sirolimus and Atherosclerosis

For more than a decade, atherosclerosis has been one of the leading causes of death in developed countries. The issue of treatment and prevention of the disease is especially acute. Despite the huge amount of basic and clinical research, a significant number of gaps remain in our understanding of the pathogenesis of atherosclerosis, and only their closure will bring us closer to understanding the causes of the disease at the cellular and molecular levels and, accordingly, to the development of an effective treatment. One of the seemingly well-studied elements of atherogenesis is the mTOR signaling pathway. However, more and more new details are still being clarified. Therapeutic strategies associated with rapamycin have worked well in a number of different diseases, and there is every reason to believe that targeting components of the mTOR pathway may pay off in atherosclerosis as well.

Topics: Atherosclerosis; Humans; Immunosuppressive Agents; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

A drug-eluting balloon is a non-stent technology in which the effective homogenous delivery of anti-proliferative drugs is processed by the vessel wall through an inflated balloon. This is done to restore luminal vascularity in order to treat atherosclerosis, in-stent restenosis and reduce the risk of late thrombosis without implanting a permanent foreign object. The balloon technology relies on the concept of targeted drug delivery, which helps in the rapid healing of the vessel wall and prevents the proliferation of smooth muscle cells. Several drug eluting devices in the form of coated balloons are currently in clinical use, namely DIOR

Topics: Angioplasty, Balloon; Animals; Atherosclerosis; Brachytherapy; Coated Materials, Biocompatible; Coronary Restenosis; Drug Delivery Systems; Drug-Eluting Stents; Humans; Lasers; Materials Testing; Paclitaxel; Polymers; Prosthesis Design; Sirolimus; Treatment Outcome

Inhibitors of the mechanistic target of rapamycin (mTOR) have unique antiatherosclerotic effects, such as depletion of plaque macrophages, induction of autophagy, and activation of cholesterol efflux. However, a common side effect of their use is dyslipidemia, a well-known risk factor for atherosclerosis. Indeed, mTOR inhibitors prevent lipid storage, increase low-density lipoprotein cholesterol levels, and activate lipolysis. Although the net effect of mTOR inhibition seems favorable, the use of cholesterol lowering drugs to manage dyslipidemia remains the most recommended strategy.

Topics: Atherosclerosis; Dyslipidemias; Everolimus; Humans; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Topics: Angioplasty, Balloon, Coronary; Atherosclerosis; Coronary Restenosis; Drug Hypersensitivity; Drug-Eluting Stents; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Paclitaxel; Shear Strength; Sirolimus

Evidence is accumulating that autophagy occurs in advanced atherosclerotic plaques. Although there is an almost relentless discovery of molecules that are involved in autophagy, studies of selective autophagy induction or inhibition using knockout mice are just now beginning to reveal its biological significance. Most likely, autophagy safeguards plaque cells against cellular distress, in particular oxidative injury, by degrading the damaged intracellular material. In this way, autophagy is protective and contributes to cellular recovery in an unfavorable environment. Pharmacological approaches have recently been developed to stabilize vulnerable, rupture-prone lesions through induction of autophagy. This approach has proven to be successful in short-term studies. However, how autophagy induction affects processes such as inflammation remains to be elucidated and is currently under investigation. This review highlights the possibilities for exploiting autophagy as a drug target for plaque stabilization.

Topics: Animals; Atherosclerosis; Autophagy; Disease Models, Animal; Everolimus; Humans; Immunosuppressive Agents; Mice; Plaque, Atherosclerotic; Rabbits; Sirolimus

During the last few decades, with the evolution of techniques and materials and the increasing experience of operators, percutaneous coronary interventions (PCI) have become an equally efficient alternative to coronary artery bypass grafts for the treatment of most coronary stenoses. Bare-metal stent implantation represented a major step forward, compared with plain old balloon angioplasty (POBA), by improving the immediate angiographic success. However, the incidence of in-stent restenosis (ISR) remained unacceptably high. Development of the drug-eluting stent (DES) significantly improved the outcome of PCI by dramatically abating the rate of ISR and reducing the incidence of target lesion revascularization. However, ISR has not been eliminated and the persistence of metal vessel scaffolding also raises concern regarding the occurrence of late or very late stent thrombosis. POBA and stent implantation have been shown to induce a local and systemic inflammatory response, whose magnitude is associated with worse clinical outcome, and they increase the risk of ISR. C-reactive protein, a marker of systemic inflammation, has been demonstrated to predict clinical and angiographic outcome after POBA or bare-metal stent implantation. However, conflicting data regarding the prognostic value of C-reactive protein following DES implantation are available. In this paper, we review the literature regarding the clinical and pathophysiological association between inflammation and prognosis after DES implantation and suggest some possible therapeutic approaches to reduce inflammatory burden with the aim to improve clinical and angiographic outcome after PCI.

Topics: Angioplasty, Balloon, Coronary; Atherosclerosis; C-Reactive Protein; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Inflammation; Myocardial Infarction; Paclitaxel; Predictive Value of Tests; Prognosis; Sirolimus

Intimal hyperplasia is central to the pathology of vein graft re-stenosis, and despite considerable advances in our understanding of vascular biology since it was first described 100 years ago, it is still a significant clinical problem. Recent decades have seen the development of many new therapeutic agents aimed at treating this condition, but the successes of laboratory studies have not been replicated in the clinic yet. This review discusses these therapeutic agents, how their modes of action relate to the pathogenesis of vein graft intimal hyperplasia, and considerations of ways in which such therapy may be improved in the future.

Topics: Animals; Anticoagulants; Atherosclerosis; Cell Proliferation; Coronary Artery Bypass; Graft Occlusion, Vascular; Humans; Hyperplasia; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Saphenous Vein; Shear Strength; Sirolimus; Stress, Mechanical; Tunica Intima; Vascular Patency; Veins

The superficial femoral artery (SFA) is a frequent target of atherosclerotic disease predominantly in the proximal section near the bifurcation to the deep femoral artery and in the distal section where the adductor muscles tend to compress the artery. In the past, SFA revascularization was the domain of vascular surgery (femoropopliteal and femorodistal bypasses). However, with the development of endovascular treatment and advancing techniques as well as more sophisticated stenting material and balloons, endovascular treatment is nowadays not just a treatment option but, in most cases, preferable at least as initial revascularization procedure in the treatment of peripheral artery vascular disease. In the last years, many efforts have been made to fight restenosis in revascularized artery segments after stenting and/or angioplasty. This article aims to give a review on this topic including the most recent experience with the various latest revascularization techniques such as drug eluting stents, coated stent grafts, brachytherapy, cryoplasty, cutting balloons, and drug coated balloons.

Topics: Angioplasty, Balloon; Arterial Occlusive Diseases; Atherosclerosis; Brachytherapy; Clinical Trials as Topic; Coronary Artery Disease; Femoral Artery; Humans; Leg; Popliteal Artery; Sirolimus; Stents; Vascular Patency

In 2001, the first human study with drug-eluting stents (DES) was published showing a nearly complete abolition of restenosis by using a sirolimus-eluting stent. This success was very encouraging to test new compounds in combination with the DES platform. Nevertheless, several other anti-restenotic compounds have been used in human clinical trials with disappointing outcomes. Little is known concerning potential adverse effects on vessel wall integrity and (re)healing, atherosclerotic lesion formation, progression, and plaque stability of these DES. Although efficacy and safety need to be determined clinically, preclinical testing of candidate drugs in well-defined animal models is extremely helpful to gain insight into the basic biological responses to candidate compounds. Here, we discuss and report an animal model which enables rapid screening of candidate drugs for DES on an atherosclerotic background. The results from drug testing using this novel model could help to quickly and cost-effectively establish the dose range of candidate drugs with reasonable potential for DES.

Topics: Animals; Atherosclerosis; Coronary Restenosis; Disease Models, Animal; Drug Delivery Systems; Drug Evaluation, Preclinical; Humans; Mice; Paclitaxel; Sirolimus; Stents

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Atherosclerosis; Bone Marrow Diseases; Cell Division; Clinical Trials as Topic; Cyclosporine; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Lymphocyte Subsets; Mice; Multicenter Studies as Topic; Muscle, Smooth, Vascular; Neoplasms; Postoperative Complications; Sirolimus; TOR Serine-Threonine Kinases; Wound Healing

The history of rapamycin dates from 1965, when it was isolated from a microorganism in soil and its antibiotic properties were confirmed. Since its discovery, many scientific papers have demonstrated its antifungal and immunosuppressive properties. Our team pioneered in the study of the mechanism of action of rapamycin, motivated by its enormous promise as a therapeutic agent in atherosclerotic disease. We reported how it can inhibit the proliferation and migration of smooth muscle cells after a mechanical aggression, and demonstrated that this effect is mediated by p27 activation by rapamycin. The participation of p27, a key cyclin in the modulation of cell replication, in rapamycin's molecular signaling also spurred expectations in the field of oncological research because it involves a non-redundant system of regulation of the cell cycle susceptible to mutatio. The interesting characteristics of this active principle suggested that it would be worthwhile to investigate its protective effect in an experimental porcine model of angioplasty. Rapamycin showed that it can notably reduce vascular wall thickening, thus helping to preserve patency after angioplasty. Shortly after this study, the use of rapamycin-coated stents designed to release the active principle into the area of the atherosclerotic lesion was accompanied by an effective preservation of the arterial lumen in experimental models. It also produced a highly significant reduction in the rate of post-stent restenosis in various clinical studies in humans. However, the potential of this type of stent in diabetic patients is still unknown and we are on the point of beginning a large clinical trial (the FREEDOM study) to investigate its impact on the management of diabetic patients. Experimental and clinical evidence indicates that the development of oral agents capable of modifying the progression of atherosclerotic disease by acting on molecular targets involved in the control of the cell cycle will be a challenge in the coming years.

Topics: Animals; Atherosclerosis; Diabetic Angiopathies; Humans; Sirolimus

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Topics: Absorbable Implants; Atherosclerosis; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Humans; Percutaneous Coronary Intervention; Polymers; Prospective Studies; Sirolimus; Stents; Treatment Outcome

Supraflex is a sirolimus-eluting stent with a biodegradable polymer coating and ultra-thin struts. We aimed to compare Supraflex with the standard of care, Xience, an everolimus-eluting stent with a durable polymer coating, regarding clinical outcomes with a randomised trial in an all-comer population.. We did a prospective, randomised, single-blind, multicentre study (TALENT) across 23 centres in Europe (the Netherlands, Poland, the UK, Spain, Bulgaria, Hungary, and Italy). Eligible participants were aged 18 years or older, had one or more coronary artery stenosis of 50% or greater in a native coronary artery, saphenous venous graft, or arterial bypass conduit, and had a reference vessel diameter of 2·25-4·50 mm. Patients underwent percutaneous coronary intervention in an all-comer manner. We randomly assigned patients (1:1) to implantation of either a sirolimus-eluting stent with a biodegradable polymer coating and ultra-thin struts (Supraflex) or an everolimus-eluting stent with a durable polymer coating (Xience). Randomisation was done by local investigators by use of a web-based software with random blocks according to centre. The primary endpoint was a non-inferiority comparison of a device-oriented composite endpoint-cardiac death, target-vessel myocardial infarction, or clinically indicated target lesion revascularisation-between groups at 12 months after the procedure, assessed in an intention-to-treat population. On assumption of 1-year composite endpoint prevalence of 8·3%, a margin of 4·0% was defined for non-inferiority of the Supraflex group compared with the Xience group. This trial is registered with ClinicalTrials.gov, number NCT02870140.. Between Oct 21, 2016, and July 3, 2017, 1435 patients with 1046 lesions were randomly assigned to Supraflex, of whom 720 received the index procedure, and 715 patients with 1030 lesions were assigned to Xience, all receiving the index procedure. At 12 months, the primary endpoint had occurred in 35 patients (4·9 %) in the Supraflex group and in 37 patients (5·3%) in the Xience group (absolute difference -0·3% [one-sided 95% upper confidence bound 1·6%], p. The Supraflex stent was non-inferior to the Xience stent for a device-oriented composite clinical endpoint at 12 months in an all-comer population. Supraflex seems a safe and effective alternative drug-eluting stent to other stents in clinical practice.. European Cardiovascular Research Institute.

Topics: Aged; Atherosclerosis; Drug-Eluting Stents; Endpoint Determination; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prospective Studies; Single-Blind Method; Sirolimus; Thrombosis

Durable polymer drug-eluting stents (DP-DES) may contribute to persistent inflammation, delayed endothelial healing and subsequent late DES thrombosis. The aim of this optical coherence tomography (OCT) substudy was to compare healing and neointimal coverage of a novel bioabsorbable polymer sirolimus-eluting stent (Firehawk®) (BP-DES) versus the DP-DES (XIENCE) at 90 days in an all-comers patient population.. The TARGET All Comers study is a prospective multicentre randomised post-market trial of 1,656 patients randomised 1:1 to Firehawk or XIENCE at 21 centres in 10 European countries. The TARGET OCT substudy enrolled 36 consecutive patients with 52 lesions at six centres proficient in OCT. Follow-up OCT was performed at three months or prior to revascularisation when occurring before the three-month window. The substudy was designed for non-inferiority of the primary endpoint of neointimal thickness. At follow-up, the mean neointimal thickness by OCT (52 lesions: Firehawk, n=24; XIENCE, n=28), was not significantly different between groups (Firehawk 75.5 μm vs. XIENCE V 82.3 μm) meeting the primary endpoint of non-inferiority (pnoninferiority<0.001). The percentage of stent strut coverage was high in both groups (strut level: 99.9±0.3% vs. 100±0.1%, p=0.26), and the proportion of malapposed struts (1.0±1.6% vs. 1.2±2.0%, p=0.51) was low in both groups.. Based on OCT, the Firehawk BP-DES has a similar healing response three months after implantation compared to the DP-DES, with near complete strut coverage, moderate neointima formation and minimal strut malapposition.

