Metabolomics, Oxidative Stress, and Vascular Function in Heart Failure Patients

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 DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Alanna Morris, a heart failure (HF) and transplant cardiologist at Emory University who is beginning her career as a young investigator in patient-oriented clinical and translational research. This K23 award will provide Dr. Morris with the support necessary to develop an independent clinical research career that will establish her expertise in: (1) patient-oriented translational research i mechanisms underlying HF disease severity, including biomarkers, metabolomics analysis, and non-invasive assessments of vascular function; (2) racial differences in these mechanisms to elucidate biologic pathways underlying racial disparities in HF risk; (3) to implement advanced biostatistical methods in clinical studies by pursuing a Master of Science in Clinical Research; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Morris has assembled a mentoring team comprised of a primary mentor, Dr. Arshed Quyyumi, Co-Director of the Emory Clinical Cardiovascular Research Institute whose research has pioneered the use of invasive and noninvasive assessments of vascular function; and three mentors: Dr. Javed Butler, former Director of HF Research at Emory and recently appointed Chief of Cardiology at University of NY-Stonybrook; Dr. Dean Jones, Director of the Emory Clinical Biomarkers Laboratory whose work focuses on biomarkers of oxidative stress and high-throughput clinical metabolomic profiles; and Dr. Tianwei Yu, who has expertise in state-of-the-art biostatistic and bioinformatics methods in high-throughput metabolomics methods. Despite improvements in the treatment of HF in the past few decades, patients with HF and reduced ejection fraction (HFrEF) are at high risk for poor clinical outcomes, including death and hospitalization. Furthermore, Black patients develop HF at younger ages and are at higher risk for HF hospitalizations and death. Oxidative stress (OS) plays an important role in HF progression, and our research will examine how the interaction between nitric oxide (NO) and OS, termed the nitroso-redox balance, contributes to the pathophysiology of worsening HF. Increasing OS disrupts NO signaling, inducing endothelial dysfunction and vascular stiffness that augment the workload for the failing heart. Our prior data suggest that Blacks have higher levels of OS, lower NO bioavailability, and impaired vascular function as compared to Whites. Although unfavorable nitroso-redox balance and impaired vascular function may contribute to the excess HF observed in Blacks, this theory has not been proven. In addition, analysis of metabolomics profiles is an innovative method that can be utilized to discover new molecular pathways involved in the pathogenesis of heart failure, and hence the identification of novel diagnostic markers and therapeutic targets. Our research plan seeks to comprehensively examine the association of nitroso-redox balance, vascular function, and metabolites in patients with HFrEF, and identify whether racial differences in these predictors contribute to the excess HF risk observed in this population. In Aim 1, we will determine if biomarkers of systemic nitroso-redox balance are associated with clinical HF related events (HFRE), including mortality, hospitalizations, and emergency department visits at one year. In Aim 2, we will verify if novel methods of assessing vascular function, including peripheral and radial arterial tonometry, predict HFRE compared to established methods such as flow-mediated dilatation. In Aim 3, we will perform a metabolomewide association study to identify candidate metabolites characteristic of heart failure severity, and use computational and bioinformatic tools to map these to metabolic profiles. For each Aim, we will specifically examine if there are racial differences in the measured markers, to determine potential biologic mechanisms for observed racial disparities in heart failure severity and clinical outcomes. We plan to execute the proposed research as part of a 5-year K23 career development award that will enhance Dr. Morris' ability to operate as an independent clinician-scientist. Dr. Morris' prior research experience examining Black-White differences in OS and vascular function provide a strong foundation for performing the proposed research in patients with HFrEF, as OS is increasingly implicated in the pathophysiology of HF. The exceptional group of mentors and co-mentors will provide both technical and intellectual supervision, while the K23 award will provide the opportunity for protected research time and didactic education. Moreover, Emory's participation in the Atlanta Clinical Translational Science Institute (ACTSI) includes a NIH-funded Clinical Research Network (CRN) that offers Dr. Morris a full complement of nursing, core laboratory support, and bioinformatics and statistical analysis to carry out her research proposal. Dr. Morris will complete a Master's of Science in Clinical Research, giving her formal training in biostatistics and clinical research design. The K23 award will help Dr. Morris achieve her long-term goal of having a successful career in translational and health disparities research, making scientific contributions to the understanding of 1) racial differences in nitroso-redox balance and its impact on racial disparities in HF, and 2) biomarkers and vascular profiles to aid in risk prediction models for HFrEF patients.