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 I-f-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/mu L, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered E-es (4.0 +/- 1.1 mmHg/mu L, 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 mu L, 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.