Contents:Volume 115， Issue 14; April 10， 20071. C-Terminal Provasopressin (Copeptin) as a Novel and Prognostic Marker in Acute Myocardial Infarction. Leicester Acute Myocardial Infarction Peptide (LAMP) Study Sohail Q. Khan MB， Onkar S. Dhillon MB， Russell J. O’Brien MB， Joachim Struck PhD， Paulene A. Quinn MPhil， Nils G. Morgenthaler PhD， Iain B. Squire MD， Joan E. Davies PhD， Andreas Bergmann PhD， and Leong L. Ng MD* From the University of Leicester， Department of Cardiovascular Sciences (S.Q.K.， O.S.D.， R.J.O.， P.A.Q.， I.B.S.， J.E.D.， L.L.N.)， Leicester Royal Infirmary， Leicester， UK; and Research Department (J.S.， N.G.M.， A.B.)， BRAHMS Aktiengesellschaft， Hennigsdorf， Germany.* To whom correspondence should be addressed. E-mail: lln1@le.ac.uk .Background--The role of the vasopressin system after acute myocardial infarction is unclear. Copeptin， the C-terminal part of the vasopressin prohormone， is secreted stoichiometrically with vasopressin. We compared the prognostic value of copeptin and an established marker， N-terminal pro-B-type natriuretic peptide (NTproBNP)， after acute myocardial infarction.Methods and Results--In this prospective single-hospital study， we recruited 980 consecutive post-acute myocardial infarction patients (718 men， median [range] age 66 [24 to 95] years)， with follow-up over 342 (range 0 to 764) days. Plasma copeptin was highest on admission (n=132， P<0.001， day 1 versus days 2 to 5) and reached a plateau at days 3 to 5. In the 980 patients， copeptin (measured at days 3 to 5) was elevated in patients who died (n=101) or were readmitted with heart failure (n=49) compared with survivors (median [range] 18.5 [0.6 to 441.0] versus 6.5 [0.3 to 267.0] pmol/L， P<0.0005). With logistic regression analysis， copeptin (odds ratio， 4.14， P<0.0005) and NTproBNP (odds ratio， 2.26， P<0.003) were significant independent predictors of death or heart failure at 60 days. The area under the receiver operating characteristic curves for copeptin (0.75) and NTproBNP (0.76) were similar. The logistic model with both markers yielded a larger area under the curve (0.84) than for NTproBNP (P<0.013) or copeptin (P<0.003) alone， respectively. Cox modeling predicted death or heart failure with both biomarkers (log copeptin [hazard ratio， 2.33]， log NTproBNP [hazard ratio， 2.70]). In patients stratified by NTproBNP (above the median of 900 pmol/L)， copeptin above the median ( 7 pmol/L) was associated with poorer outcome (P<0.0005). Findings were similar for death and heart failure as individual end points.Conclusions--The vasopressin system is activated after acute myocardial infarction. Copeptin may predict adverse outcome， especially in those with an elevated NTproBNP (more than 900 pmol/L).Key words: heart failure • myocardial infarction • natriuretic peptides • peptides • plasma2. Global Improvement of Vascular Function and Redox State With Low-Dose Folic Acid. Implications for Folate Therapy in Patients With Coronary Artery Disease Cheerag Shirodaria MRCP， Charalambos Antoniades MD， PhD， Justin Lee MRCP， Clare E. Jackson PhD， Matthew D. Robson PhD， Jane M. Francis DCR， DNM， Stuart J. Moat PhD， Chandi Ratnatunga FRCS， Ravi Pillai FRCS， Helga Refsum MD， PhD， Stefan Neubauer MD， FRCP， and Keith M. Channon MD， FRCP* From the Department of Cardiovascular Medicine， John Radcliffe Hospital， University of Oxford， Oxford， United Kingdom (C.S.， C.A.， J.L.， C.E.J.， M.D.R.， J.M.F.， C.R.， R.P.， S.N.， K.M.C.); Department of Medical Biochemistry， University Hospital of Wales， Cardiff， United Kingdom (S.J.M.); and Oxford Centre for Gene Function， Department of Physiology， Anatomy & Genetics， University of Oxford， United Kingdom and Institute of Basic Medical Sciences， University of Oslo， Norway (H.R.).* To whom correspondence should be addressed. E-mail: keith.channon@cardiov.ox.ac.uk .Background--Although dietary folate fortification lowers plasma homocysteine and may reduce cardiovascular risk， high-dose folic acid therapy appears to not alter clinical outcome. Folic acid and its principal circulating metabolite， 5-methyltetrahydrofolate， improve vascular function， but mechanisms relating folate dose to vascular function remain unclear. We compared the effects of folic acid on human vessels using pharmacological high-dose versus low-dose treatment， equivalent to dietary folate fortification.Methods and Results--Fifty-six non-folate-fortified patients with coronary artery disease were randomized to receive low-dose (400 µg/d) or high-dose (5 mg/d) folic acid or placebo for 7 weeks before coronary artery bypass grafting. Vascular function was quantified by magnetic resonance imaging before and after treatment. Vascular superoxide and nitric oxide bioavailability were determined in segments of saphenous vein and internal mammary artery. Low-dose folic acid increased nitric oxide-mediated endothelium-dependent vasomotor responses， reduced vascular superoxide production， and improved enzymatic coupling of endothelial nitric oxide synthase through availability of the cofactor tetrahydrobiopterin. No further improvement in these parameters occurred with high-dose compared with low-dose treatment. Whereas plasma 5-methyltetrahydrofolate increased proportionately with treatment dose of folic acid， vascular tissue 5-methyltetrahydrofolate showed no further increment with high-dose compared with low-dose folic acid.Conclusions--Low-dose folic acid treatment， comparable to daily intake and dietary fortification， improves vascular function through effects on endothelial nitric oxide synthase and vascular oxidative stress. High-dose folic acid treatment provides no additional benefit. These direct vascular effects are related to vascular tissue levels of 5-methyltetrahydrofolate rather than plasma levels. High-dose folic acid treatment likely confers no further benefit in subjects already receiving folate supplementation.Key words: folic acid • atherosclerosis • nitric oxide • magnetic resonance imaging • oxidative stress3. Identifying Heart Failure Patients at High Risk for Near-Term Cardiovascular Events With Serial Health Status Assessments Mikhail Kosiborod MD， Gabriel E. Soto MD， PhD， Philip G. Jones MS， Harlan M. Krumholz MD， SM， William S. Weintraub MD， Prakash Deedwania MD， and John A. Spertus MD， MPH* From the Mid America Heart Institute and University of Missouri-Kansas City， Kansas City (M.K.