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

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 I f-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 ( E es) 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 E es (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 I f-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, I f-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.