Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.
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BACKGROUND: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. CONCLUSIONS: We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.
Published Version (Please cite this version)10.1161/JAHA.115.003190
Publication InfoBain, James R; Craig, Damian; Felker, G Michael; Haynes, Carol; Hernandez, Adrian Felipe; Hunter, Wynn; ... Velazquez, Eric J (2016). Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure. J Am Heart Assoc, 5(8). 10.1161/JAHA.115.003190. Retrieved from http://hdl.handle.net/10161/13018.
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Associate Professor in Medicine
Professor of Medicine
Professor of Medicine
My overarching research interest and long-term goal is personalizing care for patients with heart failure. This is a complex, interdisciplinary endeavor requiring advancement in several areas. Presently, my research efforts are focused on the following sub-aims: clarifying mechanisms of heart failure pathogenesis, elucidating clinical and molecular phenotypes, improving risk-stratification, and characterizing physician-patient communication. To accomplish these aims, I use non-invasive metabolom
Assistant Professor of Medicine
Richard and Pat Johnson University Professor
My training, expertise and research interests range from human integrative physiology and genetics to animal exercise models to cell culture models of skeletal muscle adaptation to mechanical stretch. I am trained clinically as an internist and preventive cardiologist, with particular expertise in preventive cardiology and cardiac rehabilitation. My research training spans molecular biology and cell culture, molecular genetics, and integrative human exercise physiology and metabolism. I pr
Medical Instructor in the Department of Medicine
W. David and Sarah W. Stedman Professor of Nutrition in the School of Medicine
Over its 16 year history, our laboratory has investigated mechanisms of metabolic regulation and fuel homeostasis in mammalian systems. Major projects include: 1) Mechanisms involved in regulation of insulin secretion from pancreatic islet β-cells by glucose and other metabolic fuels; 2) Development of methods for protection of β-cells against immune-mediated damage; 3) Studies on spatial organization and regulation of systems controlling hepatic glucose balance; 4) Studies
Professor of Medicine
Adjunct Assistant Professor of Medicine
Adjunct Professor in the Department of Medicine
LeadershipEric J. Velazquez, MD, is a Professor of Medicine with tenure at Duke University. As section chief for Cardiovascular Imaging in the Division of Cardiology and director of the Cardiac Diagnostic Unit and Echocardiography Laboratories for Duke University Health System, he coordinates a high-volume enterprise and an outstanding group of clinician-investigators and clinical staff who make important contributions across patient care, research and educational
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