， P.G.J.， J.A.S.); Washington University School of Medicine， St Louis， Mo (G.E.S.); Yale University， New Haven， Conn (H.M.K.); Christiana Healthcare System， Newark， Del (W.S.W); and VA Central California Health Care System and University of California， San Francisco， Fresno (P.D.).* To whom correspondence should be addressed. E-mail: spertusj@umkc.edu .Background--Identification of heart failure outpatients at increased risk for clinical deterioration remains a critical challenge， with few tools currently available to assist clinicians. We tested whether serial health status assessments with the Kansas City Cardiomyopathy Questionnaire (KCCQ) can identify patients at increased risk for mortality and hospitalization.Methods and Results--We evaluated 1358 patients with heart failure after an acute myocardial infarction in the Eplerenone’s Neurohormonal Efficacy and Survival Study， a multicenter randomized trial that included serial KCCQ assessments. Cox proportional-hazards models were used to examine whether changes in KCCQ scores during successive outpatient visits were independently associated with all-cause mortality and cardiovascular mortality or hospitalization. Change in KCCQ ( KCCQ) was linearly associated with all-cause mortality (hazard ratio [HR]， for each 5-point decrease in KCCQ， 1.11; 95% CI， 1.04 to 1.19) and the combined outcome of cardiovascular mortality or hospitalization (HR for each 5-point decrease in KCCQ， 1.12; 95% CI 1.07 to 1.18). In Kaplan-Meier survival analysis， all-cause mortality among patients with KCCQ of -10， >-10 to <10， and >10 points was 26%， 16%， and 13%， respectively (P=0.008). After multivariable adjustment， the linear relationship between KCCQ and both all-cause mortality and combined cardiovascular death and hospitalization persisted (HR， 1.09; 95% CI， 1.00 to 1.18; and HR， 1.11; 95% CI， 1.05 to 1.17 for each 5-point decrease in KCCQ， respectively).Conclusions--In heart failure outpatients， serial health status assessments with the KCCQ can identify high-risk patients and may prove useful in directing the frequency of follow-up and the intensity of treatment.Key words: health status • heart failure • mortality • prognosis • risk factors4. Instability in the Diagnosis of Metabolic Syndrome in Adolescents Elizabeth Goodman MD*， Stephen R. Daniels MD， PhD， James B. Meigs MD， MPH， and Lawrence M. Dolan MD From the Floating Hospital for Children at Tufts-New England Medical Center， Boston， Mass (E.G.); Department of Pediatrics， Denver Children’s Hospital， and University of Colorado School of Medicine， Denver (S.R.D.); Department of Medicine， General Medicine Division， Massachusetts General Hospital and Harvard Medical School， Boston， Mass (J.B.M.); and Division of Endocrinology， Cincinnati Children’s Hospital Medical Center， Cincinnati， Ohio (L.M.D.).* To whom correspondence should be addressed. E-mail: egoodman@tufts-nemc.org .Background--Factor analyses suggest that the structure underlying metabolic syndrome is similar in adolescents and adults. However， adolescence is a period of intense physiological change， and therefore stability of the underlying metabolic structure and clinical categorization based on metabolic risk is uncertain.Methods and Results--We analyzed data from 1098 participants in the Princeton School District Study， a school-based study begun in 2001-2002， who were followed up for 3 years. We performed factor analyses of 8 metabolic risks at baseline and follow-up to assess stability of factor patterns and clinical categorization of metabolic syndrome. Metabolic syndrome was defined using the current American Heart Association/National Heart， Lung， and Blood Institute definition for adults (AHA)， a modified AHA definition used in prior pediatric metabolic syndrome studies (pediatric AHA)， and the International Diabetes Federation (IDF) guidelines. We found that factor structures were essentially identical at both time points. However， clinical categorization was not stable. Approximately half of adolescents with baseline metabolic syndrome lost the diagnosis at follow-up regardless of the definitions used: pediatric AHA=56% (95% confidence interval [CI]， 42% to 69%)， AHA=49% (95% CI， 32% to 66%)， IDF=53% (95% CI， 38% to 68%). In addition to loss of the diagnosis， new cases were identified. Cumulative incidence rates were as follows: pediatric AHA=3.8% (95% CI， 2.8% to 5.2%); AHA=4.4% (95% CI， 3.3% to 5.9%); IDF=5.2% (95% CI， 4.0% to 6.8%).Conclusions--During adolescence， metabolic risk factor clustering is consistent. However， marked instability exists in the categorical diagnosis of metabolic syndrome. This instability， which includes both gain and loss of the diagnosis， suggests that the syndrome has reduced clinical utility in adolescence and that metabolic syndrome-specific pharmacotherapy for youth may be premature.Key words: adolescents • insulin • obesity • syndrome X5. Adherence to Statin Therapy Under Drug Cost Sharing in Patients With and Without Acute Myocardial Infarction. A Population-Based Natural Experiment Sebastian Schneeweiss MD， ScD*， Amanda R. Patrick MS， Malcolm Maclure ScD， Colin R. Dormuth ScD， and Robert J. Glynn PhD， ScD From the Division of Pharmacoepidemiology and Pharmacoeconomics， Department of Medicine (S.S.， A.R.P.， C.R.D.， R.J.G.) and Division of Preventive Medicine (R.J.G.)， Brigham and Women’s Hospital， Harvard Medical School， Boston， Mass; Department of Epidemiology (S.S.， M.M.) and Department of Biostatistics (R.J.G.)， Harvard School of Public Health， Boston， Mass; and Department of Health Information Sciences (M.M.)， University of Victoria， British Columbia， Canada.