Mass General Brigham HeartShare Clinical Center

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Project Summary Heart failure with preserved ejection fraction (HFpEF) comprises approximately half of all HF and is a highly morbid condition. Pharmacotherapies that are effective in treating HF with reduced ejection fraction have more modest if any beneficial impacts on HFpEF, potentially owing to heterogeneous definitions of HFpEF and limited understanding of optimal pathways to target in HFpEF. Our team of investigators has extensive experience in HFpEF human subjects research. Complementary Dyspnea and Heart Failure Evaluation Programs attract referral of HFpEF patients as well as dyspneic control patients without HFpEF to the Massachusetts General Hospital and Brigham and Women’s Hospital (“Mass General Brigham, MGB”). In addition, our team is highly engaged in assessing therapeutic interventions for HFpEF through robust clinical trials programs. The MGB HeartShare Team’s PIs are responsible for HFpEF clinical trial conceptualization, design, implementation, and endpoint adjudication via established core laboratories in echocardiography, cardiopulmonary exercise testing, advanced cardiovascular imaging, all of which could be used to support HeartShare. Our team also has expertise in working with MGB-based electronic health record data, population study data, and clinical trials that inform our understanding of HFpEF. Our group has used comprehensive cardiopulmonary exercise testing (CPET) to simultaneously quantitate invasive hemodynamics, blood gases, cardiac function, arterial tonometry and gas exchange patterns during exercise in individuals with conventionally defined HFpEF. We have begun to delineate contributions of impaired cardiac, pulmonary, vascular, and peripheral musculoskeletal reserve capacity that are not evident at rest. Our single-center HFpEF phenotyping study already consists of >700 patients with HFpEF subjected to uniform phenotyping (echocardiography, NT-proBNP, multi-site blood sampling at rest and with exercise and comprehensive CPET). In Aim 1 we will assemble a collaborative multidisciplinary investigative team capable of recruiting, phenotyping, and retaining ≥250 HFpEF patients in the HeartShare Program while also drawing from experience with core lab oversight, bioinformatic expertise in electronic medical record research, and leadership of network, population cohort, and clinical trial research relevant to HFpEF. In Aim 2 we will refine the diagnosis and subclassification of HFpEF through comprehensive clinical assessment including multi-modality imaging of cardiac structure and function, perturbational testing with exercise to probe multi-organ system physiologic reserve and longitudinal remote physiologic monitoring and assessment of frailty and cognition. We will also expand on our experience with creation of omics-based signatures of pathophysiologic states in HFpEF and deploy unsupervised machine learning approaches to the derived data. HeartShare will enhance understanding of HFpEF and our team is poised to translate improved understanding of HFpEF subtypes into new therapeutic intervention trials in HFpEF.