In this resubmission, the applicants propose to use their previously developed fibrin-specific 99mTc small tetrameric molecule agent (99mTc-F4A) to quantify and characterize thrombus formation in left ventricular assist device (LVAD) circuits and compare the nuclear signal with pump histopathology results. The panel agreed that the applicants did a good job of responding to the concerns of the previous reviewers, including eliminating the aim regarding developing a handheld device. The ability to detect thrombus formation in VAD is an unmet clinical need with high significance, the team of investigators was considered very strong and the research environment was considered good. The tetrameric probe was considered novel, with decreased plasma interference and improved affinity over previous probes. The approach was logical within the aims, although the panel was concerned that the order of Aims seemed backwards (imaging the VAD in Aim 1 and optimizing the probe in Aim 2). It was also not clear if uptake would be detectable, especially in the presence of an attenuating medium. Reviewers also expressed concern regarding lack of access to a scanner for large animal work, because they agreed that imaging in a large animal model was needed. Although these concerns tempered the enthusiasm of the reviewers for this application, the significance was thought to outweigh the difficulties, and the panel concluded that the proposed work could have a high impact on early recognition of thrombus formation in LVADs.

Public Health Relevance

Despite the myriad major advances in cardiology, the prognosis for patients with severe, medically refractive HF is exceeding poor. Left ventricular assist devices (LVAD), a mechanical circulatory support system, have developed tremendously and offer considerable hope and benefit to patients with severe HF. However, they are associated with gastrointestinal (GI) bleeding, driveline infections, and thrombotic complications. Successful LVAD outcomes require careful management of anticoagulation and the complex interplay between increased bleeding and prevention of intrapump thrombus. Unfortunately, multicenter efforts to lower anticoagulation goals to minimize bleeding complications resulted in a tripled incidence of pump thrombotic complications. Intra-pump thrombus cannot be directly diagnosed but only inferred from nonspecific evidence and these suggestive markers of pump thrombus are late findings. Intrapump thrombus detected earlier may be responsive to anti-thrombotic treatment or progression stabilized by improved anticoagulation. Ultimately early recognition and clinical intervention could thrombotic complications and minimize surgical pump exchanges. In light of the increasing need and utilization of LVADs, we developed a novel, fibrin-specific 99mTc small tetrameric molecule agent (99mTc-F4A) able to bind to native thrombus under the high shear and high flow conditions of the axial flow pumps (9,000RPM - 5L/min). 99mTc-F4A clears rapidly into urine, has negligible serum interference, and has excellent detectability through the titanium pump's housing and cannulas.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122471-04
Application #
9418539
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Baldwin, Tim
Project Start
2015-04-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wu, Lina; Wen, Xiaofei; Wang, Xiance et al. (2018) Local Intratracheal Delivery of Perfluorocarbon Nanoparticles to Lung Cancer Demonstrated with Magnetic Resonance Multimodal Imaging. Theranostics 8:563-574
Ross, Michael H; Esser, Alison K; Fox, Gregory C et al. (2017) Bone-Induced Expression of Integrin ?3 Enables Targeted Nanotherapy of Breast Cancer Metastases. Cancer Res 77:6299-6312
Lanza, Gregory M; Cui, Grace; Schmieder, Anne H et al. (2017) An unmet clinical need: The history of thrombus imaging. J Nucl Cardiol :
Esser, Alison K; Schmieder, Anne H; Ross, Michael H et al. (2016) Dual-therapy with ?v?3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model. Nanomedicine 12:201-11
Pan, Dipanjan; Kim, Benjamin; Hu, Grace et al. (2015) A strategy for combating melanoma with oncogenic c-Myc inhibitors and targeted nanotherapy. Nanomedicine (Lond) 10:241-51
Schmieder, Anne H; Caruthers, Shelton D; Keupp, Jochen et al. (2015) Recent Advances in (19)Fluorine Magnetic Resonance Imaging with Perfluorocarbon Emulsions. Engineering (Beijing) 1:475-489