title: Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction.
abstract: Heart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na(+) /Ca(2+) exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) with HFpEF.
  
  
  
  Male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). After 8 and 24 weeks, in vivo (haemodynamics, echocardiography) and in vitro function (LV cardiomyocyte cell shortening (CS), and Ca(2+) transients (CaT)) were determined without and with SEA0400. In a subgroup of rats, SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. NXT resulted in stable compensated CKD and HFpEF [hypertrophied left ventricle, prolonged LV isovolumetric relaxation constant TAU (IVRc TAU), elevated end diastolic pressure (EDP), increased lung weight (pulmonary congestion), and preserved LV systolic function (EF, dP/dt)]. In NXT cardiomyocytes, the amplitude of CS and CaT were unchanged but relaxation and CaT decay were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. NCX forward mode activity (caffeine response) was progressively reduced, while NCX protein expression was up-regulated, suggesting increased NCX reverse mode activity in NXT. SEA0400 acutely improved relaxation in NXT in vivo and in cardiomyocytes and improved cardiac remodelling and diastolic function when given chronically.
  
  
  
  This model of renal HFpEF is associated with slowed relaxation of LV cardiomyocytes. Treatment with SEA0400 improved cardiomyocyte function, remodelling, and HFpEF.
authors.affiliation: Department of Cardiology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.|Department of Cardiology, Medical University of Graz, Graz, Austria.|German Centre for Cardiovascular Research (DZHK), partner site Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Primessnig
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.|Department of Physiology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schönleitner
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Höll
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Pfeiffer
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Taja
authors.initials: T
authors.lastname: Bracic
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rau
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Kapl
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stojakovic
authors.affiliation: Institute of Chemistry, University of Graz, Graz, Austria.
authors.forename: Toma
authors.initials: T
authors.lastname: Glasnov
authors.affiliation: Bayer Healthcare Pharmaceuticals, Wuppertal, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.affiliation: Department of Cardiology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Berlin, Germany.
authors.forename: Paulina
authors.initials: P
authors.lastname: Wakula
authors.affiliation: Department of Cardiology, Medical University of Graz, Graz, Austria.|Department of Physiology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Antoons
authors.affiliation: Department of Cardiology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.|Department of Cardiology, Medical University of Graz, Graz, Austria.|German Centre for Cardiovascular Research (DZHK), partner site Berlin, Germany.
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.affiliation: Department of Cardiology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.|Department of Cardiology, Medical University of Graz, Graz, Austria.|German Centre for Cardiovascular Research (DZHK), partner site Berlin, Germany.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Heinzel
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004452:Echocardiography; D006333:Heart Failure / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010647:Phenyl Ethers / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000503:physiopathology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013318:Stroke Volume
chemical_list: D000814:Aniline Compounds; D000697:Central Nervous System Stimulants; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D002118:Calcium
keywords: Active relaxation; Calcium; Cardiomyocyte; Diastolic dysfunction; Heart failure with preserved ejection fraction; Na+/Ca2+ exchanger; SEA0400