Topics: Atherosclerosis; Chromium; Cobalt; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Europe; Humans; Neointima; Prospective Studies; Prosthesis Design; Sirolimus; Stents; Tomography, Optical Coherence; Treatment Outcome

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Incomplete struts coverage is a predictor of late stent thrombosis after implantation of the drug-eluting stents (DES) in atherosclerotic lesions. The process of struts coverage in DES implanted for bare-metal stent (BMS) restenosis has never been described. Thirty-two patients with stable coronary artery disease were consecutively selected, 11 with BMS restenosis (group A) and 21 with de novo atherosclerotic lesions (group B). All patients underwent everolimus-eluting stent implantation; coronary angiography and optical coherence tomography were performed at 6 months follow-up. Percentage difference in struts coverage between the 2 groups was the primary end point. A total of 85,773 struts (17,891 in group A and 67,882 in group B) were analyzed: compared with group B, the percentage of uncovered stent struts was significantly lower in group A (2.6% vs 4.8%; p <0.0001). In group A, DES struts protruding out of BMS were more uncovered (5.0% vs 1.9%; p <0.0001) and malapposed (4.1% vs 2.1%; p <0.0001) compared with overlapping struts. In conclusion, when DES are implanted to treat BMS restenosis, struts coverage at 6 months follow-up is more complete compared with DES implanted in atherosclerotic lesions.

Topics: Antineoplastic Agents; Atherosclerosis; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Coronary Vessels; Drug-Eluting Stents; Electrocardiography; Everolimus; Follow-Up Studies; Immunosuppressive Agents; Prosthesis Design; Reproducibility of Results; Retrospective Studies; Single-Blind Method; Sirolimus; Time Factors; Tomography, Optical Coherence

A comparison was made of sirolimus-eluting stents and bare stents as an effective means of treatment of stenosis in crural arteries. Patients were randomly divided into two groups: (1) patients treated with sirolimus-eluting stents and (2) patients treated with bare stents. Each group consisted of 25 patients, and every patient had one stent implanted. All patients showed symptoms of ischemia of the peripheral arteries, classified according to the Rutherford scale into categories 3, 4, and 5. All patients were examined 24 h before and 24 h and 6 months after the intervention. The results were analyzed according to clinical, hemodynamic, and angiographic criteria. Technically, the procedure was successful in 100% of cases, and both groups presented an equal improvement in clinical and hemodynamic parameters. The follow-up angiographic examination demonstrated a significantly lower rate of restenosis among the sirolimus-eluting stent group (4, 16%) versus the bare stent group (19, 76%) (p < 0.001), with lower target lesion revascularization in 3 (12%) versus 14 (56%) (p < 0.05), respectively. Quantitative angiography demonstrated that all variables used to assess restenosis were superior for sirolimus-eluting stents 6 months after intervention: late lumen loss 0.46 +/- 0.72 versus 1.70 +/- 0.94 (p < 0.001) and minimal lumen diameter 2.25 +/- 0.82 versus 0.99 +/- 1.08 (p < 0.001). Results of this study reveal that the use of sirolimus-eluting stents decreases the risk of restenosis in comparison to standard stents.

Topics: Aged; Aged, 80 and over; Angiography; Arteries; Atherosclerosis; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Ischemia; Male; Middle Aged; Sirolimus; Stents

To review clinical outcomes of patients with chronic limb ischemia and TASC type C lesions treated with sirolimus-eluting versus bare SMART nitinol self-expanding stents.. Data were obtained from a randomized, multicenter, double-blinded study conducted in 2 phases. All 93 patients had chronic limb ischemia and superficial femoral artery (SFA) occlusions or stenoses (average lesion length 8.3 cm). In total, 47 patients (31 men; mean age 66.3+/-9.1 years, range 50-84) received the sirolimus-eluting SMART stent and 46 patients (36 men; mean age 65.9 +/-10.8 years, range 38-83) received a bare SMART nitinol stent. Both groups were followed for a mean 24 months.. Both the sirolimus-eluting and the bare SMART stents were effective in revascularizing the diseased SFA and in sustaining freedom from restenosis. For both types of stents, improvements in ankle-brachial indices (ABI) and symptoms of claudication were maintained over 24 months (median 24-month ABI 0.96 for the sirolimus group versus 0.87 for the bare stent group, p>0.05). At 24 months, the restenosis rate in the sirolimus group was 22.9% versus 21.1% in the bare stent group (p>0.05). The cumulative in-stent restenosis rates according to duplex ultrasound were 4.7%, 9.0%, 15.6%, and 21.9%, respectively, at 6, 9, 18, and 24 months; the rates did not differ significantly between the treatment groups. The TLR rate for the sirolimus group was 6% and for the bare stent group 13%; the TVR rates were somewhat higher: 13% and 22%, respectively. Mortality rates did not differ significantly between the groups.. These data demonstrate that the sirolimus-eluting and the bare SMART stent are effective, safe, and free from restenosis in a majority of patients for up to 24 months. Because the restenosis rate in the bare stent group is unexpectedly low, no significant difference could be found between the sirolimus-eluting and the bare SMART stents.

Topics: Adult; Aged; Aged, 80 and over; Alloys; Angioplasty, Balloon; Anti-Bacterial Agents; Atherosclerosis; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Double-Blind Method; Drug Carriers; Female; Femoral Artery; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prospective Studies; Prosthesis Failure; Recurrence; Safety; Sirolimus; Stents; Treatment Outcome

Atherosclerosis is a chronic disease initiated by lipid-mediated vascular inflammation. From the perspective of conventional treatment, it is difficult to achieve good therapeutic effects via regulation of a single lipid or anti-inflammatory effects. Herein, we designed an amphiphilic low molecular weight heparin-unsaturated fatty acid conjugate (LMWH-uFA) that acted as both an antiatherosclerotic agent and a nanocarrier with self-delivery properties. Structurally, LMWH-uFA self-assembled to form micelles with LMWH as the shell and uFA as the core, without any additives, which guaranteed their biosafety. Functionally, the hydrophilic segment, LMWH, prevented monocyte adhesion to inhibit early vascular inflammation, and the hydrophobic segment, uFA, could participate in the regulation of blood lipids. The anti-inflammatory drug rapamycin (RAP) was encapsulated in the micellar core, which improved its water solubility, and cooperated with LMWH to achieve targeted blockade of the vascular inflammation cascade at P-selectin. The three treatment modules, LMWH, uFA and RAP, were integrated into one system for different therapeutic targets in anticipation of better efficacy. In an atherosclerosis mouse model, RAP-loaded NPs significantly reduced the plaque area and showed satisfactory curative effects, which were related to the targeting of lipid regulation and inflammation. Thus, these modular micellar nanoparticles offer a promising approach for the clinical treatment of atherosclerosis.

Topics: Animals; Atherosclerosis; Drug Carriers; Heparin, Low-Molecular-Weight; Lipids; Mice; Micelles; Nanoparticles; Sirolimus

Immunomodulatory therapy has become a promising method for the clinical treatment of many diseases. Recently, pilot studies revealed that immunomodulatory therapy exhibited good effects on the treatment of cardiovascular diseases, but many problems remain to be solved, such as useful platforms for drug co-delivery and combination therapies. In this study, we designed and constructed the multifunctional nanoparticle Rapa@UiO-66-NH-FAM-IL-1Ra (RUFI) for the treatment of atherosclerotic cardiovascular disease. This nanoplatform combined the advantages of metal-organic frameworks (MOFs) for drug co-delivery, rapamycin and IL-1Ra for immunomodulation, IL-1Ra for cellular targeting, and 5-FAM for fluorescence imaging. RUFI exhibited good drug release of rapamycin and IL-1Ra and specific cytotoxicity for inflammatory macrophages in vitro. In an atherosclerotic model of diet-fed ApoE

Topics: Animals; Atherosclerosis; Interleukin 1 Receptor Antagonist Protein; Metal-Organic Frameworks; Mice; Plaque, Atherosclerotic; Sirolimus

Peripheral artery disease (PAD), defined as reduced blood flow to the lower limbs, is a serious disorder that can lead to loss of function in the lower extremities and even loss of limbs. One of the main risk factors for PAD is age, with up to 25% of adults over the age of 55 and up to 40% over the age of 80 presenting with some form of the disease. While age is the largest risk factor for PAD, other risk factors include atherosclerosis, smoking, hypertension, and diabetes. Furthermore, previous studies have suggested that the incidence of PAD is significantly increased in patients with Alzheimer's disease (AD). Attenuation of mTOR with rapamycin significantly improves cerebral blood flow and heart function in aged rodents as well as in mouse models of atherosclerosis, atherosclerosis-driven cognitive impairment, and AD. In this study, we show that rapamycin treatment improves peripheral blood flow in aged mice and in mouse models of atherosclerosis and AD. Inhibition of mTOR with rapamycin ameliorates deficits in baseline hind paw perfusion in aged mice and restores levels of blood flow to levels indistinguishable from those of young controls. Furthermore, rapamycin treatment ameliorates peripheral blood flow deficits in mouse models of atherosclerosis and AD. These data indicate that mTOR is causally involved in the reduction of blood flow to lower limbs associated with aging, atherosclerosis, and AD-like progression in model mice. Rapamycin or other mTOR inhibitors may have potential as interventions to treat peripheral artery disease and other peripheral circulation-related conditions.

Topics: Alzheimer Disease; Animals; Atherosclerosis; Mice; Peripheral Arterial Disease; Sirolimus; TOR Serine-Threonine Kinases

The activation of lymphatic vessel function is the crux to resolving atherosclerosis (AS), a chronic inflammatory disease. Rapamycin (RAPA) recently has attracted considerable attention as a potent drug to induce atherosclerotic plaque attenuation. The objective of this work was to develop a ligand-decorated, RAPA-loaded liposome for lymphatic-targeted delivery of drugs to improve abnormal lymphatic structure and function, resulting in highly effective regression of atherosclerotic plaques.. Hyaluronic acid-decorated, RAPA-loaded liposomes (HA-RL) were fabricated by emulsion-solvent evaporation. The average size, zeta potential, entrapment efficiency were characterized, and the stability and drug release in vitro were investigated. Furthermore, the in vitro and in vivo lymphatic targeting ability were evaluated on lymphatic endothelial cells and LDLR. HA-RL had a size of 100 nm, over 90% drug encapsulation efficiency, the storage stability was distinguished, demonstrating a slow release from the lipid nano-carriers. The mean retention time (MRT) and elimination half-life (t. HA-RL exhibited the most appreciable lymphatic targeting ability and best atherosclerotic plaques attenuation efficiency, opening a new paradigm and promising perspective for the treatment of arteriosclerosis.

Topics: Animals; Atherosclerosis; Drug Delivery Systems; Endothelial Cells; Hyaluronic Acid; Liposomes; Mice; Plaque, Atherosclerotic; Sirolimus

Atherosclerosis with unstable plaques is the dominant pathological basis of lethal cardio-cerebrovascular diseases, which can cause acute death due to the rupture of plaques. Plaque-targeted drug delivery to achieve promoted treatment remains the main challenge because of the systemic occurrence of atheroma. Herein, a rapamycin (RAP) spherical nucleic acid (SNA) structure, capable of specifically accumulating in plaques for synergistic atherosclerosis treatment is constructed. By designing consecutive phosphorothioate (PS) at 3' terminus of the deoxyribonucleic acid (DNA) strand, multiple hydrophobic RAPs are covalently grafted onto the PS segment to form an amphiphilic drug-grafted DNA (RAP-DNA), which successively self-assembles into micellar SNA (RAP-SNA). Moreover, the phosphodiester-DNA segment constitutes the outer shell of RAP-SNA, enabling further hybridization with functional siRNA (targeting lectin-like oxidized low-density lipoprotein receptor-1, LOX-1) to obtain the drug codelivered SNA (LOX-1/RAP-SNA). With two active ingredients inside, LOX-1/RAP-SNA can not only induce robust autophagy and decrease the evil apoptosis of the pathological macrophages, but also simultaneously prohibit the LOX-1-mediated formation of damageable foam cells, realizing the effect of synergistic therapy. As a result, the LOX-1/RAP-SNA significantly reduces the progression of atheroma and stabilizes the plaques, providing a new strategy for synergistically targeted atherosclerosis treatment.

