Intravascular Optical Coherence Tomography Detection of Atherosclerosis and Inflammation in Murine Aorta.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Tahara S, Morooka T, Wang Z, Bezerra HG, Rollins AM, Simon DI, Costa MA
Abstract
OBJECTIVE: The goal of this study was to evaluate the feasibility of imaging the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice for the detection of atherosclerosis and macrophages using optical coherence tomography (OCT) compared with histology. METHODS AND RESULTS: Atherosclerosis was induced by high-fat diet in 7-week-old ApoE(-/-) mice for 10 (n=7) and 22 (n=7) weeks. Nine-week-old ApoE(-/-) mice (n=7) fed a standard chow diet were used as controls. OCT images of a 10-mm descending aorta in situ were performed in 4 mice for each, and plaque and macrophages were determined at 0.5-mm intervals. Automated detection and quantification of macrophages were performed independently using a customized algorithm. Coregistered histological cross-sections were stained with hematoxylin-eosin, Mac-3, and von Kossa. Three mice in each group had en face OCT imaging to detect macrophages, which were compared with lipid-positive area with Sudan IV. OCT images were successfully acquired in all mice. OCT and histology were able to discriminate macrophages and plaque among the 3 groups and showed excellent correlation for (1) visual detection of plaque (r=0.98) and macrophages (r=0.93), (2) automated detection and quantification of macrophages by OCT versus Mac-3-positive area (r=0.92), and (3) en face OCT detection of macrophages versus Sudan IV-positive area (r=0.92). CONCLUSIONS: Murine intraaortic OCT is feasible and shows excellent correlation with histology for detection of atherosclerotic plaque and macrophages.
PMID: 22308042 [PubMed - as supplied by publisher]
Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Nogueira JP, Maraninchi M, Béliard S, Padilla N, Duvillard L, Mancini J, Nicolay A, Xiao C, Vialettes B, Lewis GF, Valéro R
Abstract
OBJECTIVE: Overproduction of intestinally derived apoB-48-containing triglyceride-rich lipoproteins (TRLs) (chylomicrons) has recently been described in type 2 diabetes, as is known for hepatic TRL-apoB-100 (very-low-density lipoprotein) production. Furthermore, insulin acutely inhibits both intestinal and hepatic TRL production, whereas this acute inhibitory effect on very-low-density lipoprotein production is blunted in type 2 diabetes. It is not currently known whether this acute effect on chylomicron production is similarly blunted in humans with type 2 diabetes. METHODS AND RESULTS: We investigated the effect of acute hyperinsulinemia on TRL metabolism in 18 type 2 diabetic men using stable isotope methodology. Each subject underwent 1 control (saline infusion [SAL]) lipoprotein turnover study followed by a second study, under 1 of the 3 following clamp conditions: (1) hyperinsulinemic-euglycemic, (2) hyperinsulinemic-hyperglycemic, or (3) hyperinsulinemic-euglycemic plus intralipid and heparin. TRL-apoB-48 and TRL-apoB-100 production and clearance rates were not different between SAL and clamp and between the different clamp conditions, except for significantly lower TRL-apoB-100 clearance and production rates in hyperinsulinemic-euglycemic plus intralipid and heparin clamp compared with SAL. CONCLUSIONS: This is the first demonstration in individuals with type 2 diabetes that chylomicron production is resistant to the normal acute suppressive effect of insulin. This phenomenon may contribute to the highly prevalent dyslipidemia of type 2 diabetes and potentially to atherosclerosis.Clinical Trial Registration-URL: www.clinicaltrials.gov. Unique identifier: NCT00950209.
PMID: 22308041 [PubMed - as supplied by publisher]
In Vivo Targeting of Inflammation-Associated Myeloid-Related Protein 8/14 Via Gadolinium Immunonanoparticles.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Maiseyeu A, Badgeley MA, Kampfrath T, Mihai G, Deiuliis JA, Liu C, Sun Q, Parthasarathy S, Simon DI, Croce K, Rajagopalan S
Abstract
OBJECTIVE: Myeloid-related protein (Mrp) 8/14 complex (is a highly expressed extra cellularly secreted protein, implicated in atherosclerosis. In this study, we evaluated the feasibility of targeting Mrp in vivo through synthetic immuno-nanoprobes. METHODS AND RESULTS: Anti-Mrp-14 and nonspecific IgG-conjugated gadolinium nanoprobes (aMrp-) were synthesized and characterized. Pharmacokinetics and vascular targeting via MRI of the formulations were assessed in vivo in high fat-fed apolipoprotein E deficient (ApoE(-/-)), ApoE(-/-)/Mrp14(-/-) (double knockout) and chow-fed wild-type (C57BL/6) mice were. Bone marrow-derived myeloid progenitor cells were isolated from both ApoE(-/-) and double knockout mice and differentiated to macrophages and were treated with LPS, with or without Mrp8, Mrp14, or Mrp8/14, and conditioned media was collected and used for in vitro studies. Mrp-activated cells secreted significant amounts of proinflammatory cytokines, which were abolished by pretreatment with aMrp-NP. We show in vitro that aMrp-NP binds endothelial cells previously treated with conditioned media containing Mrp8/14. MRI following intravenous delivery of aMrp-NP revealed prolonged and substantial delineation of plaque in ApoE(-/-) but not double knockout or wild-type animals. Nonspecific IgG-conjugated gadolinium nanoprobe-injected animals in all groups did not show vessel wall enhancement. Flow-cytometric analysis of aortic digesta revealed aMrp-NP presence in Ly-6G(+), CD11b(+), CD11c(+), and CD31(+) cells in ApoE(-/-) but not in double knockout animals. CONCLUSIONS: Targeted imaging with aMrp-NP demonstrates enhancement of plaque with binding to inflammatory cells and reduction in inflammation. This strategy has promise as a theranostic approach for atherosclerosis.
