circulation2010-04-27

(Circulation. 2010;121:1800-1808.)
© 2010 American Heart Association, Inc.

abstract 1 of 6

Cardiovascular Surgery
Increasing Long-Term Major Vascular Events and Resource Consumption in Patients Receiving Off-Pump Coronary Artery Bypass
A Single-Center Prospective Observational Study
Shengshou Hu, MD, PhD*; Zhe Zheng, MD, PhD*; Xin Yuan, MD, PhD*; Wei Wang, MD; Yunhu Song, MD; Hansong Sun, MD; Jianping Xu, MD
From the Department of Cardiovascular Surgery, Center for Cardiovascular Regenerative Medicine, Fuwai Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Correspondence to Shengshou Hu, 167 Beilishi Rd, Xi Chen District, Beijing, China, 100037. E-mail huss@vip.sohu.com or shengshouhu@yahoo.com
Received July 18, 2009; accepted February 25, 2010.
Background— Despite its widespread use and short-term efficacy, substantial uncertainty remains about the long-term outcomes and cost-effectiveness of off-pump coronary artery bypass (OPCAB).
Methods and Results— A retrospective review of prospectively collected data was conducted of 6665 consecutive patients undergoing isolated coronary artery bypass graft (CABG) at our institution during 1999 to 2006. All patients were followed up until September 30, 2008. Short- and long-term outcomes were compared between OPCAB and conventional CABG. The 2 main long-term outcome measures were repeat revascularization and the composite outcome of major vascular events. Cost comparison at 2 years in a propensity-matched sample during follow-up was also a study interest. The overall mean baseline age was 60.3±8.6 years, and 17.0% were women. Compared with conventional CABG, patients who underwent OPCAB had lower rates of atrial fibrillation (P=0.003) and requirements for blood transfusion (P=0.03) and ventilation time >24 hours (P<0.001). After an average of 4.5 years of follow-up, the rates of repeat revascularization (adjusted hazard ratio, 1.40; 95% confidence interval, 1.03 to 1.89) and major vascular events (adjusted hazard ratio, 1.23; 95% confidence interval, 1.09 to 1.39) were significantly higher in the OPCAB than the conventional CABG group. At 2 years, OPCAB was associated with increased additional direct costs per patient compared with conventional CABG and had a similar survival rate.
Conclusions— Compared with conventional CABG, OPCAB is associated with small short-term gain but increased long-term risks of repeat revascularization and major vascular events, especially among high-risk patients. Moreover, OPCAB consumes more resources and is less cost-effective in the long run.

abstract 2 of 6

Coronary Heart Disease
Clinical Features and Outcomes of Women With Unstable Ischemic Heart Disease
Observations From Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36)
Jessica L. Mega, MD, MPH; Judith S. Hochman, MD; Benjamin M. Scirica, MD, MPH; Sabina A. Murphy, MPH; Sarah Sloan, MA, MS; Carolyn H. McCabe, BS; Piera Merlini, MD; David A. Morrow, MD, MPH
From the TIMI Study Group, Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass (J.L.M., B.M.S., S.A.M., S.S., C.H.M., D.A.M.); Department of Medicine, New York University Medical Center and Medical School, New York (J.S.H.); and Division of Cardiology, Ospedale Niguarda, Milan, Italy (P.M.).
Correspondence to Jessica L. Mega, MD, MPH, Brigham and Women’s Hospital, 350 Longwood Ave, 1st Floor, Boston, MA 02115. E-mail jmega@partners.org
Received July 24, 2009; accepted January 29, 2010.
Background— The pathobiological basis of ischemic heart disease and thus the manifestations and response to therapy can differ between women and men. In prior studies, sex-based treatment differences have been observed with the antiischemic ranolazine, with a possibly diminished effect in women.
Methods and Results— We conducted a prospectively planned analysis of the clinical, biomarker, angiographic, and continuous ECG features and 1-year outcomes of women with unstable ischemic heart disease randomized to ranolazine or placebo in Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). Compared with men (n=4269), women (n=2291) were older with more risk factors (P<0.001). On presentation, women were less likely than men to have significant epicardial coronary artery disease (no stenosis 50% on angiography, 19.4% versus 8.6%; P<0.001) or elevated troponin (57.1% versus 68.9%; P<0.001). Yet, women were more likely to have an elevated B-type natriuretic peptide (47.0% versus 40.2%; P<0.001), worse median angina frequency scores (80 versus 100; P<0.001), and an ischemic episode on continuous ECG administered during the first 7 days (22.5% versus 19.3%; P=0.0025). Women and men were at similar adjusted risk for the primary end point of cardiovascular death, myocardial infarction, or recurrent ischemia (adjusted hazard ratio, 1.11; 95% confidence interval, 0.96 to 1.29; P=0.15). Ranolazine was associated with a significant reduction in recurrent ischemia in women (13.0% versus 18.2%; hazard ratio, 0.71; 95% confidence interval, 0.57 to 0.88; P=0.002).
Conclusions— Women with a clinical syndrome consistent with unstable ischemic heart disease, despite having less obstructive coronary artery disease, were more likely than men to report anginal episodes and had more recorded ischemic periods on continuous ECG. In this setting, ranolazine may be a particularly useful antiischemic agent in women.