* To whom correspondence should be addressed. E-mail: schneeweiss@post.harvard.edu .Background--As medication spending grows， Medicare Part D will need to adapt its coverage policies according to emerging evidence from a variety of insurance policies. We sought to evaluate the consequences of copayment and coinsurance policies on the initiation of statin therapy after acute myocardial infarction and adherence to therapy in statin initiators using a natural experiment of all British Columbia residents aged 66 years and older.Methods and Results--Three consecutive cohorts that included all patients who began statin therapy during full drug coverage (2001)， coverage with a $10 or $25 copay (2002)， and coverage with a 25% coinsurance benefit (2003-2004) were followed up with linked healthcare utilization data (n=51 561). Follow-up of cohorts was 9 months after each policy change. Adherence to statin therapy was defined as 80% of days covered. Relative to full-coverage policies， adherence to new statin therapy was significantly reduced， from 55.8% to 50.5%， under a fixed copayment policy (-5.4% points; 95% CI， -6.4% to -4.4%) and the subsequent coinsurance policy (-5.4% points; 95% CI， -6.3% to -4.4%). An uninterrupted increase in the proportion of patients initiating statin therapy after an acute myocardial infarction (1.7% points per quarter) was observed over the study period， similar to a Pennsylvania control population with full coverage. Sudden changes to full out-of-pocket spending， similar to Medicare’s Part D "doughnut hole，" almost doubled the risk of stopping statins (adjusted odds ratio， 1.94， 95% CI， 1.82 to 2.08).Conclusions--Fixed patient copayment and coinsurance policies have negative effects on adherence to statin lipid-lowering drug therapy but not on their initiation after myocardial infarction.Key words: statins • health care costs • drugs • economics， pharmaceutical6. Lack of the Antioxidant Enzyme Glutathione Peroxidase-1 (GPx1) Accelerates Atherosclerosis in Diabetic Apolipoprotein E-Deficient Mice Paul Lewis BSc， LLB (Hons)， Nada Stefanovic BSc， Josefa Pete BSc (Hons)， Anna C. Calkin PhD， Sara Giunti MD， PhD， Vicki Thallas-Bonke BAppSci， Karin A. Jandeleit-Dahm MD， PhD， Terri J. Allen PhD， Ismail Kola PhD， Mark E. Cooper MBBS， FRACP， PhD， and Judy B. de Haan MSc， PhD* From Oxidative Stress Group (P.L.， N.S.， J.B.d.H.) and Diabetic Complications Group (J.P.， A.C.C.， S.G.， V.T.-B.， K.A.J.-D.， T.J.A.， M.E.C.)， JDRF Diabetes and Metabolism Division， Baker Heart Research Institute， Melbourne， Australia; and Merck Research Laboratories (I.K.)， Merck & Co， Inc， Rahway， NJ. Dr Kola is now Senior Vice President， Discovery Research， at Schering-Plough Research Institute (SPRI)， Schering-Plough Corporation， Kenilworth， NJ. He is also Chief Scientific Officer for Schering-Plough Corporation.* To whom correspondence should be addressed. E-mail: judy.dehaan@baker.edu.au .Background--Recent clinical studies have suggested a major protective role for the antioxidant enzyme glutathione peroxidase-1 (GPx1) in diabetes-associated atherosclerosis. We induced diabetes in mice deficient for both GPx1 and apolipoprotein E (ApoE) to determine whether this is merely an association or whether GPx1 has a direct effect on diabetes-associated atherosclerosis.Methods and Results--ApoE-deficient (ApoE-/-) and ApoE/GPx1 double-knockout (ApoE-/-GPx1-/-) mice were made diabetic with streptozotocin and aortic lesion formation， and atherogenic pathways were assessed after 10 and 20 weeks of diabetes. Aortic proinflammatory and profibrotic markers were determined by both quantitative reverse-transcription polymerase chain reaction analysis after 10 weeks of diabetes and immunohistochemical analysis after 10 and 20 weeks of diabetes. Sham-injected nondiabetic counterparts served as controls. Atherosclerotic lesions within the aortic sinus region， as well as arch， thoracic， and abdominal lesions， were significantly increased in diabetic ApoE-/-GPx1-/- aortas compared with diabetic ApoE-/- aortas. This increase was accompanied by increased macrophages， -smooth muscle actin， receptors for advanced glycation end products， and various proinflammatory (vascular cell adhesion molecule-1) and profibrotic (vascular endothelial growth factor and connective tissue growth factor) markers. Quantitative reverse-transcription polymerase chain reaction analysis showed increased expression of receptors for advanced glycation end products (RAGE)， vascular cell adhesion molecule-1， vascular endothelial growth factor， and connective tissue growth factor. Nitrotyrosine levels were significantly increased in diabetic ApoE-/-GPx1-/- mouse aortas. These findings were observed despite upregulation of other antioxidants.Conclusions--Lack of functional GPx1 accelerates diabetes-associated atherosclerosis via upregulation of proinflammatory and profibrotic pathways in ApoE-/- mice. Our study provides evidence of a protective role for GPx1 and establishes GPx1 as an important antiatherogenic therapeutic target in patients with or at risk of diabetic macrovascular disease.Key words: cardiovascular diseases • aorta • atherosclerosis • diabetes mellitus • antioxidants • free radicals7. Diagnostic Thresholds for Ambulatory Blood Pressure Monitoring Based on 10-Year Cardiovascular Risk Masahiro Kikuya MD， PhD， Tine W. Hansen MD， PhD， Lutgarde Thijs MSc， Kristina Björklund-Bodegård MD， PhD， Tatiana Kuznetsova MD， PhD， Takayoshi Ohkubo MD， PhD， Tom Richart MD， MBE， Christian Torp-Pedersen MD， PhD， Lars Lind MD， PhD， Hans Ibsen MD， PhD， Yutaka Imai MD， PhD， Jan A. Staessen MD， PhD*， on Behalf of the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) Investigators From the Tohoku University Graduate School of Pharmaceutical Science and Medicine， Sendai， Japan (M.K.， T.O.， Y.I.); the Research Center for Prevention and Health， Copenhagen， Denmark (T.W.H.); the Studies Coordinating Centre， Division of Hypertension and Cardiovascular Rehabilitation， Department of Cardiovascular Diseases， University of Leuven， Leuven， Belgium (M.K.， L.T.， T.K.， T.R.， J.A.S.); the Section of Geriatrics， Department of Public Health and Caring Sciences， Uppsala University， Uppsala， Sweden (K.B.-B.， L.L.); and the Copenhagen University Hospital， Copenhagen， Denmark (T.W.H.， C.T.-P.， H.I.).