Circulation 2010年1月5日

http://circ.ahajournals.org

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Abstract 1 of 16 (Circulation. 2010;121:14-19.)
© 2010 American Heart Association, Inc.

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Cardiovascular Surgery

Open Heart Surgery in Patients With Sickle Cell Hemoglobinopathy
Sajjad M. Yousafzai, MD; Murat Ugurlucan, MD; Omar A. Al Radhwan, MD; Amal L. Al Otaibi, CP; Charles C. Canver, MD
From King Faisal Heart Institute, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Reprint requests to Charles C. Canver, MD, King Faisal Heart Institute, MBC-16, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Kingdom of Saudi Arabia. E-mail canverc@gmail.com

Received May 28, 2009; accepted October 27, 2009.

Background— In patients with sickle cell trait or disease, reduced life expectancy and a tendency for complications are believed to negatively affect likelihood of survival after open heart surgery. The aim of this study was to review retrospectively the perioperative results of patients undergoing cardiac surgery at our institution.

Methods and Results— Between January 1995 and December 2006, 47 patients with either sickle cell disease or sickle cell trait underwent open heart surgery at our institution. The average age of the 29 male and 18 female patients was 20 years. Patient outcomes were analyzed through the use of the institutional database. Clinical and echocardiographic follow-up was complete in all patients except 3, with a mean follow-up period of 46 months. Current status could be confirmed in 32 patients. The most common operations included the treatment of congenital and valvular heart diseases. There were no coronary artery bypass grafting procedures. Average weight of the patients was 45 kg. Exchange transfusion was performed both preoperatively and during surgery. Mean preoperative hemoglobin S concentration was 30.4±3.2% and decreased to 8.1±2.6% while on pump. Average on-pump hematocrit value was 25.4±3.7%; in the postoperative period, it increased to 32.7±4.9%. Mean cardiopulmonary bypass and cross-clamp times were 95 and 69 minutes, respectively. None of the patients had sickling crisis or acidosis. Postoperative complications included exploration for hemorrhage in 3 patients (6.4%), stroke in 2 patients (4.3%), renal failure in 2 patients (4.3%), and prolonged ventilation in 1 patient (2.1%). Average hospital stay was 8.3 days (range, 4 to 27 days). Early in-hospital death occurred in 1 patient (2.1%); currently, 31 patients (66%) remain alive and free of cardiac symptoms.

Conclusion— Heart valve surgery and surgery for congenital heart diseases can be performed safely in patients with sickle cell disease or sickle cell trait with acceptable outcome and survival rates.

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Abstract 2 of 16 (Circulation. 2010;121:20-25.)
© 2010 American Heart Association, Inc.

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Congenital Heart Disease

Improved Survival Among Patients With Eisenmenger Syndrome Receiving Advanced Therapy for Pulmonary Arterial Hypertension
Konstantinos Dimopoulos, MD, MSc, PhD, FESC*; Ryo Inuzuka, MD*; Sara Goletto, MD; Georgios Giannakoulas, MD, PhD, FESC; Lorna Swan, MD, MRCP; Stephen J. Wort, BA, MBBS, MRCP, PhD; Michael A. Gatzoulis, MD, PhD, FESC
From the Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK (K.D., R.I., S.G., G.G., L.S., S.J.W., M.A.G.); and National Heart and Lung Institute, Imperial College School of Medicine, London, UK (K.D., M.A.G.).

Reprint requests to Professor Michael A. Gatzoulis, Royal Brompton Hospital, Sydney St, London, SW3 6NP, UK. E-mail M.Gatzoulis@rbht.nhs.uk

Received June 1, 2009; accepted November 2, 2009.

Background— Advanced therapy (AT) for pulmonary arterial hypertension in the context of congenital heart disease (Eisenmenger syndrome) improves pulmonary hemodynamics, functional class, and the 6-minute walk test. We examined the potential effect of AT on survival in this population.

Methods and Results— Data on all Eisenmenger patients attending our center over the past decade were collected. Survival rates were compared between patients on and off AT with the use of a modified version of the Cox model, which treats AT as a time-varying covariate. Baseline differences were adjusted for the use of propensity scores. A total of 229 patients (aged 34.5±12.6 years; 35.4% male) were included. The majority had complex anatomy, and 53.7% were in New York Heart Association class III at baseline assessment. Mean resting saturations were 84.3%. Sixty-eight patients (29.7%) either were on AT or had AT initiated during follow-up. During a median follow-up of 4.0 years, 52 patients died, only 2 of them while on AT. Patients on AT were at a significantly lower risk of death, both unadjusted and after adjustment for baseline clinical differences by propensity score regression adjustment (C statistic=0.80; hazard ratio, 0.16; 95% confidence interval, 0.04 to 0.71; P=0.015) and propensity score matching (hazard ratio, 0.10; 95% confidence interval, 0.01 to 0.78; P=0.028).

Conclusions— AT for pulmonary arterial hypertension in a contemporary cohort of adults with Eisenmenger syndrome was associated with a lower risk of death. Survival benefits should be considered together with improved hemodynamics and functional class when decisions are made about AT in this population.

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Abstract 3 of 16 (Circulation. 2010;121:26-33.)
© 2010 American Heart Association, Inc.

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Congenital Heart Disease

Brain Volume and Metabolism in Fetuses With Congenital Heart Disease
Evaluation With Quantitative Magnetic Resonance Imaging and Spectroscopy
Catherine Limperopoulos, PhD; Wayne Tworetzky, MD; Doff B. McElhinney, MD; Jane W. Newburger, MD, MPH; David W. Brown, MD; Richard L. Robertson, Jr, MD; Nicolas Guizard, MEng; Ellen McGrath, BSc, RN; Judith Geva, MSW; David Annese, RT(R); Carolyn Dunbar-Masterson, BSc, RN; Bethany Trainor, BSc, RN; Peter C. Laussen, MD; Adré J. du Plessis, MBChB, MPH
From the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (C.L., N.G.); and Fetal-Neonatal Neurology Research Group, Department of Neurology (C.L., A.J.d.P.), and Departments of Cardiology and Pediatrics (W.T., D.B.M., J.W.N., D.W.B., E.M., J.G., D.A., C.D.-M., B.T.), Radiology (R.L.R.), and Cardiology and Anaesthesia (P.C.L.), Children’s Hospital Boston and Harvard Medical School, Boston, Mass.

