Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism.

Abstract

There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor-mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.

• Authors: Mark Y Jeong, Ying H Lin, Sara A Wennersten, Kimberly M Demos-Davies, Maria A Cavasin, Jennifer H Mahaffey, Valmen Monzani, Chandrasekhar Saripalli, Paolo Mascagni, T Brett Reece, Amrut V Ambardekar, Henk L Granzier, Charles A Dinarello, Timothy A McKinsey
• Journal: Science translational medicine (Sci Transl Med) Vol. 10 Issue 427 (02 07 2018) ISSN: 1946-6242 [Electronic] United States
• PMID: 29437146 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Connectin
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Histone Deacetylases
• Myosins
• givinostat hydrochloride

Topics

• Animals
• Blood Pressure (genetics, physiology)
• Connectin (metabolism)
• Female
• Heart Failure
• Hemodynamics (physiology)
• Histone Deacetylase Inhibitors (therapeutic use)
• Histone Deacetylases (metabolism)
• Humans
• Hydroxamic Acids (therapeutic use)
• Mice
• Myocardium (metabolism)
• Myocytes, Cardiac
• Myosins (metabolism)
• Rats
• Rats, Sprague-Dawley
• Ventricular Dysfunction, Left (metabolism)