* To whom correspondence should be addressed. E-mail: jan.staessen@med.kuleuven.be .Background--Current diagnostic thresholds for ambulatory blood pressure (ABP) mainly rely on statistical parameters derived from reference populations. We determined an outcome-driven reference frame for ABP measurement.Methods and Results--We performed 24-hour ABP monitoring in 5682 participants (mean age 59.0 years; 43.3% women) enrolled in prospective population studies in Copenhagen， Denmark; Noorderkempen， Belgium; Ohasama， Japan; and Uppsala， Sweden. In multivariate analyses， we determined ABP thresholds， which yielded 10-year cardiovascular risks similar to those associated with optimal (120/80 mm Hg)， normal (130/85 mm Hg)， and high (140/90 mm Hg) blood pressure on office measurement. Over 9.7 years (median)， 814 cardiovascular end points occurred， including 377 strokes and 435 cardiac events. Systolic/diastolic thresholds for optimal ABP were 116.8/74.2 mm Hg for 24 hours， 121.6/78.9 mm Hg for daytime， and 100.9/65.3 mm Hg for nighttime. Corresponding thresholds for normal ABP were 123.9/76.8， 129.9/82.6， and 110.2/68.1 mm Hg， respectively， and those for ambulatory hypertension were 131.0/79.4， 138.2/86.4， and 119.5/70.8 mm Hg. After rounding， approximate thresholds for optimal ABP amounted to 115/75 mm Hg for 24 hours， 120/80 mm Hg for daytime， and 100/65 mm Hg for nighttime. Rounded thresholds for normal ABP were 125/75， 130/85， and 110/70 mm Hg， respectively， and those for ambulatory hypertension were 130/80， 140/85， and 120/70 mm Hg.Conclusions--Population-based outcome-driven thresholds for optimal and normal ABP are lower than those currently proposed by hypertension guidelines.Key words: blood pressure monitoring， ambulatory • blood pressure • hypertension • cardiovascular diseases • epidemiology8. Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice Hafid Ait-Oufella MD， Kiyoka Kinugawa MD， Joffrey Zoll PhD， Tabassome Simon MD， PhD， Jacques Boddaert MD， PhD， Silvia Heeneman PhD， Olivier Blanc-Brude PhD， Véronique Barateau; ， Stéphane Potteaux PhD， Régine Merval; ， Bruno Esposito; ， Elisabeth Teissier PhD， Mat J. Daemen MD， PhD， Guy Lesèche MD， PhD， Chantal Boulanger PhD， Alain Tedgui PhD， and Ziad Mallat MD， PhD* From Institut National de la Santé et de la Recherche Médicale (INSERM)， Unit 689， Centre de Recherche Cardiovasculaire Lariboisière， Paris， France (H.A-O.， K.K.， J.Z.， T.S.， J.B.， O.B-B.， V.B.， S.P.， R.M.， B.E.， G.L.， C.B.， A.T.， Z.M.); Department of Pathology， Cardiovascular Research Institute Maastricht， Maastricht， the Netherlands (S.H.， M.J.D.); INSERM U545， Institut Pasteur de Lille and Faculte de Pharmacie， Universite de Lille II， Lille， France (E.T.); and Service de Chirurgie Thoracique et Vasculaire， Hôpital Bichat， Paris， France (G.L.).* To whom correspondence should be addressed. E-mail: mallat@larib.inserm.fr .Background--Atherosclerosis is an immunoinflammatory disease; however， the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood.Methods and Results--Here， we show that milk fat globule-EGF factor 8 (Mfge8， also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow-derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon- production in both the spleen and the atherosclerotic arteries. In addition， we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis.Conclusions--Lack of Mfge8 in bone marrow-derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response， which leads to an acceleration of plaque development.Key words: atherosclerosis • apoptosis • immune system • inflammation • interleukins9. Predictors of Outcome in Chronic Thromboembolic Pulmonary Hypertension Diana Bonderman MD， Nika Skoro-Sajer MD， Johannes Jakowitsch PhD， Christopher Adlbrecht MD， Daniela Dunkler MSc， Sharokh Taghavi MD， Walter Klepetko MD， Meinhard Kneussl MD， and Irene M. Lang MD* From the Departments of Cardiology (D.B.， N.S.-S.， J.J.， C.A.， I.M.L.)， Core Unit for Medical Statistics and Informatics (D.D.)， and Cardiothoracic Surgery (S.T.， W.K.)， Medical University of Vienna， and the Department of Pulmonology， Wilhelminenspital (M.K.)， Vienna， Austria.* To whom correspondence should be addressed. E-mail: irene.lang@meduniwien.ac.at .Background--Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intraluminal thrombus organization and fibrous obliteration of pulmonary arteries. Recently， associated medical conditions such as splenectomy， ventriculoatrial shunt for the treatment of hydrocephalus， permanent central intravenous lines， inflammatory bowel disease， and osteomyelitis were found to be associated with the development of CTEPH. The study aim was to define the impact of these novel risk factors on survival.Methods and Results--Between January 1992 and December 2006， 181 patients diagnosed with CTEPH were tracked with the use of our center’s customized computer database. A Cox regression model was used to examine relations between survival and associated medical conditions， age， sex， hemodynamic parameters， modified New York Heart Association functional class at diagnosis， CTEPH type， pulmonary endarterectomy， and anti-cardiolipin antibodies/lupus anticoagulant. During a median observation time of 22.1 (range， 0.03 to 152) months， the clinical end point of cardiovascular death or lung transplantation occurred in 48 cases (27%). Pulmonary endarterectomy (hazard ratio， 0.14; 95% CI， 0.05 to 0.41; P=0.0003)， associated medical conditions (hazard ratio， 3.17; 95% CI， 1.70 to 5.92; P=0.0003)， and pulmonary vascular resistance (hazard ratio， 1.02; 95% CI， 1.00 to 1.04; P=0.04) were predictors of survival. Thirty-day postoperative mortality (24% versus 9%) and the incidence of postoperative pulmonary hypertension (92% versus 20%) were substantially higher in patients with associated medical conditions.Conclusions--CTEPH-predisposing medical conditions， such as splenectomy， permanent central intravenous lines， and certain inflammatory disorders， predict poor survival in CTEPH.Key words: hypertension， pulmonary • survival • thrombosis10. Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel， Protease-Activatable Fluorescence Sensor Farouc A. Jaffer MD， PhD*， Dong-Eog Kim MD， PhD， Luisa Quinti PhD， Ching-Hsuan Tung PhD， Elena Aikawa MD， PhD， Ashvin N. Pande MD， Rainer H. Kohler PhD， Guo-Ping Shi DSc， Peter Libby MD， and Ralph Weissleder MD， PhD From the Center for Molecular Imaging Research (F.A.J.， D.K.， L.Q.， C.T.， E.A.， A.N.P.， R.H.K.， R.W.) and Cardiology Division (F.A.J.)， Massachusetts General Hospital， Boston， and Donald W. Reynolds Cardiovascular Clinical Research Center， Harvard Medical School， Boston， Mass (F.A.J.， A.N.P.， P.L.， R.W.).