abstract 3 of 6

Heart Failure
Acute Cardiovascular Effects of Apelin in Humans
Potential Role in Patients With Chronic Heart Failure
A.G. Japp, MRCP; N.L. Cruden, PhD, MRCP; G. Barnes, MRCP; N. van Gemeren, MBChB; J. Mathews, MBChB; J. Adamson, PhD; N.R. Johnston, MSc; M.A. Denvir, PhD, FRCP; I.L. Megson, PhD; A.D. Flapan, MD, FRCP; D.E. Newby, PhD, FRCP
From the Department of Cardiology, Royal Infirmary of Edinburgh, Edinburgh, UK (A.G.J., N.L.C., N.v.G., J.M., A.D.F.); Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK (G.B., N.R.J., M.A.D., D.E.N.); and Department of Diabetes & Cardiovascular Science, UHI Millennium Institute, Inverness, UK (J.A., I.L.M.).
Correspondence to Dr Alan G. Japp, Department of Cardiology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, UK EH16 4SA. E-mail alan.japp@ed.ac.uk
Received September 22, 2009; accepted February 9, 2010.
Background— Apelin, the endogenous ligand for the novel G protein–coupled receptor APJ, has major cardiovascular effects in preclinical models. The study objectives were to establish the effects of acute apelin administration on peripheral, cardiac, and systemic hemodynamic variables in healthy volunteers and patients with heart failure.
Methods and Results— Eighteen patients with New York Heart Association class II to III chronic heart failure, 6 patients undergoing diagnostic coronary angiography, and 26 healthy volunteers participated in a series of randomized, double-blind, placebo-controlled studies. Measurements of forearm blood flow, coronary blood flow, left ventricular pressure, and cardiac output were made by venous occlusion plethysmography, Doppler flow wire and quantitative coronary angiography, pressure wire, and thoracic bioimpedance, respectively. Intrabrachial infusions of (Pyr1)apelin-13, acetylcholine, and sodium nitroprusside caused forearm vasodilatation in patients and control subjects (all P<0.0001). Vasodilatation to acetylcholine (P=0.01) but not apelin (P=0.3) or sodium nitroprusside (P=0.9) was attenuated in patients with heart failure. Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum rate of rise in left ventricular pressure and reduced peak and end-diastolic left ventricular pressures (all P<0.05). Systemic infusions of (Pyr1)apelin-13 (30 to 300 nmol/min) increased cardiac index and lowered mean arterial pressure and peripheral vascular resistance in patients and healthy control subjects (all P<0.01) but increased heart rate only in control subjects (P<0.01).
Conclusions— Acute apelin administration in humans causes peripheral and coronary vasodilatation and increases cardiac output. APJ agonism represents a novel potential therapeutic target for patients with heart failure.

