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Circulation
Journal Prestige (SJR): 8.95
Citation Impact (citeScore): 9
Number of Followers: 300  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0009-7322 - ISSN (Online) 1524-4539
Published by American Heart Association Homepage  [12 journals]
  • Letter by Wu et al Regarding Article, “Antihypertrophic Memory After
           Regression of Exercise-Induced Physiological Myocardial Hypertrophy Is
           Mediated by the Long Noncoding RNA Mhrt779”

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      Authors: Guiling Wu Feng Gao Xing Zhang School of Aerospace Medicine; Fourth Military Medical University, Xi’an, China.
      Abstract: Circulation, Volume 144, Issue 16, Page e270-e270, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.055528
      Issue No: Vol. 144, No. 16 (2021)
       
  • Response by He et al to Letter Regarding Article, “Antihypertrophic
           Memory After Regression of Exercise-Induced Physiological Myocardial
           Hypertrophy Is Mediated by the Long Noncoding RNA Mhrt779”

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      Authors: Mingyuan He Hairuo Lin Yulin Liao Department of Cardiology; Nanfang Hospital, Southern Medical University, Guangzhou, China.
      Abstract: Circulation, Volume 144, Issue 16, Page e271-e272, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.056310
      Issue No: Vol. 144, No. 16 (2021)
       
  • Correction to: Cardiovascular Safety of Degarelix Versus Leuprolide in
           Patients With Prostate Cancer: The Primary Results of the PRONOUNCE
           Randomized Trial

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      Abstract: Circulation, Volume 144, Issue 16, Page e273-e273, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIR.0000000000001033
      Issue No: Vol. 144, No. 16 (2021)
       
  • A Targeted Treatment Opportunity for HFpEF: Taking Advantage of Diastolic
           Tone

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      Authors: Markus Meyer Martin M. LeWinter Michael R. Zile Lillehei Heart Institute; Department of Medicine, University of Minnesota, Minneapolis (M.M.). Cardiovascular Research Institute of Vermont, University of Vermont, Burlington (M.M.L.). Medical University of South Carolina, RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.).
      Pages: 1269 - 1271
      Abstract: Circulation, Volume 144, Issue 16, Page 1269-1271, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.056412
      Issue No: Vol. 144, No. 16 (2021)
       
  • Social Vulnerability and Premature Cardiovascular Mortality Among US
           Counties, 2014 to 2018

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      Authors: Safi U. Khan Zulqarnain Javed Ahmad N. Lone Sourbha S. Dani Zahir Amin Sadeer G. Al-Kindi Salim S. Virani Garima Sharma Ron Blankstein Michael J. Blaha Miguel Cainzos-Achirica Khurram Nasir Department of Cardiology (S.U.K.) Cardiovascular Prevention; Women’s Hospital, Boston, MA (R.B.).
      Pages: 1272 - 1279
      Abstract: Circulation, Volume 144, Issue 16, Page 1272-1279, October 19, 2021.
      Background:Substantial differences exist between United States counties with regards to premature (<65 years of age) cardiovascular disease (CVD) mortality. Whether underlying social vulnerabilities of counties influence premature CVD mortality is uncertain.Methods:In this cross-sectional study (2014–2018), we linked county-level CDC/ATSDR SVI (Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry Social Vulnerability Index) data with county-level CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiological Research) mortality data. We calculated scores for overall SVI and its 4 subcomponents (ie, socioeconomic status; household composition and disability; minority status and language; and housing type and transportation) using 15 social attributes. Scores were presented as percentile rankings by county, further classified as quartiles on the basis of their distribution among all US counties (1st [least vulnerable] = 0 to 0.25; 4th [most vulnerable = 0.75 to 1.00]). We grouped age-adjusted mortality rates per 100 000 person-years for overall CVD and its subtypes (ischemic heart disease, stroke, hypertension, and heart failure) for nonelderly (<65 years of age) adults across SVI quartiles.Results:Overall, the age-adjusted CVD mortality rate per 100 000 person-years was 47.0 (ischemic heart disease, 28.3; stroke, 7.9; hypertension, 8.4; and heart failure, 2.4). The largest concentration of counties with more social vulnerabilities and CVD mortality were clustered across the southwestern and southeastern parts of the United States. The age-adjusted CVD mortality rates increased in a stepwise manner from 1st to 4th SVI quartiles. Counties in the 4th SVI quartile had significantly higher mortality for CVD (rate ratio, 1.84 [95% CI, 1.43–2.36]), ischemic heart disease (1.52 [1.09–2.13]), stroke (2.03 [1.12–3.70]), hypertension (2.71 [1.54–4.75]), and heart failure (3.38 [1.32–8.61]) than those in the 1st SVI quartile. The relative risks varied considerably by demographic characteristics. For example, among all ethnicities/races, non-Hispanic Black adults in the 4th SVI quartile versus the 1st SVI quartile exclusively had significantly higher relative risks of stroke (1.65 [1.07–2.54]) and heart failure (2.42 [1.29–4.55]) mortality. Rural counties with more social vulnerabilities had 2- to 5-fold higher mortality attributable to CVD and subtypes.Conclusions:In this analysis, US counties with more social vulnerabilities had higher premature CVD mortality, varied by demographic characteristics and rurality. Focused public health interventions should address the socioeconomic disparities faced by underserved communities to curb the growing burden of premature CVD.
      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.054516
      Issue No: Vol. 144, No. 16 (2021)
       
  • Premature Cardiovascular Mortality in the United States: Who Will Protect
           the Most Vulnerable Among Us'

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      Authors: Apoorva Gangavelli Alanna A. Morris Division of Cardiology; Emory University School of Medicine, Atlanta, GA.
      Pages: 1280 - 1283
      Abstract: Circulation, Volume 144, Issue 16, Page 1280-1283, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.056658
      Issue No: Vol. 144, No. 16 (2021)
       
  • Antithrombotic Therapy in Patients Undergoing Transcatheter Interventions
           for Structural Heart Disease

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      Authors: Paolo Calabrò Felice Gragnano Giampaolo Niccoli Rossella Marcucci Marco Zimarino Carmen Spaccarotella Giulia Renda Giuseppe Patti Giuseppe Andò Elisabetta Moscarella Massimo Mancone Arturo Cesaro Gennaro Giustino Raffaele De Caterina Roxana Mehran Davide Capodanno Marco Valgimigli Stephan Windecker George D. Dangas Ciro Indolfi Dominick J. Angiolillo Department of Translational Medical Sciences; University of Campania “Luigi Vanvitelli, ” Naples, Italy (P.C., F.G., E.M., A.C.). Division of Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano, ” Caserta, Italy (P.C., F.G., E.M., A.C.). Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (G.N.). Department of Cardiovascular Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (G.G., R. Mehran., G.D.D.). University Cardiology Division, University of Pisa, Pisa University Hospital, Italy; Fondazione Villa Serena per la Ricerca, Città Sant’Angelo, Italy (R.D.C.). Cardio-Thoracic-Vascular Department, Centro Alte Specialità e Trapianti, Catania, Italy (D.C.). Azienda Ospedaliero Universitaria Policlinico “G. Rodolico-San Marco,” University of Catania, Italy (D.C.). Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland (M.V.). Department of Cardiology, Bern University Hospital, University of Bern, Switzerland (M.V., S.W.). Mediterranea Cardiocentro, Naples, Italy (C.I.). Division of Cardiology, University of Florida College of Medicine, Jacksonville (D.J.A.).
      Pages: 1323 - 1343
      Abstract: Circulation, Volume 144, Issue 16, Page 1323-1343, October 19, 2021.
      Contemporary evidence supports device-based transcatheter interventions for the management of patients with structural heart disease. These procedures, which include aortic valve implantation, mitral or tricuspid valve repair/implantation, left atrial appendage occlusion, and patent foramen ovale closure, profoundly differ with respect to clinical indications and procedural aspects. Yet, patients undergoing transcatheter cardiac interventions require antithrombotic therapy before, during, or after the procedure to prevent thromboembolic events. However, these therapies are associated with an increased risk of bleeding complications. To date, challenges and controversies exist regarding balancing the risk of thrombotic and bleeding complications in these patients such that the optimal antithrombotic regimens to adopt in each specific procedure is still unclear. In this review, we summarize current evidence on antithrombotic therapies for device-based transcatheter interventions targeting structural heart disease and emphasize the importance of a tailored approach in these patients.
      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.054305
      Issue No: Vol. 144, No. 16 (2021)
       
  • Highlights From the Circulation Family of Journals

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      Pages: 1344 - 1348
      Abstract: Circulation, Volume 144, Issue 16, Page 1344-1348, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.057612
      Issue No: Vol. 144, No. 16 (2021)
       
  • From the Literature

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      Authors: Tracy Hampton
      Pages: 1349 - 1350
      Abstract: Circulation, Volume 144, Issue 16, Page 1349-1350, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.057430
      Issue No: Vol. 144, No. 16 (2021)
       
  • Challenges of Interpreting Smartwatch and Implantable Loop Recorder
           Tracings

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      Authors: Mathew S. Padanilam Jasen L. Gilge Asim S. Ahmed Indiana University School of Medicine (M.S.P.); Indianapolis. Ascension St. Vincent, Indianapolis, IN (J.L.G.). Ascension Sacred Heart, Pensacola, FL (A.S.A.).
      Pages: 1351 - 1354
      Abstract: Circulation, Volume 144, Issue 16, Page 1351-1354, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.056648
      Issue No: Vol. 144, No. 16 (2021)
       
  • Rat Model of Heart Failure With Preserved Ejection Fraction: Changes in
           Contractile Proteins Regulating Ca2+ Cycling and Vascular Reactivity

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      Authors: Young Soo Han Grace M. Arteaga Korosh Sharain Gary C. Sieck Frank V. Brozovich Departments of Physiology; Biomedical Engineering (Y.S.H., G.M.A., G.C.S., F.V.B.), Mayo Clinic School of Medicine, Rochester, MN. Pediatrics Critical Care (G.M.A.), Mayo Clinic School of Medicine, Rochester, MN. Cardiovascular Diseases (K.S., F.V.B.), Mayo Clinic School of Medicine, Rochester, MN.
      Pages: 1355 - 1358
      Abstract: Circulation, Volume 144, Issue 16, Page 1355-1358, October 19, 2021.

