# Molecular Imaging of Collagen Turnover in Cardiomyopathy

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $753,807

## Abstract

Heart failure is a major cause of morbidity and mortality worldwide. Cardiomyopathy, the pathology that
underlies most cases of heart failure is often triggered by myocardial injury. This promotes inflammation,
fibroblast proliferation and myofibroblast transformation, and ultimately fibrosis, which directly contributes to
structural changes that underlie heart failure and its complications. Structural imaging modalities such as
magnetic resonance imaging can provide a snapshot of cardiac structure at a given point. However, they do
not provide any information on the fibrotic process, which is the target of therapeutic interventions to prevent
the progression and promote the regression of fibrosis. Similarly, while several new tracers have been
introduced to detect fibrosis by molecular imaging, these agents target mature collagen and cannot distinguish
between established disease and ongoing matrix remodeling which accompanies active fibrogenesis and
resolution of fibrosis. Therefore, novel non-invasive quantitative tools are needed to characterize fibrosis,
detect matrix turnover, select the patients for emerging therapies, track the effect of therapeutic interventions,
and improve prognostication. Cardiac fibrosis consists mainly of collagen types I and III. The hallmark of
collagen structure is triple helix, a right-handed helix of 3 α-chains formed by repetitive motifs, which self-
assemble to form (pro)collagen fibers. During ventricular remodeling, the highly organized mature collagen
fibers are degraded by proteases such as matrix metalloproteinases (MMPs) into single stranded α-chains that
are not normally present in the extracellular space. Based on the role of collagen turnover in cardiac
remodeling and in conjunction with our preliminary data, we hypothesize that the development and regression
of fibrosis in ventricular remodeling can be tracked by imaging single stranded collagen. To address this
hypothesis, and as a novel approach to imaging cardiac fibrosis, we propose to develop novel radiotracers to
target collagen turnover by taking advantage of collagen triple helix self-assembly. This novel class of peptide-
based radiotracers is designed with a modular structure and includes a prototype tracer which has yielded
promising results in preliminary studies. Here, we seek to further characterize and optimize the lead tracer as
needed, and evaluate it for micro single photon computed tomography (SPECT)/computed tomography (CT)
imaging in murine models of replacement and interstitial cardiac fibrosis to track fibrosis and its resolution, and
to predict ventricular remodeling in comparison with MMP-targeted imaging. Combined these studies will
introduce and validate a novel molecular imaging approach with a straightforward path to clinical translation to
track fibrosis and its resolution, for not only cardiomyopathy, but also a wide range of other fibrotic disorders.

## Key facts

- **NIH application ID:** 10518655
- **Project number:** 1R01HL161746-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MEHRAN M SADEGHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $753,807
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518655

## Citation

> US National Institutes of Health, RePORTER application 10518655, Molecular Imaging of Collagen Turnover in Cardiomyopathy (1R01HL161746-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10518655. Licensed CC0.

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