title: Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction.
abstract: OBJECTIVE
  In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model.
  
  
  RESULTS
  Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva.
  
  
  CONCLUSIONS
  In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.
authors: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße D 66421, Homburg/Saar, Germany.
authors: Jan-Christian
authors: JC
authors: Reil
authors: Mathias
authors: M
authors: Hohl
authors: Gert-Hinrich
authors: GH
authors: Reil
authors: Henk L
authors: HL
authors: Granzier
authors: Mario T
authors: MT
authors: Kratz
authors: Andrey
authors: A
authors: Kazakov
authors: Peter
authors: P
authors: Fries
authors: Andreas
authors: A
authors: Müller
authors: Matthias
authors: M
authors: Lenski
authors: Florian
authors: F
authors: Custodis
authors: Stefan
authors: S
authors: Gräber
authors: Gerd
authors: G
authors: Fröhlig
authors: Paul
authors: P
authors: Steendijk
authors: Hans-Ruprecht
authors: HR
authors: Neuberger
authors: Michael
authors: M
authors: Böhm
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001011:Aorta / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003971:Diastole; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000077550:Ivabradine; D018810:Magnetic Resonance Angiography; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013318:Stroke Volume / Q000502:physiology; D013599:Systole; D059289:Vascular Stiffness / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D000077550:Ivabradine; D003094:Collagen; D011494:Protein Kinases; C579730:titin protein, mouse