      Citation: Circulation
      PubDate: 2021-10-18T06:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.054465
      Issue No: Vol. 144, No. 16 (2021)
       
  • Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic
           Cardiomyopathy

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      Authors: Sara Ranjbarvaziri Kristina B. Kooiker Mathew Ellenberger Giovanni Fajardo Mingming Zhao Alison Schroer Vander Roest Rahel A. Woldeyes Tiffany T. Koyano Robyn Fong Ning Ma Lei Tian Gavin M. Traber Frandics Chan John Perrino Sushma Reddy Wah Chiu Joseph C. Wu Joseph Y. Woo Kathleen M. Ruppel James A. Spudich Michael P. Snyder Kévin Contrepois Daniel Bernstein Department of Pediatrics; Stanford University School of Medicine, Stanford, CA; Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, CA Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA Department of Genetics, Stanford University School of Medicine, Stanford, CA Department of Bioengineering, Stanford University, Stanford, CA Department of Cardiothoracic Surgery, Stanford University, CA Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, CA; Department of Medicine, Division of Cardiology, Stanford University, Stanford, CA Department of Radiology, Stanford University, Stanford, CA Cell Sciences Imaging Facility, Stanford University, Stanford, CA Department of Bioengineering, Stanford University, Stanford, CA; Division of Cryo-EM Bioimaging, SLAC National Accelerator Laboratory, Stanford University, Stanford, CA Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA Department of Biochemistry, Stanford University School of Medicine, Stanford, CA
      Abstract: Circulation, Ahead of Print.
      Background:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM.Methods:We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts).Results:Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites [ATP, ADP, and phosphocreatine (PCr)] and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance.Conclusions:Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.
      Citation: Circulation
      PubDate: 2021-10-21T01:25:35Z
      DOI: 10.1161/CIRCULATIONAHA.121.053575
       
  • Mitochondrial Telomerase Reverse Transcriptase Protects from Myocardial
           Ischemia/reperfusion Injury by Improving Complex I Composition and
           Function

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      Authors: Niloofar Ale-Agha Philipp Jakobs Christine Goy Mark Zurek Julia Rosen Nadine Dyballa-Rukes Sabine Metzger Jan Greulich Florian von Ameln Olaf Eckermann Klaus Unfried Fedor Brack Maria Grandoch Matthias Thielmann Markus Kamler Nilgün Gedik Petra Kleinbongard Andre Heinen Gerd Heusch Axel Gödecke Joachim Altschmied Judith Haendeler Environmentally-induced Cardiovascular Degeneration; Clinical Chemistry Heinrich-Heine University, Düsseldorf, Germany
      Abstract: Circulation, Ahead of Print.
      Background:The catalytic subunit of telomerase, Telomerase Reverse Transcriptase (TERT) has protective functions in the cardiovascular system. TERT is not only present in the nucleus, but also in mitochondria. However, it is unclear whether nuclear or mitochondrial TERT is responsible for the observed protection and appropriate tools are missing to dissect this.Methods:We generated new mouse models containing TERT exclusively in the mitochondria (mitoTERT mice) or the nucleus (nucTERT mice) to finally distinguish between the functions of nuclear and mitochondrial TERT. Outcome after ischemia/reperfusion, mitochondrial respiration in the heart as well as cellular functions of cardiomyocytes, fibroblasts, and endothelial cells were determined.Results:All mice were phenotypically normal. While respiration was reduced in cardiac mitochondria from TERT-deficient and nucTERT mice, it was increased in mitoTERT animals. The latter also had smaller infarcts than wildtype mice, whereas nucTERT animals had larger infarcts. The decrease in ejection fraction after one, two and four weeks of reperfusion was attenuated in mitoTERT mice. Scar size was also reduced and vascularization increased. Mitochondrial TERT protected a cardiomyocyte cell line from apoptosis. Myofibroblast differentiation, which depends on complex I activity, was abrogated in TERT-deficient and nucTERT cardiac fibroblasts and completely restored in mitoTERT cells. In endothelial cells, mitochondrial TERT enhanced migratory capacity and activation of endothelial NO synthase. Mechanistically, mitochondrial TERT improved the ratio between complex I matrix arm and membrane subunits explaining the enhanced complex I activity. In human right atrial appendages, TERT was localized in mitochondria and there increased by remote ischemic preconditioning. The Telomerase activator, TA-65 evoked a similar effect in endothelial cells, thereby increasing their migratory capacity, and enhanced myofibroblast differentiation.Conclusions:Mitochondrial, but not nuclear TERT, is critical for mitochondrial respiration and during ischemia/reperfusion injury. Mitochondrial TERT improves complex I subunit composition. TERT is present in human heart mitochondria, and remote ischemic preconditioning increases its level in those organelles. TA-65 has comparable effects ex vivo and improves migratory capacity of endothelial cells and myofibroblast differentiation. We conclude that mitochondrial TERT is responsible for cardioprotection and its increase could serve as a therapeutic strategy.
      Citation: Circulation
      PubDate: 2021-10-21T01:09:06Z
      DOI: 10.1161/CIRCULATIONAHA.120.051923
       
  • Predictors of Development of Atrial Fibrillation in Patients With Embolic
           Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial

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      Authors: Maria Cecilia Bahit Ralph L. Sacco J. Donald Easton Juliane Meyerhoff Lisa Cronin Eva Kleine Claudia Grauer Martina Brueckmann Hans-Christoph Diener Renato D. Lopes Michael Brainin Philippe Lyrer Rolf Wachter Tomas Segura Christopher B. Granger INECO Neurociencias; Cardiology Department, Rosario, Argentina University of Miami, Miller School of Medicine, Miami, FL University of California–San Francisco, San Francisco, CA TA CardioMetabolism Respiratory Med, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany Clinical Development Cardiometabolism, Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada Biostatistics Pneumology, University Medicine Göttingen, Germany DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany Department of Neurology, Hospital General Universitario de Albacete, Universidad de Castilla-La Mancha, Albacete, Spain
      Abstract: Circulation, Ahead of Print.
      Background:A proportion of patients with embolic stroke of undetermined source (ESUS) have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke due to underlying AF. The RE-SPECT ESUS trial provides an opportunity to assess predictors for developing AF and associated recurrent stroke.Methods:RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with ESUS. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses were performed to define predictors of AF.Results:In the multivariable model, older age (odds ratio [OR] for 10-year increase 1.99 [1.78-2.23]; P<0.001), hypertension (1.36 [1.03-1.79]; P=0.0304), diabetes (OR 0.74 [0.56-0.96]; P=0.022), and body mass index (OR for 5-unit increase 1.29 [1.16-1.43]; P<0.001) were independent predictors of AF during the study. In a sensitivity analysis restricted to 1117 patients with baseline N-terminal prohormone of brain natriuretic peptide (NT-proBNP) measurements, only older age and higher NT-proBNP were significant independent predictors of AF. Performances of several published predictive models were assessed, including the HAVOC and CHA2DS2-VASc scores, and higher scores were associated with higher rates of developing AF.Conclusions:Besides age as the most important variable, several other factors, including hypertension, higher body mass index, and lack of diabetes, are independent predictors of AF after ESUS. When baseline NT-proBNP was available, only older age and elevation of this biomarker were predictive of subsequent AF. Understanding who is at higher risk of developing AF will assist in identifying patients who may benefit from more intense, long-term cardiac monitoring.
      Citation: Circulation
      PubDate: 2021-10-15T09:00:05Z
      DOI: 10.1161/CIRCULATIONAHA.121.055176
       
  • Loss of Mitochondrial Ca2+ Uniporter Limits Inotropic Reserve and Provides
           Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy

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      Authors: Edoardo Bertero Alexander Nickel Michael Kohlhaas Mathias Hohl Vasco Sequeira Carolin Brune Julia Schwemmlein Marco Abeßer Kai Schuh Ilona Kutschka Christopher Carlein Kai Münker Sarah Atighetchi Andreas Müller Andrey Kazakov Reinhard Kappl Karina von der Malsburg Martin van der Laan Anna-Florentine Schiuma Michael Böhm Ulrich Laufs Markus Hoth Peter Rehling Michaela Kuhn Jan Dudek Alexander von der Malsburg Leticia Prates Roma Christoph Maack Department of Translational Research; Comprehensive Heart Failure Center, University Clinic Würzburg, Germany; Chair of Cardiovascular Disease, Department of Internal Medicine Molecular Biology, Center for Molecular Signaling, PZMS, Faculty of Medicine, Saarland University, Homburg/Saar, Germany Clinic for Internal Medicine III, Saarland University Clinic, Homburg/Saar, Germany; Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Germany (current address) Department of Cellular Biochemistry, Georg-August University, Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Germany; Max-Planck Institute for Biophysical Chemistry, D-37077, Göttingen, Germany Department of Translational Research, Comprehensive Heart Failure Center, University Clinic Würzburg, Germany; Department of Cellular Biochemistry, Georg-August University, Göttingen, Germany Department of Translational Research, Comprehensive Heart Failure Center, University Clinic Würzburg, Germany; Clinic for Internal Medicine III, Saarland University Clinic, Homburg/Saar, Germany; Department for Internal Medicine 1, University Clinic Würzburg, Germany
      Abstract: Circulation, Ahead of Print.
      Background:Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Since mitochondrial function and ROS formation are regulated by excitation-contraction (EC) coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy.Methods:We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz-KD) compared to wild-type (WT) littermates. Respiratory chain assembly and function, ROS emission, and Ca2+uptake were determined in isolated mitochondria. EC coupling was integrated with mitochondrial redox state, ROS, and Ca2+uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzedin vivo.Results:Taz-KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca2+affinity and slowed cross-bridge cycling caused diastolic dysfunction, partly compensated by accelerated diastolic Ca2+decay through preactivated sarcoplasmic reticulum Ca2+ATPase (SERCA).Tazdeficiency provoked heart-specific loss of mitochondrial Ca2+uniporter (MCU) protein that prevented Ca2+-induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes.In vivo,Taz-KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+export via the mitochondrial Na+/Ca2+exchanger. All alterations occurred in the absence of excess mitochondrial ROSin vitroorin vivo.Conclusions:Downregulation of MCU, increased myofilament Ca2+affinity, and preactivated SERCA provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.
      Citation: Circulation
      PubDate: 2021-10-14T06:07:48Z
      DOI: 10.1161/CIRCULATIONAHA.121.053755
       
  • Long Non-coding RNA MIAT Controls Advanced Atherosclerotic Lesion
           Formation and Plaque Destabilization

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      Authors: Francesca Fasolo Hong Jin Greg Winski Ekaterina Chernogubova Jessica Pauli Hanna Winter Daniel Y. Li Nadiya Glukha Sabine Bauer Susanne Metschl Zhiyuan Wu Marlys L. Koschinsky Muredach Reilly Jaroslav Pelisek Wolfgang Kempf Hans-Henning Eckstein Oliver Soehnlein Ljubica Matic Ulf Hedin Alexandra Bäcklund Claes Bergmark Valentina Paloschi Lars Maegdefessel Department for Vascular; Surgery, Karolinska Institutet, Stockholm, Sweden
      Abstract: Circulation, Ahead of Print.
      Background:Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The current study assessed the functional contribution of the lncRNA Myocardial Infarction Associated Transcript (MIAT) to atherosclerosis and carotid artery disease.Methods:We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies (BiKE). The lncRNAMIATwas identified as the most upregulated non-coding RNA transcript in carotid plaques compared to non-atherosclerotic control arteries, which was confirmed by quantitative real time PCR (qRT-PCR) andin situhybridization.Results:Experimental knockdown ofMIAT, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs), but also increased their apoptosis. Mechanistically,MIATregulated SMC proliferation via the EGR1-ELK1-ERK pathway.MIATis further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region ofKLF4and enhancing its transcription. Studies usingMiat−/−andMiat−/−ApoE−/−mice as well as YucatanLDLR−/−mini-pigs confirmed the regulatory role of this lncRNA in SMC de- and trans-differentiation and advanced atherosclerotic lesion formation.Conclusions:The lncRNAMIATis a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs as well as the pro-inflammatory properties of macrophages.
      Citation: Circulation
      PubDate: 2021-10-14T02:19:41Z
      DOI: 10.1161/CIRCULATIONAHA.120.052023
       
  • Systems of Care for ST-Segment–Elevation Myocardial Infarction: A Policy
           Statement From the American Heart Association

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      Authors: Alice K. Jacobs Murtuza J. Ali Patricia J. Best Mark C. Bieniarz Vincent J. Bufalino William J. French Timothy D. Henry Lori Hollowell Edward C. Jauch Michael C. Kurz Michael Levy Puja Patel Travis Spier R. Harper Stone Katie L. Tataris Randal J. Thomas Jessica K. Zègre-Hemsey
      Abstract: Circulation, Ahead of Print.
      The introduction of Mission: Lifeline significantly increased timely access to percutaneous coronary intervention for patients with ST-segment–elevation myocardial infarction (STEMI). In the years since, morbidity and mortality rates have declined, and research has led to significant developments that have broadened our concept of the STEMI system of care. However, significant barriers and opportunities remain. From community education to 9-1-1 activation and emergency medical services triage and from emergency department and interfacility transfer protocols to postacute care, each critical juncture presents unique challenges for the optimal care of patients with STEMI. This policy statement sets forth recommendations for how the ideal STEMI system of care should be designed and implemented to ensure that patients with STEMI receive the best evidence-based care at each stage in their illness.
      Citation: Circulation
      PubDate: 2021-10-13T09:00:03Z
      DOI: 10.1161/CIR.0000000000001025
       
  • Reduction in Acute Limb Ischemia with Rivaroxaban versus Placebo in
           Peripheral Artery Disease after Lower Extremity Revascularization:
           Insights from VOYAGER PAD

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      Authors: Connie N. Hess E. Sebastian Debus Mark R. Nehler Sonia S. Anand Manesh R. Patel Michael Szarek Warren H. Capell Judith Hsia Joshua A. Beckman Marianne Brodmann Rafael Diaz Peter Habertheuer Nicholas J. Leeper Richard J. Powell Henrik Sillesen Eva Muehlhofer Scott D. Berkowitz Lloyd P. Haskell Rupert M. Bauersachs Marc P. Bonaca Division of Cardiology; Department of Medicine, University of Colorado School of Medicine, Aurora, CO; CPC Clinical Research, Aurora, CO Department of Vascular Medicine, Vascular Surgery – Angiology – Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany CPC Clinical Research, Aurora, CO; University of Colorado School of Medicine, Department of Surgery, Aurora, CO Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Duke Clinical Research Institute, Division of Cardiology, Duke University Medical Center, Durham, NC Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO; CPC Clinical Research, Aurora, CO; The State University of New York Downstate Health Sciences University, Brooklyn, NY CPC Clinical Research, Aurora, CO; Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN Division of Angiology, Medical University Graz, Austria Instituto Cardiovascular de Rosario, Rosario, Argentina Vascular Surgery, Konventhospital Barmherzige Brüder Linz, Austria Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford CA Section of Vascular Surgery, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH Department of Vascular Surgery, Rigshospitalet, University of Copenhagen, Denmark Bayer AG, Research & Development, Wuppertal, Germany Bayer US LLC, Whippany, NJ Janssen Research Hemostasis, University of Mainz, Mainz
      Abstract: Circulation, Ahead of Print.
      Background:Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Prior lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking.Methods:VOYAGER PAD (NCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan Meier estimates, and Cox proportional-hazards models were used to generate hazard ratios and associated confidence intervals. Analyses were performed as intention-to-treat.Results:Among 6,564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, prior LER, baseline ABI <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (HR 2.59, 95% CI 1.98-3.39) and major amputation (HR 24.87, 95% CI 18.68-33.12). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction 2.6% at 3 years, HR 0.67, 95% CI 0.55-0.82, P=0.0001), with benefit starting early (HR 0.45, 95% CI 0.24-0.85, P=0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and ICU stay, HR 0.58, 95% CI 0.40-0.83, P=0.003) and regardless of LER type (surgical vs endovascular revascularization, p-interaction=0.42) or clopidogrel use (p-interaction=0.59).Conclusions:After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.
      Citation: Circulation
      PubDate: 2021-10-12T04:03:23Z
      DOI: 10.1161/CIRCULATIONAHA.121.055146
       
  • Interferon-gamma Impairs Human Coronary Artery Endothelial Glucose
           Metabolism via Tryptophan Catabolism and Activates Fatty Acid Oxidation

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      Authors: Laurel Yong-Hwa Lee William M. Oldham Huamei He Ruisheng Wang Ryan Mulhern Diane E. Handy Joseph Loscalzo Division of Cardiovascular Medicine; Department of Medicine, Brigham Harvard Medical School, Boston, MA
      Abstract: Circulation, Ahead of Print.
      Background:Endothelial cells depend on glycolysis for much of their energy production. Impaired endothelial glycolysis has been associated with various vascular pathobiologies, including impaired angiogenesis and atherogenesis. Interferon-gamma (IFN-γ)-producing CD4+and CD8+T-lymphocytes have been identified as the predominant pathologic cell subsets in human atherosclerotic plaques. While the immunological consequences of these cells have been extensively evaluated, their IFN-γ-mediated metabolic effects on endothelial cells remain unknown. The purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine, IFN-γ, on human coronary artery endothelial cells (HCAEC).Methods:The metabolic effects of IFN-γon primary HCAEC were assessed by unbiased transcriptomic and metabolomic analyses combined with real-time extracellular flux analyses and molecular mechanistic studies. Cellular phenotypic correlations were made by measuring altered endothelial intracellular cyclic guanosine monophosphate (cGMP) content, wound healing capacity, and adhesion molecule expression.Results:IFN-γexposure inhibited basal glycolysis of quiescent primary HCAEC by 20% through the global transcriptional suppression of glycolytic enzymes resulting from decreased basal hypoxia inducible factor 1α (HIF1α) nuclear availability in normoxia. The decrease in HIF1α activity was a consequence of IFN-γ-induced tryptophan catabolism resulting in ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF1β sequestration by the kynurenine-activated aryl hydrocarbon receptor (AHR). Additionally, IFN-γresulted in a 23% depletion of intracellular NAD+in HCAEC. This altered glucose metabolism was met with concomitant activation of fatty acid oxidation, which augmented its contribution to intracellular ATP balance by over 20%. These metabolic derangements were associated with adverse endothelial phenotypic changes, including decreased basal intracellular cGMP, impaired endothelial migration, and a switch to a pro-inflammatory state.Conclusions:IFN-γimpairs endothelial glucose metabolism via altered tryptophan catabolism destabilizing HIF1, depletes NAD+, and results in a metabolic shift toward increased fatty acid oxidation. This work suggests a novel mechanistic basis for pathologic T-lymphocyte-endothelial interactions in atherosclerosis mediated by IFN-γ, linking endothelial glucose, tryptophan, and fatty acid metabolism with NAD(H) and ATP generation, and their adverse endothelial functional consequences.
      Citation: Circulation
      PubDate: 2021-10-12T03:18:48Z
      DOI: 10.1161/CIRCULATIONAHA.121.053960
       
  • Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the
           Endothelium

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      Authors: Miguel Sáinz-Jaspeado Ross O. Smith Oscar Plunde Sven-Christian Pawelzik Yi Jin Sofia Nordling Yindi Ding Pontus Aspenström Marie Hedlund Giulia Bastianello Flora Ascione Qingsen Li Cansaran Saygili Demir Dinesh Fernando Geoffrey Daniel Anders Franco-Cereceda Jeffrey Kroon Marco Foiani Tatiana V. Petrova Manfred W. Kilimann Magnus Bäck Lena Claesson-Welsh Uppsala University; Rudbeck, Beijer Technology, Uppsala, Sweden University of Amsterdam, Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, The Netherlands Uppsala University, Dept. of Neuroscience, Uppsala, Sweden; Max Planck Institute for Experimental Medicine, Department of Molecular Neurobiology, Göttingen, Germany
      Abstract: Circulation, Ahead of Print.
      Background:Palmdelphin (PALMD) belongs to the family of Paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms (SNPs) in thePALMDlocus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis (CAVS) and predict severity of the disease.Methods:Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, co-immunoprecipitation and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in siRNA-treated EC cultures, in knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the SNP rs7543130, informed about gene regulatory changes.Results:ECs express the cytosolicPALMD-KKVIsplice variant, which associated with RAN GTPase activating protein1 (RANGAP1). RANGAP1 regulates the activity of the GTPase RAN and thereby, nucleocytoplasmic shuttling via Exportin1 (XPO1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently, in gene regulation due to the impact on localization of transcriptional regulators. Changes in EC responsiveness upon loss ofPALMDexpression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed inPALMD-deficient ECs,Palmd−/−mouse aorta and human aortic valve samples derived from CAVS patients. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms inPALMD-silenced ECs.Conclusions:We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reducedPALMDexpression provide a mechanistic underpinning for PALMD's contribution to CAVS pathology.
      Citation: Circulation
      PubDate: 2021-10-12T02:55:03Z
      DOI: 10.1161/CIRCULATIONAHA.121.054182
       
  • Effect of Long-Term Marine Omega-3 Fatty Acids Supplementation on the Risk
           of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular
           Outcomes: A Systematic Review and Meta-Analysis

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      Authors: Baris Gencer Luc Djousse Omar T. Al-Ramady Nancy R. Cook JoAnn E. Manson Christine M. Albert Cardiology division; Geneva University Hospitals, Geneva Switzerland; Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland Department of Medicine, Brigham Women's Hospital, Boston, MA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA Department of Cardiology, Smidt Heart institute, Cedars Sinai Medical Center (CMA), Los Angeles, CA
      Abstract: Circulation, Ahead of Print.
      Background:Some, but not all, large-scale randomized controlled trials (RCTs) investigating the effects of marine omega-3 fatty acids supplementation on cardiovascular outcomes have reported increased risks of atrial fibrillation (AF). The potential reasons for disparate findings may be dose related.Methods:The MEDLINE and Embase databases were searched for articles and abstracts published between January 1, 2012 and December 31, 2020 in addition to a meta-analysis of large cardiovascular RCTs published in 2019. RCTs of cardiovascular outcomes of marine omega-3 fatty acids that reported results for AF, either as pre-specified outcome, adverse event, or a cause for hospitalization, with a minimum sample size of 500 patients and a median followup of at least one year were included. RCTs specifically examining shorter term effects of omega-3 fatty acids on recurrent AF in patients with established AF or post-operative AF were not included. The hazard ratio (HR) for the reported AF outcomes within each trial was metaanalyzed using random-effects model with Knapp-Hartung adjustment and evaluated a doseresponse relationship with a meta-regression model.Results:Of 4049 screened records, seven studies were included in the meta-analysis. Of those, five were already detected in a previous meta-analysis of cardiovascular RCTs. Among the 81,210 patients from 7 trials, 58,939 (72.6%) were enrolled in trials testing ≤1gram per day (g/d) and 22,271 (27.4%) in trials testing >1g/d of omega-3 fatty acids. The mean age was 65 years and 31,842 (39%) were female. The weighted average follow-up was 4.9 years. In meta-analysis, the use of marine omega-3 fatty acid supplements was associated with an increased risk of AF (n=2,905; HR 1.25, 95%CI 1.07-1.46, P=0.013). In analyses stratified by dose, the HR was greater in the trials testing >1g/d (HR 1.49, 95%CI 1.04-2.15, P=0.042) as compared with those testing ≤1 g/d (HR 1.12, 95%CI 1.03-1.22, P=0.024, P for interaction<0.001). In metaregression, the HR for AF increased per 1 gr increase of omega-3 fatty acids dosage (HR 1.11, 95%CI 1.06-1.15, P=0.001).Conclusions:In RCTs examining cardiovascular outcomes, marine omega-3 supplementation was associated with an increased risk of AF. The risk appeared to be greater in trials testing >1g/d.
      Citation: Circulation
      PubDate: 2021-10-06T12:00:22Z
      DOI: 10.1161/CIRCULATIONAHA.121.055654
       
  • Diagnosis and Management of Patients With Myocardial Injury After
           Noncardiac Surgery: A Scientific Statement From the American Heart
           Association

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      Authors: Kurt Ruetzler Nathaniel R. Smilowitz Jeffrey S. Berger P.J. Devereaux Bradley A. Maron L. Kristin Newby Vinicio de Jesus Perez Daniel I. Sessler Duminda N. Wijeysundera
      Abstract: Circulation, Ahead of Print.
      Myocardial injury after noncardiac surgery is defined by elevated postoperative cardiac troponin concentrations that exceed the 99th percentile of the upper reference limit of the assay and are attributable to a presumed ischemic mechanism, with or without concomitant symptoms or signs. Myocardial injury after noncardiac surgery occurs in ≈20% of patients who have major inpatient surgery, and most are asymptomatic. Myocardial injury after noncardiac surgery is independently and strongly associated with both short-term and long-term mortality, even in the absence of clinical symptoms, electrocardiographic changes, or imaging evidence of myocardial ischemia consistent with myocardial infarction. Consequently, surveillance of myocardial injury after noncardiac surgery is warranted in patients at high risk for perioperative cardiovascular complications. This scientific statement provides diagnostic criteria and reviews the epidemiology, pathophysiology, and prognosis of myocardial injury after noncardiac surgery. This scientific statement also presents surveillance strategies and treatment approaches.
      Citation: Circulation
      PubDate: 2021-10-04T09:00:11Z
      DOI: 10.1161/CIR.0000000000001024
       
  • Combined Associations of Changes in Noncombustible Nicotine or Tobacco
           Product and Combustible Cigarette Use Habits With Subsequent Short-Term
           Cardiovascular Disease Risk Among South Korean Men: A Nationwide Cohort
           Study

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      Authors: Seulggie Choi Kiheon Lee Sang Min Park Department of Biomedical Sciences; Seoul National University College of Medicine, South Korea Department of Family Medicine, Seoul National University College of Medicine, South Korea; Department of Family Medicine, Seoul National University Bundang Hospital, South Korea Department of Biomedical Sciences, Department of Family Medicine, Seoul National University College of Medicine, South Korea; Department of Family Medicine, Seoul National University Hospital, South Korea
      Abstract: Circulation, Ahead of Print.

      Citation: Circulation
      PubDate: 2021-10-04T09:00:03Z
      DOI: 10.1161/CIRCULATIONAHA.121.054967
       
  • Phenotypic Expression, Natural History and Risk Stratification of
           Cardiomyopathy Caused by Filamin C Truncating Variants

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      Authors: Marta Gigli Davide Stolfo Sharon Graw Marco Merlo Caterina Gregorio Suet Nee Chen Matteo Dal Ferro Alessia Paldino Giulia De Angelis Francesca Brun Jean Jirikowic Ernesto E. Salcedo Sylvia Turja Diane Fatkin Renee Johnson J. Peter van Tintelen Anneline S.J.M. Te Riele Arthur Wilde Neal K. Lakdawala Kermshlise Picard Daniela Miani Daniele Muser Giovanni Maria Severini Hugh Calkins Cynthia A. James Brittney Murray Crystal Tichnell Victoria N. Parikh Euan A. Ashley Chloe Reuter Jiangping Song Daniel Judge William J. McKenna Matthew R.G. Taylor Gianfranco Sinagra Luisa Mestroni Cardiothoracovascular Department; Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy Cardiothoracovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy; Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Cardiovascular Institute Child Health, IRCCS Burlo Garofolo, Trieste, Italy Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD Stanford Center for Inherited Cardiovascular Disease, Stanford, CA National Center for Cardiovascular Diseases in Beijing, Beijing, China Medical University of South Carolina, Charleston, SC Institute of Cardiovascular Science, University College of London, London, United Kingdom
      Abstract: Circulation, Ahead of Print.
      Background:Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy (ACM): the mode of presentation, natural history and risk stratification ofFLNCtvremain incompletely explored. We sought to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort ofFLNCtvcarriers.Methods:FLNCtvcarriers were identified from ten tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), non-arrhythmic death/HT/LVAD and SCD/major ventricular arrhythmias (SCD/MVA). Previously established cohorts of 46 patients withLMNAand 60 withDSP-related ACM were used for prognostic comparison.Results:Eighty-five patients carryingFLNCtvwere included (42±15 years, 53% males, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction (LVEF) was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/ right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) non-arrhythmic death/HT/LVAD and 23 (27%) SCD/MVA. The SCD/MVA incidence ofFLNCtvcarriers did not significantly differ fromLMNAcarriers andDSPcarriers. InFLNCtvcarriers, LVEF was associated with the risk of D/HT/LVAD and non-arrhythmic death/HT/LVAD. CConclusions:Among patients referred to tertiary referral centers,FLNCtvACM is phenotypically heterogeneous and characterized by high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of LV dysfunction.
      Citation: Circulation
      PubDate: 2021-09-30T09:00:25Z
      DOI: 10.1161/CIRCULATIONAHA.121.053521
       