Topics: Atherosclerosis; DNA; Humans; Nucleic Acids; Plaque, Atherosclerotic; Scavenger Receptors, Class E; Sirolimus

Topics: Angioplasty, Balloon; Atherosclerosis; Coated Materials, Biocompatible; Humans; Ischemia; Limb Salvage; Peripheral Arterial Disease; Popliteal Artery; Sirolimus; Treatment Outcome; Vascular Patency

Atherosclerosis, the leading cause of death in the elderly worldwide, is typically characterized by elevated reactive oxygen species (ROS) levels and a chronic inflammatory state at the arterial plaques. Herein, pH-sensitive nanoparticles (HR

Topics: Animals; Apolipoproteins E; Atherosclerosis; Hyaluronic Acid; Hydrogen-Ion Concentration; Inflammation; Mice; Mice, Inbred C57BL; Nanoparticles; Plaque, Atherosclerotic; Reactive Oxygen Species; Retinaldehyde; Sirolimus

Atherosclerosis arising from the pro-inflammatory conditions associated with chronic kidney disease (CKD) increases major cardiovascular morbidity and mortality. Rapamycin (RAPA) is known to inhibit atherosclerosis under CKD and non-CKD conditions, but it can cause dyslipidemia; thus, the co-application of lipid-lowering agents is recommended. Atorvastatin (ATV) has been widely used to reduce serum lipids levels, but its synergistic effect with RAPA in CKD remains unclear. Here, we analyzed the effect of their combined treatment on atherosclerosis stimulated by CKD in apolipoprotein E-deficient (ApoE-/-) mice. Oil Red O staining revealed that treatment with RAPA and RAPA＋ ATV, but not ATV alone, significantly decreased the atherosclerotic lesions in the aorta and aortic sinus, compared to those seen in the control (CKD) group. The co-administration of RAPA and ATV improved the serum lipid profile and raised the expression levels of proteins involved in reverse cholesterol transport (LXRα, CYP7A1, ABCG1, PPARγ, ApoA1) in the liver. The CKD group showed increased levels of various genes encoding atherosclerosispromoting cytokines in the spleen (Tnf-α, Il-6 and Il-1β) and aorta (Tnf-α and Il-4), and these increases were attenuated by RAPA treatment. ATV and RAPA＋ATV decreased the levels of Tnf-α and Il-1β in the spleen, but not in the aorta. Together, these results indicate that, in CKD-induced ApoE-/- mice, RAPA significantly reduces the development of atherosclerosis by regulating the expression of inflammatory cytokines and the co-application of ATV improves lipid metabolism. [BMB Reports 2021; 54(3): 170-175].

Topics: Animals; Apolipoproteins E; Atherosclerosis; Atorvastatin; Cytokines; Disease Models, Animal; Female; Lipid Metabolism; Mice; Mice, Knockout; Renal Insufficiency, Chronic; Sirolimus

Interventional therapies such as drug-eluting stents (DES) and drug-coated balloons (DCB) have significantly improved the clinical outcomes of patients with coronary occlusions in recent years. Despite this marked improvement, ischemic cardiovascular disease remains the most common cause of death worldwide. To address this, research efforts are focused on improving the safety and efficacy of the next generation of these devices. However, current experimental methods are unable to account for the influence of atherosclerotic lesions on drug uptake and retention. Therefore, in this study, we used an integrated approach utilizing both in vitro and in silico methods to assess the performance of DCB therapy. This approach was validated against existing in vivo results before being used to numerically estimate the effect of the atheroma. A bolus release of sirolimus was observed with our coating matrix. This, coupled with the rapid saturation of specific and non-specific binding sites observed in our study, indicated that increasing the therapeutic dose coated onto the balloons might not necessarily result in greater uptake and/or retention. Additionally, our findings alluded to an optimal exposure time, dependent on the coating matrix, for the DCBs to be expanded against the vessel. Moreover, our findings suggest that a biphasic drug release profile might be beneficial for establishing and maintaining the saturation of bindings sites within severely occluded vessels. Ultimately, we have demonstrated that computational methods may be capable of assessing the efficacy of DCB therapy as well as predict the influence of atherosclerotic lesions on said efficacy.

Topics: Angioplasty, Balloon, Coronary; Atherosclerosis; Cardiovascular Agents; Computer Simulation; Coronary Occlusion; Coronary Restenosis; Coronary Vessels; Dose-Response Relationship, Drug; Drug Liberation; Drug-Eluting Stents; Humans; Models, Cardiovascular; Sirolimus; Treatment Outcome

The clinical characteristics and vascular computed tomography (CT) imaging characteristics of patients were explored so as to assist clinicians in diagnosing patients with atherosclerosis. 316 patients with atherosclerosis who were hospitalized for emergency treatment were treated with rapamycin (RAPA) in the hospital. A group of manually delineated left ventricular myocardia (LVM) on the patient's coronary computed tomography angiography (CCTA) were selected as the region of interest for imaging features extracted. The CCTA images of 80% of patients were randomly selected for training, and those of 20% of patients were used for verification. The correlation matrix method was used to remove redundant image omics features under different correlation thresholds. In the validation set, CCTA diagnostic parameters were about 40 times higher than the manually segmented data. The average dice similarity coefficient was 91.6%. The proposed method also produced a very small centroid distance (mean 1.058 mm, standard deviation 1.245 mm) and volume difference (mean 1.640), with a segmentation time of about 1.45 ± 0.51 s, compared to about 744.8 ± 117.49 s for physician manual segmentation. Therefore, the deep learning model effectively segmented the atherosclerotic lesion area, measured and assisted the diagnosis of future atherosclerosis clinical cases, improved medical efficiency, and accurately identified the patient's lesion area. It had great application potential in helping diagnosis and curative effect analysis of atherosclerosis.

Topics: Atherosclerosis; Computed Tomography Angiography; Deep Learning; Humans; Image Processing, Computer-Assisted; Sirolimus; Tomography, X-Ray Computed

p62/SQSTM1, encoded by gene

Topics: Animals; Atherosclerosis; Autophagy; Humans; Neurodegenerative Diseases; Osteitis Deformans; Protein Domains; Sequestosome-1 Protein; Signal Transduction; Tumor Suppressor Proteins

Topics: Acetylation; Adaptor Proteins, Signal Transducing; Animals; Atherosclerosis; Autophagy; Autophagy-Related Proteins; Cells, Cultured; Disease Models, Animal; Female; Hippo Signaling Pathway; Human Umbilical Vein Endothelial Cells; Humans; Mechanotransduction, Cellular; Mice, Knockout, ApoE; Plaque, Atherosclerotic; Protein Serine-Threonine Kinases; Proteolysis; Regional Blood Flow; Sirolimus; Sirtuin 1; Stress, Mechanical; Transcription Factors; YAP-Signaling Proteins

Atherosclerosis (AS) is one of the leading causes of vascular disease, producing high morbidity and mortality in many countries. Autophagy plays an important role when cells are facing serious circumstances, such as oxidative stress induced by Ox-LDL (oxidized low-density lipoprotein). Recent studies have revealed that DEX (dexamethasone acetate) and RAPA (rapamycin) exhibit efficient AS therapeutic ability by protecting endothelial cells and killing foam cells, respectively. Herein, we hypothesize that combining DEX and RAPA together in a specific nanocarrier system can achieve better AS therapy while limiting harmful effects. As a proof of concept, DEX and RAPA coloaded mPEG

Topics: Animals; Atherosclerosis; Autophagy; Calcium Phosphates; Dexamethasone; Endothelial Cells; Lipoproteins, LDL; Mice; Nanoparticles; Phosphatidylethanolamines; Sirolimus

NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation contributes to the progression of atherosclerosis, and autophagy inhibits inflammasome activation by targeting macrophages. We investigated whether fucoidan, a marine sulfated polysaccharide derived from brown seaweeds, could reduce NLRP3 inflammasome activation by enhancing sequestosome 1 (p62/SQSTM1)-dependent selective autophagy to alleviate atherosclerosis in high-fat-fed ApoE-/- mice with partial carotid ligation and differentiated THP-1 cells incubated with oxidized low-density lipoprotein (oxLDL). Fucoidan significantly ameliorated lipid accumulation, attenuated progression of carotid atherosclerotic plaques, deregulated the expression of NLRP3 inflammasome, autophagy receptor p62, and upregulated microtubule-associated protein light chain 3 (LC3)-II/I levels. Transmission electron microscopy and GFP-RFP-LC3 lentivirus transfection further demonstrated that fucoidan could activate autophagy. Mechanistically, fucoidan remarkably inhibited NLRP3 inflammasome activation, which was mostly dependent on autophagy. The inhibitory effects of fucoidan on NLRP3 inflammasome were enhanced by autophagy activator rapamycin (Rapa) and alleviated by autophagy inhibitor 3-methyladenine (3-MA). Fucoidan promoted the colocalization of NLRP3 and p62. Knockdown of p62 and ATG5 by small interfering RNA significantly reduced the inhibitory effects of fucoidan treatment on NLRP3 inflammasome. The data suggest that fucoidan can inhibit NLRP3 inflammasome activation by enhancing p62/SQSTM1-dependent selective autophagy to alleviate atherosclerosis.

Topics: Adenine; Animals; Atherosclerosis; Autophagosomes; Autophagy; Autophagy-Related Protein 5; Gene Knockdown Techniques; Humans; Inflammasomes; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Microtubule-Associated Proteins; NLR Family, Pyrin Domain-Containing 3 Protein; Plaque, Atherosclerotic; Polysaccharides; Sequestosome-1 Protein; Sirolimus

To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages.. An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a CCK-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-β-gal (senescence-associated β-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot.. Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects.. Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells.

Topics: Adenine; Animals; Atherosclerosis; Autophagy; Cell Survival; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Disease Progression; Foam Cells; Hepatocyte Growth Factor; Lipid Metabolism; Lipoproteins, LDL; Mice; Proto-Oncogene Proteins; Quercetin; RAW 264.7 Cells; Sirolimus; Up-Regulation

Although certain success has been achieved in atherosclerosis treatment, tremendous challenges remain in developing more efficient strategies to treat atherosclerosis. Platelets have inherent affinity to plaques and naturally home to atherosclerotic sites. Rapamycin features potent anti-atherosclerosis effect, but its clinical utility is limited by its low concentration at the atherosclerotic site and severe systemic toxicity. In the present study, we used platelet membrane-coated nanoparticles (PNP) as a targeted drug delivery platform to treat atherosclerosis through mimicking platelets' inherent targeting to plaques. PNP displayed 4.98-fold greater radiant efficiency than control nanoparticles in atherosclerotic arterial trees, indicating its effective homing to atherosclerotic plaques in vivo. In an atherosclerosis model established in apolipoprotein E-deficient mice, PNP encapsulating rapamycin significantly attenuated the progression of atherosclerosis and stabilized atherosclerotic plaques. These results demonstrated the perfect efficacy and pro-resolving potential of PNP as a targeted drug delivery platform for atherosclerosis treatment.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Platelets; Cell Membrane; Cells, Cultured; Drug Delivery Systems; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nanoparticles; Plaque, Atherosclerotic; Platelet Adhesiveness; Sirolimus

Topics: Atherosclerosis; Drug-Eluting Stents; Humans; Prospective Studies; Sirolimus; Stents

Hyperhomocysteinemia (HHcy) is a highly-related risk factor in vascular smooth muscle cell (VSMC) phenotypic modulation and atherosclerosis. Growing evidence indicated that autophagy is involved in pathological arterial changes. However, the risk mechanisms by which homocysteine and VSMC autophagy interact with cardiovascular disease are poorly understood. This study verified the homocysteine-responsive endoplasmic reticulum protein promotion of VSMC phenotypic switching, and the formation of atherosclerotic plaque in vitro. We found that impaired autophagy, as evidenced by decreased levels of MAP1LC3B II/MAP1LC3B I, has a vital role in HHcy-induced human aortic (HA)-VSMC phenotypic switching, with a decrease in contractile proteins (SM α-actin and calponin) and an increase in osteopontin. Knockdown of the essential autophagy gene Atg7 by small interfering RNA promoted HA-VSMC phenotypic switching, indicating that impaired autophagy induces phenotypic switching in these cells. HHcy co-treatment with rapamycin triggered autophagy, which alleviated HA-VSMC phenotypic switching. Finally, we found that Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor for maintaining genomic stability by resisting oxidative stress and restoring autophagy, is closely involved in this process. HHcy clearly decreased KLF4 expression. KLF4-specific siRNA aggravated defective autophagy and phenotypic switching. Mechanistically, KLF4 regulated the HHcy-induced decrease in HA-VSMC autophagy via the m-TOR signaling pathway. In conclusion, these results demonstrated that the KLF4-dependent rapamycin signaling pathway is a novel mechanism underlying HA-VSMC phenotypic switching and is crucial for HHcy-induced HA-VSMCs with defective autophagy to accelerate early atherosclerosis.

Topics: Aorta; Atherosclerosis; Autophagy; Humans; Hyperhomocysteinemia; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Microtubule-Associated Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Signal Transduction; Sirolimus

Early-generation drug-eluting stents (DESs) have been shown to accelerate neoatherogenesis. Limited optical coherence tomography (OCT) data on the very long-term neoatherosclerotic progression after DES implantation are available.. The aim of this study was a serial OCT evaluation of neoatherosclerosis at three and nine years after implantation of sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs).. Consecutive patients undergoing elective percutaneous coronary intervention with SES (Cypher, Cordis) or PES (Taxus, Boston Scientific) were included in this single-centre, longitudinal study. OCT analysis was performed after three and nine years by an independent core laboratory.. A total of 39 OCT recordings were assessed at three years after the index procedure; of them, 22 (eight SES and 14 PES) OCT pullbacks were evaluated in a paired analysis at three and nine years post implantation. Overall, neoatheroscle-rosis was identified in 23.1% of stents at three years and in 30.8% at nine years after the index procedure (p = 0.289). No features of significant neoatherosclerotic progression were found in either group between three- and nine-year assessment.. At nine years after implantation of early-generation DES no significant neoatherosclerotic progression was observed among patients with uneventful follow-up at three years after PCI, as assessed by OCT. These observations need to be confirmed in larger studies including the current generation of DESs.