PMID: 22308043 [PubMed - as supplied by publisher]
Sphingosine-1-Phosphate Receptor 3 Promotes Neointimal Hyperplasia in Mouse Iliac-Femoral Arteries.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Shimizu T, De Wispelaere A, Winkler M, D’Souza T, Caylor J, Chen L, Dastvan F, Deou J, Cho A, Larena-Avellaneda A, Reidy M, Daum G
Abstract
OBJECTIVE: The objective of this study was to define a role for sphingosine-1-phosphate receptor 3 (S1PR3) in intimal hyperplasia. METHODS AND RESULTS: A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 was higher in these arteries compared with carotid arteries. At 28 days after surgery, wild-type arteries formed significantly larger lesions than S1PR3-null arteries.T Bromodeoxyuridine labeling experiments demonstrated that on injury, wild-type arteries exhibited higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro was low, we expressed S1PR3 in S1PR3-null smooth muscle cells (SMCs) using retroviral-mediated gene transfer to study the effects of S1PR3 on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, responded to sphingosine-1-phosphate stimulation with activation of Rac, Erk, and Akt. SMCs expressing S1PR3 also migrated more. CONCLUSIONS: In humans and mice, S1PR3 expression was higher in iliac-femoral arteries compared with carotid arteries. S1PR3 promoted neointimal hyperplasia on denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt, and Rac.
PMID: 22308044 [PubMed - as supplied by publisher]
Newest-generation drug-eluting and bare-metal stents combined with prasugrel-based antiplatelet therapy in large coronary arteries: The BAsel Stent Kosten Effektivitäts Trial PROspective Validation Examination part II (BASKET-PROVE II) trial design.
Am Heart J. 2012 Feb;163(2):136-141.e1
Authors: Jeger R, Pfisterer M, Alber H, Eberli F, Galatius S, Naber C, Pedrazzini G, Rickli H, Jensen JS, Vuilliomenet A, Gilgen N, Kaiser C
Abstract
BACKGROUND: In the BAsel Stent Kosten Effektivitäts Trial PROspective Validation Examination (BASKET-PROVE), drug-eluting stents (DESs) had similar 2-year rates of death and myocardial infarction but lower rates of target vessel revascularization and major adverse cardiac events compared with bare-metal stents (BMSs). However, comparative clinical effects of newest-generation DES with biodegradable polymers vs second-generation DES or newest-generation BMS with biocompatible coatings, all combined with a prasugrel-based antiplatelet therapy, on 2-year outcomes are not known.
METHODS: In BASKET-PROVE II, 2,400 patients with de novo lesions in native vessels ≥3 mm in diameter are randomized 1:1:1 to receive a conventional DES, a DES with a biodegradable polymer, or a BMS with biocompatible coating. In addition to aspirin, stable patients with BMS will receive prasugrel for 1 month, whereas all others will receive prasugrel for 12 months. The primary end point will be combined cardiac death, nonfatal myocardial infarction, and target vessel revascularization up to 2 years. Secondary end points include stent thrombosis and major bleeding. The primary aim is to test (1) the noninferiority of a biodegradable-polymer DES to a conventional DES and (2) the superiority of both DESs to BMS. A secondary aim is to compare the outcomes with those of BASKET-PROVE regarding the effects of prasugrel-based vs clopidogrel-based antiplatelet therapy.
RESULTS: By the end of 2010, 878 patients (37% of those planned) were enrolled.
CONCLUSIONS: This study will test the comparative long-term safety and efficacy of newest-generation stents on the background of contemporary antiplatelet therapy in a large all-comer population undergoing large native coronary artery stenting.
Rationale and design of the TAXUS Libertē Post-Approval Study: Examination of patients receiving the TAXUS Liberté stent with concomitant prasugrel therapy in routine interventional cardiology practice.
Am Heart J. 2012 Feb;163(2):142-148.e6
Authors: Garratt KN, Lee DP, Rose EM, Windle KJ, Liao H, Nwachuku CE, Winters KJ, Bowman TS, Dawkins KD
Abstract
BACKGROUND: Observational studies of new coronary stents are necessary to assess performance in a variety of complex patient and lesion types. Furthermore, the optimal dose and duration of thienopyridine treatment is unclear, particularly in patients with complex clinical conditions. The TAXUS Libertē Post-Approval Study is designed to provide 5-year data on the TAXUS Liberté paclitaxel-eluting stent with concomitant prasugrel therapy in routine clinical practice and to contribute data to the DAPT study.
