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

Eur Heart J. 2013 Sep;34(36):2839-49. doi: 10.1093/eurheartj/ehs218. Epub 2012 Jul 24.


Aims: 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.

Methods and 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.

Conclusion: 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.

Keywords: Diastolic dysfunction; HFPEF; Heart rate reduction; Vascular stiffness; Ventricular-arterial coupling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Aorta / metabolism
  • Benzazepines / pharmacology*
  • Blood Glucose / metabolism
  • Collagen / metabolism
  • Diastole
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Heart Rate / drug effects*
  • Hemodynamics / drug effects
  • Insulin / metabolism
  • Ivabradine
  • Magnetic Resonance Angiography
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Kinases / metabolism
  • RNA, Messenger / metabolism
  • Stroke Volume / physiology
  • Systole
  • Vascular Stiffness / drug effects
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / physiopathology


  • Anti-Arrhythmia Agents
  • Benzazepines
  • Blood Glucose
  • Insulin
  • RNA, Messenger
  • Ivabradine
  • Collagen
  • Protein Kinases
  • titin protein, mouse