* To whom correspondence should be addressed. E-mail: fjaffer@partners.org .Background--Cathepsin K (CatK)， a potent elastinolytic and collagenolytic cysteine protease， likely participates in the evolution and destabilization of atherosclerotic plaques. To assess better the biology of CatK activity in vivo， we developed a novel near-infrared fluorescence (NIRF) probe for imaging of CatK and evaluated it in mouse and human atherosclerosis.Methods and Results--The NIRF imaging agent consists of the CatK peptide substrate GHPGGPQGKC-NH2 linked to an activatable fluorogenic polymer. In vitro， CatK produced a 2- to 14-fold activation of the agent over other cysteine and matrix metalloproteinases (P<0.0001)， as well as a >8-fold activation over a control imaging agent (P<0.001). Optical imaging of atheroma revealed >100% NIRF signal increases in apolipoprotein E-/- mice in vivo (n=13; P<0.05， CatK imaging agent versus control agent) and in human carotid endarterectomy specimens ex vivo (n=14; P<0.05). Fluorescence microscopy of plaque sections demonstrated that enzymatically active CatK (positive NIRF signal) localized primarily in the vicinity of CatK-positive macrophages. Augmented NIRF signal (reflecting CatK activity) colocalized with disrupted elastin fibers within the media underlying plaques.Conclusions--Use of this novel protease-activatable NIRF agent for optical imaging in vivo demonstrated preferential localization of enzymatically active CatK to macrophages， consistent with their known greater elastinolytic capabilities compared with smooth muscle cells. Augmented CatK proteolysis in atheromata further links CatK to vascular remodeling and plaque vulnerability.Key words: atherosclerosis • cathepsin K • fluorescence • imaging • inflammation11. Mechanism Underlying Initiation of Paroxysmal Atrial Flutter/Atrial Fibrillation by Ectopic Foci. A Simulation Study Yunfan Gong PhD*， Fagen Xie PhD， Kenneth M. Stein MD， Alan Garfinkel PhD， Calin A. Culianu MS， Bruce B. Lerman MD， and David J. Christini PhD From the Department of Medicine， Division of Cardiology， Weill Medical College of Cornell University， New York， NY (Y.G.， K.M.S.， C.A.C.， B.B.L.， D.J.C.); Department of Physiology and Biophysics， Weill Graduate School of Medical Sciences of Cornell University， New York， NY (D.J.C.); and Department of Medicine， Division of Cardiology， University of California， Los Angeles (F.X.， A.G.).* To whom correspondence should be addressed. E-mail: yfgong@hotmail.com .Background--The mechanisms underlying paroxysmal atrial flutter/atrial fibrillation initiation by ectopic foci from various locations are unclear.Methods and Results--We used parallel computational techniques to study an anatomically accurate 3-dimensional atrial structure incorporating a detailed ionic-current model of an atrial myocyte. At the single-cell level， upregulation of the L-type Ca2+ current ICa，L steepened restitution curves of action potential duration and conduction velocity compared with the control. Spontaneous firings of ectopic foci， coupled with sinus activity， produced dynamic spatial dispersions of repolarization， including discordant alternans， which caused conduction block and reentry only for the elevated ICa，L case. For each foci location， a vulnerable window for atrial flutter/atrial fibrillation induction was identified as a function of the coupling interval and focus cycle length. For ectopic foci in the pulmonary veins and left atrium， the site of conduction block and reentry gradually shifted， as a function of coupling interval， from the right atrium to the interatrial area and finally to the left atrium. The size of the vulnerable window was largest for pulmonary vein foci， becoming markedly smaller for right atrial foci， especially those near the sinoatrial node.Conclusions--These findings suggest that a mechanism of dynamically induced repolarization dispersion， especially discordant alternans， underlies the induction of atrial flutter/atrial fibrillation by atrial ectopic foci. The sites and likelihood of reentry induction varied according to ectopic focus location and timing， with the largest vulnerable window corresponding to the pulmonary vein region.Key words: action potentials • arrhythmia • atrial flutter • dynamics • fibrillation • reentry • waves12. Compartmentalization of Cardiac -Adrenergic Inotropy Modulation by Phosphodiesterase Type 5 Eiki Takimoto MD， PhD， Diego Belardi MD， Carlo G. Tocchetti MD， PhD， Susan Vahebi PhD， Gianfrancesco Cormaci MD， Elizabeth A. Ketner BS， An L. Moens MD， PhD， Hunter C. Champion MD， PhD， and David A. Kass MD* From the Division of Cardiology， Department of Medicine， Johns Hopkins Medical Institutions， Baltimore， Md.* To whom correspondence should be addressed. E-mail: dkass@jhmi.edu .Background--Recent cell-based studies have found that cGMP synthesis and hydrolysis by phosphodiesterase (PDE) appear compartmentalized， with nitric oxide synthase-derived and/or PDE type 5 (PDE-5)-hydrolyzable cGMP undetected at the sarcolemmal membrane in contrast to cGMP stimulated by natriuretic peptide. In the present study， we determine the functional significance of such compartments with a comparison of -adrenergic modulation by PDE-5 inhibition to that of natriuretic peptide stimulation in both cardiomyocytes and intact hearts. The potential role of differential cGMP and protein kinase G stimulation by these 2 modulators was also studied.Methods and Results--Intact C57/BL6 mouse hearts were studied with pressure-volume analysis， and adult isolated myocytes were studied with fluorescence microscopy. PDE-5 inhibition with 0.1 to 1 µmol/L sildenafil (SIL) suppressed isoproterenol (ISO)-stimulated contractility， whereas 10 µmol/L atrial natriuretic peptide (ANP) had no effect. ISO suppression by SIL was prevented in cells pretreated with a protein kinase G inhibitor. Surprisingly， myocardial cGMP changed little with SIL+ISO yet rose nearly 5-fold with ANP， whereas protein kinase G activation (vasodilator-stimulated protein phosphorylation; ELISA assay) displayed the opposite: increased with SIL+ISO but unaltered by ANP+ISO. PDE-5 and ANP compartments were functionally separated， as inhibition of nitric oxide synthase by Nw-nitro-L-arginine methyl ester eliminated antiadrenergic effects of SIL， yet this was not restorable by co-stimulation with ANP.Conclusions--Regulation of cardiac -adrenergic response by cGMP is specifically linked to a nitric oxide-synthesis/PDE-5-hydrolyzed pool signaling via protein kinase G. Natriuretic peptide stimulation achieves greater detectable increases in cGMP but not protein kinase G activity and does not modulate -adrenergic response. Such disparities likely contribute to differential cardiac regulation by drugs that modulate cGMP synthesis and hydrolysis.Key words: catecholamines • contractility • myocytes • natriuretic peptides • nitric oxide synthase • cyclic GMP • phosphodiesterases， type 513. Defining Obesity Cut Points in a Multiethnic Population Fahad Razak BASc， MSc， Sonia S. Anand MD， PhD， FRCP*， Harry Shannon PhD， Vladimir Vuksan PhD， Bonnie Davis RN， Ruby Jacobs RN， Koon K. Teo M***h， PhD， Matthew McQueen FRCP， Salim Yusuf MBBS， DPhil， FRCP， for the SHARE Investigators From the Population Health Research Institute (F.R.