  • Epigenetic Age and the Risk of Incident Atrial Fibrillation

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      Authors: Jason D. Roberts Eric Vittinghoff Ake T. Lu Alvaro Alonso Biqi Wang Colleen M. Sitlani Pedrum Mohammadi-Shemirani Myriam Fornage Jelena Kornej Jennifer A. Brody Dan E. Arking Honghuang Lin Susan R. Heckbert Ivana Prokic Mohsen Ghanbari Allan C. Skanes Traci M. Bartz Marco V. Perez Kent D. Taylor Steven A. Lubitz Patrick T. Ellinor Kathryn L. Lunetta James S. Pankow Guillaume Paré Nona Sotoodehnia Emelia J. Benjamin Steve Horvath Gregory M. Marcus Population Health Research Institute; McMaster University, Boston University's Framingham Heart Study, Framingham, MA; Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA; Department of Epidemiology, Boston University School of Public Health, Boston, MA Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; Department of Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, CA
      Abstract: Circulation, Ahead of Print.
      Background:The most prominent risk factor for atrial fibrillation (AF) is chronological age, however underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge, a phenomenon termed epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.Methods:Measures for 4 epigenetic clocks (Horvath, Hannum, DNAm PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 levels (DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analysis. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.Results:Among 5,600 individuals (mean age: 65.5 years; 60.1% female; 50.7% black), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. Following multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR]: 1.19; 95% confidence intervals [CI]: 1.09-1.31; p<0.01) and 15% (adjusted HR: 1.15; 95% CI: 1.05-1.25; p<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.Conclusions:Our study identified adjusted associations between EAA measures and incident AF, suggesting biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.
      Citation: Circulation
      PubDate: 2021-09-30T09:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.056456
       
  • Integrated Stress Response Couples Mitochondrial Protein Translation with
           Oxidative Stress Control

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      Authors: Guangyu Zhang Xiaoding Wang Chao Li Qinfeng Li Yu A. An Xiang Luo Yingfeng Deng Thomas G. Gillette Philipp E. Scherer Zhao V. Wang Division of Cardiology; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
      Abstract: Circulation, Ahead of Print.
      Background:The integrated stress response (ISR) is an evolutionarily conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery reperfusion is the most effective means to mitigate cardiac damage of myocardial infarction, which however causes additional reperfusion injury. This study aimed to investigate the role of the ISR in myocardial ischemia/reperfusion (I/R).Methods:Cardiac-specific gain- and loss-of-function approaches for the ISR were employedin vivo. Myocardial I/R was achieved by the ligation of the cardiac left anterior descending artery for 45 minutes, followed by reperfusion for different times. Cardiac function was assessed by echocardiography. Additionally, cultured H9c2 cells, primary rat cardiomyocytes, and mouse embryonic fibroblasts were used to dissect underlying molecular mechanisms. Moreover, tandem mass tag (TMT) labeling and mass spectrometry was conducted to identify protein targets of the ISR. Pharmacological means were tested to manipulate the ISR for therapeutic exploration.Results:We show that the PERK/eIF2α axis of the ISR is strongly induced by I/R in cardiomyocytesin vitroandin vivo. We further reveal a physiological role of PERK/eIF2α signaling by showing that acute activation of PERK in the heart confers robust cardioprotection against reperfusion injury. In contrast, cardiac-specific deletion of PERK aggravates cardiac responses to reperfusion. Mechanistically, the ISR directly targets mitochondrial complexes via translational suppression. We identify NDUFAF2, an assembly factor of mitochondrial complex I, as a selective target of PERK. Overexpression of PERK suppresses the protein expression of NDUFAF2 while PERK inhibition causes an increase of NDUFAF2. Silencing of NDUFAF2 significantly rescues cardiac cell survival from PERK knockdown under I/R. Further, we show that activation of PERK/eIF2α signaling reduces mitochondrial complex-derived reactive oxygen species and improves cardiac cell survival in response to I/R. Moreover, pharmacological stimulation of the ISR protects the heart against reperfusion damage, even after the restoration of occluded coronary artery, highlighting a clinical relevance for myocardial infarction treatment.Conclusions:These studies suggest that the ISR improves cell survival and mitigate reperfusion damage by selectively suppressing mitochondrial protein synthesis and reducing oxidative stress in the heart.
      Citation: Circulation
      PubDate: 2021-09-29T09:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.120.053125
       
  • Incidence and Predictors of Progression to Chagas Cardiomyopathy:
           Long-Term Follow-Up of Trypanosoma Cruzi Seropositive Individuals

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      Authors: Maria Carmo P. Nunes Lewis F. Buss Jose Luiz P. da Silva Larissa Natany Almeida Martins Claudia Di Lorenzo Oliveira Clareci Silva Cardoso Bruno Oliveira de Figueiredo Brito Ariela Mota Ferreira Lea Campos Oliveira Ana Luiza Bierrenbach Fabio Fernandes Michael P. Busch Viviane Tiemi Hotta Luiz Mario Baptista Martinelli Maria Carolina F. Almeida Soeiro Adriana Brentegani Vera M.C. Salemi Marcia M. Menezes Antonio Luiz P. Ribeiro Ester Cerdeira Sabino Hospital das Clínicas; Education Institute - Hospital Sírio-Libanês, São Paulo, SP, Brazil Instituto do Coração/ Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil Blood Systems Research Institute, San Francisco, CA Instituto de Medicina Tropical e Departamento de Moléstias Infecciosas e Parasitarias da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
      Abstract: Circulation, Ahead of Print.
      Background:There are few contemporary cohorts ofTrypanosoma cruzi-seropositive individuals, and the basic clinical epidemiology of Chagas disease is poorly understood. Herein, we report the incidence of cardiomyopathy and death associated withT. cruziseropositivity.Methods:Participants were selected in blood banks at 2 Brazilian centers. Cases were defined asT. cruzi-seropositive blood donors.T. cruzi-seronegative controls were matched for age, sex, and period of donation. Patients with established Chagas cardiomyopathy were recruited from a tertiary outpatient service. Participants underwent medical examination, blood collection, electrocardiogram, and echocardiogram at enrollment (2008 to 2010) and at follow-up (2018 to 2019). The primary outcomes were all-cause mortality and development of cardiomyopathy, defined as the presence of a left ventricular ejection fraction <50% and/or QRS complex duration ≥ 120 ms. To handle loss to follow-up, a sensitivity analysis was performed using inverse probability weights for selection.Results:We enrolled 499T. cruzi-seropositive donors (age 48 ± 10 years, 52% male), 488T. cruzi-seronegative donors (age 49 ± 10 years, 49% male), and 101 patients with established Chagas cardiomyopathy (age 48 ± 8 years, 59% male). The mortality in patients with established cardiomyopathy was 80.9 deaths/1000 person-years (py) (54/101, 53%) and 15.1 deaths/1000py (17/114, 15%) inT. cruzi-seropositives with cardiomyopathy at baseline. AmongT. cruzi-seropositive donors without cardiomyopathy at baseline mortality was 3.7 events/1000py (15/385, 4%), which was no different fromT. cruzi-seronegative donors with 3.6 deaths/1000py (17/488, 3%). The incidence of cardiomyopathy inT. cruzi-seropositive donors was 13.8 (95% CI 9.5-19.6) events/1000py (32/262, 12%) compared with 4.6 (95% CI 2.3-8.3) events/1000 py (11/277, 4%) in seronegative controls, with an absolute incidence difference associated withT. cruziseropositivity of 9.2 (95% CI 3.6 - 15.0) events/1000py.T. cruziantibody level at baseline was associated with development of cardiomyopathy (adjusted OR of 1.4, 95% CI 1.1-1.8).Conclusions:We present a comprehensive description of the natural history ofT. cruziseropositivity in a contemporary patient population. The results highlight the central importance of anti-T. cruziantibody titer as a marker of Chagas disease activity and risk of progression.
      Citation: Circulation
      PubDate: 2021-09-27T09:01:05Z
      DOI: 10.1161/CIRCULATIONAHA.121.055112
       
