Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model

Nazha Hamdani, Constantijn Franssen, Andre Lourenço, Inês Falca o-Pires, Dulce Fontoura, Sara Leite, Luisa Plettig, Begona Lopez, Coen A. Ottenheijm, Peter Moritz Becher, Arantxa Gonzalez, Carsten Tscho pe, Javier Diez, Wolfgang A. Linke, Adelino F. Leite-Moreira, Walter J. Paulus

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

Abstract

BackgroundObesity 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 ResultsFour 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 (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, 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. ConclusionsObese ZSF1 rats developed heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.

Original languageEnglish (US)
Pages (from-to)1239-1249
Number of pages11
JournalCirculation: Heart Failure
Volume6
Issue number6
DOIs
StatePublished - Nov 2013
Externally publishedYes

Keywords

  • Diabetes mellitus
  • Diastole
  • Heart failure
  • Myocardium
  • Obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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