， S.S.A.， K.K.T.， M.M.， S.Y.)， Department of Medicine (S.S.A.， K.K.T.， M.M.， S.Y.)， and Department of Clinical Epidemiology and Biostatistics (S.S.A.， K.K.T.， M.M.， S.Y.)， McMaster University， Hamilton， Canada; Faculty of Medicine (F.R.) and Department of Medicine (V.V.)， University of Toronto， Toronto， Canada; and Six Nations Health Services (B.D.， R.J.)， Ohsweken， Ontario， Canada.* To whom correspondence should be addressed. E-mail: anands@mcmaster.ca .Background--Body mass index (BMI) is widely used to assess risk for cardiovascular disease and type 2 diabetes. Cut points for the classification of obesity (BMI >30 kg/m2) have been developed and validated among people of European descent. It is unknown whether these cut points are appropriate for non-European populations. We assessed the metabolic risk associated with BMI among South Asians， Chinese， Aboriginals， and Europeans.Methods and Results--We randomly sampled 1078 subjects from 4 ethnic groups (289 South Asians， 281 Chinese， 207 Aboriginals， and 301 Europeans) from 4 regions in Canada. Principal components factor analysis was used to derive underlying latent or "hidden" factors associated with 14 clinical and biochemical cardiometabolic markers. Ethnic-specific BMI cut points were derived for 3 cardiometabolic factors. Three primary latent factors emerged that accounted for 56% of the variation in markers of glucose metabolism， lipid metabolism， and blood pressure. For a given BMI， elevated levels of glucose- and lipid-related factors were more likely to be present in South Asians， Chinese， and Aboriginals compared with Europeans， and elevated levels of the blood pressure-related factor were more likely to be present among Chinese compared with Europeans. The cut point to define obesity， as defined by distribution of glucose and lipid factors， is lower by 6 kg/m2 among non-European groups compared with Europeans.Conclusions--Revisions may be warranted for BMI cut points to define obesity among South Asians， Chinese， and Aboriginals. Using these revised cut points would greatly increase the estimated burden of obesity-related metabolic disorders among non-European populations.Key words: epidemiology • glucose • hypertension • lipids • obesity • risk factors14. Reduced Ventricular Volumes and Improved Systolic Function With Cardiac Resynchronization Therapy. A Randomized Trial Comparing Simultaneous Biventricular Pacing， Sequential Biventricular Pacing， and Left Ventricular Pacing Rajni K. Rao MD， Uday N. Kumar MD， Jill Schafer MS， Esperanza Viloria RN， MS， David De Lurgio MD， and Elyse Foster MD* From the Department of Medicine， University of California， San Francisco (R.K.R.， E.V.， E.F.); Department of Medicine， Stanford University， Stanford， Calif (U.N.K.); Boston Scientific Corporation， St Paul， Minn (J.S.); and Carlyle Fraser Heart Center， Emory University， Atlanta， Ga (D.D.L.).* To whom correspondence should be addressed. E-mail: foster@medicine.ucsf.edu .Background--Cardiac resynchronization therapy has emerged as an important therapy for advanced systolic heart failure. Among available cardiac resynchronization therapy pacing modes that restore ventricular synchrony， it is uncertain whether simultaneous biventricular (BiV)， sequential BiV， or left ventricular (LV) pacing is superior. The Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure (DECREASE-HF) trial is the first randomized trial comparing these 3 cardiac resynchronization therapy modalities.Methods and Results--The DECREASE-HF Trial is a multicenter trial in which 306 patients with New York Heart Association class III or IV heart failure， an LV ejection fraction 35%， and a QRS duration 150 ms were randomized to simultaneous BiV， sequential BiV， or LV pacing. LV volumes and systolic and diastolic function were assessed with echocardiography at baseline， 3 months， and 6 months. All groups had a significant reduction in LV end-systolic and end-diastolic dimensions (P<0.001). The simultaneous BiV pacing group had the greatest reduction in LV end-systolic dimension (P=0.007). Stroke volume (P<0.001) and LV ejection fraction (P<0.001) improved in all groups with no difference across groups.Conclusions--Compared with LV pacing， simultaneous BiV pacing was associated with a trend toward greater improvement in LV size. There is little difference between simultaneous BiV pacing and sequential BiV pacing as programmed in this trial.Key words: echocardiography • heart failure • pacing • remodeling15. Randomized Trial Comparing Same-Day Discharge With Overnight Hospital Stay After Percutaneous Coronary Intervention. Results of the Elective PCI in Outpatient Study (EPOS) Gerlind S. Heyde MD， Karel T. Koch MD， PhD*， Robbert J. de Winter MD， PhD， Marcel G.W. Dijkgraaf PhD， Margriet I. Klees RN， Lea M. Dijksman MSc， Jan J. Piek MD， PhD， and Jan G.P. Tijssen PhD From the Departments of Cardiology (G.S.H.， K.T.K.， R.J.d.W.， M.I.K.， L.M.D.， J.J.P.， J.G.P.T.) and Biostatistics and Clinical Epidemiology (M.G.W.D.)， Academic Medical Center， University of Amsterdam， Amsterdam， the Netherlands.