title: Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction.
abstract: OBJECTIVE
  The present study investigated whether systemic, low-grade inflammation of metabolic risk contributed to diastolic left ventricular (LV) dysfunction and heart failure with preseved ejection fraction (HFpEF) through coronary microvascular endothelial activation, which alters paracrine signalling to cardiomyocytes and predisposes them to hypertrophy and high diastolic stiffness.
  
  
  BACKGROUND
  Metabolic risk is associated with diastolic LV dysfunction and HFpEF.
  
  
  METHODS
  We explored inflammatory endothelial activation and its effects on oxidative stress, nitric oxide (NO) bioavailability, and cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling in myocardial biopsies of HFpEF patients and validated our findings by comparing obese Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1)-HFpEF rats to ZSF1-Control (Ctrl) rats.
  
  
  RESULTS
  In myocardium of HFpEF patients and ZSF1-HFpEF rats, we observed the following: 1) E-selectin and intercellular adhesion molecule-1 expression levels were upregulated; 2) NADPH oxidase 2 expression was raised in macrophages and endothelial cells but not in cardiomyocytes; and 3) uncoupling of endothelial nitric oxide synthase, which was associated with reduced myocardial nitrite/nitrate concentration, cGMP content, and PKG activity.
  
  
  CONCLUSIONS
  HFpEF is associated with coronary microvascular endothelial activation and oxidative stress. These lead to a reduction of NO-dependent signalling from endothelial cells to cardiomyocytes, which can contribute to the high cardiomyocyte stiffness and hypertrophy observed in HFpEF.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Constantijn
authors.initials: C
authors.lastname: Franssen
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Sophia
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unger
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Department of Pathology and Cardiac Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: H Ibrahim
authors.initials: HI
authors.lastname: Korkmaz
authors.affiliation: Laboratory of Physiology, University of Antwerp, Antwerp, Belgium.
authors.forename: Gilles W
authors.initials: GW
authors.lastname: De Keulenaer
authors.affiliation: Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal.
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Musters
authors.affiliation: Department of Pathology and Cardiac Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands. Electronic address: wj.paulus@vumc.nl.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D003326:Coronary Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006333:Heart Failure / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008833:Microcirculation; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D051381:Rats; D011924:Rats, Zucker; D013318:Stroke Volume / Q000502:physiology*; D016277:Ventricular Function, Left / Q000502:physiology
keywords: endothelium; heart failure; inflammation; nitric oxide; oxidative stress