EditorialsDiff’rent Strokes, Different Folks: Advanced Heart Failure’s Changing OutlookLarry A. Allen, MD, MHS; Amrut V. Ambardekar, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

β-Adrenergic Blockade for Anthracycline- and Trastuzumab-Induced Cardiotoxicity: Is Prevention Better Than Cure?Anju Nohria, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358

Perspective on a Risk Score for Cardiac TransplantationJack G. Copeland, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

Original ArticlesInsulin Resistance and Risk of Incident Heart Failure: Cardiovascular Health StudyDipanjan Banerjee, MD, MS; Mary L. Biggs, PhD, MPH; Laina Mercer, MS; Kenneth Mukamal, MD; Robert Kaplan, PhD; Joshua Barzilay, MD; Lewis Kuller, MD, DrPH; Jorge R. Kizer, MD; Luc Djousse, MD, ScD; Russell Tracy, PhD; Susan Zieman, MD, PhD; Donald Lloyd-Jones, MD, ScM; David Siscovick, MD, MPH; Mercedes Carnethon, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

Association of Lipids With Incident Heart Failure Among Adults With and Without Diabetes Mellitus: Multiethnic Study of AtherosclerosisImo A. Ebong, MD, MS; David C. Goff Jr, MD, PhD; Carlos J. Rodriguez, MD, MPH; Haiying Chen, PhD; Christopher T. Sibley, MD; Alain G. Bertoni, MD, MPH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Outcome Differences in Community- Versus Hospital-Acquired Hyponatremia in Patients With a Diagnosis of Heart FailureDmitry Y. Shchekochikhin, MD; Robert W. Schrier, MD; JoAnn Lindenfeld, MD; Lori Lyn Price, MAS; Bertrand L. Jaber, MD; Nicolaos E. Madias, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379

Depression, Healthcare Utilization, and Death in Heart Failure: A Community StudyAmanda R. Moraska, MD; Alanna M. Chamberlain, PhD, MPH; Nilay D. Shah, PhD; Kristin S. Vickers, PhD; Teresa A. Rummans, MD; Shannon M. Dunlay, MD, MSc; John A. Spertus, MD, MPH; Susan A. Weston, MS; Sheila M. McNallan, MPH; Margaret M. Redfield, MD; Véronique L. Roger, MD, MPH . . . . . . . . . . . . . . . . . . . . . 387

Comparative Safety and Effectiveness of Metformin in Patients With Diabetes Mellitus and Heart Failure: Systematic Review of Observational Studies Involving 34 000 PatientsDean T. Eurich, PhD; Daniala L. Weir, BSc; Sumit R. Majumdar, MD, MPH; Ross T. Tsuyuki, PharmD, MSc; Jeffrey A. Johnson, PhD; Lisa Tjosvold, MLIS; Saskia E. Vanderloo, MSc; Finlay A. McAlister, MD, MSc . . . . . . . 395

Resting Heart Rate and the Risk of Heart Failure in Healthy Adults: The Rotterdam StudyDavid Nanchen, MD, MSc; Maarten J.G. Leening, MD, MSc; Isabella Locatelli, PhD; Jacques Cornuz, MD, MPH; Jan A. Kors, PhD; Jan Heeringa, MD, PhD; Jaap W. Deckers, MD, PhD; Albert Hofman, MD, PhD; Oscar H. Franco, MD, PhD; Bruno H.Ch. Stricker, MB, PhD; Jacqueline C.M. Witteman, PhD; Abbas Dehghan, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

Temporal Trends in Treatment and Outcomes for Advanced Heart Failure With Reduced Ejection Fraction From 1993–2010: Findings From a University Referral CenterJohn C. Loh, BS; Julie Creaser, RN, MN, CHFN; Darlene A. Rourke, RN, MSN, CHFN; Nancy Livingston, RN, MN, NP; Tamara K. Harrison, ACNP; Elizabeth Vandenbogaart, ACNP; Jaime Moriguchi, MD; Michele A. Hamilton, MD; Chi-Hong Tseng, PhD; Gregg C. Fonarow, MD; Tamara B. Horwich, MD, MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

Volume 6 ■ Number 3May 2013

CIRCULATION: HEART FAILURE (ISSN 1941-3289) is published bimonthly by Lippincott Williams & Wilkins at 16522 Hunters Green Parkway, Hagerstown, MD 21740. Business offices are located at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103. Production offices are located at 351 West Camden Street, Baltimore, MD 21201-2436. Postage paid at Hagerstown, MD, and additional mailing offices. POSTMASTER: Send address changes to CIRCULATION: HEART FAILURE, Lippincott Williams & Wilkins, 16522 Hunters Green Parkway, Hagerstown, MD 21740.

