Selective heart rate reduction with ivabradine in a diabetic mouse model of HFPEF significantly lowered left ventricular end-systolic elastance (4.0 vs 6.0 mmHg/µL, P<0.01).
Does selective heart rate reduction by If-inhibition improve vascular stiffness and left ventricular function in a mouse model of HFPEF?
In a diabetic mouse model of HFpEF, heart rate reduction with ivabradine improved vascular stiffness, LV contractility, and diastolic function.
Absolute Event Rate: 4% vs 6%
p-value: p=<0.01
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.
Reil et al. (2012) studied Heart failure with preserved ejection fraction (HFPEF) in diabetes mellitus. If-inhibitor ivabradine vs. Untreated diabetic mice (db/db) and healthy control mice was evaluated on Left ventricular end-systolic elastance (Ees) (p=<0.01). Selective heart rate reduction with ivabradine in a diabetic mouse model of HFPEF significantly lowered left ventricular end-systolic elastance (4.0 vs 6.0 mmHg/µL, P<0.01).