  • Outcomes of Participants with Diabetes in the ISCHEMIA Trials

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      Authors: Jonathan D. Newman Rebecca Anthopolos G. B. John Mancini Sripal Bangalore Harmony R. Reynolds Dennis F. Kunichoff Roxy Senior Jesus Peteiro Balram Bhargava Pallav Garg Jorge Escobedo Rolf Doerr Tomasz Mazurek Jose Gonzalez-Juanatey Grzegorz Gajos Carlo Briguori Hong Cheng Andras Vertes Sandeep Mahajan Luis A. Guzman Matyas Keltai Aldo P. Maggioni Gregg W. Stone Jeffrey S. Berger Yves D. Rosenberg William E. Boden Bernard R. Chaitman Jerome L. Fleg Judith S. Hochman David J. Maron NYU Grossman School of Medicine; New York, NY Center for Cardiovascular Innovation, University of British Columbia, Vancouver, British Columbia, Canada Northwick Park Hospital-Royal Brompton Hospital, London, UK CHUAC, Universidad de A Coruña, CIBERCV, A Coruna, Spain AIIMS, New Delhi, India London Health Sciences Center, Western University, London, Ontario, Canada Instituto Mexicano del Seguro Social, Mexico City, Mexico Praxisklinik Herz und Gefaesse, Dresden, Germany Medical University of Warsaw, Warsaw, Poland Cardiology Department, Hospital Clínico Universitario. IDIS, CIBERCV Institution, Santiago de Compostela, Spain Department of Coronary Disease Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, Cardiovascular Research Foundation, New York, NY National Institute of Health- NHLBI, Bethesda, MD VA New England Healthcare System, Boston University School of Medicine, Boston, MA St Louis University School of Medicine Center for Comprehensive Cardiovascular Care, St. Louis, MO Department of Medicine, Stanford University, Stanford, CA
      Abstract: Circulation, Ahead of Print.
      Background:Among patients with diabetes mellitus (diabetes) and chronic coronary disease (CCD), it is unclear if invasive management improves outcomes when added to medical therapy.Methods:The ISCHEMIA Trials (ISCHEMIA and ISCHEMIA CKD) randomized CCD patients to an invasive (medical therapy + angiography and revascularization if feasible) or a conservative approach (medical therapy alone with revascularization if medical therapy failed). Cohorts were combined after no trial-specific effects were observed. Diabetes was defined by history, HbA1c ≥6.5%, or use of glucose-lowering medication. The primary outcome was all-cause death or myocardial infarction (MI). Heterogeneity of effect of invasive management on death or MI was evaluated using a Bayesian approach to protect against random high or low estimates of treatment effect for patients with vs. without diabetes and for diabetes subgroups of clinical (female sex and insulin use) and anatomic features (coronary artery disease [CAD] severity or left ventricular function).Results:Of 5,900 participants with complete baseline data, the median age was 64 years interquartile range (IQR) [57-70], 24% were female, and the median estimated glomerular filtration was 80 ml/min/1.732IQR [64-95]. Among the 2,553 (43%) of participants with diabetes, median percent hemoglobin A1c was 7% IQR [7-8%], and 30% were insulin treated. Participants with diabetes had a 49% increased hazard of death or MI (HR 1.49; 95% CI: 1.31-1.70, P<0.001). At median 3.1-year follow-up the adjusted event-free survival was 0.54 (95% bootstrapped CI: 0.48, 0.60) and 0.66 (95% bootstrapped CI: 0.61, 0.71) for patients with vs. without diabetes - a 12% (95% bootstrapped CI: 4%, 20%) absolute decrease in event-free survival among participants with diabetes. Female and male patients with insulin-treated diabetes had an adjusted event-free survival of 0.52 (95% bootstrapped CI: 0.42, 0.56) and 0.49 (95% bootstrapped CI: 0.42, 0.56), respectively. There was no difference in death or MI between strategies for patients with vs. without diabetes, or for clinical (female sex or insulin use) or anatomic features (CAD severity or left ventricular function) of patients with diabetes.Conclusions:Despite higher risk for death or MI, CCD patients with diabetes did not derive incremental benefit from routine invasive management compared with initial medical therapy alone.Clinical Trial Registration:URL: http://www.clinicaltrials.gov Unique identifier: NCT01471522
      Citation: Circulation
      PubDate: 2021-09-15T09:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.054439
       
  • Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone
           Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A
           Multicenter Randomized Controlled Trial

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      Authors: Kai-ni Shen Wei-jun Fu Yu Wu Yu-jun Dong Zhong-xia Huang Yong-qiang Wei Chun-rui Li Chun-yan Sun Ye Chen Hui-lei Miao Yue-lun Zhang Xin-xin Cao Dao-bin Zhou Jian Li Department of Hematology; Peking Union Medical College Hospital, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing, People's Republic of China
      Abstract: Circulation, Ahead of Print.
      Background:Doxycycline was demonstrated in a retrospective study to be associated with greater survival in patients with light chain (AL) amyloidosis. Therefore, we prospectively compared the efficacy of bortezomib-cyclophosphamide-dexamethasone (CyBorD) and CyBorD combined with doxycycline for cardiac AL amyloidosis.Methods:This was a multicenter, open-label randomized controlled trial. Patients with Mayo 2004 stage II-III AL amyloidosis were included. Patients were randomized to doxycycline 100 mg twice daily along with 9 cycles of CyBorD (doxycycline group) or to 9 cycles of CyBorD alone (control group). The primary outcome was 2-year progression-free survival (PFS). PFS was defined as the time from randomization to death, hematologic progression or organ progression (heart, kidney or liver). Hematologic progression was defined based on substantial increase in free light chain. Increase in either N-terminal pro B-type natriuretic peptide or cardiac troponin was the main criterion for defining cardiac progression. Cardiac PFS, defined as the time from randomization to cardiac progression or death, was compared between groups in an exploratory analysis. The corresponding treatment hazard ratio was estimated using a Cox regression model.Results:140 patients underwent randomization, with 70 in each group. The median age was 61 (range, 33-78) years with a male: female ratio of 1.75:1. Stage II disease was present in 34 (48.6%) and 33 (47.1%) patients in the doxycycline and control groups, respectively. After a median follow-up duration of 24.4 months, 32/70 (45.7%) of patients in the doxycycline group and 30/70 (42.9%) of patients in the control group experienced progression. PFS was not significantly different between groups (hazard ratio 0.97, 95% CI, 0.59-1.60,p=0.91). Cardiac progression occurred in 29/70 (41.4%) of patients in the doxycycline group and 26/70 (37.1%) of patients in the control group. The death rates for both groups by the end of follow-up was the same, 25/70 (35.7%). There were no significant differences observed for either cardiac PFS (hazard ratio 0.91, 95% CI, 0.54-1.55,p=0.74) or overall survival (hazard ratio 1.04, 95% CI, 0.60-1.81,p=0.89).Conclusions:Our trial demonstrated that doxycycline combined with CyBorD failed to prolong PFS or cardiac PFS compared with CyBorD alone in cardiac AL amyloidosis.Clinical Trial Registration:URL: https://clinicaltrials.gov Unique Identifier: NCT03401372.
      Citation: Circulation
      PubDate: 2021-09-10T09:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.055953
       
  • Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After
           Heart Transplantation

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      Authors: Joo Myung Lee Ki Hong Choi Jin-Oh Choi Doosup Shin Yoonjee Park Juwon Kim Seung Hun Lee Darae Kim Jeong Hoon Yang Yang Hyun Cho Kiick Sung Ji Yeon Choi Meesoon Park Jung-Sun Kim Taek Kyu Park Young Bin Song Joo-Yong Hahn Seung-Hyuk Choi Hyeon-Cheol Gwon Jae K. Oh Eun-Seok Jeon Division of Cardiology; Department of Internal Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA Division of Cardiology, Department of Internal Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Internal Medicine Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Division of Cardiology, Department of Internal Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN
      Abstract: Circulation, Ahead of Print.
      Background:Acute cellular rejection is a major determinant of mortality and re-transplantation after heart transplantation. We sought to evaluate prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for risk of acute cellular rejection after heart transplantation.Methods:The current study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiologic assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure × hyperemic mean transit time. The primary endpoint was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared using multivariable Cox proportional hazard regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of c-index, net reclassification index (NRI), and integrated discrimination index (IDI).Results:Mean age of recipients was 51.2±13.1 years (81.2% male), and cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 vs. 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-unit increase: adjusted HR 1.18, 95% CI 1.04-1.34, P=0.011) and the optimal cut-off value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% vs. 3.8%, adjusted HR 15.3, 95% CI 3.6-65.7, P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 vs. 0.74, P<0.001; NRI 1.05, P<0.001, IDI 0.20, P<0.001).Conclusions:Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation.Clinical Trial Registration:URL: https://clinicaltrials.gov Unique Identifier: NCT02798731
      Citation: Circulation
      PubDate: 2021-09-03T09:00:02Z
      DOI: 10.1161/CIRCULATIONAHA.121.056158
       
  • Influenza Vaccination after Myocardial Infarction: A Randomized,
           Double-Blind, Placebo-Controlled, Multicenter Trial