Topics: Aged; Atherosclerosis; Coronary Artery Disease; Coronary Restenosis; Disease Progression; Drug-Eluting Stents; Female; Humans; Longitudinal Studies; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Period; Sirolimus; Tomography, Optical Coherence

Delayed healing and endothelial dysfunction may occur with drug-eluting stents (DES), promoting accelerated infiltration of lipids in the neointima and development of neoatherosclerosis (NA). Pathology data suggest durable polymer (DP) of DES to play a major role in this process. Whether biodegradable polymer (BP) may address these issues is uncertain. We compared in vivo vessel healing and NA of current generation BP- or DP-DES using serial optical coherence tomography (OCT) assessments.. Ninety patients with multivessel coronary artery disease were randomized 1:1 to BP everolimus-eluting stents (EES, Synergy) or DP zotarolimus-eluting stents (ZES, Resolute Integrity). Co-primary endpoints were the maximum length of uncovered struts at 3 months (powered for non-inferiority) and the percentage of patients presenting with frames of NA at 18 months (powered for superiority) as measured by OCT. The maximum length of uncovered struts at 3 months was 10 ± 8 mm in the BP-EES group and 11 ± 7 mm in the DP-ZES group (mean difference -1 mm; upper 97.5% confidence interval +2 mm; P = 0.05 for non-inferiority; P = 0.45 for superiority). The percentage of patients presenting with frames of NA at 18 months was low and similar between BP-EES and DP-ZES groups (11.6% vs. 15.9%; P = 0.56). There was no stent thrombosis in both groups at 24 months.. BP-EES and DP-ZES showed a similar healing response at 3 months and a low incidence of NA at 18 months. Biocompatible polymers, regardless of whether they are durable or biodegradable, may favourably impact the long-term vascular response to current-generation DES.

Topics: Absorbable Implants; Aged; Atherosclerosis; Biocompatible Materials; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neointima; Percutaneous Coronary Intervention; Sirolimus; Time Factors; Tomography, Optical Coherence; Wound Healing

Foam cell formation and macrophage polarization are involved in the pathologic development of atherosclerosis, one of the most important human diseases affecting large and medium artery walls. This study was designed to assess the effects of rapamycin and FTY720 (fingolimod) on macrophages and foam cells. Mouse peritoneal macrophages were collected and treated with rapamycin and FTY720 to study autophagy, polarization, and lipid accumulation. Next, foam cells were formed by oxidizing low-density lipoprotein to observe changes in lipid accumulation, autophagy, and polarization in rapamycin-treated or FTY720-treated foam cells. Lastly, foam cells that had been treated with rapamycin and FTY720 were evaluated for sphingosine 1-phosphate receptor (S1prs) expression. Autophagy microtubule-associated protein 1 light chain 3- (LC3-) II was increased, and classically activated macrophage phenotype markers interleukin- (IL-) 6, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) were increased, whereas alternatively activated macrophage phenotype markers transforming growth factor- (TGF-)

Topics: Animals; Arginase; Atherosclerosis; Autophagy; Biomarkers; Cyclooxygenase 2; Fingolimod Hydrochloride; Foam Cells; Interleukin-6; Lipoproteins, LDL; Macrophages, Peritoneal; Membrane Glycoproteins; Mice; Microtubule-Associated Proteins; Nitric Oxide Synthase Type II; Receptors, Lysosphingolipid; Sirolimus; Transforming Growth Factor alpha

Thioredoxin (TRX)-1, a ubiquitous 12-kDa protein, exerts antioxidant and anti-inflammatory effects. In contrast, the truncated form, called TRX80, produced by macrophages induces upregulation of proinflammatory cytokines. TRX80 also promotes the differentiation of mouse peritoneal and human macrophages toward a proinflammatory M1 phenotype.. TRX1 and TRX80 plasma levels were determined with a specific ELISA. A disintegrin and metalloproteinase domain-containing protein (ADAM)-10, ADAM-17, and ADAM-10 activities were measured with SensoLyte 520 ADAM10 Activity Assay Kit, Fluorimetric, and InnoZyme TACE Activity Kit, respectively. Western immunoblots were performed with specific antibodies to ADAM-10 or ADAM-17. Angiogenesis study was evaluated in vitro with human microvascular endothelial cells-1 and in vivo with the Matrigel plug angiogenesis assay in mice. The expression of macrophage phenotype markers was investigated with real-time polymerase chain reaction. Phosphorylation of Akt, mechanistic target of rapamycin, and 70S6K was determined with specific antibodies. The effect of TRX80 on NLRP3 inflammasome activity was evaluated by measuring the level of interleukin-1β and -18 in the supernatants of activated macrophages with ELISA. Hearts were used for lesion surface evaluation and immunohistochemical studies, and whole descending aorta were stained with Oil Red O. For transgenic mice generation, the human scavenger receptor (SR-A) promoter/enhancer was used to drive macrophage-specific expression of human TRX80 in mice.. In this study, we observed a significant increase of plasma levels of TRX80 in old subjects compared with healthy young subjects. In parallel, an increase in expression and activity of ADAM-10 and ADAM-17 in old peripheral blood mononuclear cells compared with those of young subjects was observed. Furthermore, TRX80 was found to colocalize with tumor necrosis factor-α, a macrophage M1 marker, in human atherosclerotic plaque. In addition, TRX80 induced the expression of murine M1 macrophage markers through Akt2/mechanistic target of rapamycin-C1/70S6K pathway and activated the inflammasome NLRP3, leading to the release of interleukin-1β and -18, potent atherogenic cytokines. Moreover, TRX80 exerts a powerful angiogenic effect in both in vitro and in vivo mouse studies. Finally, transgenic mice that overexpress human TRX80 specifically in macrophages of apoE. TRX80 showed an age-dependent increase in human plasma. In mouse models, TRX80 was associated with a proinflammatory status and increased atherosclerosis.

Topics: ADAM10 Protein; ADAM17 Protein; Adult; Aged; Aging; Animals; Apolipoproteins E; Atherosclerosis; Biomarkers; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Inflammation; Interleukin-18; Interleukin-1beta; Leukocytes, Mononuclear; Lipopolysaccharides; Macrophages; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Multiprotein Complexes; Neovascularization, Physiologic; NLR Family, Pyrin Domain-Containing 3 Protein; Peptide Fragments; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Sirolimus; Thioredoxins; TOR Serine-Threonine Kinases

Topics: Acetylation; Animals; Atherosclerosis; beta-Cyclodextrins; Delayed-Action Preparations; Drug Delivery Systems; Hydrogen-Ion Concentration; Immunosuppressive Agents; Inflammation; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Plaque, Atherosclerotic; RAW 264.7 Cells; Reactive Oxygen Species; Sirolimus

Lectin-like oxidized low-density lipoprotein-1 (LOX-1) is the major receptor for oxidized low density lipoprotein (ox-LDL) uptake in human umbilical vein endothelial cells (HUVECs). Previously, we found that rapamycin inhibited ox-LDL accumulation in HUVECs, and this effect was related to its role in increasing the activity of autophagy-lysosome pathway. In this study, we determined whether rapamycin could also reduce ox-LDL uptake in HUVECs and investigated the underlying signaling mechanisms.. Flow cytometry and live cell imaging showed that rapamycin reduced Dil-ox-LDL accumulation in HUVECs. Furthermore, rapamycin reduced the ox-LDL-induced increase in LOX-1 mRNA and protein levels. Western blotting showed that rapamycin inhibited mechanistic target of rapamycin (mTOR), p70s6k and IκBα phosphorylation triggered by ox-LDL. Flow cytometry implied that mTOR, NF-κB knockdown and NF-κB inhibitors significantly reduced Dil-ox-LDL uptake. Moreover, immunofluorescent staining showed that rapamycin reduced the accumulation of p65 in the nucleus after ox-LDL treatment for 30 h. mTOR knockdown decreased LOX-1 protein production and IκBα phosphorylation induced by ox-LDL. NF-κB knockdown and NF-κB inhibitors reduced LOX-1 protein production, but did not inhibit mTOR phosphorylation stimulated by ox-LDL.. These findings demonstrate that rapamycin reduce mTOR phosphorylation and subsequently inhibit NF-κB activation and suppresses LOX-1, resulting in a reduction in ox-LDL uptake in HUVECs.

Topics: Atherosclerosis; Autophagy; Cell Nucleus; Cell Proliferation; Disease Progression; Gene Expression Regulation, Enzymologic; Human Umbilical Vein Endothelial Cells; Humans; Immunosuppressive Agents; Lipoproteins, LDL; Lysosomes; NF-kappa B p50 Subunit; Phosphorylation; Scavenger Receptors, Class E; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transfection

Drug-eluting stents (DES) have reduced late loss and target lesion revascularization through the inhibition of neointimal hyperplasia, but instead increased the risk of very late stent failure due to incomplete neointimal coverage and neoatherosclerosis. Although newer DES are more effective and safer than the first-generation DES, the difference in the condition of the stented lesions between Resolute zotarolimus-eluting stents (R-ZES) and Endeavor zotarolimus-eluting stents (E-ZES) on angioscopy has not been reported.. Consecutive patients who received R-ZES (n=46) or E-ZES (n=46) for de novo lesion of native coronary artery and had 1-year follow-up angioscopy were examined. Yellow color (grade 0-3), neointimal coverage (grade 0-2), heterogeneity score (maximum-minimum neointimal coverage grade) and thrombus (presence or absence) at stented lesion were evaluated. The maximum yellow color grade (1.2±0.9 vs. 0.7±1.0, P=0.005) was higher in R-ZES than in E-ZES. The maximum (1.9±0.3 vs. 1.5±0.5, P<0.001) and minimum (1.1±0.7 vs. 0.4±0.5, P<0.001) coverage grade was higher in E-ZES than in R-ZES. The heterogeneity score was higher in R-ZES than in E-ZES (1.0±0.5 vs. 0.7±0.7, P=0.007). Prevalence of thrombus was not different between the 2 stents (6.5% vs. 2.2%, P=0.4).. E-ZES had better neointimal coverage with less yellow plaque and lower heterogeneity score than R-ZES. The lesions with E-ZES appeared more stable than those with R-ZES. (Circ J 2016; 80: 650-656).

Topics: Aged; Angioscopy; Atherosclerosis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neointima; Plaque, Atherosclerotic; Sirolimus

Angiotensin-converting enzyme 2 (ACE2) has been shown to prevent atherosclerotic lesions and renal inflammation. However, little was elucidated upon the effects and mechanisms of ACE2 in atherosclerotic kidney fibrosis progression. Here, we examined regulatory roles of ACE2 in renal fibrosis in the apolipoprotein E (ApoE) knockout (KO) mice. The ApoEKO mice were randomized to daily deliver either angiotensin (Ang) II (1.5mg/kg) and/or human recombinant ACE2 (rhACE2; 2mg/kg) for 2 weeks. Downregulation of ACE2 and upregulation of phosphorylated Akt, mTOR and ERK1/2 levels were observed in ApoEKO kidneys. Ang II infusion led to increased tubulointerstitial fibrosis in the ApoEKO mice with greater activation of the mTOR/ERK1/2 signaling. The Ang II-mediated renal fibrosis and structural injury were strikingly rescued by rhACE2 supplementation, associated with reduced mRNA expression of TGF-β1 and collagen I and elevated renal Ang-(1-7) levels. In cultured mouse kidney fibroblasts, exposure with Ang II (100nmolL(-1)) resulted in obvious elevations in superoxide generation, phosphorylated levels of mTOR and ERK1/2 as well as mRNA levels of TGF-β1, collagen I and fibronectin 1, which were dramatically prevented by rhACE2 (1mgmL(-1)) or mTOR inhibitor rapamycin (10μmolL(-1)). These protective effects of rhACE2 were eradicated by the Ang-(1-7)/Mas receptor antagonist A779 (1μmolL(-1)). Our results demonstrate the importance of ACE2 in amelioration of kidney fibrosis and renal injury in the ApoE-mutant mice via modulation of the mTOR/ERK signaling and renal Ang-(1-7)/Ang II balance, thus indicating potential therapeutic strategies by enhancing ACE2 action for preventing atherosclerosis and fibrosis-associated kidney disorders.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Apolipoproteins E; Atherosclerosis; Fibrosis; Kidney; Kidney Diseases; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Peptidyl-Dipeptidase A; Sirolimus; TOR Serine-Threonine Kinases

Increasing evidence has demonstrated special advantages of the nanomedicinal approach for the management of cardiovascular disease. We hypothesize that sustained delivery of rapamycin (RAP) may provide more desirable therapeutic effects than traditional oral administration by selectively inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. To evidence this assumption and develop an effective, safe, and translational nanotherapy for atherosclerosis, this study was designed to examine antiatherosclerotic efficacy of a RAP nanotherapy based on an acetalated β-cyclodextrin (Ac-bCD) material in apolipoprotein E-deficient (ApoE(-/-)) mice. First, biodegradable and biocompatible materials of Ac-bCDs were synthesized by kinetically controlled acetalation, giving rise to carrier materials that may not generate acidic byproducts after hydrolysis. Then RAP-loaded nanoparticles base on various Ac-bCDs were prepared by a nanoemulsion technique, which can sustain drug release for different periods of time, depending on the composition of Ac-bCDs. For a RAP/Ac-bCD180-derived nanotherapy (RAP-NP) that may continue RAP release for up to 20days in vitro, it afforded constant drug levels in both the blood and aortic tissue after subcutaneous injection, while orally administered free RAP showed typical peak-valley profiles with remarkably high peak concentrations. Therapeutic studies conducted in an experimental model of atherosclerosis established in ApoE(-/-) mice revealed that RAP-NP significantly reduced the formation of atherosclerotic lesions and dramatically enhanced the stability of plaques, which was more efficacious than orally delivered free RAP. Moreover, rupture-prone proinflammatory factors in both serum and aortas were significantly decreased after treatment. Whereas oral administration of RAP simultaneously inhibited mTORC1 and mTORC2 in the aorta, sustained delivery by RAP-NP selectively suppressed mTORC1, agreeing with in vitro results in smooth muscle cells. These findings demonstrated that antiatherosclerotic activity of RAP may be considerably improved by sustained release via the Ac-bCD material-derived nanocarrier, which was achieved through selectively inhibiting mTORC1.