* To whom correspondence should be addressed. E-mail: k.t.koch@amc.uva.nl .Background--Percutaneous coronary intervention (PCI) in a day-case setting might reduce logistic constraints on hospital resources， but data on safety are limited. We evaluated the safety and feasibility of same-day discharge after PCI.Methods and Results--Eight hundred consecutive patients scheduled for elective PCI by femoral approach were randomized to same-day discharge or overnight hospital stay. Four hours after PCI， patients were triaged as suitable for early discharge or not. Suitable patients were discharged immediately or kept overnight， according to randomization. Patients with an indication for extended hospital stay were not discharged regardless of randomization. Primary end points were death， myocardial infarction， coronary artery bypass graft surgery， repeat PCI， or puncture-related complications occurring within 24 hours after PCI. A total of 403 patients were assigned to same-day discharge， of whom 77 (19%) were identified for extended observation; 397 patients were assigned to overnight stay， of whom 85 (21%) were identified for extended observation. Among all patients， the composite primary end point occurred in 9 (2.2%) same-day discharge patients and in 17 (4.2%) overnight stay patients (risk difference， -0.020; 95% CI， -0.045 to -0.004; P for noninferiority <0.0001). Among patients deemed suitable for early discharge， the composite end point occurred in 1 of 326 (0.3%) same-day discharge patients and 2 of 312 (0.6%) overnight-stay patients (risk difference， -0.003; 95% CI， -0.014 to 0.007; P for noninferiority <0.0001). The last 3 events were related to puncture site.Conclusions--Same-day discharge after elective PCI is feasible and safe in the majority (80%) of patients selected for day-case PCI. Same-day discharge does not lead to additional complications compared with overnight stay.Key words: aftercare • angioplasty • cost-benefit analysis • day care • randomized controlled trials认领第13篇！13.Defining Obesity Cut Points in a Multiethnic Population 13.在多民族东说念主群中笃定肥壮的分界点Fahad Razak BASc， MSc， Sonia S. Anand MD， PhD， FRCP*， Harry Shannon PhD， Vladimir Vuksan PhD， Bonnie Davis RN， Ruby Jacobs RN， Koon K. Teo M***h， PhD， Matthew McQueen FRCP， Salim Yusuf MBBS， DPhil， FRCP， for the SHARE Investigators From the Population Health Research Institute (F.R.， S.S.A.， K.K.T.， M.M.， S.Y.)， Department of Medicine (S.S.A.， K.K.T.， M.M.， S.Y.)， and Department of Clinical Epidemiology and Biostatistics (S.S.A.， K.K.T.， M.M.， S.Y.)， McMaster University， Hamilton， Canada; Faculty of Medicine (F.R.) and Department of Medicine (V.V.)， University of Toronto， Toronto， Canada; and Six Nations Health Services (B.D.， R.J.)， Ohsweken， Ontario， Canada.* To whom correspondence should be addressed. E-mail: anands@mcmaster.ca .Background--Body mass index (BMI) is widely used to assess risk for cardiovascular disease and type 2 diabetes. Cut points for the classification of obesity (BMI >30 kg/m2) have been developed and validated among people of European descent. It is unknown whether these cut points are appropriate for non-European populations. We assessed the metabolic risk associated with BMI among South Asians， Chinese， Aboriginals， and Europeans.配景：BMI被庸碌用于评估心血管疾病和2型糖尿病的发病风险。恰当于欧洲东说念主群的肥壮的界说为BMI >30 kg/m2。然则该界说是否适用于非欧洲东说念主群尚不行笃定。本议论评估了BMI对南亚、中国、土著东说念主及欧洲东说念主群的代谢风险的影响。Methods and Results--We randomly sampled 1078 subjects from 4 ethnic groups (289 South Asians， 281 Chinese， 207 Aboriginals， and 301 Europeans) from 4 regions in Canada. Principal components factor analysis was used to derive underlying latent or "hidden" factors associated with 14 clinical and biochemical cardiometabolic markers. Ethnic-specific BMI cut points were derived for 3 cardiometabolic factors. Three primary latent factors emerged that accounted for 56% of the variation in markers of glucose metabolism， lipid metabolism， and blood pressure. For a given BMI， elevated levels of glucose- and lipid-related factors were more likely to be present in South Asians， Chinese， and Aboriginals compared with Europeans， and elevated levels of the blood pressure-related factor were more likely to be present among Chinese compared with Europeans. The cut point to define obesity， as defined by distribution of glucose and lipid factors， is lower by 6 kg/m2 among non-European groups compared with Europeans.设施和成果：咱们在加拿大的四个地区飞速抽取了四个不同种族的1078个样本（289个南亚东说念主，281个中国东说念主，207个土著东说念主和301个欧洲东说念主）。主成份分析设施被用来分析与14个临床和生化心血管代谢符号相干的潜在的或荫藏的影响因素。种族特异的BMI的分界点主要源于3个心血管代谢因子。三个主要的潜在影响因子离别是葡萄糖代谢，脂代谢和血压水平，这三个因素不错解说总变异的56%。对兼并个给定的BMI，南亚东说念主群、土著东说念主及中国东说念主群同欧洲东说念主群比拟具有更高的血糖以及和脂相干的因子的水平，况兼中国东说念主群的血压相干的因子要显赫高于欧洲东说念主群。非欧洲东说念主群由血糖和脂相干因子的散播决定的肥壮的分界点较欧洲东说念主群约低6 kg/m2。Conclusions--Revisions may be warranted for BMI cut points to define obesity among South Asians， Chinese， and Aboriginals. Using these revised cut points would greatly increase the estimated burden of obesity-related metabolic disorders among non-European populations.论断：应该修正南亚，中国及土著东说念主群的肥壮的BMI的分界点。使用修正后的分界点将较猛进度地造就非欧洲东说念主群肥壮相干的代谢疾病的臆度包袱。Key words: epidemiology • glucose • hypertension • lipids • obesity • risk factors关节词：流行病学• 葡萄糖 • 高血压 • 脂肪 • 肥壮 • 危急因素固然楼主这个不是4月10日的Circulation，全球相同不错认领翻译.认领4！请战友们发布4月10日论著纲领！4.Instability in the Diagnosis of Metabolic Syndrome in Adolescents 4.青少年代谢概括征会诊的不镇静性Elizabeth Goodman MD*， Stephen R. Daniels MD， PhD， James B. Meigs MD， MPH， and Lawrence M. Dolan MD From the Floating Hospital for Children at Tufts-New England Medical Center， Boston， Mass (E.G.); Department of Pediatrics， Denver Children’s Hospital， and University of Colorado School of Medicine， Denver (S.R.D.); Department of Medicine， General Medicine Division， Massachusetts General Hospital and Harvard Medical School， Boston， Mass (J.B.M.); and Division of Endocrinology， Cincinnati Children’s Hospital Medical Center， Cincinnati， Ohio (L.M.D.).* To whom correspondence should be addressed. E-mail: egoodman@tufts-nemc.org .Background--Factor analyses suggest that the structure underlying metabolic syndrome is similar in adolescents and adults. However， adolescence is a period of intense physiological change， and therefore stability of the underlying metabolic structure and clinical categorization based on metabolic risk is uncertain.配景：因子分析提醒青少年和成年东说念主代谢概括征构成结构近似。关联词91porn downloader，由于芳华期的生理改造格外热烈91porn downloader，导致代谢结构的镇静性及基于代谢危急的临床分类变得不笃定。Methods and Results--We analyzed data from 1098 participants in the Princeton School District Study， a school-based study begun in 2001-2002， who were followed up for 3 years. We performed factor analyses of 8 metabolic risks at baseline and follow-up to assess stability of factor patterns and clinical categorization of metabolic syndrome. Metabolic syndrome was defined using the current American Heart Association/National Heart， Lung， and Blood Institute definition for adults (AHA)， a modified AHA definition used in prior pediatric metabolic syndrome studies (pediatric AHA)， and the International Diabetes Federation (IDF) guidelines. We found that factor structures were essentially identical at both time points. However， clinical categorization was not stable. Approximately half of adolescents with baseline metabolic syndrome lost the diagnosis at follow-up regardless of the definitions used: pediatric AHA=56% (95% confidence interval [CI]， 42% to 69%)， AHA=49% (95% CI， 32% to 66%)， IDF=53% (95% CI， 38% to 68%). In addition to loss of the diagnosis， new cases were identified. Cumulative incidence rates were as follows: pediatric AHA=3.8% (95% CI， 2.8% to 5.2%); AHA=4.4% (95% CI， 3.3% to 5.9%); IDF=5.2% (95% CI， 4.0% to 6.8%).