abstract 4 of 6

Molecular Cardiology
Erythropoietin Suppresses the Formation of Macrophage Foam Cells
Role of Liver X Receptor
Kuo-Yun Lu, MS; Li-Chieh Ching, BS; Kuo-Hui Su, BS; Yuan-Bin Yu, MD; Yu Ru Kou, PhD; Sheng-Huang Hsiao, MD, PhD; Yu-Chu Huang, MS; Chien-Yu Chen, BS; Li-Ching Cheng, MS; Ching-Chian Pan, BS; Tzong-Shyuan Lee, DVM, PhD
From the Institute of Physiology, National Yang-Ming University, Taipei (K.-Y.L., L.-C.C., K.-H.S., Y.R.K., Y.-C.H., C.-Y.C., C.-C.P., T.-S.L.); Division of Hematology and Oncology, Taipei Veterans General Hospital, Taipei (Y.-B.Y.); Department of Surgery, Ren-Ai Taipei City Hospital, Taipei (S.-H.H.); and Department of Nursing, Chang-Gung Institute of Technology, Taoyuan (L.-C.C.), Taiwan.
Reprint requests to Dr Tzong-Shyuan Lee, DVM, PhD, Department of Physiology, National Yang-Ming University, Taipei 112, Taiwan. E-mail tslee@ym.edu.tw
Received April 30, 2009; accepted February 25, 2010.
Background— In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoietin and its underlying mechanism in macrophage foam cell formation are poorly understood.
Methods and Results— Compared with wild-type specimens, erythropoietin was increased in atherosclerotic aortas of apolipoprotein E–deficient (apoE–/–) mice, mainly in the macrophage foam cells of the lesions. Erythropoietin levels in culture medium and macrophages were significantly elevated in response to oxidized low-density lipoprotein in a dose-dependent manner. Furthermore, erythropoietin markedly attenuated lipid accumulation in oxidized low-density lipoprotein–treated macrophages, a result that was due to an increase in cholesterol efflux. Erythropoietin treatment significantly increased ATP-binding cassette transporters (ABC) A1 and ABCG1 mRNA and protein levels without affecting protein expression of scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI. The upregulation of ABCA1 and ABCG1 by erythropoietin resulted from liver X receptor activation, which was confirmed by its prevention on expression of ABCA1 and ABCG1 after pharmacological or small interfering RNA inhibition of liver X receptor . Moreover, the erythropoietin-mediated attenuation on lipid accumulation was abolished by such inhibition. Finally, reduced lipid accumulation and marked increase in ABCA1 and ABCG1 were demonstrated in erythropoietin-overexpressed macrophages.
Conclusion— Our data suggest that erythropoietin suppresses foam cell formation via the liver X receptor –dependent upregulation of ABCA1 and ABCG1.

abstract 5 of 6

Valvular Heart Disease
Transcatheter Valve-in-Valve Implantation for Failed Bioprosthetic Heart Valves
John G. Webb, MD; David A. Wood, MD; Jian Ye, MD; Ronen Gurvitch, MD; Jean-Bernard Masson, MD; Josep Rodés-Cabau, MD; Mark Osten, MD; Eric Horlick, MD; O. Wendler, MD; Eric Dumont, MD; Ronald G. Carere, MD; Namal Wijesinghe, MD; Fabian Nietlispach, MD; Mark Johnson, MD; Chrisopher R. Thompson, MD; Robert Moss, MD; Jonathon Leipsic, MD; Brad Munt, MD; Samuel V. Lichtenstein, MD, PhD; Anson Cheung, MD
From St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada (J.G.W., D.A.W., J.Y., R.G., J.-B.M., R.G.C., N.W., F.N., M.J., C.R.T., R.M., J.L., B.M., S.V.L., A.C.); Quebec Heart and Lung Institute, Quebec City, Quebec, Canada (J.R.-C., E.D.); Toronto General Hospital, Toronto, Ontario, Canada (M.O., E.H.); and King’s College Hospital, London, UK (O.W.).
Correspondence to John G. Webb, MD, St. Paul’s Hospital, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6. E-mail john.webb@vch.ca
Received November 24, 2009; accepted February 18, 2010.
Background— The majority of prosthetic heart valves currently implanted are tissue valves that can be expected to degenerate with time and eventually fail. Repeat cardiac surgery to replace these valves is associated with significant morbidity and mortality. Transcatheter heart valve implantation within a failed bioprosthesis, a "valve-in-valve" procedure, may offer a less invasive alternative.
Methods and Results— Valve-in-valve implantations were performed in 24 high-risk patients. Failed valves were aortic (n=10), mitral (n=7), pulmonary (n=6), or tricuspid (n=1) bioprostheses. Implantation was successful with immediate restoration of satisfactory valve function in all but 1 patient. No patient had more than mild regurgitation after implantation. No patients died during the procedure. Thirty-day mortality was 4.2%. Mortality was related primarily to learning-curve issues early in this high-risk experience. At baseline, 88% of patients were in New York Heart Association functional class III or IV; at the last follow-up, 88% of patients were in class I or II. At a median follow-up of 135 days (interquartile range, 46 to 254 days) and a maximum follow-up of 1045 days, 91.7% of patients remained alive with satisfactory valve function.
Conclusions— Transcatheter valve-in-valve implantation is a reproducible option for the management of bioprosthetic valve failure. Aortic, pulmonary, mitral, and tricuspid tissue valves were amenable to this approach. This finding may have important implications with regard to valve replacement in high-risk patients.