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Cardioprotective Effect of β-Adrenoceptor Blockade in Patients With Breast Cancer Undergoing Chemotherapy: Follow-Up Study of Heart FailureSinziana Seicean, MD, MPH, PhD; Andreea Seicean, PhD, MPH; Nima Alan, BS; Juan Carlos Plana, MD; G. Thomas Budd, MD; Thomas H. Marwick, MBBS, PhD, MPH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420

Echocardiography-Guided Left Ventricular Lead Placement for Cardiac Resynchronization Therapy: Results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region TrialSamir Saba, MD; Josef Marek, MD; David Schwartzman, MD; Sandeep Jain, MD; Evan Adelstein, MD; Pamela White, RN; Olusegun A. Oyenuga, MD; Tetsuari Onishi, MD; Prem Soman, MD; John Gorcsan III, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

Right Ventricular Function, Pulmonary Pressure Estimation, and Clinical Outcomes in Cardiac Resynchronization TherapyPatricia Campbell, MB, BCh; Madoka Takeuchi, MS; Mikhail Bourgoun, MD; Amil Shah, MD; Elyse Foster, MD; Mary W. Brown, MS; Ilan Goldenberg, MD; David T. Huang, MD; Scott McNitt, MS; W. Jackson Hall, PhD; Arthur Moss, MD; Marc A. Pfeffer, MD; Scott D. Solomon, MD; for the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) Investigators . . . . . . . . . . . . . . . . . . . . 435

Influence of Crossover on Mortality in a Randomized Study of Revascularization in Patients With Systolic Heart Failure and Coronary Artery DiseaseTorsten Doenst, MD; John G.F. Cleland, MD; Jean L. Rouleau, MD; Lilin She, PhD; Stanislaw Wos, MD; E. Magnus Ohman, MD; Maria Krzeminska-Pakula, MD; Balram Airan, MD; Robert H. Jones, MD; Matthias Siepe, MD; George Sopko, MD; Eric J. Velazquez, MD; Normand Racine, MD; Lars Gullestad, MD; Jose Luis Filgueira, MD; Kerry L. Lee, PhD; on behalf of the STICH Investigators . . . . . . . . . . . . . . . . . . . . . . . . . 443

Left Ventricular Systolic Dysfunction, Heart Failure, and the Risk of Stroke and Systemic Embolism in Patients With Atrial Fibrillation: Insights From the ARISTOTLE TrialJohn J.V. McMurray, MD; Justin A. Ezekowitz, MB, BCh; Basil S. Lewis, MD; Bernard J. Gersh, MB, ChB, D.Phil.; Sean van Diepen, MD, MSc; John Amerena, MBBS, FRACP; Jozef Bartunek, MD, PhD; Patrick Commerford, MB, ChB, FCP(SA); Byung-Hee Oh, MD, PhD; Veli-Pekka Harjola, MD, PhD; Sana M. Al-Khatib, MD, MHS; Michael Hanna, MD; John H. Alexander, MD, MHS; Renato D. Lopes, MD, PhD; Daniel M. Wojdyla, MSc; Lars Wallentin, MD, PhD; Christopher B. Granger, MD; for the ARISTOTLE Committees and Investigators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

Prognostic Significance of Biomarkers in Predicting Outcome in Patients With Coronary Artery Disease and Left Ventricular Dysfunction: Results of the Biomarker Substudy of the Surgical Treatment for Ischemic Heart Failure TrialsArthur M. Feldman, MD, PhD; Douglas L. Mann, MD; Lilin She, PhD; Michael R. Bristow, MD, PhD; Alan S. Maisel, MD; Dennis M. McNamara, MD; Ryan Walsh, MS; Dorellyn L. Lee, MS; Stanislaw Wos, MD; Irene Lang, MD; Gretchen Wells, MD, PhD; Mark H. Drazner, MD; John F. Schmedtje Jr, MD; Daniel F. Pauly, MD, PhD; Carla A. Sueta, MD; Michael Di Maio, MD; Irving L. Kron, MD; Eric J. Velazquez, MD; Kerry L. Lee, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461

Multicenter Prospective Observational Study on Acute and Chronic Heart Failure: One-Year Follow-up Results of IN-HF (Italian Network on Heart Failure) Outcome RegistryLuigi Tavazzi, MD; Michele Senni, MD; Marco Metra, MD; Marco Gorini, MS; Giuseppe Cacciatore, MD; Alessandra Chinaglia, MD; Andrea Di Lenarda, MD; Andrea Mortara, MD; Fabrizio Oliva, MD; Aldo P. Maggioni, MD; on the behalf of IN-HF (Italian Network on Heart Failure) Outcome Investigators . . . . . . 473

