CHIcago Center for Accelerating nextGen Omics, deep phenotyping, and data science in Heart Failure (CHICAGO-HF)

This application proposing the CHIcago Center for Accelerating nextGen Omics (CHICAGO-HF) is in response to the RFA entitled “HeartShare: Next-Generation Phenomics to Define Heart Failure Subtypes and Treatment Targets-Clinical Centers”. There are currently no therapies that improve survival for heart failure with preserved ejection fraction (HFpEF). There are several potential reasons for the lack of progress in identifying disease-modifying therapies in HFpEF. First, detailed phenotyping that characterize the distinct myocardial phenotypes across the spectrum of HFpEF is needed and we will propose leverageing magnetic resonance imaging (MRI) and endomyocardial biopsies for this purpose. Second, distinct subtypes of HFpEF may exist that result from the complex interplay of extra-cardiac organ dysfunction and characterized by an inflammatory milieu (such as elevated levels of plasminogen activator inhibitor-1 [PAI-1]), and we propose to elucidate these further. Third, few diverse large observational studies of HFpEF have been performed; these studies are badly needed and must include a diverse racial/ethnic and socioeconomic group of patients to prevent worsening of health disparities in HFpEF. The proposed CHICAGO-HF Clinical Center (CC) headquartered at Northwestern is uniquely qualified to participate in the HeartShare Network and contribute to the development and successful completion of the network’s goals. Our CC has extensive experience in recruiting patients with HFpEF in clinical trials, participating as a field center for multiple NHLBI population-based cohorts, and includes a study team with extensive relevant expertise in epidemiology, clinical informatics, imaging and molecular phenotyping, data analytics, as well as a long track-record of mentoring junior investigators. In collaboration with multiple health centers across Chicago, our CC will have access to a large, diverse population of patients with HFpEF. We will leverage our experience with our robust electronic health record infrastructure that dates back to 2000 with our Enterprise Data Warehouse and is integrated across Chicago within the Chicago Area Patient-Centered Outcomes Research Network to prospectively recruit and follow patients with HFpEF and age- and sex-matched controls. We propose to lead the network in multiparametric MRI for deep phenotyping myocardial, vascular, and extra-cardiac structures to identify key HFpEF subtypes. We will leverage our imaging and systems biology expertise to define distinct HFpEF endophenotypes and determine whether PAI-1 plays a central role in the pathobiology of HFpEF through nitric oxide signaling pathways. The participation of CHICAGO-HF in the HeartShare Network will allow the network to successfully accelerate the identification of novel therapeutic targets, foster a transition towards personalized medicine y matching endophenotypes of HFpEF with precision therapeutic approaches (e.g. small molecule inhibitor of PAI-1), and equitably improve management of HFpEF.