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Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure with Preserved Ejection Fraction in a Rat Metabolic Risk Model.
MedLine Citation:
PMID:  24014826     Owner:  NLM     Status:  Publisher    
BACKGROUND: -Obesity and diabetes are important metabolic risk factors and frequent comorbidities in heart failure with preserved ejection fraction (HFPEF). They contribute to myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance for myocardial DD of collagen deposition and titin modification was investigated in obese, diabetic ZSF1 rats after HFPEF development at 20 weeks of age.
METHODS AND RESULTS: -Four groups or rats (Wystar Kyoto, n=11; lean ZSF1, n=11; obese ZSF1, n=11 and obese ZSF1 with high fat diet, n=11) were followed over 20 weeks with repeat metabolic, renal and echocardiographic evaluations and hemodynamically assessed at sacrifice. Myocardial collagen, collagen crosslinking, titin isoforms and phosphorylation were also determined. Resting tension (Fpassive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular-matrix to Fpassive to be discerned. At 20 weeks of age, the lean ZSF1 group was hypertensive whereas both obese ZSF1 groups were hypertensive and diabetic. Only the obese ZSF1 groups had developed HFPEF, which was evident from increased lung weight, preserved LVEF and LV DD. The underlying myocardial DD was obvious from high muscle strip stiffness, which was largely (±80%) attributable to titin hypophosphorylation. The latter occurred specifically at the S3991 site of the elastic N2Bus segment and at the S12884 site of the PEVK segment.
CONCLUSIONS: -Obese ZSF1 rats developed HFPEF over a 20 weeks time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.
Nazha Hamdani; Constantijn Franssen; André Lourenço; Inês Falcão-Pires; Dulce Fontoura; Sara Leite; Luisa Plettig; Begoña López; Coen A Ottenheijm; Moritz P Becher; Arantxa González; Carsten Tschöpe; Javier Díez; Wolfgang A Linke; Adelino F Leite-Moreira; Walter J Paulus
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-9-6
Journal Detail:
Title:  Circulation. Heart failure     Volume:  -     ISSN:  1941-3297     ISO Abbreviation:  Circ Heart Fail     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-9-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101479941     Medline TA:  Circ Heart Fail     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Ruhr University Bochum, Bochum, Germany.
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