| 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. | |
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MedLine Citation:
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PMID: 22833515 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Jan-Christian Reil; Mathias Hohl; Gert-Hinrich Reil; Henk L 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 |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-7-24 |
Journal Detail:
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Title: European heart journal Volume: - ISSN: 1522-9645 ISO Abbreviation: - Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-7-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8006263 Medline TA: Eur Heart J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße D 66421, Homburg/Saar, Germany. |
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