Sustained Cardiovascular Actions of APJ Agonism During Renin–Angiotensin System Activation and in Patients With Heart FailureGareth D. Barnes, MRCP; Shirjel Alam, MRCP; Gordon Carter; Christian M. Pedersen, MD, PhD; Kristina M. Lee; Thomas J. Hubbard, MBChB; Scott Veitch; Herim Jeong; Audrey White; Nicholas L. Cruden, MRCP, PhD; Les Huson, PhD; Alan G. Japp, MCRP; David E. Newby, MD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

Galectin-3 and Cardiac Function in Survivors of Acute Myocardial InfarctionRobin A.P. Weir, MD; Colin J. Petrie, MBChB; C. Aengus Murphy, MD; Suzanne Clements, BSc; Tracey Steedman, BSc; Ashley M. Miller, PhD; Iain B. McInnes, PhD; Iain B. Squire, MD; Leong L. Ng, MD; Henry J. Dargie, MBChB; John J.V. McMurray, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

Prolonged Mean Vo2 Response Time in Systolic Heart Failure: An Indicator of Impaired Right Ventricular-Pulmonary Vascular FunctionNeal A. Chatterjee, MD; Ryan M. Murphy, BA; Rajeev Malhotra, MD; Bishnu P. Dhakal, MD; Aaron L. Baggish, MD; Paul P. Pappagianopoulos, MEd; Stacyann S. Hough, MS; Marc J. Semigran, MD; Gregory D. Lewis, MD . . . . . . 499

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Effects of Exercise on Left Ventricular Systolic and Diastolic Properties in Patients With Heart Failure and a Preserved Ejection Fraction Versus Heart Failure and a Reduced Ejection FractionMichael R. Zile, MD; Barbro Kjellstrom, BMA, PhD; Tom Bennett, PhD; Yong Cho, PhD; Catalin F. Baicu, PhD; Mark F. Aaron, MD; William T. Abraham, MD; Robert C. Bourge, MD; Fred J. Kueffer, MS . . . . . . . . . . . . . . . . . . 508

Pulsatility and the Risk of Nonsurgical Bleeding in Patients Supported With the Continuous-Flow Left Ventricular Assist Device HeartMate IIOmar Wever-Pinzon, MD; Craig H. Selzman, MD; Stavros G. Drakos, MD, PhD; Abdulfattah Saidi, MD; Gregory J. Stoddard, MPH; Edward M. Gilbert, MD; Mohamed Labedi, MD; Bruce B. Reid, MD; Erin S. Davis, RN, BSN; Abdallah G. Kfoury, MD; Dean Y. Li, MD, PhD; Josef Stehlik, MD, MPH; Feras Bader, MD, MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

Preoperative Assessment of High-Risk Candidates to Predict Survival After Heart TransplantationP. Christian Schulze, MD, PhD; Jeffrey Jiang, BS; Jonathan Yang, MD; Faisal H. Cheema, MD; Kenneth Schaeffle, BS; Tomoko S. Kato, MD, PhD; Maryjane Farr, MD; Susan Restaino, MD; Mario Deng, MD; Mathew Maurer, MD; Evelyn Horn, MD; Farhana Latif, MD; Paolo C. Colombo, MD; Ulrich Jorde, MD; Nir Uriel, MD; Jennifer Haythe, MD; Rachel Bijou, MD; Ron Drusin, MD; Sun Hi Lee, MD; Hiroo Takayama, MD; Yoshifumi Naka, MD, PhD; Donna M. Mancini, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527

Tumor Necrosis Factor Receptor–Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian HeartVijay G. Divakaran, MD; Sarah Evans, PhD; Veli K. Topkara, MD; Abhinav Diwan, MD; Jana Burchfield, PhD; Feng Gao, MD; Jianwen Dong, PhD; Huei-Ping Tzeng, PhD; Natarajan Sivasubramanian, PhD; Philip M. Barger, MD; Douglas L. Mann, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535

Impaired Assembly and Post-translational Regulation of 26S Proteasome in Human End-Stage Heart FailureSharlene M. Day, MD; Andras Divald, PhD; Ping Wang, MS; Frank Davis, BS; Sarah Bartolone, BS; Richard Jones, PhD; Saul R. Powell, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544

