Research Article: Metabolic modulation predicts heart failure tests performance

Date Published: June 20, 2019

Publisher: Public Library of Science

Author(s): Daniel Contaifer, Leo F. Buckley, George Wohlford, Naren G. Kumar, Joshua M. Morriss, Asanga D. Ranasinghe, Salvatore Carbone, Justin M. Canada, Cory Trankle, Antonio Abbate, Benjamin W. Van Tassell, Dayanjan S. Wijesinghe, Claudio Passino.


The metabolic changes that accompany changes in Cardiopulmonary testing (CPET) and heart failure biomarkers (HFbio) are not well known. We undertook metabolomic and lipidomic phenotyping of a cohort of heart failure (HF) patients and utilized Multiple Regression Analysis (MRA) to identify associations to CPET and HFBio test performance (peak oxygen consumption (Peak VO2), oxygen uptake efficiency slope (OUES), exercise duration, and minute ventilation-carbon dioxide production slope (VE/VCO2 slope), as well as the established HF biomarkers of inflammation C-reactive protein (CRP), beta-galactoside-binding protein (galectin-3), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)). A cohort of 49 patients with a left ventricular ejection fraction < 50%, predominantly males African American, presenting a high frequency of diabetes, hyperlipidemia, and hypertension were used in the study. MRA revealed that metabolic models for VE/VCO2 and Peak VO2 were the most fitted models, and the highest predictors’ coefficients were from Acylcarnitine C18:2, palmitic acid, citric acid, asparagine, and 3-hydroxybutiric acid. Metabolic Pathway Analysis (MetPA) used predictors to identify the most relevant metabolic pathways associated to the study, aminoacyl-tRNA and amino acid biosynthesis, amino acid metabolism, nitrogen metabolism, pantothenate and CoA biosynthesis, sphingolipid and glycerolipid metabolism, fatty acid biosynthesis, glutathione metabolism, and pentose phosphate pathway (PPP). Metabolite Set Enrichment Analysis (MSEA) found associations of our findings with pre-existing biological knowledge from studies of human plasma metabolism as brain dysfunction and enzyme deficiencies associated with lactic acidosis. Our results indicate a profile of oxidative stress, lactic acidosis, and metabolic syndrome coupled with mitochondria dysfunction in patients with HF tests poor performance. The insights resulting from this study coincides with what has previously been discussed in existing literature thereby supporting the validity of our findings while at the same time characterizing the metabolic underpinning of CPET and HFBio.

Partial Text

The prevalence of heart failure (HF) has increased over time in the aging population. In people older than 20, the incidence of HF has increased from 5.7 million Americans between 2009 and 2012 to 6.5 million Americans in 2011. Despite aggressive measures to improve HF management, the five-year mortality rate of HF patients remains approximately 40%—comparable to many forms of cancer[1,2]. Investigations into diagnosis of HF has revealed promising cardiopulmonary tests and biomarkers that allow better disease management following diagnosis[3,4]. Combining patient’s metabolic profiles from HF compromised organs and tissues with HF tests has been demonstrated to provide physicians with an efficient source of clinical information used to both manage and diagnose patients[5]. However, the complex association of these HF tests with changes in the peripheral metabolism of compromised individuals is still under investigation and has failed to reveal the value of circulating metabolites as HF biomarkers[6].




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