设施和论断：咱们分析的数据来自于普林斯顿的学校社区议论的1098个插足者，该议论是一个以学校为基础的议论，初始于2001-2002年，也曾随访了3年。咱们对基线的8个代谢因子进行了因子分析然后随访并评价因子时势和代谢概括征临床分类的镇静性。代谢概括征依据现行的好意思国腹黑协会/国度心肺血议论所成东说念主代谢概括征的界说(AHA)，该界说是一个修自新的AHA的界说，之前曾用于儿科代谢概括征议论（儿科AHA）和外洋糖尿病定约(IDF)指南。咱们发现因子结构在两个时点上基本探求。关联词，临床分类是不镇静的。不论接管何种会诊圭臬，约莫有一半的基线被定为代谢概括征的青少年随访后不邂逅诊为代谢概括征：儿科AHA=56% (95%CI， 42%-69%)，AHA=49%(95% CI， 32%-66%)， IDF=53% (95% CI， 38% to 68%)。除了有部分病例会诊隐藏外，也出现了一些新的病例。累计的发病率为：儿科AHA=3.8% (95% CI， 2.8%-5.2%)；AHA=4.4% (95% CI， 3.3%- 5.9%)；IDF=5.2% (95% CI， 4.0% to 6.8%)。Conclusions--During adolescence， metabolic risk factor clustering is consistent. However， marked instability exists in the categorical diagnosis of metabolic syndrome. This instability， which includes both gain and loss of the diagnosis， suggests that the syndrome has reduced clinical utility in adolescence and that metabolic syndrome-specific pharmacotherapy for youth may be premature.论断：芳华时间，代谢危急因子的集结是一致的。关联词，代谢概括征的分类会诊上存在显赫的不镇静性。不镇静性包括取得和失去原先的会诊，这提醒该概括征在青少年的临床应用性下落，对年青东说念主进行代谢概括征特异的药物诊治还不教训。Key words: adolescents • insulin • obesity • syndrome X关节词：青少年 胰岛素 肥壮 X概括征认领6和8.期待看到全文。谢谢应sheepthief条目，上传6和8全文。鸠集硬盘存放时辰为3天，请实时下载！！！您上传的文献： 大小 文献名 2.9M 6.pdf 也曾见效地保存在Mofile 文献提真金不怕火码： 0810807274217505 当您的一又友需要提真金不怕火此文献时只需: 匿名提真金不怕火文献连气儿 > 或登录Mofile，使用提真金不怕火码 3723711531616913 提真金不怕火文献6. Lack of the Antioxidant Enzyme Glutathione Peroxidase-1 (GPx1) Accelerates Atherosclerosis in Diabetic Apolipoprotein E-Deficient Mice 清寒抗氧化酶谷胱甘肽过氧化酶-1加快糖尿病载脂卵白E颓势小鼠的动脉粥样硬化[/color]* To whom correspondence should be addressed. E-mail: judy.dehaan@baker.edu.au .Background--Recent clinical studies have suggested a major protective role for the antioxidant enzyme glutathione peroxidase-1 (GPx1) in diabetes-associated atherosclerosis. We induced diabetes in mice deficient for both GPx1 and apolipoprotein E (ApoE) to determine whether this is merely an association or whether GPx1 has a direct effect on diabetes-associated atherosclerosis.[color=blue]配景：最近的临床议论标明抗氧化酶谷胱甘肽过氧化酶-1(GPx1)在糖尿病相干动脉粥样硬化中起主要的保护作用。咱们在GPx1和载脂卵白E颓势小鼠身上衔尾出了糖尿病，并思通过此来决定是否这只是是一种相干或是否GPx1在糖尿病相干动脉粥样硬化中具有径直作用。Methods and Results--ApoE-deficient (ApoE-/-) and ApoE/GPx1 double-knockout (ApoE-/-GPx1-/-) mice were made diabetic with streptozotocin and aortic lesion formation， and atherogenic pathways were assessed after 10 and 20 weeks of diabetes. Aortic proinflammatory and profibrotic markers were determined by both quantitative reverse-transcription polymerase chain reaction analysis after 10 weeks of diabetes and immunohistochemical analysis after 10 and 20 weeks of diabetes. Sham-injected nondiabetic counterparts served as controls. Atherosclerotic lesions within the aortic sinus region， as well as arch， thoracic， and abdominal lesions， were significantly increased in diabetic ApoE-/-GPx1-/- aortas compared with diabetic ApoE-/- aortas. This increase was accompanied by increased macrophages， -smooth muscle actin， receptors for advanced glycation end products， and various proinflammatory (vascular cell adhesion molecule-1) and profibrotic (vascular endothelial growth factor and connective tissue growth factor) markers. Quantitative reverse-transcription polymerase chain reaction analysis showed increased expression of receptors for advanced glycation end products (RAGE)， vascular cell adhesion molecule-1， vascular endothelial growth factor， and connective tissue growth factor. Nitrotyrosine levels were significantly increased in diabetic ApoE-/-GPx1-/- mouse aortas. These findings were observed despite upregulation of other antioxidants.设施和成果：诈诈骗欺链脲霉素将ApoE颓势小鼠和ApoE/GPx1双敲除小鼠衔尾出糖尿病，同期伴有主动脉毁伤造成，小鼠患糖尿病10周或20周后对其进行致动脉粥样硬化路线的分析。10周后诈欺定量RT—PCR和10或20周后诈欺免疫组化分析对主动脉促炎症响应和促纤维化符号物进行分析。打针非糖尿病性相似物手脚对照。在ApoE-/-GPx1-/- 双颓势小鼠中主动脉窦区、弓、胸主动脉和腹主动脉的毁伤齐显然高于ApoE-/-颓势小鼠。同期跟随之增多的还有巨噬细胞、平滑肌肌动卵白、高档糖化最后产品以及各式促炎症（血管细胞粘附分子-1）和促纤维化(血管内皮滋长因子和结缔组织滋长因子)符号物。定量RT-PCR分析成果标明高档糖化最后产品、血管细胞粘附分子-1、血管内皮滋长因子和结缔组织滋长因子有所增多。ApoE-/-GPx1-/-双颓势小鼠主动脉中硝基酪氨酸水平显然增多。固然其他的抗氧化剂有所上调，当上述成果仍然发生。Conclusions--Lack of functional GPx1 accelerates diabetes-associated atherosclerosis via upregulation of proinflammatory and profibrotic pathways in ApoE-/- mice. Our study provides evidence of a protective role for GPx1 and establishes GPx1 as an important antiatherogenic therapeutic target in patients with or at risk of diabetic macrovascular disease.论断：清寒功能性GPx1的ApoE-/-颓势小鼠中通过上调促炎和促纤维化路线加快了糖尿病相干动脉粥样硬化的发生。咱们的议论为GPx1的保护性作用和将GPx1手脚正处于或处在糖尿病大血管病变挟制中的病东说念主的诊治靶点提供了凭据。Key words: cardiovascular diseases • aorta • atherosclerosis • diabetes mellitus • antioxidants • free radicals8. Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice lactadherin 清寒导致小鼠凋一火细胞千里积和动脉粥样硬化的加快* To whom correspondence should be addressed. E-mail: mallat@larib.inserm.fr .Background--Atherosclerosis is an immunoinflammatory disease; however， the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood.配景：动脉粥样硬化是一种免疫调整性疾病：关联词，对在系数这个词促炎环境中起免疫调整守护作用的主要因子却知之甚少。Methods and Results--Here， we show that milk fat globule-EGF factor 8 (Mfge8， also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow-derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon- production in both the spleen and the atherosclerotic arteries. In addition， we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis.设施和成果：咱们深切的是在平素和东说念主类动脉粥样动脉均抒发的乳脂球-EGF因子8 (Mfge8，也叫 lactadherin)与腹膜巨噬细胞对凋一火细胞的并吞性取销关系。在一个鼠类动脉粥样硬化模子中，骨髓起原的Mfge8崩溃后，导致原发脂质毁伤区和全身系统试验性凋一火碎屑千里积。凋一火物资的千里积与脾内白介素10的产生减少和脾以及粥样硬化动脉内侵犯素产生的增多相干。另外，咱们报说念了自然调整性T细胞在不存在Mfge8情况下的一种树突细胞依赖的变化。这些事件齐与动脉粥样硬化的显然加快相干。Conclusions--Lack of Mfge8 in bone marrow-derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response， which leads to an acceleration of plaque development.论断：骨髓起原的细胞中清寒Mfge8加快凋一火细胞身分在粥样硬化中的千里积，况兼改造了保护性免疫响应，从而导致斑块发展的加快。Key words: atherosclerosis • apoptosis • immune system • inflammation • interleukins另外格外感谢geweili的全文濑亚美莉喷奶番号