abstract 6 of 6

Stroke
Impact of Thrombophilia on Risk of Arterial Ischemic Stroke or Cerebral Sinovenous Thrombosis in Neonates and Children
A Systematic Review and Meta-Analysis of Observational Studies
Gili Kenet, MD*; Lisa K. Lütkhoff*; Manuela Albisetti, MD; Timothy Bernard, MD; Mariana Bonduel, MD; Leonardo Brandao, MD; Stephane Chabrier, MD; Anthony Chan, MD; Gabrielle deVeber, MD, MAS; Barbara Fiedler, MD; Heather J. Fullerton, MD, MAS; Neil A. Goldenberg, MD, PhD; Eric Grabowski, MD; Gudrun Günther, MD; Christine Heller, MD; Susanne Holzhauer, MD; Alfonso Iorio, MD; Janna Journeycake, MD; Ralf Junker, MD; Fenella J. Kirkham, MD; Karin Kurnik, MD; John K. Lynch, MD; Christoph Male, MD; Marilyn Manco-Johnson, MD; Rolf Mesters, MD; Paul Monagle, MD; C. Heleen van Ommen, MD; Leslie Raffini, MD; Kevin Rostásy, MD; Paolo Simioni, MD; Ronald D. Sträter, MD; Guy Young, MD; Ulrike Nowak-Göttl, MD
From the Israel National Haemophilia Centre, Sheba Medical Centre, Tel-Hashomer, Israel (G.K.); Department of Pediatric Hematology/Oncology, University Hospital of Münster, Münster, Germany (L.K.L., R.D.S., U.N.-G.); Division of Hematology, University Children’s Hospital, Zurich, Switzerland (M.A.); Department of Pediatrics, Hematology/Oncology/BMT, and the Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado, and Children’s Hospital, Denver/Aurora, Colo (T.B., N.A.G., M.M.-J.); Servicio de Hematolgía y Oncología, Hospital de Pediatría "Prof Dr J.P. Garrahan," Buenos Aires, Argentina (M.B.); Hospital for Sick Children, Toronto, Canada (L.B., G.d.V.); Unit of Néonatologie et Réanimation Pédiatrique, Centre Hospitalier Universitaire, Saint-Etienne, France (S.C.); McMaster University, Hamilton, Canada (A.C.); Department of Pediatric Neurology, University Hospital of Münster, Münster, Germany (B.F.); Department of Neurology and Pediatrics, University of California, San Francisco (H.J.F.); Massachusetts General Hospital, Harvard Medical School, Boston (E.G.); Department of Pediatrics, University Hospital Magdeburg, Magdeburg, Germany (G.G.); Department of Pediatric Hematology/Oncology, University Hospital Frankfurt, Frankfurt, Germany (C.H.); Department of Pediatric Hematology/Oncology, Charite, Berlin, Germany (S.H.); Internal and Vascular Medicine and Hemophilia Centre, University of Perugia, Perugia, Italy (A.I.); Department of Pediatrics, Children’s Medical Centre Dallas, University of Texas Southwestern, Medical Center, Dallas (J.J.); Department of Clinical Chemistry, University Hospital of Kiel, Kiel, Germany (R.J.); Neurosciences Unit, Institute of Child Health (University College London), London, UK (F.J.K.); Department of Child Health, Southampton General Hospital, Southampton, UK (F.J.K.); Department of Pediatrics, University Hospital Munich, Munich, Germany (K.K.); Division of Stroke Diagnostics and Therapeutics, National Institutes of Neurological Disorders and Stroke, Bethesda, Md (J.K.L.); Department for Pediatrics, Medical University Vienna, Vienna, Austria (C.M.); Department of Internal Medicine, University Hospital of Münster, Münster, Germany (R.M.); Royal Children’s Hospital, Victoria, Australia (P.M.); Department of Pediatric Hematology, Emma Children’s Hospital AMC, Amsterdam, the Netherlands (C.H.v.O.); Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia (L.R.); Department of Pediatrics IV, Division of Pediatric Neurology and Inherited Metabolic Disorders, Medical University Innsbruck, Innsbruck, Austria (K.R.); Department of Cardiologic, Thoracic and Vascular Sciences, Second Chair of Internal Medicine, University of Padua, Padua, Italy (P.S.); and Division of Hematology/Oncology, Children’s Hospital, Los Angeles, Calif (G.Y.).
Correspondence to Prof Dr U. Nowak-Göttl, Pediatric Hematology and Oncology, University Hospital of Münster, Albert-Schweitzer-Str 33, D-48149 Münster, Germany. E-mail leagottl@uni-muenster.de
Received October 2, 2009; accepted February 10, 2010.
Background— The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies.
Methods and Results— A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99).
Conclusions— The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.