Correspondence to Catherine Limperopoulos, PhD, Montreal Children’s Hospital, Pediatric Neurology, 2300 Tupper St A-334, Montreal, Quebec, H3H 1P3, Canada. E-mail catherine.limperopoulos@mcgill.ca

Received December 12, 2008; accepted October 5, 2009.

Background— Adverse neurodevelopmental outcome is an important source of morbidity in children with congenital heart disease (CHD). A significant proportion of newborns with complex CHD have abnormalities of brain size, structure, or function, which suggests that antenatal factors may contribute to childhood neurodevelopmental morbidity.

Methods and Results— Brain volume and metabolism were compared prospectively between 55 fetuses with CHD and 50 normal fetuses with the use of 3-dimensinal volumetric magnetic resonance imaging and proton magnetic resonance spectroscopy. Fetal intracranial cavity volume, cerebrospinal fluid volume, and total brain volume were measured by manual segmentation. Proton magnetic resonance spectroscopy was used to measure the cerebral N-acetyl aspartate: choline ratio (NAA:choline) and identify cerebral lactate. Complete fetal echocardiograms were performed. Gestational age at magnetic resonance imaging ranged from 25 to 37 weeks (median, 30 weeks). During the third trimester, there were progressive and significant declines in gestational age–adjusted total brain volume and intracranial cavity volume in CHD fetuses relative to controls. NAA:choline increased progressively over the third trimester in normal fetuses, but the rate of rise was significantly slower (P<0.001) in CHD fetuses. On multivariable analysis adjusted for gestational age and weight percentile, cardiac diagnosis and percentage of combined ventricular output through the aortic valve were independently associated with total brain volume. Independent predictors of lower NAA:choline included diagnosis, absence of antegrade aortic arch flow, and evidence of cerebral lactate (P<0.001).

Conclusions— Third-trimester fetuses with some forms of CHD have smaller gestational age– and weight-adjusted total brain volumes than normal fetuses and evidence of impaired neuroaxonal development and metabolism. Hemodynamic factors may play an important role in this abnormal development.

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Abstract 4 of 16 (Circulation. 2010;121:34-42.)
© 2010 American Heart Association, Inc.

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Congenital Heart Disease

Laboratory Measures of Exercise Capacity and Ventricular Characteristics and Function Are Weakly Associated With Functional Health Status After Fontan Procedure
Brian W. McCrindle, MD, MPH; Victor Zak, PhD; Lynn A. Sleeper, ScD; Stephen M. Paridon, MD; Steven D. Colan, MD; Tal Geva, MD; Lynn Mahony, MD; Jennifer S. Li, MD; Roger E. Breitbart, MD; Renee Margossian, MD; Richard V. Williams, MD; Welton M. Gersony, MD; Andrew M. Atz, MD, for the Pediatric Heart Network Investigators
From the Hospital for Sick Children, University of Toronto, Toronto, Canada (B.W.M.), New England Research Institutes, Watertown, Mass (V.Z., L.A.S.); Children’s Hospital of Philadelphia, Philadelphia, Pa (S.M.P.); Children’s Hospital Boston, Boston, Mass (S.D.C., R.E.B., R.M., T.G.); University of Texas Southwestern Medical Center, Dallas (L.M.); Duke University Medical Center, Durham, NC (J.S.L.); University of Utah, Salt Lake City (R.V.W.); Columbia University Medical Center, New York, NY (W.M.G.); and Medical University of South Carolina, Charleston (A.M.A.).

Correspondence to Dr Brian McCrindle, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail brian.mccrindle@sickkids.ca

Received April 1, 2009; accepted October 23, 2009.

Background— Patients after the Fontan procedure are at risk for suboptimal functional health status, and associations with laboratory measures are important for planning interventions and outcome measures for clinical trials.

Methods and Results— Parents completed the generic Child Health Questionnaire for 511 Fontan Cross-Sectional Study patients 6 to 18 years of age (61% male). Associations of Child Health Questionnaire Physical and Psychosocial Functioning Summary Scores (FSS) with standardized measurements from prospective exercise testing, echocardiography, magnetic resonance imaging, and measurement of brain natriuretic peptide were determined by regression analyses. For exercise variables for maximal effort patients only, the final model showed that higher Physical FSS was associated only with higher maximum work rate, accounting for 9% of variation in Physical FSS. For echocardiography, lower Tei index (particularly for patients with extracardiac lateral tunnel connections), lower indexed end-systolic volume, and the absence of atrioventricular valve regurgitation for patients having Fontan procedure at age <2 years were associated with higher Physical FSS, accounting for 14% of variation in Physical FSS. For magnetic resonance imaging, ratio of lower mass to end-diastolic volume and midquartiles of indexed end-systolic volume (nonlinear) were associated with higher Physical FSS, accounting for 11% of variation. Lower brain natriuretic peptide was significantly but weakly associated with higher Physical FSS (1% of variation). Significant associations for Psychosocial FSS with laboratory measures were fewer and weaker than for Physical FSS.

Conclusions— In relatively healthy Fontan patients, laboratory measures account for a small proportion of the variation in functional health status and therefore may not be optimal surrogate end points for trials of therapeutic interventions.

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Abstract 5 of 16 (Circulation. 2010;121:43-51.)
© 2010 American Heart Association, Inc.