Topics: Animals; Aorta; Atherosclerosis; beta-Cyclodextrins; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Drug Synergism; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Mice, Knockout, ApoE; Nanoparticles; Sirolimus; Tissue Distribution

Autophagy participates in plaque formation and progression; however, its association with foam cells' fate is unknown. To investigate autophagy features and its effect on the fate of different-stage macrophage foam cells (FCs). Different-stage FCs were obtained through incubation of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein LDL (oxLDL, 80 μg/mL) for various durations (0-72 h). Autophagy in THP-1 macrophage FCs and in apoE-/- mice was regulated by Rapamycin (80 ug/mL) or 3-MA (10 mM). Lipid droplet accumulation, LC3 I/II, P62 expression level, and autophagic flux were measured. Vascular ultrasound, TUNEL, IHC, and DHE staining were used to detect the artery plaques in apoE-/- mice.. In early-stage FCs, the amount of autophagosomes gradually increased, and autophagic flux intensity accelerated, but in mid-late stage FCs, autophagic flux was suppressed. For early stage FCs, treatment with autophagy activator rapamycin markedly decreased intracellular lipid content and prevented them from transforming into foam cells, while the autophagy inhibitor 3-MA considerably increased the intracellular lipid-droplet accumulation. During the process of foam cell development, upregulating autophagy not only reduced intracellular lipid-droplet accumulation, but also inhibited cell apoptosis through clearing dysfunctional mitochondria and lowering intracellular ROS level. The in vivo experiments produced consistent results that rapamycin administration in apoE-/- mice reduced the death rate of macrophages and delayed plaque progression.. The fate of macrophage FCs was associated with autophagy. Early autophagy enhancement inhibits the formation and progression of macrophage FCs and prevents atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Autophagy; Cell Line, Tumor; Foam Cells; Humans; Male; Mice; Mice, Knockout; Sirolimus

Adhesion molecules play an important role in inflammation, atherosclerosis and coronary artery disease (CAD). These molecules are expressed on the surface of dysfunctional endothelial cells, causing inflammatory cells from the circulation to adhere and migrate through the endothelium. Their expression is upregulated in acute coronary syndrome (ACS) and after percutaneous coronary intervention (PCI). The contact between stent struts and endothelium upregulates endothelial cell gene expression, endothelial cell activation and inflammation. The paclitaxel or sirolimus eluting stents inhibited expression of adhesion molecules in several studies and reduced the incidence of major adverse cardiac events (MACE) after drug-eluting stent (DES) over bare metal stent (BMS) implantation. Therefore, we propose that elevated serum levels of the soluble adhesion molecules after primary PCI in patients treated with BMS or DES implantation versus drug-coated balloon (DCB) application to the vulnerable coronary plaque might be a predictor of MACE and further adverse outcomes. Consequently, DCB-only strategy in patients with ACS might be a superior approach in comparison to BMS implantation and non-inferior approach when compared to DES implantation.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Atherosclerosis; Cell Adhesion Molecules; Coronary Artery Disease; Coronary Restenosis; Drug Delivery Systems; Drug-Eluting Stents; Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Metals; P-Selectin; Paclitaxel; Percutaneous Coronary Intervention; Sirolimus; Up-Regulation; Vascular Cell Adhesion Molecule-1

Atherosclerosis accounts for most adult cases of renal artery stenoses (RAS). Revascularization of atherosclerotic RAS is beneficial in terms of improved blood pressure control, preservation of renal function and overall decrease of cardiovascular risk, in particular in mononephric patients. Endovascular stenting has been proven superior to percutaneous transluminal angioplasty (PTA) alone in terms of initial success and restenosis rates in atherosclerotic RAS. In this case report revascularization of atherosclerotic RAS in a mononephric patient is presented and the long-term follow-up and complications of PTA and stenting are illustrated. Our case is the first report of fracture of a sirolimus-eluting stent overlapped to a previously implanted Palmaz-Schatz in the left renal artery. The mechanisms and possible remedies of this complication are discussed.

Topics: Angioplasty; Atherosclerosis; Drug-Eluting Stents; Humans; Male; Middle Aged; Renal Artery; Renal Artery Obstruction; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography

We determined growth rates, cholesterol esterification and mRNA levels for caveolin-1 (Cav-1), neutral cholesterol esters hydrolase (n-CEH) and ATP-binding cassette transporter (ABCA-1), in quiescent and growth-stimulated peripheral blood mononuclear cells (PBMCs) and intimal vascular smooth muscle cells (VSMCs) from blood and primary atherosclerotic plaques, respectively. These cells were cultured in the presence or absence of the mTOR inhibitor 40-O-(2-hydroxyethyl) rapamycin (RAD).. The rate of cell proliferation was determined by 3H-thymidine incorporation into DNA and that of lipid metabolism by utilizing 14C-acetate and 14C-oleate as precursors. Lipid deposit in the vascular cells was evaluated by Oil Red O staining and lipid mass by thin layer chromatography-linked enzymatic assay.. Growth stimulation of PBMCs and VSMCs caused a rapid increase in intracellular cholesterol esterification and an accumulation of cholesterol esters (CEs) accompanied by a reduction of free cholesterol (FC) and Cav-1, ABCA-1 and n-CEH mRNAs. RAD reduced intracellular lipid accumulation in growth-stimulated cells and also increased expression of Cav-1, n-CEH and ABCA-1 genes.. Collectively, these data provide evidence that the determination of CEs in PBMCs may be an easy prescreening test to identify subjects at risk for vascular proliferative disease and that FC, CE, Cav-1, n-CEH and ABCA-1 may be suitable targets for antiproliferative therapies.

Topics: Aged; Atherosclerosis; ATP Binding Cassette Transporter 1; Biomarkers; Caveolin 1; Cell Proliferation; Cells, Cultured; Cholesterol Esters; Esterification; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plaque, Atherosclerotic; Protein Kinase Inhibitors; RNA, Messenger; Sirolimus; Sterol Esterase; Time Factors; TOR Serine-Threonine Kinases

Macrophage infiltration contributes to the instability of atherosclerotic plaques. In the present study, we investigated whether selective inhibition of PI3K/Akt/mTOR signaling pathway can enhance the stability of atherosclerotic plaques by activation of macrophage autophagy. In vitro study, selective inhibitors or siRNA of PI3K/Akt/mTOR pathways were used to treat the rabbit's peritoneal primary macrophage cells. Inflammation related cytokines secreted by macrophages were measured. Ultrastructure changes of macrophages were examined by transmission electron microscope. mRNA or protein expression levels of autophagy related gene Beclin 1, protein 1 light chain 3 II dots (LC3-II) or Atg5-Atg12 conjugation were assayed by quantitative RT-PCR or Western blot. In vivo study, vulnerable plaque models were established in 40 New Zealand White rabbits and then drugs or siRNA were given for 8 weeks to inhibit the PI3K/Akt/mTOR signaling pathway. Intravascular ultrasound (IVUS) was performed to observe the plaque imaging. The ultrastructure of the abdominal aortic atherosclerosis lesions were analyzed with histopathology. RT-PCR or Western blot methods were used to measure the expression levels of corresponding autophagy related molecules. We found that macrophage autophagy was induced in the presence of Akt inhibitor, mTOR inhibitor and mTOR-siRNA in vitro study, while PI3K inhibitor had the opposite role. In vivo study, we found that macrophage autophagy increased significantly and the rabbits had lower plaque rupture incidence, lower plaque burden and decreased vulnerability index in the inhibitors or siRNA treated groups. We made a conclusion that selective inhibition of the Akt/mTOR signal pathway can reduce macrophages and stabilize the vulnerable atherosclerotic plaques by promoting macrophage autophagy.

Topics: Animals; Atherosclerosis; Autophagy; Cells, Cultured; Chromones; Cytokines; Lipids; Macrophages, Peritoneal; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Plaque, Atherosclerotic; Proto-Oncogene Proteins c-akt; Rabbits; Ribonucleosides; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To assess the late postinterventional response to iliac stenting in atheromatous rabbits using the Xience V everolimus-eluting stent (Xience V EES; Abbott Vascular) and the Resolute zotarolimus-eluting stent (Resolute ZES; Medtronic Vascular) with the MultiLink Vision bare metal stent (BMS; Abbott Vascular) as a reference.. Xience V EES and Resolute ZES were developed to overcome shortcomings of first-generation DES.. Functional and microscopic changes were assessed by organ bath experiments and histopathologic examination. Gene expression was investigated using RT-PCR.. After 91 days, re-endothelialization was nearly complete (BMS: 93 ± 3%; Resolute ZES: 92 ± 2%; Xience V EES: 94 ± 3%; P = 0.10). Neointima thickness was similar in Resolute ZES (0.17 ± 0.08 mm) and BMS (0.17 ± 0.09 mm), and reduced in Xience V EES (0.03 ± 0.01 mm; P < 0.0001). Xience V EES had less peri-strut inflammation compared with BMS (P = 0.001) and Resolute ZES (P = 0.0001), while arterial segments distal to Xience V EES were more sensitive to acetylcholine than those distal to BMS and Resolute ZES (P = 0.02). Lectin-like oxidized receptor-1 was overexpressed in stented arteries (P < 0.001), whereas thrombomodulin was downregulated in Resolute ZES (P = 0.01) and BMS (P = 0.02) compared to unstented arteries of rabbits on regular chow. No significant changes were seen for vascular cell adhesion molecule-1, nitric oxide synthase 3, or endothelin-1.. At 3-month follow-up, nearly complete re-endothelialization was achieved for all stent groups. Xience V EES induced greater suppression of neointimal growth and peri-strut inflammation, higher vasorelaxation to acetylcholine, and expression of thrombomodulin at the level of unstented controls.

Topics: Acetylcholine; Angioplasty, Balloon; Animals; Atherosclerosis; Disease Models, Animal; Down-Regulation; Drug-Eluting Stents; Endothelium, Vascular; Everolimus; Iliac Artery; Inflammation; Neointima; Rabbits; Scavenger Receptors, Class E; Sirolimus; Thrombomodulin; Vasodilator Agents

The long-term coronary arterial response of biodegradable polymer biolimus-eluting stents (BES) remains unclear. We sought to evaluate the coronary arterial response of biodegradable polymer BES at 5 years after stent implantation using optical coherence tomography (OCT) as compared with that of durable polymer sirolimus-eluting stents (SES) and bare-metal stents (BMS).. Five-year follow-up OCT was performed in 30 patients with 33 stents (10 with 12 BES; 10 with 11 SES; 10 with 10 BMS). Quantitative parameters and qualitative characteristics of the neointima were evaluated. A total of 5178 struts (BES, n = 2056; SES, n = 1410; BMS, n = 1712) were analyzed.. Uncovered struts were found in 15 out of 2055 struts in the BES (weighted estimate 0.01%, 95% confidence intervals [CI]: 0.00-0.33%) and 54 out of 1410 struts in the SES (0.11%, 95% CI: 0.00-3.33%) (odds ratio [OR] 0.12, 95% CI: 0.01-1.95, p = 0.13). None of 1712 struts were uncovered in the BMS. Cross-sectional qualitative analysis of neointimal tissue showed that the frequency of lipid-laden neointima tended to be lower in the BES (2.26%, 95% CI: 0.38-12.3%) compared with the SES (9.90%, 95% CI: 4.37-20.9%; OR 0.21, 95% CI 0.03-1.16, p = 0.07), and was similar to the BMS (2.23%, 95% CI: 0.54-8.74%; OR 0.98, 95% CI 0.13-7.14, p = 0.98).. Biodegradable polymer BES shows a favorable coronary arterial response compared with SES, but different response with BMS at 5 years follow-up. The observed frequency of in-stent neoatherosclerosis within BES was similar to BMS and tended to be lower than SES.

