Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization
Introduction
CAD is the leading cause of death in developed countries and is projected to become the largest cause of mortality in some developing countries by the year 2015 [1], [2]. CAD is a complex, heritable disease and CAD risk models remain incomplete. As such, metabolomics (the study of small-molecule metabolites that are byproducts of cellular metabolism) could be instrumental in better understanding the development of CAD and identifying factors that discriminate the severity of CAD lesions noninvasively.
We previously used targeted, quantitative metabolic profiling in a case–control study of CAD [3]. In that study, we found that a PCA derived metabolite factor composed of BCAA and related metabolites, and another factor composed of some amino acids involved in the urea cycle pathway, were associated with extremes of CAD burden after adjusting for known clinical risk factors. We sought to validate these findings using a similarly-selected nested-case–control population with extremes of CAD. These individuals were selected from within a larger, sequential cohort of individuals referred for cardiac catheterization at Duke University Medical Center (DUMC). This analysis was carried out as a component of the Measurement to Understand Reclassification of Disease of Cabarrus and Kannapolis Horizon 1 Cardiovascular Disease Study (MURDOCK CV) [4]. To better understand the relationship of metabolite factors with CAD burden, we also conducted an exploratory analysis to evaluate the relationship of CAD severity as a continuous variable with metabolite factor levels in the entire cohort.
Section snippets
Study population
The CATHGEN biorepository consists of consenting, consecutive patients who underwent cardiac catheterization at DUMC between 2001 and 2010. All subjects were fasting for at least 6 h and arterial blood was collected through the femoral sheath at the time of catheterization. The blood samples were immediately chilled to 4 °C, centrifuged (within 30 min of collection), plasma separated, aliquoted, and frozen at −80 °C. As part of the MURDOCK CV study, 2023 sequential CATHGEN participants
Results
The baseline clinical characteristics of the overall MURDOCK CV study population were previously presented [4]. Table 1 presents clinical characteristics of the CAD cases and controls used in this study. As expected, CAD cases had higher rates of clinical risk factors than controls, with the exception of low-density lipoprotein (LDL) cholesterol [14].
Discussion
In this study we validated results from our previous smaller case–control study using patients from a large sequential cohort. We found metabolites within the BCAA catabolic pathway are independently associated with significant CAD and expanded our previous findings by including a more detailed assessment of glucose control (glycated albumin). These results lend support to the hypothesis that these metabolites may mediate CAD development independently of their relationship with IR and diabetes.
Conclusions
We have validated our previous findings showing BCAAs and related metabolites are independently associated with extremes of CAD severity, even after adjusting for diabetes and measures of IR. More studies are needed to elucidate the underlying biologic pathways that mediate the association of BCAAs with CAD severity.
Funding sources
The MURDOCK study was funded through a gift to Duke from the David H. Murdock Institute for Business and Culture; R01HL095987 (Shah, PI); UL1RR024128-01 (National Center for Research Resources [NCRR]).
Disclosures
Shah, Kraus, Newgard and Newby hold a patent on an unrelated finding.
Acknowledgements
We thank the CATHGEN participants and Z. Elaine Dowdy for study coordination.
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2022, Cell MetabolismCitation Excerpt :Most research in cardiac metabolism has to date focused on glucose, fatty acid, and lactate as fuels, but there is now increasing evidence for altered metabolism of amino acids and ketones. Among the most striking recent findings is an elevation of circulating plasma branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) in patients with coronary artery disease (CAD) (Bhattacharya et al., 2014; McGarrah et al., 2018; Shah et al., 2010, 2012), which is associated with subsequent adverse events (Du et al., 2018b, 2018a). The expression of BCAA catabolic genes is suppressed in failing human heart and is the most significantly suppressed metabolic pathway in failing murine heart (Sun et al., 2016).