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Coronary Heart Disease

Prognostic Modeling of Individual Patient Risk and Mortality Impact of Ischemic and Hemorrhagic Complications
Assessment From the Acute Catheterization and Urgent Intervention Triage Strategy Trial
Stuart J. Pocock, PhD; Roxana Mehran, MD; Tim C. Clayton, MSc; Eugenia Nikolsky, MD, PhD; Helen Parise, ScD; Martin Fahy, MSc; Alexandra J. Lansky, MD; Michel E. Bertrand, MD; A. Michael Lincoff, MD; Jeffrey W. Moses, MD; E. Magnus Ohman, MD; Harvey D. White, MD, DSc; Gregg W. Stone, MD
From the London School of Hygiene and Tropical Medicine, London, UK (S.J.P., T.C.C.); Columbia University Medical Center and Cardiovascular Research Foundation, New York, NY (R.M., E.N., H.P., M.F., A.J.L., J.W.M., G.W.S.); Hopital Cardiologique, Lille, France (M.E.B.); The Cleveland Clinic, Cleveland, Ohio (A.M.L.); Duke University Medical Center, Durham, NC (E.M.O.); and Auckland City Hospital, Auckland, New Zealand (H.D.W.).

Correspondence to Stuart J. Pocock, PhD, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. E-mail Stuart.Pocock@lshtm.ac.uk

Received May 7, 2009; accepted October 2, 2009.

Background— Both ischemic and hemorrhagic complications increase mortality rate in acute coronary syndromes. Their frequency and relative importance vary according to individual patient risk profiles. We sought to develop prognostic models for the risk of myocardial infarction (MI) and major bleeding to assess their impact on risk of death and to examine the manner in which alternative antithrombotic regimens affect these risks in individual patients.

Methods and Results— The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial randomized 13 819 patients with acute coronary syndrome to heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. By logistic regression, there were 5 independent predictors of MI within 30 days (n=705; 5.1%) and 8 independent predictors of major bleeding (n=645; 4.7%), only 2 of which were common to both event types. In a covariate-adjusted, time-updated Cox regression model, both MI and major bleeding significantly affected subsequent mortality rate (hazard ratios, 2.7 and 2.9, respectively; both P<0.001). Treatment with bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor was associated with a nonsignificant 8% increase in MI and a highly significant 50% decrease in major bleeding. Given the individual patient risk profiles and the fact that bivalirudin prevented 6 major bleeds for each MI that might occur from its use, the estimated reduction in bleeding was greater than the estimated increase in MI by bivalirudin alone rather than heparin plus a glycoprotein IIb/IIIa inhibitor for nearly all patients.

Conclusions— Consideration of the individual patient risk profile for MI and major bleeding and the relative treatment effects of alternative pharmacotherapies permits personalized decision making to optimize therapy of patients with acute coronary syndrome.

Clinical Trial Registration— clinicaltrials.gov Identifier: NCT00093158.

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Abstract 6 of 16 (Circulation. 2010;121:52-62.)
© 2010 American Heart Association, Inc.

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Genetics

Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms
Reecha Sofat, MRCP*; Aroon D. Hingorani, PhD, FRCP*; Liam Smeeth, MRCGP, PhD; Steve E. Humphries, PhD, MRCP, FRCPath; Philippa J. Talmud, PhD; Jackie Cooper, MSc; Tina Shah, PhD; Manjinder S. Sandhu, PhD; Sally L. Ricketts, PhD; S. Matthijs Boekholdt, MD, PhD; Nicholas Wareham, MBBS, FRCP; Kay Tee Khaw, M***h, FRCP; Meena Kumari, PhD; Mika Kivimaki, PhD; Michael Marmot, PhD, FRCP; Folkert W. Asselbergs, MD, PhD; Pim van der Harst, MD, PhD; Robin P.F. Dullaart, MD, PhD; Gerjan Navis, MD, PhD; Dirk J. van Veldhuisen, MD, PhD; Wiek H. Van Gilst, PhD; John F. Thompson, PhD; Pamela McCaskie, PhD; Lyle J. Palmer, PhD; Marcello Arca, MD; Fabiana Quagliarini, MSc; Carlo Gaudio, MD; François Cambien, MD; Viviane Nicaud, MA; Odette Poirer, PhD; Vilmundur Gudnason, MD, PhD; Aaron Isaacs, PhD; Jacqueline C.M. Witteman, PhD; Cornelia M. van Duijn, PhD; Michael Pencina, PhD; Ramachandran S. Vasan, MD; Ralph B. D'Agostino, Sr, PhD; Jose Ordovas, PhD; Tricia Y. Li, MSc; Sakari Kakko, MD, PhD; Heikki Kauma, MD, PhD; Markku J. Savolainen, MD, PhD; Y. Antero Kesäniemi, MD, PhD; Anton Sandhofer, MD; Bernhard Paulweber, MD; Jose V. Sorli, MD, PhD; Akimoto Goto, MD, PhD; Shinji Yokoyama, MD, PhD, FRCPC; Kenji Okumura, MD, PhD; Benjamin D. Horne, MPH, PhD; Chris Packard, DSc; Dilys Freeman, BSc, PhD; Ian Ford, PhD; Naveed Sattar, PhD, FRCPath; Valerie McCormack, PhD; Debbie A. Lawlor, PhD; Shah Ebrahim, DM, MSc, FFPHM; George Davey Smith, MD, DSc, FFPHM; John J.P. Kastelein, MD, PhD; John Deanfield, BA, BCh, MB, FRCP; Juan P. Casas, MD, PhD
From the Centre for Clinical Pharmacology, Department of Medicine (R.S., A.D.H., T.S.), Department of Epidemiology and Public Health (A.D.H., M. Kumari, M. Kivimaki, M.M., J.P.C.), and Centre for Cardiovascular Genetics (S.E.H., P.J.T., J.C.), University College London, London, United Kingdom; Department of Epidemiology and Population Health (L.S., V.M., S.E., J.P.C.), London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Public Health and Primary Care (M.S.S., S.L.R., S.M.B.), Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom; MRC Epidemiology Unit (N.W.), Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom; Department of Clinical Gerontology (K.T.K.), University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom; Departments of Cardiology, Endocrinology, and Nephrology (F.W.A., P.v.d.H., R.P.F.D., G.N., D.J.v.V., W.H.V.G.), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Helicos BioSciences (J.F.T.), Cambridge, Mass; Centre for Genetic Epidemiology and Biostatistics (P.M., L.J.P.), University of Western Australia, Perth, Australia; Dipartimento di Clinica e Terapia Medica (M.A., F.Q.) and Dipartimento Cuore e Grossi Vasi Attilio Reale (C.G.), La Sapienza Università di Roma, Rome, Italy; INSERM UMRS 937, Université Pierre et Marie Curie–Paris 6 (F.C., V.N.), Paris, France; INSERM UMRS 956, Université Pierre et Marie Curie–Paris 6 (O.P.), Paris, France; University of Iceland (V.G.), Reykjavik, Iceland; Department of Epidemiology and Biostatistics (A.I., J.C.M.W., C.M.v.D.), Erasmus MC, Rotterdam, the Netherlands; Boston University (F.W.A., M.P., R.S.V., R.B.D., J.O.), Department of Mathematics and School of Medicine, Boston, Mass; Department of Nutrition (T.Y.L.), Harvard School of Public Health, Boston, Mass; Institute of Clinical Medicine (S.K., H.K., M.J.S., Y.A.K.), Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland; Department of Internal Medicine I (A.S.), Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine (B.P.), Clinical Division of General Internal Medicine, University of Innsbruck Austria/Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria; Preventive Medicine Department (J.V.S.), University of Valencia, Spain and CIBER Fisiopatologia de la Obesidad y Nutricion (ISCIII); Cardiovascular Division (A.G.), JA Aichi Bisai Hospital, Sobuecho, Inazawa, Japan; Biochemistry (S.Y.), Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Cardiovascular Research Medicine (K.O.), Nagoya University School of Medicine, Nagoya, Japan; Cardiovascular Department (B.D.H.), Intermountain Medical Centre/Department of Biomedical Informatics, University of Utah, Murray, Utah; Glasgow Royal Infirmary (C.P., D.F.), Glasgow, United Kingdom; Robertson Centre for Biostatistics (I.F.) and Faculty of Medicine (N.S.), BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; Lifestyle and Cancer Group (V.M.), International Agency for Research on Cancer, Lyon, France; MRC Centre of Causal Analyses in Translational Epidemiology (D.A.L., G.D.S.), Department of Social Medicine, University of Bristol, United Kingdom; Department of Vascular Medicine (J.J.P.K., S.M.B.), Academic Medical Centre, Meibergdreef, Amsterdam, the Netherlands; and Vascular Physiology Unit (J.D.), UCL Institute of Child Health, London, United Kingdom.

