Prevention of remodeling by image guided epicardial delivery of hydrogels to the heart

Myocardial infarction (MI) remains a leading cause of morbidity and death in the Western world and often leads to left ventricular remodeling and progressive heart failure with reduced ejection fraction (HFrEF). The local intramyocardial delivery of biomaterials to the MI region and/or the peri-infarct border zone has been shown to reduce post-MI remodeling in both small and large animal models. These injectable biomaterials can be used to release incorporated payload of small molecule therapeutics. However, while these approaches are promising, the delivery strategies and basic understand of these injectable biomaterials in terms of biomechanical properties in the absence of a therapeutic payload remains poorly understood. In our prior work we have demonstrated in porcine models of reperfused and non-reperfused MI that local delivery of hydrogels by minimally invasive surgical approaches to the MI region with and without the local release of inhibitors of matrix metalloproteinases (MMPs) stabilizes hemodynamics, reduces wall stress and results in sustained improvement in regional and global function reducing post-MI remodeling in association with increases in integrin activation a marker of angiogenesis, and decreased activation of MMPs. We have employed multi- isotope hybrid SPECT/CT imaging to non-invasively track the changes in these molecular process in relation to changes in regional mechanics and their therapeutic benefit. Other studies have demonstrated that the degradation kinetics and stiffness of these biomaterials may influence the therapeutic outcomes after MI. We will build upon this past work by development of a percutaneous transthoracic approach for multi-modality image guided intramyocardial delivery of hydrogel of variable stiffness that alter regional mechanics by modulation of fibroblast transformation both locally and remotely reducing post-MI remodeling. We hypothesize that early hydrogel-induced changes in mechanical stress and strain will result in fibroblast transdifferentiation and structural remodeling that can be tracked with targeted molecular imaging of fibroblast activation protein (FAP) along with serial echocardiography and computed tomography. We will employ hybrid SPECT/CT imaging to noninvasively track markers of inflammation, and fibroblast activation with novel SPECT probes that target FAP, interrogating critical pathways involved in mechano-transduction and post-MI remodeling. To address this mechanistic hypothesis and evaluate therapeutic effects of image-guided delivery of therapeutic hydrogel we propose two specific aims. Aim 1 will develop a multimodality imaging approach to guide optimal transthoracic epicardial intramyocardial delivery of therapeutic hydrogels based on early hyperintensity of the MI region on non-contrast CT images for prevention of remodeling early post-MI, using a porcine model of reperfused MI, taking advantage of our integrated translational ultrasound fluoroscopy interventional suite. Aim 2 will apply multi-isotope hybrid SPECT/CT imaging to evaluate early mechanical and molecular mechanisms underlying therapeutic efficacy of soft and stiffening hydrogels and associated longer term therapeutic benefit. Project Number: 1R01HL175990-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Albert Sinusas (+2 co-PIs) | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $758,862 | Activity Code: R01 | Study Section: Imaging Guided Interventions and Surgery Study Section[IGIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17599001A1