Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction

Moon, B. F.; Zhou, I. Y.; Ning, Y.; Chen, Y. I.; Le Fur, M.; Shuvaev, S.; Akam, E. A.; Ma, H.; Molinos Solsona, C.; Weigand-Whittier, J.; Rotile, N.; Hariri, L. P.; Drummond, M.; Boice, A. T.; Zygmont, S. E.; Sharma, Y.; Warburton, R.; Martin, G.; Blanton, R. M.; Fanburg, B. L.; Hill, N. S.; Caravan, P.; Penumatsa, K. C.

doi:10.1101/2023.12.15.571959

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bioRxiv · 10.1101/2023.12.15.571959

Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction

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Abstract

BackgroundAging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in an LV dysfunction model. MethodsLV dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone (SAMP8) mice, a subset of mice received sham surgery. Three weeks post-surgery, mice underwent simultaneous PET-MR imaging at 4.7 T. Collagen-targeted PET and fibrogenesis MR probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent signal increase (%SI) and {Delta}LMR were computed from the pre-/post-injection MR images. Tissue specimens were analyzed for hydroxyproline (Hyp) and allysine content. Ventricular structure and function were measured by echocardiography and hemodynamic pressure-volume (PV) loop analysis. ResultsAllysine in the heart (22{+/-}5 (TAC), 13{+/-}5 (sham) nmol/g, P=0.02) and lungs (7.5{+/-}4 (TAC), 5.8{+/-}2 (sham) nmol/lung, P=0.17) of TAC mice corresponded to an increase in myocardial MRI %SI (29{+/-}15 (TAC), 6.1{+/-}4 (sham), P<0.0001) and {Delta}LMR (0.3{+/-}0.1 (TAC), 0.08{+/-}0.1 (sham), P<0.0001). Hyp in the heart (555{+/-}90 (TAC), 400{+/-}80 (sham) {micro}g/g, P<0.0001) and lungs (189{+/-}63 (TAC), 143{+/-}31 (sham) {micro}g/lung, P<0.01) were elevated in TAC mice, which corresponded to an increase in PET signal (MMR: 1.8{+/-}0.1 (TAC), 1.6{+/-}0.2 (sham), P=0.02; LMR: 1.5{+/-}0.1 (TAC), 1.2{+/-}0.1 (sham), P<0.001). PV loop and echocardiography demonstrated adverse LV remodeling, function, and increased right ventricular systolic pressure in TAC mice. ConclusionsAdministration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-MRI signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-MR imaging protocol.

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Moon, B. F., Zhou, I. Y., Ning, Y., Chen, Y. I., Le Fur, M., Shuvaev, S., Akam, E. A., Ma, H., Molinos Solsona, C., Weigand-Whittier, J., Rotile, N., Hariri, L. P., Drummond, M., Boice, A. T., Zygmont, S. E., Sharma, Y., Warburton, R., Martin, G., Blanton, R. M., Fanburg, B. L., Hill, N. S., Caravan, P., Penumatsa, K. C.. 2023-12-17. Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction. https://doi.org/10.1101/2023.12.15.571959

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