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In Vitro Assessment of Cardiac Function Using Skinned Cardiomyocytes
Published on: June 22, 2020
Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction
Nazha Hamdani1, Kalkidan G Bishu, Marion von Frieling-Salewsky
1Department of Cardiovascular Physiology, Ruhr University, MA 3/56, D-44780 Bochum, Germany.
Cardiovascular Research
|December 6, 2012
Summary
Heart failure with preserved ejection fraction (HFpEF) involves stiffening of the heart muscle due to changes in titin protein. This stiffening, driven by altered protein phosphorylation, contributes to diastolic dysfunction in HFpEF.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Biophysics
Background:
- Heart failure with preserved ejection fraction (HFpEF) is a significant clinical problem characterized by diastolic dysfunction.
- Left ventricular (LV) stiffness and impaired relaxation are hallmarks of HFpEF.
- The giant elastic protein titin plays a crucial role in determining LV stiffness.
Purpose of the Study:
- To investigate alterations in myofilament protein phosphorylation and function in an experimental model of HFpEF.
- To determine the role of titin's structural and functional changes in HFpEF-associated LV stiffness.
Main Methods:
- Utilized a canine model of hypertension-induced LV hypertrophy and diastolic dysfunction (OHT/HFpEF) compared to controls (CTRL).
- Quantified myofilament protein expression and phosphorylation, including titin.
- Assessed protein kinase/phosphatase activity, myofilament calcium sensitivity (pCa50), and passive cardiomyocyte tension (F(passive)).
Main Results:
- HFpEF hearts showed decreased protein kinase-G (PKG) activity and increased protein kinase C-alpha (PKCα) and phosphatase 1/2a (PP1/PP2a) activity/expression.
- Myofilament proteins were hypophosphorylated, leading to increased myofilament calcium sensitivity (pCa50).
- Titin isoform ratio shifted towards stiffer N2B, with altered phosphorylation patterns contributing to increased cardiomyocyte passive tension.
Conclusions:
- HFpEF is characterized by titin stiffening due to altered isoform composition and phosphorylation, increasing LV stiffness.
- Myofilament hypophosphorylation and increased calcium sensitivity suggest early sarcomeric functional impairment in HFpEF.
- PKG and PKA, but not PKCα, could normalize cardiomyocyte passive tension, indicating potential therapeutic targets.
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