Correspondence to Professor Aroon Hingorani, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom (e-mail a.hingorani@ucl.ac.uk), or to Dr Juan P Casas, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom (e-mail Juan.Pablo-Casas@lshtm.ac.uk).

Received March 17, 2009; accepted October 20, 2009.

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target.

Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib.

Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

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Abstract 7 of 16 (Circulation. 2010;121:63-70.)
© 2010 American Heart Association, Inc.

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Health Services and Outcomes Research

Relationship Between Cardiac Rehabilitation and Long-Term Risks of Death and Myocardial Infarction Among Elderly Medicare Beneficiaries
Bradley G. Hammill, MS; Lesley H. Curtis, PhD; Kevin A. Schulman, MD; David J. Whellan, MD, MHS
From Duke Clinical Research Institute (B.G.H., L.H.C., K.A.S., D.J.W.) and Department of Medicine (L.H.C., K.A.S.), Duke University School of Medicine, Durham, NC; and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa (D.J.W.).

Correspondence to Bradley G. Hammill, MS, Center for Clinical and Genetic Economics, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail brad.hammill@duke.edu

Received April 28, 2009; accepted September 21, 2009.

Background— For patients with coronary heart disease, exercise-based cardiac rehabilitation improves survival rate and has beneficial effects on risk factors for coronary artery disease. The relationship between the number of sessions attended and long-term outcomes is unknown.

Methods and Results— In a national 5% sample of Medicare beneficiaries, we identified 30 161 elderly patients who attended at least 1 cardiac rehabilitation session between January 1, 2000, and December 31, 2005. We used a Cox proportional hazards model to estimate the relationship between the number of sessions attended and death and myocardial infarction (MI) at 4 years. The cumulative number of sessions was a time-dependent covariate. After adjustment for demographic characteristics, comorbid conditions, and subsequent hospitalization, patients who attended 36 sessions had a 14% lower risk of death (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77 to 0.97) and a 12% lower risk of MI (HR, 0.88; 95% CI, 0.83 to 0.93) than those who attended 24 sessions; a 22% lower risk of death (HR, 0.78; 95% CI, 0.71 to 0.87) and a 23% lower risk of MI (HR, 0.77; 95% CI, 0.69 to 0.87) than those who attended 12 sessions; and a 47% lower risk of death (HR, 0.53; 95% CI, 0.48 to 0.59) and a 31% lower risk of MI (HR, 0.69; 95% CI, 0.58 to 0.81) than those who attended 1 session.

Conclusions— Among Medicare beneficiaries, a strong dose–response relationship existed between the number of cardiac rehabilitation sessions and long-term outcomes. Attending all 36 sessions reimbursed by Medicare was associated with lower risks of death and MI at 4 years compared with attending fewer sessions.

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Abstract 8 of 16 (Circulation. 2010;121:71-79.)
© 2010 American Heart Association, Inc.

