Molecular Imaging of Collagen Turnover in Myocardial Infarction

Neishabouri, A.; Ghim, M.; Varli, O.; Ahmad, A.; Kukreja, G.; Zhang, Z.; Li, J.; Toczek, J.; Salarian, M.; Zhang, J.; Ein Alshaeba, D.; Akar, F. G.; Liu, C.; Yu, S. M.; Sadeghi, M. M.

doi:10.64898/2026.01.16.699986

bioRxiv · 10.64898/2026.01.16.699986

Molecular Imaging of Collagen Turnover in Myocardial Infarction

Neishabouri, A.·Ghim, M.·Varli, O.·Ahmad, A.·Kukreja, G.·Zhang, Z.·Li, J.·Toczek, J.·Salarian, M.·Zhang, J.·Ein Alshaeba, D.·Akar, F. G.·Liu, C.·Yu, S. M.·Sadeghi, M. M.

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Abstract

Cardiac fibrosis is a key contributor to cardiomyopathy after myocardial infarction (MI). Existing imaging techniques can detect established fibrotic changes; however, they lack sensitivity for ongoing collagen turnover--a dynamic process involving the denaturation of collagen triple helix. Molecular imaging of this process could enhance risk assessment and aid in the development of anti-fibrotic treatments. This study aimed to evaluate 99mTc-(HE)-(GPO), a radiotracer designed to target denatured collagen, as a biomarker of collagen turnover after MI. Methods99mTc-(HE)-(GPO) incorporates glycine-proline-hydroxyproline (GPO) repeats and can hybridize with denatured single- or double-stranded collagen. MI was induced in mice by ligation of the left anterior descending artery; sham-operated animals served as controls. At 2 weeks post-MI, animals underwent myocardial perfusion imaging or contrast-enhanced CT to detect the infarct zone, followed by SPECT/CT imaging using 99mTc-(HE)-(GPO) or a control scrambled tracer. Tracer uptake was quantified in vivo and ex vivo with gamma counting and autoradiography. Different aspects of fibrosis were examined by tissue analysis, along with autoradiography with a matrix metalloproteinase-targeted radiotracer, 99mTc-RYM1. Tracer binding was also assessed in human cardiac tissue through ex vivo autoradiography. Results99mTc-(HE)-(GPO) SPECT/CT revealed significantly higher tracer uptake in the infarct zone of MI mice compared to the remote zone and sham controls (P < 0.0001 for both). Tracer uptake was confirmed by autoradiography, which showed a strong correlation between SPECT and autoradiography (R = 0.81, P < 0.01). The scrambled tracer exhibited minimal cardiac uptake, demonstrating the specificity of 99mTc-(HE)-(GPO) signal. Denatured collagen staining and 99mTc-RYM1 autoradiography showed similar patterns as ex vivo 99mTc-(HE)-(GPO) autoradiography, while the ratio of denatured collagen to procollagen in the infarct zone significantly increased from day 3 to 2 weeks post-MI. Finally, 99mTc-(HE)-(GPO) bound to human fibrotic (but not normal) cardiac tissue. Conclusion99mTc-(HE)-(GPO) enables non-invasive detection of denatured collagen as a marker of collagen remodeling in vivo, offering a promising tool for assessing fibrotic remodeling after MI. Collagen, procollagen, and denatured collagen, along with MMP activation, exhibit distinct patterns, and their combined imaging may provide a comprehensive molecular fingerprint of cardiac fibrosis, advancing personalized management of cardiomyopathy.

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Neishabouri, A., Ghim, M., Varli, O., Ahmad, A., Kukreja, G., Zhang, Z., Li, J., Toczek, J., Salarian, M., Zhang, J., Ein Alshaeba, D., Akar, F. G., Liu, C., Yu, S. M., Sadeghi, M. M.. 2026-01-20. Molecular Imaging of Collagen Turnover in Myocardial Infarction. https://doi.org/10.64898/2026.01.16.699986

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