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      Authors: Ole Frøbert Matthias Götberg David Erlinge Zubair Akhtar Evald H. Christiansen Chandini R. MacIntyre Keith G. Oldroyd Zuzana Motovska Andrejs Erglis Rasmus Moer Ota Hlinomaz Lars Jakobsen Thomas Engstrøm Lisette O. Jensen Christian O. Fallesen Svend E. Jensen Oskar Angerås Fredrik Calais Amra Kåregren Jörg Lauermann Arash Mokhtari Johan Nilsson Jonas Persson Per Stalby Abu K.M.M. Islam Afzalur Rahman Fazila Malik Sohel Choudhury Timothy Collier Stuart J. Pocock John Pernow Örebro University; Faculty of Health, Department of Cardiology, Örebro, Sweden Department of Cardiology, Skane University Hospital, Clinical Sciences, Lund University, Lund, Sweden International Centre for Diarrhoeal Disease Research, Bangladesh, (icddr, b) Dhaka, Bangladesh Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark The Kirby Institute, UNSW Medicine, University of New South Wales, Sydney, New South Wales, Australia British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular Karolinska University Hospital, Stockholm, Sweden
      Abstract: Circulation, Ahead of Print.
      Background:Observational and small randomized studies suggest that influenza vaccine may reduce future cardiovascular events in patients with cardiovascular disease.Methods:We conducted an investigator-initiated, randomized, double-blind trial to compare inactivated influenza vaccine with saline placebo administered shortly after myocardial infarction (MI) (99.7% of patients) or high-risk stable coronary heart disease (0.3%). The primary endpoint was the composite of all-cause death, MI, or stent thrombosis at 12 months. A hierarchical testing strategy was used for the key secondary endpoints: all-cause death, cardiovascular death, MI, and stent thrombosis.Results:Due to the Covid-19 pandemic, the data safety and monitoring board decided to halt the trial before attaining the prespecified sample size. Between October 1, 2016, and March 1, 2020, 2571 participants were randomized at 30 centers across eight countries; 1290 assigned to influenza vaccine and 1281 to placebo. Over the 12-month follow-up, the primary outcome occurred in 67 participants (5.3%) assigned influenza vaccine and 91 participants (7.2%) assigned placebo (hazard ratio, 0.72; 95% confidence interval, 0.52 to 0.99; P=0.040). Rates of all-cause death were 2.9% and 4.9% (hazard ratio, 0.59; 0.39 to 0.89; P=0.010), of cardiovascular death 2.7% and 4.5%, (hazard ratio, 0.59; 0.39 to 0.90; P=0.014), and of MI 2.0% and 2.4% (hazard ratio, 0.86; 0.50 to 1.46, P=0.57) in the influenza vaccine and placebo groups, respectively.Conclusions:Influenza vaccination early after an MI or in high-risk coronary heart disease resulted in a lower risk of a composite of all-cause death, MI, or stent thrombosis, as well as a lower risk of all-cause death and cardiovascular death at 12 months compared with placebo.Clinical Trial Registration:URL: http://www.clinicaltrials.gov Unique identifier: NCT02831608
      Citation: Circulation
      PubDate: 2021-08-30T12:00:17Z
      DOI: 10.1161/CIRCULATIONAHA.121.057042
       
  • AMPLATZER™ AMULET™ LEFT ATRIAL APPENDAGE OCCLUDER VERSUS WATCHMAN™
           

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      Authors: Dhanunjaya Lakkireddy David Thaler Christopher R. Ellis Vijendra Swarup Lars Sondergaard John Carroll Michael R. Gold James Hermiller Hans-Christoph Diener Boris Schmidt Lee MacDonald Moussa Mansour Brijeshwar Maini Laura O'Brien Stephan Windecker Kansas City Heart Rhythm Institute; Research Foundation, Overland Park, KS Tufts Medical Center, Boston, MA Vanderbilt Heart Institute, Nashville, TN Arizona Cardiovascular Research Center, Phoenix, AZ Righospitalet, Copenhagen, Denmark Univ. of CO Hospital, Anschultz Med. Campus, Aurora, CO Medical University of South Carolina, Charleston, SC St. Vincent Medical Group, Inc., Indianapolis, IN University Duisburg-Essen, Essen, Germany Cardioangiologisches Centrum Bethanien, Frankfurt, Germany Cardiology, South Denver Cardiology Associates P.C., Littleton, CO, UNITED STATES Massachusetts General Hospital, Boston, MA Delray Medical Center, Delray, FL Abbott Structural Heart, Plymouth, MN Inselspital, University of Bern, Bern, Switzerland On Behalf of the Amulet IDE Investigators
      Abstract: Circulation, Ahead of Print.
      Background:Percutaneous closure of the left atrial appendage (LAA) is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with non-valvular atrial fibrillation (NVAF). The Amplatzer™ Amulet™ LAA Occluder IDE Trial (Amulet IDE Trial) was designed to evaluate the safety and effectiveness of the dual-seal mechanism of the Amulet LAA occluder compared with the Watchman™ device.Methods:Patients with NVAF at increased risk of stroke were randomly assigned (1:1) to undergo percutaneous implantation of a LAA occluder with the Amulet occluder or Watchman device. The primary endpoints included safety (composite of procedure-related complications, all-cause death, or major bleeding at 12 months) and effectiveness (composite of ischemic stroke or systemic embolism at 18 months) and the rate of LAA occlusion at 45 days. Pre-specified secondary endpoints included a composite of all stroke, systemic embolism, or cardiovascular/unexplained death at 18 months, major bleeding at 18 months, and superiority test of the three primary endpoints.Results:A total of 1878 patients were enrolled. The Amulet occluder was noninferior to the Watchman device for the primary safety endpoint (14.5% vs. 14.7%; difference=-0.14, 95% CI, -3.42-3.13; p<0.001 for noninferiority). Major bleeding and all-cause death were similar between groups (10.6% vs 10.0% and 3.9% vs 5.1%, respectively). Procedure-related complications were higher for the Amulet occluder (4.5% vs. 2.5%), largely related to more frequent pericardial effusion and device embolization. The Amulet occluder was noninferior to the Watchman device for the primary effectiveness endpoint (2.8% vs. 2.8%; difference=0.00, 95% CI, -1.55-1.55; p<0.001 for non-inferiority), and the composite of stroke, systemic embolism or cardiovascular/unexplained death (5.6% vs 7.7%, difference=-2.12, 95% CI, -4.45-0.21; p<0.001 for noninferiority). The rate of major bleeding was similar between groups (11.6% vs. 12.3%; difference=-0.71, 95% CI -3.72-2.31; p=0.32 for superiority). LAA occlusion was higher for the Amulet occluder compared with the Watchman device (98.9% vs. 96.8%; difference=2.03, 95% confidence interval [CI], 0.41-3.66; p<0.001 for noninferiority; p=0.003 for superiority).Conclusions:The Amulet occluder was non-inferior for safety and effectiveness of stroke prevention for NVAF compared with the Watchman device, and superior for LAA occlusion. Procedure-related complications were higher with the Amulet device and decreased with operator experience.Clinical Trial Registration:URL https://clinicaltrials.gov Unique Identifier NCT02879448
      Citation: Circulation
      PubDate: 2021-08-30T03:55:00Z
      DOI: 10.1161/CIRCULATIONAHA.121.057063
       
  • Native Aortic Valve Disease Progression and Bioprosthetic Valve
           Degeneration in Patients with Transcatheter Aortic Valve Implantation

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      Authors: Jacek Kwiecinski Evangelos Tzolos Timothy R.G. Cartlidge Alexander Fletcher Mhairi K. Doris Rong Bing Jason M. Tarkin Michael A. Seidman Gaurav S. Gulsin Nicholas L. Cruden Anna K. Barton Neal G. Uren Michelle C. Williams Edwin J.R. Van Beek Jonathon Leipsic Damini Dey Raj R. Makkar Piotr J. Slomka James H.F. Rudd David E. Newby Stephanie L. Sellers Daniel S. Berman Marc R. Dweck Department of Interventional Cardiology; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
      Abstract: Circulation, Ahead of Print.
      Background:There remain major uncertainties regarding disease activity within the retained native aortic valve as well as bioprosthetic valve durability following transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison to subjects with bioprosthetic surgical aortic valve replacement (SAVR).Methods:In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, CT angiography and18F-sodium fluoride (18F-NaF) positron emission tomography (PET). Participants (n=47) were imaged once with18F-NaF PET/CT either at one-month (n=9, 19%), 2 years (n=22, 47%) or 5 years (16, 34%) after valve implantation. Subsequently patients underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made to matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol.Results:In patients with TAVI, native aortic valves demonstrated18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, p=0.023).18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio 1.3 [1.2-1.7] versus 1.3 [1.2-1.5] respectively, p=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8% respectively, p=0.78), CT (15% versus 14% respectively, p=0.87) and PET (15% versus 29% respectively, p=0.09). Baseline18F-NaF uptake was associated with subsequent change in peak aortic velocity for both TAVI (r=0.7, p<0.001) and SAVR (r=0.7, p<0.001). On multivariable analysis,18F-NaF uptake was the only predictor of peak velocity progression (p<0.001).Conclusions:In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR suggesting comparable mid-term durability.Clinical Trial Registration:URL: https://www.clinicaltrials.gov/ Unique Identifier: NCT02304276
      Citation: Circulation
      PubDate: 2021-08-29T08:30:00Z
      DOI: 10.1161/CIRCULATIONAHA.121.056891
       
  • Cardiovascular Benefit of Lowering LDL Cholesterol Below 40 mg/dl

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      Authors: Nicholas A. Marston Robert P. Giugliano Jeong-Gun Park Andrea Ruzza Peter S. Sever Anthony C. Keech Marc S. Sabatine TIMI Study Group; Division of Cardiovascular Medicine, Brigham Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
      Abstract: Circulation, Ahead of Print.

