TY - JOUR
T1 - 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
AU - Reil, Jan Christian
AU - Hohl, Mathias
AU - Reil, Gert Hinrich
AU - Granzier, Henk L.
AU - Kratz, Mario T.
AU - Kazakov, Andrey
AU - Fries, Peter
AU - Müller, Andreas
AU - Lenski, Matthias
AU - Custodis, Florian
AU - Gräber, Stefan
AU - Fröhlig, Gerd
AU - Steendijk, Paul
AU - Neuberger, Hans Ruprecht
AU - Böhm, Michael
N1 - Funding Information:
H.G. was supported by HL062881. J.C.R. was supported by the ADUMED foundation. M.H. and J.C.R. were also supported by the Hans and Gertie Fischer Foundation.
Funding Information:
We thank Jeannette Zimolong for excellent experimental support and Chandrasekhar Saripalli for carefully performed titin protein analysis. J.C.R., M.H., H.R.N., and M.B. were supported by Deutsche Forschungsgemeinschaft (DFG, KFO 196).
PY - 2013/9/21
Y1 - 2013/9/21
N2 - 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 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 (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/L, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/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 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.
AB - 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 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 (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/L, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/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 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.
KW - Diastolic dysfunction
KW - HFPEF
KW - Heart rate reduction
KW - Vascular stiffness
KW - Ventricular-arterial coupling
UR - https://www.scopus.com/pages/publications/84884867961
UR - https://www.scopus.com/pages/publications/84884867961#tab=citedBy
U2 - 10.1093/eurheartj/ehs218
DO - 10.1093/eurheartj/ehs218
M3 - Article
C2 - 22833515
AN - SCOPUS:84884867961
SN - 0195-668X
VL - 34
SP - 2839
EP - 2849
JO - European Heart Journal
JF - European Heart Journal
IS - 36
ER -