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Health Services and Outcomes Research

Cost-Effectiveness of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndromes and Planned Percutaneous Coronary Intervention
Results From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction TRITON-TIMI 38
Elizabeth M. Mahoney, ScD; Kaijun Wang, PhD; Suzanne V. Arnold, MD, MHA; Irina Proskorovsky, BSc; Stephen Wiviott, MD; Elliott Antman, MD; Eugene Braunwald, MD; David J. Cohen, MD, MSc
From Saint Luke’s Mid America Heart Institute, Kansas City, Mo (E.M.M., K.W., S.V.A., D.J.C.); University of Missoun - Kansas City School of Medicine (E.M.M., D.J.C.); United BioSource Corporation, Dorval, Quebec, Canada (I.P.); and TIMI Study Group, Brigham and Women’s Hospital, Boston, Mass (S.W., E.A., E.B.).

Correspondence to Elizabeth M. Mahoney, ScD, Saint Luke’s Mid America Heart Institute, 4401 Wornall Rd, Kansas City, MO 64111. E-mail emahoney1@saint-lukes.org

Received August 10, 2009; accepted October 29, 2009.

Background— In patients with acute coronary syndromes and planned percutaneous coronary intervention, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) demonstrated that treatment with prasugrel versus clopidogrel was associated with reduced rates of cardiovascular death, MI, or stroke and an increased risk of major bleeding. We evaluated the cost-effectiveness of prasugrel versus clopidogrel from the perspective of the US healthcare system by using data from TRITON-TIMI 38.

Methods and Results— Detailed resource use data were prospectively collected for all patients recruited from 8 countries (United States, Australia, Canada, Germany, Italy, Spain, United Kingdom, and France; n=3373 prasugrel, n=3332 clopidogrel). Hospitalization costs were estimated on the basis of diagnosis-related group and in-hospital complications. Cardiovascular medication costs were estimated by using net wholesale prices (clopidogrel=$4.62/d; prasugrel=$5.45/d). Life expectancy was estimated from in-trial cardiovascular and bleeding events with the use of statistical models of long-term survival from a similar population from the Saskatchewan Health Database. Over a median follow-up of 14.7 months, average total costs (including study drug) were $221 per patient lower with prasugrel (95% confidence interval, –759 to 299), largely because of a lower rate of rehospitalization involving percutaneous coronary intervention. Prasugrel was associated with life expectancy gains of 0.102 years (95% confidence interval, 0.030 to 0.180), primarily because of the decreased rate of nonfatal MI. Thus, compared with clopidogrel, prasugrel was an economically dominant treatment strategy. If a hypothetical generic cost for clopidogrel of $1/d is used, the incremental net cost with prasugrel was $996 per patient, yielding an incremental cost-effectiveness ratio of $9727 per life-year gained.

Conclusion— Among acute coronary syndrome patients with planned percutaneous coronary intervention, treatment with prasugrel versus clopidogrel for up to 15 months is an economically attractive treatment strategy.

Clinical Trial Registration— clinicaltrials.gov. Unique identifier: NCT00097591.

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Abstract 9 of 16 (Circulation. 2010;121:80-90.)
© 2010 American Heart Association, Inc.

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Molecular Cardiology

Myocardial Ischemia/Reperfusion Injury Is Mediated by Leukocytic Toll-Like Receptor-2 and Reduced by Systemic Administration of a Novel Anti–Toll-Like Receptor-2 Antibody
Fatih Arslan, MD; Mirjam B. Smeets, PhD; Luke A.J. O'Neill, PhD; Brian Keogh, PhD; Peter McGuirk, PhD; Leo Timmers, MD, PhD; Claudia Tersteeg, MSc; Imo E. Hoefer, MD, PhD; Pieter A. Doevendans, MD, PhD; Gerard Pasterkamp, MD, MSc, PhD; Dominique P.V. de Kleijn, PhD
From the Laboratory of Experimental Cardiology, University Medical Center Utrecht (F.A., M.B.S., L.T., C.T., I.E.H., P.A.D., G.P., D.P.V.d.K.), and Interuniversity Cardiology Institute of the Netherlands (F.A., P.A.D., G.P., D.P.V.d.K.), Utrecht, the Netherlands; School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland (L.A.J.O.); and Opsona Therapeutics Ltd, Trinity Centre for Health Sciences, St James Hospital, Dublin 8, Ireland (B.K., P.M.).

Correspondence to D.P.V. de Kleijn, PhD, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail d.dekleijn@umcutrecht.nl

Received May 14, 2009; accepted October 19, 2009.

Background— Reperfusion therapy for myocardial infarction is hampered by detrimental inflammatory responses partly via Toll-like receptor (TLR) activation. Targeting TLR signaling may optimize reperfusion therapy and enhance cell survival and heart function after myocardial infarction. Here, we evaluated the role of TLR2 as a therapeutic target using a novel monoclonal anti-TLR2 antibody.

Method and Results— Mice underwent 30 minutes of ischemia followed by reperfusion. Compounds were administered 5 minutes before reperfusion. Cardiac function and dimensions were assessed at baseline and 28 days after infarction with 9.4-T mouse magnetic resonance imaging. Saline and IgG isotype treatment resulted in 34.5±3.3% and 31.4±2.7% infarction, respectively. Bone marrow transplantation experiments between wild-type and TLR2-null mice revealed that final infarct size is determined by circulating TLR2 expression. A single intravenous bolus injection of anti-TLR2 antibody reduced infarct size to 18.9±2.2% (P=0.001). Compared with saline-treated mice, anti-TLR2–treated mice exhibited less expansive remodeling (end-diastolic volume 68.2±2.5 versus 76.8±3.5 µL; P=0.046) and preserved systolic performance (ejection fraction 51.0±2.1% versus 39.9±2.2%, P=0.009; systolic wall thickening 3.3±6.0% versus 22.0±4.4%, P=0.038). Anti-TLR2 treatment significantly reduced neutrophil, macrophage, and T-lymphocyte infiltration. Furthermore, tumor necrosis factor-, interleukin-1, granulocyte macrophage colony-stimulating factor, and interleukin-10 were significantly reduced, as were phosphorylated c-jun N-terminal kinase, phosphorylated p38 mitogen-activated protein kinase, and caspase 3/7 activity levels.