STUDY DESIGN: The TAXUS Libertē Post-Approval Study is a prospective, multicenter, observational study. Enrollment of approximately 4,200 patients receiving ≥1 TAXUS Liberté stents is planned. All patients without a contraindication will be prescribed prasugrel plus aspirin for 1 year. The 12-month primary end point of cardiac death or myocardial infarction in on-label stent patients will be compared with historical TAXUS Express stent data from the TAXUS ATLAS and TAXUS ARRIVE studies. Secondary clinical end points include stent thrombosis, all-cause death, stroke, revascularization, and bleeding in all patients. In addition, this study will be the first to evaluate prasugrel use in a routine practice setting (including 5 and 10 mg daily doses) and will contribute data to the DAPT Study, comparing 12 versus 30 months of dual antiplatelet therapy after drug-eluting stent placement.
SUMMARY: The TAXUS Libertē Post-Approval Study will be the first to provide long-term real-world data on use of the TAXUS Liberté Stent with prasugrel treatment. The study is currently enrolling, and primary end point data are expected in mid 2013.
Design of the RELAXin in Acute Heart Failure Study.
Am Heart J. 2012 Feb;163(2):149-155.e1
Authors: Ponikowski P, Metra M, Teerlink JR, Unemori E, Felker GM, Voors AA, Filippatos G, Greenberg B, Teichman SL, Severin T, Mueller-Velten G, Cotter G, Davison BA
Abstract
BACKGROUND: Acute heart failure (AHF) remains a major public health burden with a high prevalence and poor prognosis. Relaxin is a naturally occurring peptide hormone that increases cardiac output, arterial compliance, and renal blood flow during pregnancy. The RELAX-AHF-1 study will evaluate the effect of RLX030 (recombinant form of human relaxin 2) on symptom relief and clinical outcomes in patients with AHF.
METHODS: The protocol includes a completed phase 2 234-patient dose-finding study (Pre-RELAX-AHF) and an ongoing phase 3 1,160-patient trial (RELAX-AHF-1). Patients with AHF and systolic blood pressure >125 mm Hg are randomized within 16 hours of presentation to a 48-hour IV infusion of RLX030 or placebo. The 30 μg/kg per day dose of RLX030 was chosen for RELAX-AHF-1 based on effects on dyspnea, clinical outcomes, and safety observed in Pre-RELAX-AHF. Primary efficacy end points in RELAX-AHF-1 are (1) the area under the curve of change of the dyspnea Visual Analog Scale from baseline through day 5 and (2) whether the patient reports moderately to markedly better dyspnea at 6, 12, and 24 hours. Secondary efficacy end points include days alive and out of the hospital through day 60 and cardiovascular death or rehospitalization for heart failure or renal failure through day 60. Patients will be followed up through day 180 for mortality. As of September 19, 2011, 978 patients have been enrolled.
CONCLUSIONS: Pre-RELAX-AHF results suggested that infusion of RLX030 may accelerate dyspnea relief and improve prognosis in patients hospitalized with AHF. RELAX-AHF-1 will further evaluate these effects.
BACKGROUND: Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects.
METHODS: The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel’s expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs.
RESULTS AND CONCLUSIONS: The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy.
Detection of periodontal bacteria in thrombi of patients with acute myocardial infarction by polymerase chain reaction.
Am Heart J. 2012 Feb;163(2):164-7
Authors: Ohki T, Itabashi Y, Kohno T, Yoshizawa A, Nishikubo S, Watanabe S, Yamane G, Ishihara K
Abstract
BACKGROUNDS: Numerous reports have demonstrated that periodontal bacteria are present in plaques from atherosclerotic arteries. Although periodontitis has recently been recognized as a risk factor for coronary artery disease, the direct relationship between periodontal bacteria and coronary artery disease has not yet been clarified. It has been suggested that these bacteria might contribute to inflammation and plaque instability. We assumed that if periodontal bacteria induce inflammation of plaque, the bacteria would be released into the bloodstream when vulnerable plaque ruptures. To determine whether periodontal bacteria are present in thrombi at the site of acute myocardial infarction, we tried to detect periodontal bacteria in thrombi of patients with acute myocardial infarction by polymerase chain reaction (PCR).
METHODS: We studied 81 consecutive adults with ST-segment elevation acute myocardial infarction who underwent primary percutaneous coronary intervention (PCI). All patients underwent removal of thrombus with aspiration catheters at the beginning of percutaneous coronary intervention, and a small sample of thrombus was obtained for PCR.
RESULTS: The detection rates of periodontal bacteria by PCR were 19.7% for Aggregatibacter actinomycetemcomitans, 3.4% for Porphyromonas gingivalis, and 2.3% for Treponema denticola.
CONCLUSIONS: Three species of periodontal bacteria were detected in the thrombi of patients with acute myocardial infarction. This raises the possibility that such bacteria are latently present in plaque and also suggests that these bacteria might have a role in plaque inflammation and instability.
PMID: 22305832 [PubMed - in process]
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