Topics: Absorbable Implants; Aged; Aged, 80 and over; Atherosclerosis; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Lipids; Male; Metals; Neointima; Polymers; Sirolimus; Stents; Ticlopidine; Time Factors; Tomography, Optical Coherence

Oxidized lipoproteins stimulate autophagy in advanced atherosclerotic plaques. However, the mechanisms underlying autophagy induction and the role of autophagy in atherogenesis remain to be determined. This study was designed to investigate the mechanisms by which 7-ketocholesterol (7-KC), a major component of oxidized lipoproteins, induces autophagy. This study was also designed to determine the effect of autophagy induction on apoptosis, a central event in the development of atherosclerosis. Exposure of human aortic smooth muscle cells to 7-KC increased autophagic flux. Autophagy induction was suppressed by treating the cells with either a reactive oxygen species scavenger or an antioxidant. Administration of 7-KC concomitantly up-regulated Nox4 expression, increased intracellular hydrogen peroxide levels, and inhibited autophagy-related gene 4B activity. Catalase overexpression to remove hydrogen peroxide or Nox4 knockdown with siRNA reduced intracellular hydrogen peroxide levels, restored autophagy-related gene 4B activity, and consequently attenuated 7-KC-induced autophagy. Moreover, inhibition of autophagy aggravated both endoplasmic reticulum (ER) stress and cell death in response to 7-KC. In contrast, up-regulation of autophagic activity by rapamycin had opposite effects. Finally, activation of autophagy by chronic rapamycin treatment attenuated ER stress, apoptosis, and atherosclerosis in apolipoprotein E knockout (ApoE(-/-)) mouse aortas. In conclusion, we demonstrate that up-regulation of autophagy is a cellular protective response that attenuates 7-KC-induced cell death in human aortic smooth muscle cells.

Topics: Animals; Aorta; Apoptosis; Atherosclerosis; Autophagy; Autophagy-Related Proteins; Cardiovascular Agents; Cell Death; Cells, Cultured; Cysteine Endopeptidases; Enzyme Inhibitors; Free Radical Scavengers; Humans; Hydrogen Peroxide; Ketocholesterols; Male; Mice; Microtubule-Associated Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidase 4; NADPH Oxidases; Reactive Oxygen Species; Sirolimus; Up-Regulation

To evaluate differences in strut coverage, inflammation and endothelialization between two second-generation polymer-based drug-eluting stents (DES) in an atherosclerotic rabbit double-injury iliac artery model at 28 days follow-up.. Rabbits with induced atheroma received bilateral iliac artery stents: everolimus-eluting stent (Xience V EES; Abbott Vascular), zotarolimus-eluting stent (Resolute ZES; Medtronic CardioVascular), or bare-metal stent (BMS; MultiLink Vision; Abbott Vascular). After 28 days, total neointimal coverage examined by scanning electron microscopy was >98% for all three stent types. Neointimal thickness above stent struts was decreased by 50% in Xience V EES (0.06 ± 0.01 mm; P = 0.00001) compared with BMS (0.15 ± 0.03 mm) and Resolute ZES (0.12 ± 0.04 mm). Luminal area was largest for Xience V EES (3.79 ± 0.33 mm(2) ; P = 0.0003 for Xience V EES vs. BMS), followed by Resolute ZES (3.46 ± 0.45 mm(2) ; P = 0.083 for Resolute ZES vs. BMS) and BMS (3.07 ± 0.53 mm(2) ). Percentage area stenosis was smallest for Xience V EES (17.23 ± 3.64%; P = 0.00001), while BMS (30.25 ± 7.48%) and Resolute ZES (30.79 ± 7.15%) did not differ. Endothelial monolayer regrowth was significantly lower in Resolute ZES (65 ± 13%) versus BMS (79 ± 11%; P = 0.004). There was no difference between Xience V EES (74 ± 10%) and BMS. Xience V EES was further associated with a lower number of inflammatory cells surrounding the stent struts (7 ± 2 per strut) in comparison to Resolute ZES (15 ± 6; P = 0.0001) and BMS (17 ± 9; P = 0.0005).. In this atherosclerotic rabbit model, Xience V EES suppressed neointimal thickening better, with normal endothelial regrowth as compared with BMS, and less strut-induced inflammation.

Topics: Angioplasty, Balloon; Animals; Atherosclerosis; Cardiovascular Agents; Cell Proliferation; Disease Models, Animal; Drug-Eluting Stents; Endothelial Cells; Everolimus; Iliac Artery; Inflammation; Male; Neointima; Prosthesis Design; Rabbits; Radiography; Sirolimus; Time Factors; Vascular System Injuries

Although Virtual Histology intravascular ultrasound (VH-IVUS) is increasingly used in clinical research, the reproducibility of plaque composition remains unexplored in significant coronary artery and stented lesions. The purpose of this study was to assess the reproducibility of necrotic core and calcium content in atherosclerotic coronary lesions that were treated with a bioresorbable everolimus-eluting vascular scaffold (BVS) using a new measurement method (Shin's method) by VH-IVUS. Eight patients treated with a BVS (Abbott Vascular, Santa Clara, CA, USA) were analyzed with serial VH-IVUS assessments, i.e., pre- and post-stenting, and at 6 months and 2 years follow-up. A total of 32 coronary segments were imaged to evaluate the reproducibility of volumetric VH-IVUS measurements. In Shin's method, contours are drawn around the IVUS catheter (instead of the lumen) and vessel. Overall, in the imaged coronary segment, for necrotic core and dense calcium volumes, the relative intra-observer differences were 0.30 ± 0.22, 0.19 ± 0.16% for observer 1 and 0.45 ± 0.41, 0.36 ± 0.47% for observer 2, respectively. The inter-observer relative differences of necrotic core and dense calcium volumes were 0.51 ± 0.79 and 0.56 ± 1.01%, respectively. The present study demonstrates a good reproducibility for both, intra-observer and inter-observer measurements using Shin's method. This method is suitable for the measurement of necrotic core and dense calcium using VH-IVUS in longitudinal studies, especially studies on bioresorbable scaffolds, because the degradation process will be fully captured independently of the location of the struts and their greyscale appearance.

Topics: Absorbable Implants; Angioplasty, Balloon, Coronary; Atherosclerosis; Cardiovascular Agents; Cohort Studies; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Necrosis; Observer Variation; Prosthesis Design; Reproducibility of Results; Sirolimus; Treatment Outcome; Ultrasonography, Interventional; Vascular Calcification

To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.. Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry.. The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both).. This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia.

Topics: Absorbable Implants; Angioplasty, Balloon; Animals; Atherosclerosis; Cardiovascular Agents; Constriction, Pathologic; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Hypercholesterolemia; Hyperplasia; Iliac Artery; Inflammation; Male; Metals; Neointima; Plaque, Atherosclerotic; Polymers; Prosthesis Design; Rabbits; Sirolimus; Stents; Time Factors

To present the 5-year angiographic and clinical results of a retrospective registry assessing the performance of sirolimus-eluting stents (SES) in the treatment of infrapopliteal atherosclerotic disease.. From 2004 to 2009, 158 patients (95 men; mean age 71.9 years) with chronic lower limb ischemia (Rutherford categories 3-6) underwent primary SES placement in focal infrapopliteal lesions. The angiographic endpoint was patency, defined as freedom from in-stent stenosis (ISS) >50%. Clinical endpoints were death, amputation, and bypass surgery. Results were correlated with patient and lesion characteristics and cumulative outcomes were assessed with Kaplan-Meier analysis.. Technical success was achieved in all cases. The primary patency rates were 97.0% after 6 months, 87.0% after 12 months, and 83.8% at 60 months. In-stent stenosis was predominantly observed in the first year after stent placement. Female gender was associated with a higher rate of ISS. During clinical follow-up of 144 (91%) patients over a mean 31.1±20.3 months, there were 27 (18.8%) deaths, 4 (2.8%) amputations, and no bypass surgery. Clinical status improved in 92% of the patients with critical limb ischemia (CLI) and 77% of the patients suffering from claudication (p=0.022).. Treatment of focal infrapopliteal lesions with SES showed encouraging long-term angiographic results in this registry. Clinical improvement was evident, but more pronounced in CLI patients than in patients suffering from claudication. Further studies are needed to evaluate the potential clinical benefit of SES as compared to balloon angioplasty or bare metal stents in the treatment of infrapopliteal lesions.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Chi-Square Distribution; Chronic Disease; Constriction, Pathologic; Drug-Eluting Stents; Female; Germany; Humans; Ischemia; Kaplan-Meier Estimate; Lower Extremity; Male; Middle Aged; Popliteal Artery; Proportional Hazards Models; Prosthesis Design; Radiography; Registries; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures

Topics: Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Drug-Eluting Stents; Female; Humans; Ischemia; Lower Extremity; Male; Popliteal Artery; Sirolimus

Proliferation signal inhibitors/mTOR-inhibitors have been shown to reduce de novo development of hypercholesterolemic atherosclerosis in animal models. However, their effect on pre-existing atherosclerosis has not yet been studied.. Feeding LDL-R-KO mice a high cholesterol diet for 12 weeks resulted in formation of moderate fibroatheroma (induction phase). Sixty mice received either everolimus (1 or 5 mg/kg) or no everolimus for further 12 weeks (treatment phase). Everolimus significantly enhanced hypercholesterolemia (plasma cholesterol +45%, p<0.001). Atherosclerosis progressed obstructively in treated and non-treated mice. Everolimus (5 mg/kg) tended to reduced progression in aortic root lesions (0.28±0.02 vs. 0.33±0.03 mm(2), p=ns) and brachiocephalic lesions (0.044±0.006 vs. 0.066±0.012 mm(2), p=ns) but without significance. Everolimus (5mg/kg) resulted in an arrest of CD68 positive plaque area (p=0.03) and nearly halved CD68 fraction (p=0.05) in aortic root lesions but not in brachiocephalic lesions. Taken together, despite a trend to reduced progression and inflammatory cell content there was less conclusive net effect of everolimus treatment than expected.. A higher potential of everolimus in the treatment of atherosclerosis might be obscured by its concomitant hypercholesterolemia. Considering stronger effects in previous studies we suggest that everolimus might exert more potent anti-atherogenic properties in earlier stages of atherogenesis than in advanced atherosclerosis.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta; Atherosclerosis; Biomarkers; Brachiocephalic Trunk; Cholesterol; Disease Models, Animal; Everolimus; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Protein Kinase Inhibitors; Receptors, LDL; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

Recent studies have reported the development of neoatherosclerosis inside stents and subsequent acute coronary syndrome secondary to disruption of neointimal hyperplasia. The aim of the study was to compare the characteristics of neointimal hyperplasia and its time course between bare metal stents (BMSs) and drug-eluting stents (DESs) using optical coherence tomography. A total of 138 stents were divided into 3 groups according to the follow-up period: early phase, <9 months (25 BMSs and 27 DESs); intermediate phase, ≥9 and <48 months (18 BMSs and 43 DESs); and delayed phase, ≥48 months (13 BMSs and 12 DESs). Optical coherence tomographic analysis included the presence of lipid-laden intima, percentage of lipid-rich plaque, and signal attenuation. The optical coherence tomographic findings were compared between the BMSs and DESs in each period, and the difference between the periods was also determined. In the early phase, a greater incidence of lipid-laden plaque (37% vs 8%, p = 0.02) and a greater percentage of lipid-rich plaque (12.9 ± 25.1% vs 1.2 ± 4.3%, p = 0.01) were found in the DESs than in the BMSs. In the intermediate phase, the DES group continuously showed a significantly greater incidence of lipid-laden plaque (63% vs 28%, p = 0.03) and greater percentage of lipid-rich plaque (24.8 ± 28.1% vs 4.1 ± 7.3%, p <0.01). In addition, signal attenuation was greater in the DES group, suggesting early changes in neointimal hyperplasia properties. In the delayed phase, lipid-laden plaque was the predominant type in both groups. In conclusion, lipid-rich neoatherosclerosis develops inside stents earlier in DESs than in BMSs. After 48 months, most restenotic stents will have developed lipid-laden neointima in both groups.

