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HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling
Joshua G Travers1,2, Sara A Wennersten1,2, Brisa Peña1,2
1Department of Medicine, Division of Cardiology (J.G.T., S.A.W., B.P., R.A.B., Y.-H.L., K.M.D.-D., M.A.C., L.M., K.C.W., M.P.Y.L., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora.
Circulation
|March 8, 2021
Summary
Histone deacetylase (HDAC) inhibition reversed established diastolic dysfunction (DD) by blocking extracellular matrix expansion and reducing cardiac stiffness. This therapeutic approach offers a novel strategy for treating heart failure with preserved ejection fraction.
Area of Science:
- Cardiovascular Medicine
- Molecular Biology
- Pharmacology
Background:
- Diastolic dysfunction (DD) is a key factor in heart failure development and atrial fibrillation pathogenesis.
- Histone deacetylase (HDAC) inhibition has shown promise in preventing DD by improving myofibril relaxation.
- This study investigates the therapeutic potential of HDAC inhibition in established DD with preserved ejection fraction.
Purpose of the Study:
- To evaluate the efficacy of the clinical-stage HDAC inhibitor ITF2357/Givinostat in a mouse model of established diastolic dysfunction.
- To elucidate the mechanisms by which HDAC inhibition impacts cardiac structure and function in this model.
Main Methods:
- Established diastolic dysfunction in mice via uninephrectomy and deoxycorticosterone acetate pellet implantation.
- Administered ITF2357/Givinostat and assessed cardiac function using echocardiography, hemodynamic analysis, and ex vivo myofibril mechanics.
- Evaluated cardiac fibrosis, extracellular matrix protein expression, and left ventricular stiffness using advanced microscopy, mass spectrometry, and atomic force microscopy.
Main Results:
- HDAC inhibition normalized diastolic dysfunction without affecting blood pressure.
- While traditional fibrosis markers were absent, mass spectrometry revealed significant extracellular matrix expansion and increased left ventricular stiffness.
- ITF2357/Givinostat treatment effectively inhibited extracellular matrix expansion and reduced cardiac stiffness by suppressing cardiac fibroblast activation via BRD4.
Conclusions:
- HDAC inhibition demonstrates therapeutic potential for reversing existing diastolic dysfunction.
- Blockade of extracellular matrix remodeling represents a novel mechanism for HDAC inhibitors to improve ventricular filling.
- The study highlights the existence of 'hidden' cardiac fibrosis and the necessity of diverse methodologies for its detection.
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