Conclusions— Circulating TLR2 expression mediates myocardial ischemia/reperfusion injury. Antagonizing TLR2 just 5 minutes before reperfusion reduces infarct size and preserves cardiac function and geometry. Anti-TLR2 therapy exerts its action by reducing leukocyte influx, cytokine production, and proapoptotic signaling. Hence, monoclonal anti-TLR2 antibody is a potential candidate as an adjunctive for reperfusion therapy in patients with myocardial infarction.

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Abstract 10 of 16 (Circulation. 2010;121:91-97.)
© 2010 American Heart Association, Inc.

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Resuscitation Science

Dispatcher-Assisted Cardiopulmonary Resuscitation
Risks for Patients Not in Cardiac Arrest
Lindsay White, MPH; Joseph Rogers, MS; Megan Bloomingdale; Carol Fahrenbruch, MSPH; Linda Culley, BA; Cleo Subido, RPL; Mickey Eisenberg, MD, PhD; Thomas Rea, MD, MPH
From Public Health Seattle–King County, Emergency Medical Services Division (L.W., M.B., C.F., L.C., C.S., M.E., T.R.), and the University of Washington, Department of Medicine (J.R., M.B., M.E., T.R.), Seattle.

Correspondence to Lindsay White, MPH, Emergency Medical Services Division, Public Health Seattle-King County, 401 Fifth Ave, Suite 1200, Seattle, WA 98104. E-mail lindsay.white@kingcounty.gov

Received April 9, 2009; accepted September 21, 2009.

Background— Dispatcher-assisted cardiopulmonary resuscitation (CPR) instructions can increase bystander CPR and thereby increase the rate of survival from cardiac arrest. The risk of bystander CPR for patients not in arrest is uncertain and has implications for how assertive dispatch is in instructing CPR. We determined the frequency of dispatcher-assisted CPR for patients not in arrest and the frequency and severity of injury related to chest compressions.

Methods and Results— The investigation was a prospective cohort study of adult patients not in cardiac arrest for whom dispatchers provided CPR instructions in King County, Washington, between June 1, 2004, and January 31, 2007. The study focused on those who received chest compressions. Information was collected through review of the audio and written dispatch report, written emergency medical services report, hospital record, and telephone survey. Of the 1700 patients for whom dispatcher CPR instructions were initiated, 55% (938 of 1700) were in arrest, 45% (762 of 1700) were not in arrest, and 18% (313 of 1700) were not in arrest and received bystander chest compressions. Of the 247 not in arrest who received chest compressions and had complete outcome ascertainment, 12% (29 of 247) experienced discomfort, and 2% (6 of 247) sustained injuries likely or possibly caused by bystander CPR. Only 2% (5 of 247) suffered a fracture, and no patients suffered visceral organ injury.

Conclusions— In this prospective study, the frequency of serious injury related to dispatcher-assisted bystander CPR among nonarrest patients was low. When coupled with the established benefits of bystander CPR among those with arrest, these results support an assertive program of dispatcher-assisted CPR.

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CLINICAL PERSPECTIVE
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Abstract 11 of 16 (Circulation. 2010;121:151-156.)
© 2010 American Heart Association, Inc.

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Valvular Heart Disease

Natural History of Very Severe Aortic Stenosis
Raphael Rosenhek, MD; Robert Zilberszac; Michael Schemper, PhD; Martin Czerny, MD; Gerald Mundigler, MD; Senta Graf, MD; Jutta Bergler-Klein, MD; Michael Grimm, MD; Harald Gabriel, MD; Gerald Maurer, MD
From the Department of Cardiology (R.R., R.Z., G.M., S.G., J.B.-K., H.G., G.M.), Department of Medical Statistics and Informatics, Section of Clinical Biometrics (M.S.), and Department of Cardiac Surgery (M.C., M.G.), Medical University of Vienna, Vienna, Austria.

Correspondence to Raphael Rosenhek, MD, Department of Cardiology, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail raphael.rosenhek@meduniwien.ac.at

Received July 14, 2009; accepted November 4, 2009.

Background— We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis.

Methods and Results— We prospectively followed 116 consecutive asymptomatic patients (57 women; age, 67±16 years) with very severe isolated aortic stenosis defined by a peak aortic jet velocity (**-Vel) 5.0 m/s (average **-Vel, 5.37±0.35 m/s; valve area, 0.63±0.12 cm2). During a median follow-up of 41 months (interquartile range, 26 to 63 months), 96 events occurred (indication for aortic valve replacement, 90; cardiac deaths, 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. **-Vel but not aortic valve area was shown to independently affect event-free survival. Patients with an **-Vel 5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively, compared with 76%, 43%, 33%, and 17% for patients with an **-Vel between 5.0 and 5.5 m/s (P<0.0001). Six cardiac deaths occurred in previously asymptomatic patients (sudden death, 1; congestive heart failure, 4; myocardial infarction, 1). Patients with an initial **-Vel 5.5 m/s had a higher likelihood (52%) of severe symptom onset (New York Heart Association or Canadian Cardiovascular Society class >II) than those with an **-Vel between 5.0 and 5.5 m/s (27%; P=0.03).

Conclusions— Despite being asymptomatic, patients with very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration. Early elective valve replacement surgery should therefore be considered in these patients.

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CLINICAL PERSPECTIVE
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Abstract 12 of 16 (Circulation. 2010;121:143-150.)
© 2010 American Heart Association, Inc.

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Stroke

Rosuvastatin in the Prevention of Stroke Among Men and Women With Elevated Levels of C-Reactive Protein
Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)
Brendan M. Everett, MD, MPH; Robert J. Glynn, ScD; Jean G. MacFadyen, BA; Paul M Ridker, MD, MPH
From the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (B.M.E., R.J.G., J.G.M., P.M.R.), and the Cardiovascular Medicine Division (B.M.E., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Brendan M. Everett, MD, MPH, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave, Boston, MA 02215. E-mail beverett@partners.org

Received April 21, 2009; accepted November 2, 2009.

