# Imaging Histone Deacetylase in the Heart and Bone Marrow

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $826,447

## Abstract

Project Summary
Heart failure with preserved ejection fraction (HFpEF) is frequently accompanied by left ventricular hypertrophy
(LVH) and myocardial fibrosis. The pathogenesis of these processes, however, remains poorly understood. In
addition, no medical therapies have been developed that consistently attenuate the development of myocardial
fibrosis and cause it to regress. Histone Deacetylases (HDACs) are a class of enzymes that cause
conformational changes in the 3D architecture of DNA, modifying its transcription. Class I HDACs, in particular,
have been implicated in the development of LVH and myocardial fibrosis. In preclinical models, HDAC
inhibition attenuates these pathological processes and preserves the integrity of the myocardium. However, the
role of HDACs in the human heart, and the utility of HDAC inhibition, remains unknown. We have recently
developed a novel radiotracer, 11C-Martinostat, which binds with high affinity to class I HDACs. Preliminary
studies have been performed in six healthy volunteers and show that the agent accumulates strongly in the
myocardium and bone marrow, while being rapidly washed out of the blood pool and lungs. Blocking studies
with suberanilohydroxamic acid (SAHA) in a large animal model confirm the specificity of 11C-Martinostat
uptake in these tissues. We now aim to use 11C-Martinostat to further characterize the role of HDAC
expression in the development of LVH and fibrosis. In addition to myocardial HDAC expression, we aim to
assess whether HDAC expression in the bone marrow affects the secretion of fibrosis-modulating monocytes
and cytokines. In aim 1 of the proposal, the impact of age, gender and diabetes on HDAC activity in the heart
and bone marrow will be characterized. In aim 2, patients with severe aortic stenosis will be imaged to
determine whether 11C-Martinostat uptake correlates with the degree of LVH and myocardial fibrosis. In aim 3,
repeat imaging of these patients will be performed 6 months after transcatheter aortic valve replacement
(TAVR) to correlate HDAC activity with changes in LVH and fibrosis. Imaging in all cases will be performed on
a commercial whole body PET-MR system, allowing MR-derived metrics of myocardial function and fibrosis to
be integrated with the PET readout of HDAC expression. Completion of the proposed studies will provide
important insights into the role of HDACs in the human heart and bone marrow during aging, LVH and HFpEF.
The uptake of 11C-Martinostat in the heart could provide a valuable biomarker to help guide the development of
novel anti-fibrotic therapies, and is thus of major medical and

## Key facts

- **NIH application ID:** 10171890
- **Project number:** 5R01HL141563-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David E Sosnovik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $826,447
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171890

## Citation

> US National Institutes of Health, RePORTER application 10171890, Imaging Histone Deacetylase in the Heart and Bone Marrow (5R01HL141563-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10171890. Licensed CC0.

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