Document Detail

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.
MedLine Citation:
PMID:  22833515     Owner:  NLM     Status:  MEDLINE    
AIMS: 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.
METHODS AND RESULTS: 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.
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-24
Journal Detail:
Title:  European heart journal     Volume:  34     ISSN:  1522-9645     ISO Abbreviation:  Eur. Heart J.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-09-23     Completed Date:  2014-04-16     Revised Date:  2014-10-15    
Medline Journal Info:
Nlm Unique ID:  8006263     Medline TA:  Eur Heart J     Country:  England    
Other Details:
Languages:  eng     Pagination:  2839-49     Citation Subset:  IM    
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MeSH Terms
Anti-Arrhythmia Agents / pharmacology*
Aorta / metabolism
Benzazepines / pharmacology*
Blood Glucose / metabolism
Collagen / metabolism
Heart Failure / drug therapy*,  physiopathology
Heart Rate / drug effects*
Hemodynamics / drug effects
Insulin / metabolism
Magnetic Resonance Angiography
Mice, Inbred C57BL
Protein Kinases / metabolism
RNA, Messenger / metabolism
Stroke Volume / physiology
Vascular Stiffness / drug effects
Ventricular Dysfunction, Left / drug therapy,  physiopathology
Grant Support
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Benzazepines; 0/Blood Glucose; 0/Insulin; 0/RNA, Messenger; 155974-00-8/ivabradine; 9007-34-5/Collagen; EC 2.7.-/Protein Kinases; EC protein, mouse

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