Background— Prior primary prevention trials of statin therapy that used cholesterol criteria for enrollment have not reported significant decreases in stroke risk. We evaluated whether statin therapy might reduce stroke rates among individuals with low levels of cholesterol but elevated levels of high-sensitivity C-reactive protein.

Methods and Results— In Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), 17 802 apparently healthy men and women with low-density lipoprotein cholesterol levels <130 mg/dL and high-sensitivity C-reactive protein levels 2.0 mg/L were randomly allocated to rosuvastatin 20 mg daily or placebo and then followed up for the occurrence of a first stroke. After a median follow-up of 1.9 years (maximum, 5.0 years), rosuvastatin resulted in a 48% reduction in the hazard of fatal and nonfatal stroke as compared with placebo (incidence rate, 0.18 and 0.34 per 100 person-years of observation, respectively; hazard ratio 0.52; 95% confidence interval, 0.34 to 0.79; P=0.002), a finding that was consistent across all examined subgroups. This finding was due to a 51% reduction in the rate of ischemic stroke (hazard ratio, 0.49; 95% confidence interval, 0.30 to 0.81; P=0.004), with no difference in the rates of hemorrhagic stroke between the active and placebo arms (hazard ratio, 0.67; 95% confidence interval, 0.24 to 1.88; P=0.44).

Conclusion— Rosuvastatin reduces by more than half the incidence of ischemic stroke among men and women with low levels of low-density lipoprotein cholesterol levels who are at risk because of elevated levels of high-sensitivity C-reactive protein.

Clinical Trial Registration— clinicaltrial.gov. Unique identifier: NCT00239681.

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CLINICAL PERSPECTIVE
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Abstract 13 of 16 (Circulation. 2010;121:98-109.)
© 2010 American Heart Association, Inc.

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Vascular Medicine

Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase–Dependent Nitric Oxide Generation
Brian S. Zuckerbraun, MD*; Sruti Shiva, PhD*; Emeka Ifedigbo, BA; Michael A. Mathier, MD; Kevin P. Mollen, MD; Jayashree Rao, BS; Philip M. Bauer, PhD; Justin J.W. Choi; Erin Curtis, BA; Augustine M.K. Choi, MD; Mark T. Gladwin, MD
From the Department of Surgery (B.S.Z., K.P.M., J.R., P.M.B.), Department of Pharmacology and Chemical Biology (S.S.), Division of Pulmonary, Allergy, and Critical Care Medicine (E.I., J.J.W.C., A.M.K.C., M.T.G.), and Division of Cardiology (M.A.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pa; VA Pittsburgh Health Care System, Pittsburgh, Pa (B.S.Z.); Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (S.S., J.J.W.C., E.C., M.T.G.); and Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (E.I., A.M.K.C.).

Correspondence to Dr Augustine M.K. Choi, Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115 (e-mail amchoi@rics.bwh.harvard.edu); or Dr Mark T. Gladwin, Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, NW628 MUH, 3459 Fifth Ave, Pittsburgh, PA 15213 (e-mail gladwinmt@upmc.edu).

Received November 25, 2008; accepted October 19, 2009.

Background— Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension.

Methods and Results— We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide–dependent induction of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well.

Conclusion— These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension.

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CLINICAL PERSPECTIVE
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Abstract 14 of 16 (Circulation. 2010;121:110-122.)
© 2010 American Heart Association, Inc.

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Vascular Medicine

Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy
Sajoscha A. Sorrentino, MD*; Christian Besler, MD*; Lucia Rohrer, PhD; Martin Meyer, MD; Kathrin Heinrich, BS; Ferdinand H. Bahlmann, MD, PhD; Maja Mueller, BS; Tibor Horváth, BS; Carola Doerries, DVM; Mariko Heinemann, BS; Stella Flemmer, BS; Andrea Markowski, BS; Costantina Manes, MD; Matthias J. Bahr, MD; Hermann Haller, MD; Arnold von Eckardstein, MD; Helmut Drexler, MD; Ulf Landmesser, MD
From Klinik für Kardiologie und Angiologie (S.A.S., C.B., M. Meyer, M. Mueller, T.H., C.D., M.H., S.F., A.M., C.M., H.D., U.L.), Klinik für Nieren- und Hochdruck-erkrankungen (S.A.S., F.H.B., H.H.), and Klinik für Gastroenterologie, Hepatologie, and Endokrinologie (A.M., M.J.B.), Medizinische Hochschule Hannover, Hannover, Germany; Cardiovascular Center, University Hospital Zürich, Zürich, Switzerland (C.B., M. Meyer, K.H., M. Mueller, C.D., C.M., U.L.); and Institute of Clinical Chemistry (L.R., A.v.E.) and Zürich Center of Integrated Human Physiology (C.B., L.R., A.v.E., U.L.), University of Zürich, Zürich, Switzerland.

Correspondence to Ulf Landmesser, MD, Cardiovascular Center, University Hospital Zürich, Rämistr 100 (C-Hof 111), 8091 Zürich, Switzerland. E-mail Ulf.Landmesser@usz.ch

Received November 19, 2008; accepted October 27, 2009.

Background— High-density lipoprotein (HDL)–raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL.

Methods and Results— HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell–mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy.

Conclusions— HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important.

Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00346970.

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CLINICAL PERSPECTIVE
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Abstract 15 of 16 (Circulation. 2010;121:123-131.)
© 2010 American Heart Association, Inc.