Peroxisome Proliferator–Activated Receptor-γ Activation Prevents Sepsis-Related Cardiac Dysfunction and Mortality In MiceKonstantinos Drosatos, MSc, PhD; Raffay S. Khan, MD; Chad M. Trent, MPhil; Hongfeng Jiang, MD, PhD; Ni-Huiping Son, MD; William S. Blaner, PhD; Shunichi Homma, MD; P. Christian Schulze, MD, PhD; Ira J. Goldberg, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550

Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart FailureHani N. Sabbah, PhD; Ramesh C. Gupta, PhD; Smita Kohli, MD; Mengjun Wang, MD; Sharad Rastogi, MD; Kefei Zhang, MD; Katja Zimmermann, PhD; Nicole Diedrichs, PhD; Barbara E. Albrecht-Küpper, PhD . . . . . . . 563

Potential Role of BNIP3 in Cardiac Remodeling, Myocardial Stiffness, and Endoplasmic Reticulum: Mitochondrial Calcium Homeostasis in Diastolic and Systolic Heart FailureAntoine H. Chaanine, MD; Ronald E. Gordon, PhD; Erik Kohlbrenner, BS; Ludovic Benard, PhD; Dongtak Jeong, PhD; Roger J. Hajjar, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

Advances in Heart FailureLeft Ventricular Dysfunction With Pulmonary Hypertension: Part 2: Prognosis, Noninvasive Evaluation, Treatment, and Future ResearchAndreas P. Kalogeropoulos, MD, PhD; Vasiliki V. Georgiopoulou, MD; Barry A. Borlaug, MD; Mihai Gheorghiade, MD; Javed Butler, MD, MPH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584

Renin–Angiotensin Blockade Combined With Natriuretic Peptide System Augmentation: Novel Therapeutic Concepts to Combat Heart FailureThomas G. von Lueder, MD, PhD; S. Jeson Sangaralingham, PhD; Bing H. Wang, PhD; Andrew R. Kompa, PhD; Dan Atar, MD, PhD; John C. Burnett Jr, MD; Henry Krum, MBBS, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594

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AHA Policy StatementForecasting the Impact of Heart Failure in the United States: A Policy Statement From the American Heart AssociationPaul A. Heidenreich, MD, MS, FAHA, Chair; Nancy M. Albert, PhD, RN, FAHA; Larry A. Allen, MD, MHS; David A. Bluemke, MD, PhD, FAHA; Javed Butler, MD, MPH, FAHA; Gregg C. Fonarow, MD, FAHA; John S. Ikonomidis, MD, PhD, FRCS(C), FAHA; Olga Khavjou, MA; Marvin A. Konstam, MD; Thomas M. Maddox, MD, MSc; Graham Nichol, MD, MPH, FRCP(C), FAHA; Michael Pham, MD, MPH; Ileana L. Piña, MD, MPH, FAHA; Justin G. Trogdon, PhD; on behalf of the American Heart Association Advocacy Coordinating Committee, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Radiology and Intervention, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Stroke Council . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606

Images and Case Reports in Heart FailureTreatment of Left Ventricular Assist Device Thrombosis With Extended Catheter-Directed Intraventricular Thrombolytic Therapy Thenappan Thenappan, MD; Allen S. Anderson, MD; Valluvan Jeevanadham, MD; Jonathan D. Rich, MD; Atman P. Shah, MD, FACC, FSCAI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e27

Migration of a HeartMate II Left Ventricular Assist DeviceAli Abdul Jabbar, MD; Whitson B. Etheridge, MD; O.H. Frazier, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e30

Coronary Vasospasm Attributable to Fibromuscular Dysplasia: The Long Bridge to TransplantJose M. Castellano, MD, PhD; Prashant Vaishnava, MD; Javier G. Castillo, MD; Anelechi C. Anyanwu, MD; Valentin Fuster, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e31

Circulation: Heart Failure Topic ReviewCirculation: Heart Failure Editors’ Picks: Most Important Articles in Heart Failure With Preserved Ejection FractionRobb D. Kociol, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e33

CorrespondenceLetter by Bandera et al Regarding Article, “Value of Peak Exercise Oxygen Consumption Combined With B-Type Natriuretic Peptide Levels for Optimal Timing of Cardiac Transplantation”Francesco Bandera, MD; Marco Guazzi, MD, PhD; Ross Arena, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e41

Response to Letter Regarding Article, “Value of Peak Exercise Oxygen Consumption Combined With B-Type Natriuretic Peptide Levels for Optimal Timing of Cardiac Transplantation”Tomoko S. Kato, MD, PhD; Elias Collado, MD; Tuba Khawaja, MD; Yumeko Kawano, BS; Margaret Kim, BS; Maryjane Farr, MD; Donna M. Mancini, MD; P. Christian Schulze, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e42

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