title: Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model.
abstract: 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.
  
  
  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 (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.
  
  
  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.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Constantijn
authors.initials: C
authors.lastname: Franssen
authors.forename: André
authors.initials: A
authors.lastname: Lourenço
authors.forename: Inês
authors.initials: I
authors.lastname: Falcão-Pires
authors.forename: Dulce
authors.initials: D
authors.lastname: Fontoura
authors.forename: Sara
authors.initials: S
authors.lastname: Leite
authors.forename: Luisa
authors.initials: L
authors.lastname: Plettig
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.forename: Coen A
authors.initials: CA
authors.lastname: Ottenheijm
authors.forename: Peter Moritz
authors.initials: PM
authors.lastname: Becher
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
mesh_terms: D000818:Animals; D064211:Connectin / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011921:Rats, Inbred WKY; D013318:Stroke Volume / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D064211:Connectin
keywords: diabetes mellitus; diastole; heart failure; myocardium; obesity