      Citation: Circulation
      PubDate: 2021-08-28T06:00:01Z
      DOI: 10.1161/CIRCULATIONAHA.121.056536
       
  • Health Impact and Cost-Effectiveness of Achieving the National Salt and
           Sugar Reduction Initiative Voluntary Sugar Reduction Targets in the United
           States: A Micro-Simulation Study

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      Authors: Siyi Shangguan Dariush Mozaffarian Stephen Sy Yujin Lee Junxiu Liu Parke E. Wilde Andrea L. Sharkey Erin A. Dowling Matti Marklund Shafika Abrahams-Gessel Thomas A. Gaziano Renata Micha Friedman School of Nutrition Science; Human Nutrition, University of Thessaly, Volos, Thessaly 38221 Greece
      Abstract: Circulation, Ahead of Print.
      Background:High intake of added sugar is linked to weight gain and cardiometabolic risk. In 2018, the US National Salt and Sugar Reduction Initiative (NSSRI) proposed government supported voluntary national sugar reduction targets. This intervention's potential health and equity impacts, and cost-effectiveness are unclear.Methods:A validated microsimulation model, CVD-PREDICT, coded in C++, was used to estimate incremental changes in type 2 diabetes, cardiovascular disease (CVD), quality-adjusted life-years (QALYs), costs and cost-effectiveness of the NSSRI policy. The model was run at the individual-level, incorporating the annual probability of each person's transition between health status based on their risk factors. The model incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey across 3 cycles (2011-2016), added sugar-related diseases from meta-analyses, and policy costs and health-related costs from established sources. A simulated nationally representative US population was created and followed until age 100 years or death, with 2019 as the year of intervention start. Findings were evaluated over 10 years and a lifetime from healthcare and societal perspectives. Uncertainty was evaluated in a one-way analysis by assuming 50% industry compliance, and probabilistic sensitivity analyses via a second-order Monte Carlo approach. Model outputs included averted diabetes cases, CVD events and CVD deaths, QALYs gained, and formal healthcare cost savings, stratified by age, race, income and education.Results:Achieving the NSSRI sugar reduction targets could prevent 2.48 million CVD events, 0.49 million CVD deaths, and 0.75 million diabetes cases; gain 6.67 million QALYs; and save $160.88 billion net costs from a societal perspective over a lifetime. The policy became cost-effective (<150K/QALYs) at 6 years, highly cost-effective (< 50K/QALYs) at 7 years, and cost-saving at 9 years. Results were robust from a healthcare perspective, with lower (50%) industry compliance, and in probabilistic sensitivity analyses. The policy could also reduce disparities, with greatest estimated health gains per million adults among Black and Hispanic, lower income, and less educated Americans.Conclusions:Implementing and achieving the NSSRI sugar reformation targets could generate substantial health gains, equity gains and cost-savings.
      Citation: Circulation
      PubDate: 2021-08-27T09:00:03Z
      DOI: 10.1161/CIRCULATIONAHA.121.053678
       
  • Hemoglobin and Clinical Outcomes in the VerICiguaT Global Study in
           Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA)

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      Authors: Justin A. Ezekowitz Yinggan Zheng Alain Cohen-Solal Vojtěch Melenovský Jorge Escobedo Javed Butler Adrian F. Hernandez Carolyn S.P. Lam Christopher M. O'Connor Burkert Pieske Piotr Ponikowski Adriaan A. Voors Christopher deFilippi Cynthia M. Westerhout Ciaran McMullan Lothar Roessig Paul W. Armstrong Canadian VIGOUR Centre; University of Alberta, Edmonton, Alberta, Canada Paris University, UMR-S 942, Hôpital Lariboisière, Paris, France Department of Cardiology, Institute for Clinical Vascular Institute, Falls Church, VA Merck & Co. Inc., Kenilworth, NJ Bayer AG, Wuppertal, Germany for the VICTORIA Study Group
      Abstract: Circulation, Ahead of Print.
      Background:In the VICTORIA trial, anemia occurred more often in patients treated with vericiguat (7.6%) than placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia and whether the benefit of vericiguat related to baseline hemoglobin.Methods:Anemia was defined as hemoglobin <13.0 g/dL in men and <12.0 g/dL in women (World Health Organization [WHO] Anemia). Adverse events (AEs) reported as anemia were also evaluated. We assessed the risk-adjusted relationship between hemoglobin and hematocrit with the primary outcome (composite of cardiovascular death or heart failure hospitalization), and the time-updated hemoglobin relationship to outcomes.Results:At baseline, 1719 (35.7%) had WHO anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had WHO anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo (p<0.001). After 16 weeks, no further decline in hemoglobin occurred over 96 weeks of follow-up and the ratio of hemoglobin/hematocrit remained constant. Overall, AE anemia occurred in 342 patients (7.1%). A lower hemoglobin was unrelated to the treatment benefit of vericiguat (vs. placebo) on the primary outcome. Additionally, analysis of time-updated hemoglobin revealed no association with the treatment effect of vericiguat (vs. placebo) on the primary outcome.Conclusions:Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat.Clinical Trial Registration:Clinical Trials.gov (NCT02861534)
      Citation: Circulation
      PubDate: 2021-08-25T09:56:42Z
      DOI: 10.1161/CIRCULATIONAHA.121.056797
       
  • Effect of Empagliflozin on Worsening Heart Failure Events in Patients with
           Heart Failure and a Preserved Ejection Fraction: The EMPEROR-Preserved
           Trial

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      Authors: Milton Packer Javed Butler Faiez Zannad Gerasimos Filippatos Joao Pedro Ferreira Stuart J. Pocock Peter Carson Inder Anand Wolfram Doehner Markus Haass Michel Komajda Alan Miller Steen Pehrson John R. Teerlink Sven Schnaidt Cordula Zeller Janet M. Schnee Stefan D. Anker Baylor Heart; Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT for the EMPEROR-Preserved Trial Study Group
      First page: 1284
      Abstract: Circulation, Ahead of Print.
      Background:Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events.Methods:We randomly assigned 5988 patients with class II-IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite endpoints.Results:Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (432 vs 546 patients; empagliflozin vs placebo, respectively; hazard ratio 0.77, 95% CI: 0.67-0.87), P <0.0001. This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio 0.71, 95% CI 0.52-0.96, P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio 0.73, 95% CI: 0.55-0.97,P=0.033). As compared with placebo, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 vs 610, hazard ratio 0.76, 95% CI: 0.67-0.86, P<0.0001), and patients assigned to empagliflozin were 20-50% more likely to have a better NYHA functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40-<50% and 50-<60%, but was attenuated at higher ejection fractions.Conclusions:In patients with heart failure and a preserved ejection fraction, empagliflozin produced a meaningful, early and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events.Clinical Trial Registration:The registration identifier at ClinicalTrials.gov is NCT03057977
      Citation: Circulation
      PubDate: 2021-08-29T02:01:36Z
      DOI: 10.1161/CIRCULATIONAHA.121.056824
       
  • Cardiovascular Safety of Degarelix versus Leuprolide in Patients with
           Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial

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      Authors: Renato D. Lopes Celestia S. Higano Susan F. Slovin Adam J. Nelson Robert Bigelow Per S. Sørensen Chiara Melloni Shaun G. Goodman Christopher P. Evans Jan Nilsson Deepak L. Bhatt Noel W. Clarke Tine K. Olesen Belinda T. Doyle-Olsen Henriette Kristensen Lauren Arney Matthew T. Roe John H. Alexander Department of Medicine; Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC Division of Medical Oncology, University of Washington Salford Royal Hospitals Manchester, United Kingdom Department of Medicine, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; Verana Health, San Francisco, CA
      First page: 1295
      Abstract: Circulation, Ahead of Print.
      Background:The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease (ASCVD) remains controversial.Methods:In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial infarction, or stroke) through 12 months.Results:Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease and 20.4% had metastatic disease. MACE occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53).Conclusions:PRONOUNCE is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved.Clinical Trial Registration:URL: https://clinicaltrials.gov Unique Identifier: NCT02663908
      Citation: Circulation
      PubDate: 2021-08-30T12:30:00Z
      DOI: 10.1161/CIRCULATIONAHA.121.056810
       
  • The Role of Venous Endothelial Cells in Developmental and Pathologic
           Angiogenesis

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      Authors: Heon-Woo Lee Yanying Xu Liqun He Woosoung Choi David Gonzalez Suk-Won Jin Michael Simons Yale Cardiovascular Research Center; Yale University School of Medicine, New Haven, CT Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT; Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China Department of Immunology, Genetics Technology (GIST), Gwangju, Korea
      First page: 1308
      Abstract: Circulation, Ahead of Print.
      Background:Angiogenesis is a dynamic process that involves expansion of a pre-existing vascular network that can occur in a number of physiologic and pathologic settings. Despite its importance, the origin of the new angiogenic vasculature is poorly defined. In particular, the primary subtype of endothelial cells (capillary, venous, arterial) driving this process remains undefined.Methods:Endothelial cells were fate-mapped using genetic markers specific to arterial, capillary cells. In addition, we identified a novel venous endothelial marker gene (Gm5127) used it to generate inducible venous endothelial-specific Cre and Dre driver mouse lines. Contributions of these various types of endothelial cells to angiogenesis were examined during normal postnatal development and in disease-specific setting.Results:Using a comprehensive set of endothelial subtype-specific inducible reporter mice, including tip-, arterial- and venous- endothelial reporter lines, we showed that venous endothelial cells are the primary endothelial subtype responsible for the expansion of an angiogenic vascular network. During physiologic angiogenesis, venous endothelial cells proliferate, migrating against the blood flow, and differentiating into tip, capillary and arterial endothelial cells of the new vasculature. Using intravital 2-photon imaging, we observed venous endothelial cells migrating against the blood flow to form new blood vessels. Venous endothelial cell migration also plays a key role in pathologic angiogenesis. This was observed both in formation of arterio-venous malformations in mice with inducible endothelial-specific Smad4 deletion mice and in pathologic vessel growth seen in oxygen-induced retinopathy.Conclusions:Our studies establish venous endothelial cells are primary endothelial subtype responsible for the normal expansion of vascular networks, formation of arterio-venous malformations and pathologic angiogenesis. These observations highlight the central role of the venous endothelium in normal development and disease pathogenesis.
      Citation: Circulation
      PubDate: 2021-09-03T09:01:01Z
      DOI: 10.1161/CIRCULATIONAHA.121.054071
       
 
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