Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure With Preserved Ejection Fraction in a Rat Metabolic Risk Model

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Hamdani, N (Author) Other; Franssen, C (Author) Other; Andre P Lourenco (Author) FMUP; Falcao Pires, I (Author) FMUP; Fontoura, D (Author) Other; Leite, S (Author) FMUP; Plettig, L (Author) Other; Lopez, B (Author) Other; Ottenheijm, CA (Author) Other; Becher, PM (Author) Other; Gonzalez, A (Author) Other; Tschoepe, C (Author) Other; Diez, J (Author) Other; Linke, WA (Author) Other; Leite-Moreira AF (Author) FMUP; Paulus, WJ (Author) Other

Journal

Title: Circulation: Heart Failure

Vol. 6

Pages: 1239-1249

ISSN: 1941-3289

Publisher: Wolters Kluwer Health

Indexing

ISI Web of Knowledge - 215 Citations

Scopus - 230 Citations

Other information

Authenticus ID: P-009-7VT

DOI: 10.1161/circheartfailure.113.000539

Abstract (EN): Background Obesity and diabetes mellitus are important metabolic risk factors and frequent comorbidities in heart failure with preserved ejection fraction. 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 heart failure with preserved ejection fraction development at 20 weeks. Methods and Results Four groups of rats (Wistar-Kyoto, n=11; lean ZSF1, n=11; obese ZSF1, n=11, and obese ZSF1 with high-fat diet, n=11) were followed up for 20 weeks with repeat metabolic, renal, and echocardiographic evaluations and hemodynamically assessed at euthanization. Myocardial collagen, collagen cross-linking, titin isoforms, and phosphorylation were also determined. Resting tension (F-passive)-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 F-passive to be discerned. At 20 weeks, the lean ZSF1 group was hypertensive, whereas both obese ZSF1 groups were hypertensive and diabetic. Only the obese ZSF1 groups had developed heart failure with preserved ejection fraction, which was evident from increased lung weight, preserved left ventricular ejection fraction, and left ventricular 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 heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11