Heart failure affects 5.7 million people in the United States and that number is growing. In the event of a heart attack, known as myocardial infarction (MI), early evaluation may prevent changes in the shape and structure of the heart. Typically, this is performed with an ultrasound.
A team of researchers from the Yale School of Medicine (YSM) and the University of Washington (UW) will use ultrasound to guide the delivery of theranostic hydrogels into the heart to prevent dilation of the heart post-MI and subsequent heart failure. Albert Sinusas, MD, professor of medicine in radiology and biomedical imaging, along with his longtime collaborator James Duncan, PhD, the Ebenezer K. Hunt Professor of Radiology and Biomedical Imaging and professor of biomedical engineering, and Matthew O’Donnell, PhD, at UW have been recently awarded a grant from the National Institutes of Health (NIH) to further their development of quantitative echocardiography for novel image-guided delivery of theranostics to the heart.
Image-Guided Delivery of Hydrogels to the Heart
A grant from the NIH National Heart, Lung and Blood Institute titled, “A Biomarker for Image-Guided, Post-MI Hydrogel Therapy,” was awarded on April 1, 2019 for $3.2 million. This project builds on a NIH-funded collaboration with Jason Burdick, PhD, at the University of Pennsylvania.
The researchers use targeted single photon emission computed tomography (SPECT) imaging of matrix metalloproteinases (MMPs), enzymes known to modulate the repair of the heart after a heart attack, to guide the delivery of therapeutic bioresponsive hydrogels to the heart. Once inserted, the hydrogels break down in the presence of MMPs and locally release inhibitors of MMPs. The Yale investigators also incorporated iodine to visualize the hydrogel within the cardiac muscle using either conebeam or multi-detector computed tomography (CT).
Sinusas, in collaboration with Frank Spinale, MD, PhD, at the University of South Carolina received an NIH fast-track Small Business Technology Transfer (STTR) grant for $1.5 million. Combined with support from the NIH Science Moving Towards Research Translation and Therapy (SMARTT) program, the project will perform the first human MMP-targeted nuclear imaging studies at Yale New Haven Hospital this academic year. Visit yalestudies.org to view this study and other clinical trials enrolling for patients with heart disease.
Hydrogels are inexpensive to produce and have a variety of other benefits and applications. For example, a recent study published in Nature Biomedical Engineering showed that a hydrogel-based patch applied to the heart could reduce oxidative stress and scar tissue accumulation, and other biomechanical effects associated with cardiac remodeling.
Sinusas and Duncan will employ a 3D ultrasound to guide the delivery of theranostic hydrogels and evaluate the biomechanical effects on the cardiac muscle.
The Yale investigators developed quantitative 3D differential deformation measures for stress echocardiography that can localize and quantify the extent and severity of myocardial injury. They also established a cardiac image analysis strategy that yields robust differential (rest-stress) deformation parameters centered around deep learning by developing a neural network to regularize displacement patches coming from two sources (radio frequency speckle tracking and B-mode shape tracking) based on a well-established synthetic global model of cardiac electro-mechanical and ultrasound imaging. The approach will be validated in an established porcine model of cardiac remodeling, and then translated to pilot clinical studies in patients.
Duncan and Sinusas have worked together for over 25 years. Sinusas is the founding director of the Yale Translational Research Imaging Center (Y-TRIC), a leader in molecular and translational cardiac imaging research.
The unique facilities at Y-TRIC provide state-of-the-art imaging resources and an interventional laboratory. Duncan directs the Yale Image Processing and Analysis Group which specializes in biomedical image analysis projects. These Yale investigators with complementary expertise also direct a currently funded NIH T32 grant for “Training in Multi-Modality Molecular and Translational Cardiovascular Imaging.” The training program prepares postdoctoral fellows for research careers in the emerging field of molecular and multimodality imaging of cardiovascular disease and image-guided delivery of novel theranostics. The training program supports six research fellows per year for a two-to-three year period of dedicated research training.
“I look forward to working with this interdisciplinary team of faculty and fellows to develop and evaluate the potential use of image-guided therapy in the cardiovascular system,” added Sinusas.