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

Jan Christian Reil, Mathias Hohl, Gert Hinrich Reil, Hendrikus "Henk" Granzier, Mario T. Kratz, Andrey Kazakov, Peter Fries, Andreas Müller, Matthias Lenski, Florian Custodis, Stefan Gräber, Gerd Fröhlig, Paul Steendijk, Hans Ruprecht Neuberger, Michael Böhm

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2839-2849
Number of pages11
JournalEuropean Heart Journal
Volume34
Issue number36
DOIs
StatePublished - Sep 21 2013

Fingerprint

Vascular Stiffness
Heart Failure
Heart Rate
ivabradine
Fibrosis
Connectin
Ventricular Function
Ventricular Pressure
Hypertrophy
Comorbidity
Diabetes Mellitus
Phosphorylation
Magnetic Resonance Imaging
Phenotype
Therapeutics

Keywords

  • Diastolic dysfunction
  • Heart rate reduction
  • HFPEF
  • Vascular stiffness
  • Ventricular-arterial coupling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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, Jan Christian; Hohl, Mathias; Reil, Gert Hinrich; Granzier, Hendrikus "Henk"; Kratz, Mario T.; Kazakov, Andrey; Fries, Peter; Müller, Andreas; Lenski, Matthias; Custodis, Florian; Gräber, Stefan; Fröhlig, Gerd; Steendijk, Paul; Neuberger, Hans Ruprecht; Böhm, Michael.

In: European Heart Journal, Vol. 34, No. 36, 21.09.2013, p. 2839-2849.

Research output: Contribution to journalArticle

Reil, JC, Hohl, M, Reil, GH, Granzier, HH, Kratz, MT, Kazakov, A, Fries, P, Müller, A, Lenski, M, Custodis, F, Gräber, S, Fröhlig, G, Steendijk, P, Neuberger, HR & Böhm, M 2013, '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', European Heart Journal, vol. 34, no. 36, pp. 2839-2849. https://doi.org/10.1093/eurheartj/ehs218
Reil, Jan Christian ; Hohl, Mathias ; Reil, Gert Hinrich ; Granzier, Hendrikus "Henk" ; Kratz, Mario T. ; Kazakov, Andrey ; Fries, Peter ; Müller, Andreas ; Lenski, Matthias ; Custodis, Florian ; Gräber, Stefan ; Fröhlig, Gerd ; Steendijk, Paul ; Neuberger, Hans Ruprecht ; Böhm, Michael. / 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. In: European Heart Journal. 2013 ; Vol. 34, No. 36. pp. 2839-2849.
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abstract = "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.",
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AU - Reil, Jan Christian

AU - Hohl, Mathias

AU - Reil, Gert Hinrich

AU - Granzier, Hendrikus "Henk"

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

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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 - Heart rate reduction

KW - HFPEF

KW - Vascular stiffness

KW - Ventricular-arterial coupling

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