Abstract 12858: Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure with Preserved Ejection Fraction in a Rat Cardiometabolic Risk Model
Background: Obesity, diabetes and arterial hypertension are key constituents of cardiometabolic risk (CMR) and frequent comorbidities in HFPEF. They can induce myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance of these two mechanisms for HFPEF associated with CMR remains uncertain.
Methods: Obese Zucker spontaneously hypertensive diabetic fatty rats were fed with normal (ZSF1 Obese, n=11) or high fat diet (ZSF1 Obese+HFD, n=11). Hypertensive lean ZSF1 (ZSF1-Lean,n=11) and Wistar Kyoto (WKY,n=11) rats served as controls. Obese rats had developed HFPEF, evident from echocardiographic, invasive and morphometric assessment at 20 weeks of age. Resting tension (Fpassive)-sarcomere length relations were obtained in isolated cardiomyocytes (LV free wall) and in muscle strips (LV papillary muscle) before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular-matrix (E-matrix) to Fpassive to be discerned. Expression and phosphorylation of titin were assessed by electrophoresis.
Results: In strips, total Fpassive was increased in both obese groups. E-matrix based Fpassive was similar in all groups at sarcomere lengths 1.9 to 2.2μm, but rose sharply at higher lengths. Titin based Fpassive was increased in obese rats (figure). Fpassive was higher in single cardiomyocytes from obese rats compared to controls and in-vitro protein kinase G (PKG) administration lowered Fpassive to control values. No titin isoform-shifts were observed, but titin was hyphosphorylated in obese rats.
Conclusion: This CMR-rat model is associated with HFPEF at 20 weeks of age. The underlying DD mainly results from a titin phosphorylation deficit, which is more prominent than changes in the E-matrix.
- © 2013 by American Heart Association, Inc.