Topics: Acute Coronary Syndrome; Atherosclerosis; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Hyperplasia; Immunosuppressive Agents; Incidence; Male; Massachusetts; Middle Aged; Myocardial Ischemia; Myocardial Revascularization; Neointima; Sirolimus; Time Factors; Tomography, Optical Coherence

A novel self-expanding, drug-eluting stent (DES) was designed to slowly release everolimus in order to prevent restenosis after percutaneous peripheral intervention. The purpose of this experimental animal study was to test the hypothesis that long-term local, stent-mediated delivery of everolimus would reduce neointimal hyperplasia in porcine iliac arteries.. The iliac arteries of 24 Yucatan mini-swine were percutaneously treated with overlapping 8- × 28-mm self-expanding nitinol stents loaded with everolimus (225 μg/cm2 stent surface area) formulated in a poly(ethylene-co-vinyl alcohol) copolymer intended to deliver the drug in a sustained fashion over about 6 months (DES). Bare nitinol self-expanding stents (bare metal stent [BMS]) were implanted in an identical fashion on the contralateral side to serve as controls. After 3, 6, or 12 months, the animals were sacrificed and the stented arteries perfusion-fixed for histomorphometric analysis.. The chronic presence of everolimus in arterial tissue reduced stent-induced inflammation after 3 months (inflammation score: BMS 2.29±0.44 vs DES 0.17±0.17; P=.001) and 6 months (BMS 2.06±0.43 vs DES 0.50±0.5; P=.007), although some late inflammation was observed after drug exhaustion (BMS 1.00±0.25 vs DES 2.56±0.62 after 12 months; P=not significant [NS]). Treatment with locally delivered everolimus significantly reduced neointimal hyperplasia after 3 months (neointimal thickness: BMS 0.79±0.20 vs DES 0.37±0.04 mm; P=.03) and 6 months (BMS 0.73±0.14 vs DES 0.41±0.08 mm; P=.05), although the effect had dissipated after 12 months (BMS 0.68±0.11 vs DES 0.67±0.11 mm; P=NS). Remarkably, stent-induced neoatherosclerosis, characterized by the histologic presence of foamy macrophages and cholesterol clefts, was significantly attenuated by treatment with everolimus (atherogenic change scores at 3 months: BMS 0.56±0.15 vs DES 0.04±0.04; P=.003; 6 months: BMS 0.84±0.23 vs DES 0.00±0.00; P=.004; and 12 months: BMS 0.09±0.10 vs DES 0.19±0.19; P=NS).. In this experimental animal model, local arterial stent-mediated delivery of everolimus inhibited the formation of neointimal hyperplasia and neoatherosclerosis during the first 6 months. The effect was transient, however, as arterial morphology and histology appeared similar to control stented arteries after 12 months.

Topics: Animals; Atherosclerosis; Disease Models, Animal; Drug-Eluting Stents; Endovascular Procedures; Everolimus; Graft Occlusion, Vascular; Hyperplasia; Iliac Artery; Immunosuppressive Agents; Neointima; Sirolimus; Swine; Swine, Miniature

Lipid disturbances are one of the most frequent side effects of SRL; however, clinical consequences are not known. The aim of the study was to evaluate the risk of AS in children after LTx treated with SRL. In 17 children with median age 13.2 yr (1.9-17.9) who received SRL on average for 4.1 yr (s.d. ± 2.9) we measured and compared with age-matched healthy control group (n = 45) lipid parameters and markers of AS: ADMA, oxyLDL, GSH, GPx, TC, TG, HDL cholesterol, LDL cholesterol, VLDL cholesterol, ApoAI, ApoB, ApoE, lipoprotein (a) (Lp(a)). We found no major differences in cholesterol, cholesterol in lipoprotein fractions and TG concentrations between patients receiving SRL and the control group. ApoE was markedly increased in the study group (19.1 g/L [±1.8]) when compared to controls (9.8 [±3.9]). ApoA1 was decreased in the study group: 1.30 g/L (±0.2) vs. 1.45 (±0.25), p = 0.04. ApoB and Lpa concentrations were similar in both groups. There were differences in oxidative stress markers: GSH 743 (±66.2) mol/mL vs. 780 (±48.2), p = 0.02 and GPx 32.8 (±5.5) U/gHb vs. 34.3(±2.6), p = 0.01. Markers of AS: ADMA did not differ between groups and oxidized LDLc was significantly lower in SRL group: 190 mU/mL (±113) vs. 237 (±107) in control, p < 0.05. SRL does not significantly disturb lipid metabolism and oxidative status in children after LTx.

Topics: Adolescent; Antioxidants; Atherosclerosis; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Lipid Metabolism; Lipids; Liver Transplantation; Male; Oxidative Stress; Sirolimus

Although rapamycin (rapa) is a fungicide, it is now believed to possess the capacity to extend mammalian life span. Because rapamycin is insoluble in water, its study in the aqueous phase has been limited. We therefore solubilized rapamycin in isotonic buffer using reconstituted high-density lipoprotein containing V156K-apolipoprotein A-I (V156K-rHDL). Rapamycin (final concentration, 0.1 mg/mL) was solubilized in rHDL containing either wild-type (WT) or V156K-apoA-I (1 mg/mL of protein) prepared using the sodium cholate dialysis method. V156K-rHDL containing rapamycin (V156K-rapa-rHDL) had a slightly larger particle size than rapamycin-loaded WT-rHDL (WT-rapa-rHDL). V156K-rapa-rHDL exhibited enhanced antioxidant ability, cholesteryl ester transfer protein inhibitory activity, and anti-atherosclerotic activity. Treatment with V156K-rapa-rHDL resulted in attenuation of senescence in human cells with increased cell survival and enhancement of tissue regenerative activities in zebrafish model compared with WT-rapa-rHDL or rHDL alone.

Topics: Amino Acid Substitution; Animal Fins; Animals; Antioxidants; Apolipoprotein A-I; Atherosclerosis; Cell Line; Cellular Senescence; Cholesterol Ester Transfer Proteins; Drug Delivery Systems; Humans; Lipoproteins, LDL; Macrophages; Recombinant Proteins; Regeneration; Sirolimus; Solubility; Zebrafish

Though stents are deployed in diseased arteries drug distribution has only been quantified in intact, non-diseased vessels. We correlated steady-state arterial drug distribution with tissue ultrastructure and composition in abdominal aortae from atherosclerotic human autopsy specimens and rabbits with lesions induced by dietary manipulation and controlled injury. Paclitaxel, everolimus, and sirolimus depositions in the human aortae were maximal in the media and scaled inversely with lipid content. Net tissue paclitaxel and everolimus levels were indistinguishable in mildly injured rabbit arteries independent of diet. Yet, serial sectioning of cryopreserved arterial segments demonstrated a differential transmural deposition pattern that was amplified with disease and correlated with the expression of their intracellular targets, tubulin and FKBP-12. Tubulin distribution and paclitaxel binding increased with vascular injury and macrophage infiltration, and were reduced with lipid content. Sirolimus analogs and their specific binding target FKBP-12 were less sensitive to alterations of diet in mildly injured arteries, presumably reflecting a faster transient response of FKBP-12 to injury. The data demonstrate that disease-induced changes in the distribution of drug-binding proteins and interstitial lipid alter the distribution of these drugs, forcing one to consider how disease might affect the evaluation and efficacy of the local release of these and like compounds.

Topics: Animals; Aorta, Abdominal; Atherosclerosis; Cholesterol; Disease Models, Animal; Drug Delivery Systems; Drug-Eluting Stents; Everolimus; Humans; Male; Paclitaxel; Protein Binding; Rabbits; Sirolimus; Tissue Distribution; Tunica Intima

Inflammatory stress accelerates the progression of atherosclerosis. Sirolimus, a new immunosuppressive agent, has been shown to have pleiotropic antiatherosclerotic effects. In this study we hypothesized that sirolimus inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR)-mediated cholesterol synthesis in human vascular smooth muscle cells (VSMCs) under inflammatory stress. Using radioactive assay, we demonstrated that sirolimus inhibited the increase of interleukin-1beta (IL-1beta)-induced cholesterol synthesis in VSMCs. Further studies showed that sirolimus inhibited both the HMGR gene and protein expression in VSMCs treated with or without IL-1beta. These effects were mediated by inhibiting the gene expression of sterol regulatory element-binding protein-2 (SREBP-2) and SREBP-2 cleavage-activating protein (SCAP) as checked by real-time PCR, Western blot analysis, and confocal microscopy for the observation of decreased protein translocation of the SCAP/SREBP-2 complex from the endoplasmic reticulum (ER) to the Golgi. Insulin-induced gene-1 (Insig-1) is a key ER protein controlling the feedback regulation of HMGR at transcriptional and posttranscriptional levels. We demonstrated that sirolimus increased Insig-1 expression which may bind to the SCAP, preventing the exit of SCAP-SREBP complexes from the ER. The increased Insig-1 also accelerated HMGR protein degradation in VSMCs as shown by pulse-chase analysis. In conclusion, sirolimus inhibits cholesterol synthesis induced by inflammatory stress through the downregulation of HMGR expression and the acceleration of HMGR protein degradation. These findings may improve our understanding of the molecular mechanisms of the antiatherosclerosis properties of sirolimus.

Topics: Acyl Coenzyme A; Atherosclerosis; Cells, Cultured; Cholesterol; Coronary Vessels; Endoplasmic Reticulum; Golgi Apparatus; Humans; Immunosuppressive Agents; Inflammation; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Muscle, Smooth, Vascular; Sirolimus; Sterol Regulatory Element Binding Protein 2

Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis.. Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg.kg(-1)) in their diet for 8 or 16 weeks.. In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon gamma, tumour necrosis factor alpha and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen.. The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Atherosclerosis; Cholesterol; Collagen; Creatinine; Cytokines; Diet, Atherogenic; Dose-Response Relationship, Drug; Inflammation; Isoprostanes; Male; Mice; Mice, Knockout; Random Allocation; Receptors, LDL; Sirolimus; Thromboxane B2; Time Factors; Triglycerides

Atherosclerotic plaque rupture and thrombosis are the main cause of acute coronary syndrome. The study was aimed to test the hypothesis that oral administration of rapamycin may attenuate inflammation, inhibit progression and enhance stability of atherosclerotic plaques.. Thirty New Zealand rabbits were subjected to balloon-induced endothelial injury of the abdominal aorta and were fed a diet of 1% cholesterol for 20 weeks. From week 9 to week 20, the animals were treated with oral rapamycin (0.5 mg x kg(-1) x day(-1); group A), oral simvastatin (5 mg x kg(-1) x day(-1); group B) and no drugs (group C). At the end of week 20, all rabbits were challenged with injection of Chinese Russell's viper venom and histamine. Serological, ultrasonographic, pathological, immunohistochemical and gene expression studies were performed.. Rapamycin significantly increased the thickness of the fibrous caps and decreased plaque vulnerability index in group A rabbits. Serum lipid levels were higher whereas plaque burden was lower in group A than in group B (P < 0.05). The incidence of plaque rupture in group A (0%) and group B (0%) was significantly lower than that in group C (56.0%, P < 0.05).. Oral administration of rapamycin effectively attenuated inflammation, inhibited progression and enhanced stability of atherosclerotic plaques in rabbits, without altering serum lipid levels. Our findings suggest a novel approach to the treatment of atherosclerosis.

Topics: Administration, Oral; Animals; Aorta, Abdominal; Atherosclerosis; Biomarkers; C-Reactive Protein; Chemokine CCL2; Inflammation; Interleukins; Lipids; Matrix Metalloproteinase 1; P-Selectin; Rabbits; Sirolimus; Ultrasonography

Stent fracture is a cause of in-stent restenosis (ISR) after sirolimus-eluting stent (SES) implantation, so this study investigated the incidence, predictors and prognosis of stent fracture.. The 273 consecutive patients (364 lesions) after SES implantation and who had 6-9 month' scheduled follow-up coronary angiography (CAG) were divided into groups with and without stent fracture. Deltaangle was defined as the difference in the angle in the target lesion between diastole and systole before the procedure. The incidence of stent fracture was 4.9% (18 of 364 lesions). Deltaangle in the target lesion was larger in the fracture group (28.3 +/-11.5 degrees vs 12.3 +/-9.0 degrees , P<0.0001). Independent predictors of stent fracture were Deltaangle and total stent length. The rates of binary restenosis and target lesion revascularization (TLR) were higher in the fracture group (33% vs 4.0%, P=0.0002 and 28% vs 3.5%, P=0.0007, respectively). There were no major adverse cardiac events (MACE) in the fracture group during a mean 24-month follow-up after follow-up CAG.. Predictors of stent fracture were Deltaangle and total stent length. Although stent fracture was associated with ISR and TLR, it was not associated with MACE during long-term follow-up.

Topics: Aged; Angioplasty, Balloon, Coronary; Atherosclerosis; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Equipment Failure Analysis; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Motion; Prognosis; Prosthesis Failure; Sirolimus

The objective of the present study was to assess the effects of the immunosuppressant rapamycin (Rapamune, Sirolimus) on both resistance vessel responsiveness and atherosclerosis in apolipoprotein E-deficient 8-week-old male mice fed a normal rodent diet. Norepinephrine (NE)-induced vasoconstriction, acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced vasorelaxation of isolated mesenteric bed, and atherosclerotic lesions were evaluated. After 12 weeks of orally administered rapamycin (5 mg.kg-1.day-1, N = 9) and compared with untreated (control, N = 9) animals, rapamycin treatment did not modify either NE-induced vasoconstriction (maximal response: 114 +/- 4 vs 124 +/- 10 mmHg, respectively) or ACh- (maximal response: 51 +/- 8 vs 53 +/- 5%, respectively) and SNP-induced vasorelaxation (maximal response: 73 +/- 6 vs 74 +/- 6%, respectively) of the isolated vascular mesenteric bed. Despite increased total cholesterol in treated mice (982 +/- 59 vs 722 +/- 49 mg/dL, P < 0.01), lipid deposition on the aorta wall vessel was significantly less in rapamycin-treated animals (37 +/- 12 vs 68 +/- 8 microm(2) x 10(3)). These results indicate that orally administered rapamycin is effective in attenuating the progression of atherosclerotic plaque without affecting the responsiveness of resistance vessels, supporting the idea that this immunosuppressant agent might be of potential benefit against atherosclerosis in patients undergoing therapy.

