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

• Published in: European heart journal 2013-09, Vol.34 (36), p.2839-2849
• Main Authors: Reil, Jan-Christian, Hohl, Mathias, Reil, Gert-Hinrich, Granzier, Henk L, Kratz, Mario T, Kazakov, Andrey, Fries, Peter, Müller, Andreas, Lenski, Matthias, Custodis, Florian, Gräber, Stefan, Fröhlig, Gerd, Steendijk, Paul, Neuberger, Hans-Ruprecht, Böhm, Michael
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Aorta - metabolism; Basic Science; Benzazepines - pharmacology; Blood Glucose - metabolism; Collagen - metabolism; Diastole; Heart Failure - drug therapy; Heart Failure - physiopathology; Heart Rate - drug effects; Hemodynamics - drug effects; Insulin - metabolism; Magnetic Resonance Angiography; Male; Mice; Mice, Inbred C57BL; Protein Kinases - metabolism; RNA, Messenger - metabolism; Stroke Volume - physiology; Systole; Vascular Stiffness - drug effects; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - physiopathology
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehs218

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. 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. 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.