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.