Topics: Administration, Oral; Animals; Apolipoproteins E; Atherosclerosis; Endothelium, Vascular; Immunosuppressive Agents; Male; Mice; Mice, Knockout; Sirolimus; Vascular Resistance; Vasoconstriction; Vasodilation

Everolimus inhibits the mammalian target of rapamycin (mTOR) in proliferating cells. It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease. However, there is only limited data on the pathophysiological effects of mTOR-inhibitors on the vascular wall. We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient (LDLR(-/-)) mice. Male hypercholesterolemic LDLR(-/-) mice received either solvent (group A; n=28) or everolimus at 0.05 mg/kg (group B, n=22) and 1.5 mg/kg (group C, n=29) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks. Group B showed 44% reduction of atherosclerotic lesions at the brachiocephalic artery (BCA). In group C atherosclerotic lesions were reduced by 85% in the BCA and by 60% at the aortic root. This was associated with a significantly lower complexity of lesions in both treated groups (p<0.001) and despite a 40% increase of plasma cholesterol. Everolimus caused a significant reduction of circulating cell mediators such as interleukin-1alpha, interleukin-5, GM-CSF and interleukin-12p40. Everolimus increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied. Everolimus strongly inhibits atherosclerosis development in LDL-receptor(-/-) mice despite severe hypercholesterolemia. Everolimus application had only small effects on circulating cell mediators. The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques.

Topics: Animals; Atherosclerosis; Body Weight; Cholesterol, LDL; Cytokines; Everolimus; Hypercholesterolemia; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Kinases; Receptors, LDL; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

Topics: Angioplasty, Balloon; Animals; Anti-Bacterial Agents; Atherosclerosis; Cardiovascular Diseases; Constriction, Pathologic; Endothelium, Vascular; Femoral Artery; Humans; Nanomedicine; Nanoparticles; Rabbits; Sirolimus

Sirolimus (SIR) alone or in combination with cyclosporine (CsA) or tacrolimus (TAC) are used in solid organ transplantation, but uncertainty remains regarding their respective atherogenic potentials.. THP-1 cells were cultured as macrophages and then treated with plasma trough and peak concentration doses of SIR, SIR/CsA or SIR/TAC to assess the time- and dose-dependent mRNA or protein expression of selected atherogenic genes. The selected atherogenic genes included: the macrophage scavenger receptors (MSRs) CD36, CD68, scavenger receptor (SR)-A, SR-BII, and LOX-1; the nuclear hormone receptors peroxisome proliferator activated receptor gamma (PPARgamma) and liver-X-receptor alpha (LXRalpha); and the cholesterol efflux transporter (ABCA-1).. SIR-mediated changes in mRNA included the upregulation of ABCA1, downregulation of CD68, SR-A and SR-BII, and concentration- and/or time-dependent effects on CD36, LOX-1, PPARgamma, and LXRalpha that did not translate into significant protein changes. With SIR/CsA, the protein expressions of PPARgamma and ABCA-1 were downregulated at 8 h. In contrast, with SIR/TAC, PPARgamma, and ABCA-1 protein expressions were upregulated at 8 h.. Combination results differed from findings with SIR alone, supporting the observed clinical phenotype with calcineurin inhibitors. These findings may provide a rationale for the development of novel drug delivery strategies to mitigate adverse pharmacodynamic responses.

Topics: Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Calcineurin Inhibitors; CD36 Antigens; Cell Line; Cyclosporine; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Interactions; Gene Expression Regulation; Humans; Immunosuppressive Agents; Liver X Receptors; Macrophages; Orphan Nuclear Receptors; PPAR gamma; Receptors, Cytoplasmic and Nuclear; Receptors, Scavenger; RNA, Messenger; Sirolimus; Tacrolimus; Time Factors

The purpose of this study was to investigate whether stent-based delivery of an inhibitor of mammalian target of rapamycin (mTOR) can selectively clear macrophages in rabbit atherosclerotic plaques.. Current pharmacologic approaches to stabilize atherosclerotic plaques have only partially reduced the incidence of acute coronary syndromes and sudden death. Macrophages play a pivotal role in plaque destabilization, whereas smooth muscle cells (SMC) promote plaque stability.. Stents eluting the mTOR inhibitor everolimus were implanted in atherosclerotic arteries of cholesterol-fed rabbits. In addition, in vitro experiments using explanted atherosclerotic segments and cultured macrophages as well as SMC were performed.. Stents eluting everolimus led to a marked reduction in macrophage content without altering the amount of SMC compared with polymer control stents. In vitro studies showed that everolimus treatment induced inhibition of translation in both cultured macrophages and SMC. However, cell death occurred only in macrophages and was characterized by bulk degradation of long-lived proteins, processing of microtubule-associated protein light chain 3, and cytoplasmic vacuolization, which are all markers of autophagy. Everolimus-induced autophagy was mediated by mTOR inhibition, because cell viability was not affected using tacrolimus, an mTOR-independent everolimus analog. Moreover, mTOR gene silencing was associated with selective induction of macrophage cell death. Autophagic macrophage cell death was confirmed by transmission electron microscopy both in cultured cells and in atherosclerotic explants.. Stent-based delivery of everolimus selectively cleared macrophages in rabbit atherosclerotic plaques by autophagy, an mTOR inhibition-dependent and novel mechanism to induce cell death in mammalian cells.

Topics: Animals; Atherosclerosis; Autophagy; Cell Line; Drug Delivery Systems; Everolimus; Gene Silencing; Immunosuppressive Agents; Macrophages; Protein Kinases; Rabbits; Sirolimus; Stents; TOR Serine-Threonine Kinases

Sirolimus is a potent immunosuppressive agent and has an anti-atherosclerotic effect through its anti-proliferative property. The present study was undertaken to investigate the effect of sirolimus on intracellular cholesterol homeostasis in human vascular smooth muscle cells (VSMCs) in the presence of inflammatory cytokine IL-1 beta. We explored the effect of sirolimus on the lipid accumulation of VSMCs in the presence of IL-1 beta, using Oil Red O staining and quantitative measurement of intracellular cholesterol. The effect of sirolimus on the gene and protein expression of lipoprotein receptors and ATP binding cassettes (ABCA1 and ABCG1) was examined by real-time PCR and Western blotting, respectively. Furthermore, the effect of sirolimus on cholesterol efflux from VSMCs in the presence or absence of IL-1 beta was also investigated using [(3)H] cholesterol efflux. Finally, we examined the effect of sirolimus on the production of inflammatory cytokines in VSMCs using ELISA. Sirolimus reduced intracellular lipid accumulation in VSMCs mediated by IL-1 beta possibly due to the reduction of expression of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) receptors. Sirolimus increased cholesterol efflux from VSMCs and overrode the suppression of cholesterol efflux induced by IL-1 beta. Sirolimus also increased ABCA1 and ABCG1 genes expression, even in the presence of IL-1 beta. We further confirmed that sirolimus inhibited mRNA and protein expression of inflammatory cytokines IL-6, tumor necrosis factor-alpha, IL-8, and monocyte chemoattractant protein-1. Inhibition of lipid uptake together with increasing cholesterol efflux and the inhibition of inflammatory cytokines are all important aspects of the anti-atherosclerotic effects of sirolimus on VSMCs.

Topics: Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Azo Compounds; Cardiovascular Agents; Cells, Cultured; Cholesterol; Coloring Agents; Coronary Vessels; Cytokines; Dose-Response Relationship, Drug; Gene Expression; Homeostasis; Humans; Inflammation; Interleukin-1beta; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptors, LDL; RNA, Messenger; Sirolimus; Staining and Labeling

Drug-eluting stents (DES) have been introduced successfully in clinical practice to prevent post-angioplasty restenosis. Nevertheless, concerns about the safety of DES still exist.. To investigate the vascular pathology and transcriptional responses to sirolimus and paclitaxel in a murine model for restenosis on underlying diseased atherosclerotic arteries.. Atherosclerotic lesions were induced by placement of a perivascular cuff around the femoral artery of hypercholesterolaemic ApoE*3-Leiden transgenic mice. Two weeks later these cuffs were replaced either by sirolimus- or paclitaxel-eluting cuffs. The vascular pathological effects were evaluated after two additional weeks.. Both anti-restenotic compounds significantly inhibited restenotic lesion progression on the atherosclerotic plaques. Vascular histopathological analyses showed that local delivery of sirolimus has no significant adverse effects on vascular disease. Conversely, high dosages of paclitaxel significantly increased apoptosis, internal elastic lamina disruption, and decreased medial and intimal smooth muscle cells and collagen content. Moreover, transcriptional analysis by real-time RT-PCR showed an increased level of pro-apoptotic mRNA transcripts (FAS, BAX, caspase 3) in paclitaxel-treated arteries.. Sirolimus and paclitaxel are effective in preventing restenosis. Sirolimus has no significant effect on arterial disease. In contrast, paclitaxel at high concentration demonstrated adverse vascular pathology and transcriptional responses, suggesting a narrower therapeutic range of this potent drug. Since the use of overlapping stents is becoming more common in DES technology, this factor is important, given that higher dosages of paclitaxel may lead to increased apoptosis in the vessel wall and, consequently, to a more unstable phenotype of the pre-existing atherosclerotic lesion.

Topics: Actins; Animals; Apoptosis; Atherosclerosis; Cell Proliferation; Collagen; Drug Implants; Femoral Artery; Image Interpretation, Computer-Assisted; In Situ Nick-End Labeling; Male; Mice; Mice, Mutant Strains; Models, Animal; Muscle, Smooth, Vascular; Paclitaxel; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; Stents; Tunica Intima

To test the feasibility of self-expanding drug-coated nitinol stents for prevention of restenosis in an animal model. Stent implantation in the carotid artery (CA) has been shown to be feasible for treatment of CA stenosis. Even though the restenosis rate in CA is reported to be lower than in the coronary and peripheral arteries, problems may arise with increasing numbers of treated patients and lengthier follow-up.. After predilatation with 8-mm balloons, 8 Goettinger minipigs were randomly selected to receive a sirolimus-eluting self-expanding nitinol stent (7 mm/80 mm) as well as the same stent without sirolimus/polymer coating in the right or left CA. Aspirin was given starting 3 days before the intervention and administered for an additional 4 weeks. Clopidogrel was administered for 10 days.. After 6 weeks, 2 subacute occlusions were observed in both groups. In the remaining vessels, the neointima was significantly reduced by sirolimus/polymer-coated stents (5.9+/-2.5 versus 0.7+/-1.0 mm2).. Sirolimus self-expanding nitinol stents may be an effective tool in reducing neointimal formation in CA.

Topics: Alloys; Angioplasty, Balloon, Coronary; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atherosclerosis; Carotid Arteries; Clopidogrel; Coronary Angiography; Coronary Restenosis; Disease Models, Animal; Male; Polymers; Sirolimus; Stents; Swine; Ticlopidine; Time Factors; Ultrasonics

Over the last decade, there has been a decrease in acute graft rejection rates following renal transplantation; however, this has not corresponded with an improvement in long-term outcomes of transplantation. One of the major causes of long-term morbidity and mortality in renal transplant recipients is cardiovascular disease. Immunosuppressive regimens, especially those including steroids and calcineurin inhibitors, have a negative role in the induction of cardiovascular risk factors. The proliferation signal inhibitors (PSIs)/mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown considerable promise in reducing acute rejection in renal transplant recipients. Although PSIs are associated with an increase in hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia), which is a major risk factor for atherosclerosis and associated cardiovascular disease, recent studies with sirolimus have demonstrated protection from atheroma progression in hyperlipidaemic apolipoprotein E-deficient mice. Here, we summarize the results of pre-clinical and clinical studies with sirolimus and everolimus, with particular emphasis on the beneficial and adverse effects that these drugs exert on the cardiovascular system, and the underlying molecular mechanisms.

Topics: Atherosclerosis; Cell Proliferation; Everolimus; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Although CD4(+)CD25(+) regulatory T cells are pivotal in the suppression of autoimmunity, little is known about the effect of antigen-specific regulatory T cells on the formation of atheromatous plaques. Here, we describe the induction of heat-shock protein 60 (HSP60)-specific CD4(+)CD25(high) T cells by rapamycin (RPM)-treated immature dendritic cells in vitro and explore their effect on plaques in apolipoprotein E-deficient mice. Rapamycin-treated bone marrow-derived dendritic cells (DC) were immature, expressing a low level of co-stimulation factors CD86 and CD80. Naive CD4(+) T cells expressed high levels of CD25 and forkhead box P3 (Foxp3) after incubation with rapamycin-treated and HSP60-loaded DC and displayed moderate antigen-specific, IL-10-independent inhibitory function in vitro. After adoptive transfer, HSP60-specific CD4(+)CD25(high) T cells inhibited the formation of plaques, while ovalbumin-specific cells did not. These findings suggest that RPM-treated DC can induce antigen-specific CD4(+)CD25(high) Treg cells that have inhibitory activity in vitro and prevent the development of plaques in vivo.

Topics: Animals; Apolipoproteins E; Atherosclerosis; CD4-Positive T-Lymphocytes; Cell Differentiation; Chaperonin 60; Dendritic Cells; Forkhead Transcription Factors; Interleukin-2 Receptor alpha Subunit; Male; Mice; Mice, Inbred C57BL; Sirolimus; T-Lymphocytes, Regulatory