Abstract
Coronary artery disease (CAD) remains the leading cause of death worldwide. Expanding patients' metabolic phenotyping beyond clinical chemistry investigations could lead to earlier recognition of disease onset and better prevention strategies. Additionally, metabolic phenotyping, at the molecular species level, contributes to unravel the roles of metabolites in disease development. In this cross-sectional study, we investigated clinically healthy individuals (n = 116, 65% male, 70.8 ± 8.7 years) and patients with CAD (n = 54, 91% male, 67.0 ± 11.5 years) of the COmPLETE study. We applied a high-coverage quantitative liquid chromatography-mass spectrometry approach to acquire a comprehensive profile of serum acylcarnitines, free carnitine and branched-chain amino acids (BCAAs), as markers of mitochondrial health and energy homeostasis. Multivariable linear regression analyses, adjusted for confounders, were conducted to assess associations between metabolites and CAD phenotype. In total, 20 short-, medium- and long-chain acylcarnitine species, along with L-carnitine, valine and isoleucine were found to be significantly (adjusted p ≤ 0.05) and positively associated with CAD. For 17 acylcarnitine species, associations became stronger as the number of affected coronary arteries increased. This implies that circulating acylcarnitine levels reflect CAD severity and might play a role in future patients' stratification strategies. Altogether, CAD is characterized by elevated serum acylcarnitine and BCAA levels, which indicates mitochondrial imbalance between fatty acid and glucose oxidation.
Highlights
Coronary artery disease (CAD) remains the leading cause of death worldwide [1]
The present work quantified a larger panel of acylcarnitines, which allowed the identification of novel associations between acylcarnitine species and CAD phenotype [17–19]
This study showed that altered mitochondrial metabolism reflected in high levels of circulating carnitine, acylcarnitines and branched-chain amino acids (BCAAs) is a hallmark of CAD, a chronic ischemic situation
Summary
Coronary artery disease (CAD) remains the leading cause of death worldwide [1]. In spite of this, in clinical practice, patients’ biochemical stratification is still mainly limited to total cholesterol and triglyceride quantification [2]. Elevated serum concentration of branched-chain amino acids (BCAAs), whose metabolism is tightly related to that of short-chain acylcarnitines, was observed in patients with insulin resistance [20–22], obesity [23, 24], diabetes [25–27], dyslipidemia, and CAD [19, 28, 29]. These studies, investigated patients already suffering from cardiometabolic diseases without including healthy controls [12, 13, 15, 17–19, 23–28] or with poorly characterized controls [14, 16, 20, 22, 29]. Comparing diseased against healthy metabolic signature is essential to reveal disease-associated alterations and to improve our understanding of metabolites’ roles in pathophysiological processes [30, 31] These studies investigating a limited number of acylcarnitines with a maximum of 12 species detected [19]. This number can be outranged due to technological advancements [32]
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