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

Reil, J.C.; Hohl, M.; Reil, G.H.; Granzier, H.L.; Kratz, M.T.; Kazakov, A.; ... ; Bohm, M. (2012)

Article / Letter to editor

AimsIn 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 resultsControl 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/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.ConclusionIn 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.

• All authors: Reil, J.C.; Hohl, M.; Reil, G.H.; Granzier, H.L.; Kratz, M.T.; Kazakov, A.; Fries, P.; Muller, A.; Lenski, M.; Custodis, F.; Graber, S.; Frohlig, G.; Steendijk, P.; Neuberger, H.R.; Bohm, M.
• Date: 2012-07-24
• Journal: European Heart Journal
• DOI: doi:10.1093/eurheartj/ehs218