of renal failure was not thrombotic micrangiopathy, and she received a 5-antigen mismatched cadaveric renal transplant. Because of preexisting nephrosclerosis in the renal transplant, this patient was never administered a calcineurin inhibitor but was always maintained on sirolimus. With recent animal data showing that sirolmus can be nephrotoxic in a renal ischemic-reperfusion model (similar to what happens with a renal transplant), the authors speculate on a mechanism for this adverse reaction.

Topics: Adult; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Middle Aged; Nephrosclerosis; Postoperative Complications; Sirolimus; Smoking; Thrombosis; Tissue Donors; Transplantation; Vascular Diseases

The present study was devised to elucidate the influence of immunogenicity, immunosuppression, and ischemia on the development of transplant vasculopathy (TVP) as well as to investigate myointimal proliferation in syngeneic transplantation.. Fischer 344 and Brown Norway rat heart allografts and Lewis isografts were treated with rapamycin or cyclosporine, exposed to 4 hr of cold ischemia, and observed for 100 to 300 days before the incidence and degree of TVP and perivascular infiltration were assessed.. The incidence of TVP in Fischer 344-->Lewis allografts (rapamycin, 0.5 mg/kg for 14 days) rose steadily, with dense mononuclear infiltration present in coronary lesions at all times (from 10+/-2% at 50 days to 85+/-15% at 150 days). Increased immunogenicity (Brown Norway-->Lewis) intensified TVP (62+/-13%) as compared with its control (25+/-15%, P<0.005). Enhanced immunosuppression (rapamycin, 0.5 mg/kg daily) decreased the incidence of TVP (22+/-11%, P<0.005), and additional low-dose cyclosporine was ineffective (1.5 mg/kg daily, 40+/-14%, NS). Four hours of cold ischemia before transplantation failed to have any effect on allografts, but promoted TVP in isografts (0 vs. 11+/-8%).. The antigenic stimulus has probably the most important impact on the development of TVP, but is not necessarily essential. In most allografts, TVP probably reflects ongoing sublethal acute rejection, whereas myointimal proliferation in isografts presumably results from a perioperative antigen-independent response-to-injury mechanism.

Topics: Animals; Chronic Disease; Cyclosporine; Dose-Response Relationship, Drug; Graft Rejection; Heart Transplantation; Histocompatibility Testing; Immunosuppressive Agents; Male; Myocardial Reperfusion Injury; Polyenes; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Inbred Lew; Sirolimus; Transplantation, Heterotopic; Vascular Diseases

We have examined the effects of rapamycin (RPM) on transplant vasculopathy in long-surviving F344 rat heart allografts transplanted heterotopically into Lewis recipients. RPM was administered intraperitoneally for the first 14 days in groups 1 and 2 (0.5 and 2 mg/kg/day), and daily throughout the follow-up period in groups 3 (0.5 mg/kg/day) and 4 (5 mg/kg for 14 days, followed by a maintenance dose of 2.5 mg/kg/day). Treatment with low dose cyclosporine (CsA; 1.5 mg/kg/day) in combination with RPM (0.5 mg/kg/day for 14 days) (group 5) and immunosuppression with CsA only (5 mg/kg for 14 days, followed by 1.5 mg/kg/day) (group 6) were also examined. F344 isograft recipients treated with RPM (0.5 mg/kg/day for 14 days) (group 7), those that were untreated (group 8), and hearts in naive F344 animals (group 9) served as controls. Grafts of group 1 were removed at 50, 75, 100, 150, and 200 days and infiltrating cell populations and surface molecules were compared with those of the other groups at 100 days. All allografts in treated hosts functioned > 100 days; in contrast, grafts in untreated recipients were rejected acutely by 8 +/- 1 days (MST +/- SD). The incidence of transplant vasculopathy in group 1 increased progressively (MST +/- SD = 10 +/- 2%, 59 +/- 7%, 85 +/- 15%, and 80 +/- 12% at 50, 100, 150, and 200 days, respectively), as manifested by myointimal proliferation with dense mononuclear infiltration (predominantly ED1+ macrophages). Numbers of MHC class II+ infiltrating cells were prominent, as was expression of adhesion molecules and cytokines. The incidence of graft disease and extent of cellular infiltration at 100 days was significantly lower in animals receiving increased maintenance doses of RPM (for groups 2, 3, and 4: 25 +/- 15%, 22 +/- 11%, and 10 +/- 3%, respectively; P < 0.005). CsA treatment either in combination with RPM or alone (groups 5 and 6) failed to improve transplant vasculopathy, but reduced mononuclear cell infiltration. Isografts (groups 7 and 8) and naive hearts (group 9) developed no structural abnormalities throughout the follow-up period, regardless of RPM treatment. We conclude that the extent of transplant vasculopathy can be reduced markedly in this rat cardiac transplant model with maintenance RPM. Addition of CsA modifies the morphological picture but does not improve myointimal proliferation.

Topics: Animals; Cell Division; Cyclosporine; Dose-Response Relationship, Drug; Heart Transplantation; Immunohistochemistry; Immunosuppressive Agents; Male; Polyenes; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sirolimus; Time Factors; Tunica Intima; Vascular Diseases; Ventricular Function