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Vascular Medicine

Endothelial-Specific Deletion of Connexin40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion
C.E. Chadjichristos, PhD*; K.E.L. Scheckenbach, MD, PhD*; T.A.B. van Veen, PhD; M.Z. Richani Sarieddine, MSc; C. de Wit, MD, PhD; Z. Yang, MD; I. Roth; M. Bacchetta; H. Viswambharan, PhD; B. Foglia; T. Dudez; M.J.A. van Kempen, PhD; F.E.J. Coenjaerts, PhD; L. Miquerol, PhD; U. Deutsch, PhD; H.J. Jongsma, PhD; M. Chanson, PhD*; B.R. Kwak, PhD*
From the Division of Cardiology (C.E.C., I.R., B.F., B.R.K.) and Department of Pediatrics (K.E.L.S., M.Z.R.S., M.B., B.F., T.D., M.C.), Geneva University Hospitals and University of Geneva, Geneva, Switzerland; Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands (T.A.B.v.V., M.J.A.v.K., F.E.J.C., H.J.J.); Institut für Physiologie, Universität zu Lübeck, Lübeck, Germany (C.d.W.); Division of Physiology, University of Fribourg, Fribourg, Switzerland (Z.Y., H.V.); Developmental Biology Institute of Marseille-Luminy, CNRS UMR6216, Marseille, France (L.M.); and Theodor Kocher Institute, University of Bern, Bern, Switzerland (U.D.).

Correspondence to Marc Chanson, PhD, Laboratory of Clinical Investigation III, HUG, PO Box 14, 4 Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland. E-mail Marc.Chanson@hcuge.ch

Received March 20, 2009; accepted October 28, 2009.

Background— Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease.

Methods and Results— Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Cx40del mice). Cx40del mice were indeed not hypertensive. The progression of atherosclerosis was increased in Cx40del mice after 5 and 10 weeks of a high-cholesterol diet, and spontaneous lesions were observed in the aortic sinuses of young mice without such a diet. These lesions showed monocyte infiltration into the intima, increased expression of vascular cell adhesion molecule-1, and decreased expression of the ecto-enzyme CD73 in the endothelium. The proinflammatory phenotype of Cx40del mice was confirmed in another model of induced leukocyte recruitment from the lung microcirculation. Endothelial CD73 is known to induce antiadhesion signaling via the production of adenosine. We found that reducing Cx40 expression in vitro with small interfering RNA or antisense decreased CD73 expression and activity and increased leukocyte adhesion to mouse endothelial cells. These effects were reversed by an adenosine receptor agonist.

Conclusions— Cx40-mediated gap junctional communication contributes to a quiescent nonactivated endothelium by propagating adenosine-evoked antiinflammatory signals between endothelial cells. Alteration in this mechanism by targeting Cx40 promotes leukocyte adhesion to the endothelium, thus accelerating atherosclerosis.

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CLINICAL PERSPECTIVE
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Abstract 16 of 16 (Circulation. 2010;121:132-142.)
© 2010 American Heart Association, Inc.

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Vascular Medicine

Histone Deacetylase 3 Is Critical in Endothelial Survival and Atherosclerosis Development in Response to Disturbed Flow
Anna Zampetaki, PhD*; Lingfang Zeng, PhD*; Andriana Margariti, PhD; Qingzhong Xiao, PhD; Hongling Li, Msc; Zhongyi Zhang, Msc; Anna Elena Pepe, BSc; Gang Wang, BSc; Ouassila Habi, PhD; Elena deFalco, PhD; Gillian Cockerill, PhD; Justin C. Mason, PhD; Yanhua Hu, MD; Qingbo Xu, MD, PhD
From the Cardiovascular Division, King’s College London BHF Centre (A.Z., L.Z., A.M., Q.X., H.L., Z.Z., A.E.P., G.W., O.H., E.d.F., Y.H., Q.X.); Department of Cardiovascular Medicine, St George’s University of London (G.C.); and Bywaters Center for Vascular Inflammation, Imperial College, Hammersmith Hospital (J.C.M.), London, UK.

Correspondence to Professor Qingbo Xu, Division of Cardiology, King’s College London, James Black Centre, 125 Coldharbour Ln, London SE5 9NU, UK. E-mail qingbo.xu@kcl.ac.uk

Received March 24, 2009; accepted October 9, 2009.

Background— Histone deacetylase 3 (HDAC3) is known to play a crucial role in the differentiation of endothelial progenitors. The role of HDAC3 in mature endothelial cells, however, is not well understood. Here, we investigated the function of HDAC3 in preserving endothelial integrity in areas of disturbed blood flow, ie, bifurcation areas prone to atherosclerosis development.

Methods and Results— En face staining of aortas from apolipoprotein E-knockout mice revealed increased expression of HDAC3, specifically in these branching areas in vivo, whereas rapid upregulation of HDAC3 protein was observed in endothelial cells exposed to disturbed flow in vitro. Interestingly, phosphorylation of HDAC3 at serine/threonine was observed in these cells, suggesting that disturbed flow leads to posttranscriptional modification and stabilization of the HDAC3 protein. Coimmunoprecipitation experiments showed that HDAC3 and Akt form a complex. Using a series of constructs harboring deletions, we found residues 136 to 206 of HDAC3 to be crucial in this interaction. Enforced expression of HDAC3 resulted in increased phosphorylation of Akt and upregulation of its kinase activity. In line with these findings, knockdown of HDAC3 with lentiviral vectors (shHDAC3) led to a dramatic decrease in cell survival accompanied by apoptosis in endothelial cells. In aortic isografts of apolipoprotein E-knockout mice treated with shHDAC3, a robust atherosclerotic lesion was formed. Surprisingly, 3 of the 8 mice that received shHDAC3-infected grafts died within 2 days after the operation. Miller staining of the isografts revealed disruption of the basement membrane and rupture of the vessel.

Conclusions— Our findings demonstrated that HDAC3 serves as an essential prosurvival molecule with a critical role in maintaining the endothelial integrity via Akt activation and that severe atherosclerosis and vessel rupture in isografted vessels of apolipoprotein E-knockout mice occur when HDAC3 is knocked down.

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