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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2016-07-29
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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.
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Hunter, Wynn G, Jacob P Kelly, Robert W McGarrah, Michel G Khouri, Damian Craig, Carol Haynes, Olga Ilkayeva, Robert D Stevens, et al. (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 https://hdl.handle.net/10161/13018.
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Scholars@Duke
Robert W. McGarrah
Michel Georges Khouri
Olga Ilkayeva
Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.
Robert David Stevens
James R. Bain
Christopher Bang Newgard
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 on the mechanisms involved in lipid-induced impairment of insulin secretion and action in diabetes.
Gary Michael Felker
William Erle Kraus
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 practice as a preventive cardiologist with a focus on cardiometabolic risk and exercise physiology for older athletes. My research space has both a basic wet laboratory component and a human integrative physiology one.
One focus of our work is an integrative physiologic examination of exercise effects in human subjects in clinical studies of exercise training in normal individuals, in individuals at risk of disease (such as pre-diabetes and metabolic syndrome; STRRIDE), and in individuals with disease (such as coronary heart disease, congestive heart failure and cancer).
A second focus of my research group is exploration of genetic determinates of disease risk in human subjects. We conduct studies of early onset cardiovascular disease (GENECARD; CATHGEN), congestive heart failure (HF-ACTION), peripheral arterial disease (AMNESTI), and metabolic syndrome. We are exploring analytic models of predicting disease risk using established and innovative statistical methodology.
A third focus of my group’s work is to understand the cellular signaling mechanisms underlying the normal adaptive responses of skeletal muscle to physiologic stimuli, such as occur in exercise conditioning, and to understand the abnormal maladaptive responses that occur in response to pathophysiologic stimuli, such as occur in congestive heart failure, aging and prolonged exposure to microgravity.
Recently we have begun to investigate interactions of genes and lifestyle interventions on cardiometabolic outcomes. We have experience with clinical lifestyle intervention studies, particularly the contributions of genetic variants to interventions responses. We call this Lifestyle Medicopharmacogenetics.
KEY WORDS:
exercise, skeletal muscle, energy metabolism, cell signaling, gene expression, cell stretch, heart failure, aging, spaceflight, human genetics, early onset cardiovascular disease, lifestyle medicine
Svati Hasmukh Shah
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