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1351398 - Molecular PET-MR imaging targeting cardiopulmonary collagen deposition and active fibrosis in a model of left ventricular dysfunction produced by transverse aortic constriction

Wednesday, January 25, 2023

Location: E-POSTER

Presenting Author(s)

Brianna F. Moon, PhD

Research Fellow
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School
Charlestown, Massachusetts, United States

Primary Author(s)

Brianna F. Moon, PhD

Research Fellow
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School
Charlestown, Massachusetts, United States

Co-Author(s)

IZ

Iris Y. Zhou, PhD

Assistant Professor
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States
YN

Yingying Ning, PhD

Research Fellow
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School
Charlestown, Massachusetts, United States
SS

Sergey Shuvaev, PhD

Research Fellow
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School
Charlestown, Massachusetts, United States
ML

Mariane M. Le Fur, PhD

Instructor
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States
YC

YinChing I. Chen, PhD

Assistant professor/Neuroscience Assistant
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School
Charlestown, Massachusetts, United States
EA

Eman A. Akam, PhD

Instructor
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States
JW

Jonah P. Weigand-Whittier, BSc

Research Technician II
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, Massachusetts, United States
NR

Nicholas Rotile, BA

Research Technologist
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States
MD

Matthew Drummond, BSc

Research Technician I
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States
AB

Avery T. Boice, BSc

Research Technician I
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States
SZ

Samantha E. Zygmont, BSc

Research Technician I
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States
RW

Rod R. Warburton, BA

Lab Manager
Tufts University School of Medicine
Boston, Massachusetts, United States
BF

Barry L. Fanburg, MD

Professor
Tufts University School of Medicine, United States
KP

Krishna C. Penumatsa, PhD

Scientific Staff
Tufts University School of Medicine, United States
PC

Peter Caravan, PhD

Professor
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, United States

Background: Left ventricular (LV) dysfunction promotes Group 2 pulmonary hypertension, right ventricular failure, cardiopulmonary congestion, and fibrosis^1,2. Multiple tests aid in diagnosing disease severity and progression in the heart and lungs including echocardiogram, and right heart catheterization. Tissue remodeling could potentially be assessed through a single imaging session. Here, we sought to develop a molecular PET-MR imaging protocol to detect both cardiopulmonary fibrosis with collagen-targeted ⁶⁸Ga-CBP8 PET³ and fibrotic disease activity with allysine-targeted Gd-1,4 MRI⁴ in a LV dysfunction model.

Methods: LV dysfunction was induced by left thoracotomy transverse aortic constriction surgery (TAC)¹ in 6-month-old SAMP8 mice² (n=5). Control SAMP8 mice (n=5) received sham surgery. 3-weeks post-surgery, mice were imaged at a 4.7T Bruker MRI equipped with a PET insert. Type I collagen–targeted PET probe (⁶⁸Ga-CBP8)³ was intravenously administered prior to imaging with an injected dose between 18-34 MBq. MRI sequences were interleaved to image the lungs (UTE: TR/TE=4/0.012 ms, FA=16°) and heart (T1 FLASH: TR/TE=18.2/3.5 ms, FA=50°), pre- and post-injection of Gd-1,4 [100 µmol/kg], a dual binding fibrogenesis probe targeting allysine⁴. PET was analyzed using the ratio of tissue signal (heart or lung) to muscle. %SI increase and ΔCNR were computed between pre- and post-injection MR images that were normalized to a phantom. Right lung (RL), left lung (LL), LV, and septum (Sep) specimens were analyzed by HPLC for hydroxyproline (Hyp) and allysine content⁵. LV end diastolic pressure (LVEDP) and RV systolic pressure (RVSP) were measured by invasive hemodynamic PV loop analysis. Results are reported as mean±SD with t-test comparison.

Results: MRI and PET were simultaneously acquired in the heart (Fig. 1A,B) and lungs (2A,B). MRI showed an increase in mean myocardial %SI increase of TAC mice 20-40min post-injection of Gd-1,4 (Sham=10±5, TAC=23±9, P=0.046) and an increase in mean pulmonary ΔCNR (Sham=0.8±1, TAC=3±1, P=0.005) (1,2C), which corresponded to elevated allysine in the heart (Sep: Sham=13±5, TAC=22±5 nmol/g, P=0.02) and lungs (LL: Sham=6±3, TAC=9±7 nmol/lung, P=0.23) (1,2D). TAC mice showed an increase in mean PET signal 65-95min post-injection of ⁶⁸Ga-CBP8 (heart: Sham=1.4±0.1, TAC=1.7±0.1, P=0.003, lungs: Sham=1.1±0.1, TAC=1.5±0.1, P< 0.001) (1,2E), which corresponded to elevated Hyp in the heart (LV: Sham=403±49, TAC=526±91 µg/g, P=0.001) and lungs (RL: Sham=148±16, TAC=189±76 µg/lung, P=0.15) (1,2F). LVEDP (Sham=4.7±1.5, TAC=12.3±2.1 mmHg, P=0.003) and RVSP (Sham=20.7±1.5, TAC=23.5±6.1 mmHg, P=0.48) indicate early signs of pulmonary hypertension (3A,B).

Conclusion: Injection of collagen-targeted ⁶⁸Ga-CBP8 and allysine-targeted Gd-1,4 probes led to elevated PET and MRI signal, respectively, which correlated with fibrosis and fibrogenesis markers. Overall, the study demonstrates the potential to stage heart and lung disease through a dual molecular PET-MR imaging protocol.