Abstract
A variety of atherosclerosis and cardiovascular disease (ASCVD) phenotypes are tightly linked to changes in the cardiac energy metabolism that can lead to a loss of metabolic flexibility and to unfavorable clinical outcomes. We conducted an association analysis of 31 ASCVD phenotypes and 97 whole blood amino acids, acylcarnitines and derived ratios in the LIFE-Adult (n = 9646) and LIFE-Heart (n = 5860) studies, respectively. In addition to hundreds of significant associations, a total of 62 associations of six phenotypes were found in both studies. Positive associations of various amino acids and a range of acylcarnitines with decreasing cardiovascular health indicate disruptions in mitochondrial, as well as peroxisomal fatty acid oxidation. We complemented our metabolite association analyses with whole blood and peripheral blood mononuclear cell (PBMC) gene-expression analyses of fatty acid oxidation and ketone-body metabolism related genes. This revealed several differential expressions for the heart failure biomarker N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in peripheral blood mononuclear cell (PBMC) gene expression. Finally, we constructed and compared three prediction models of significant stenosis in the LIFE-Heart study using (1) traditional risk factors only, (2) the metabolite panel only and (3) a combined model. Area under the receiver operating characteristic curve (AUC) comparison of these three models shows an improved prediction accuracy for the combined metabolite and classical risk factor model (AUC = 0.78, 95%-CI: 0.76–0.80). In conclusion, we improved our understanding of metabolic implications of ASCVD phenotypes by observing associations with metabolite concentrations and gene expression of the mitochondrial and peroxisomal fatty acid oxidation. Additionally, we demonstrated the predictive potential of the metabolite profile to improve classification of patients with significant stenosis.
Highlights
The human heart hydrolyzes a total of 6 kg of adenosine tri-phosphate (ATP) per day to maintain contractile function [1]
We studied the relationships of metabolic profiles (AAs, ACs and physiological quotients, n = 97, see methods, Table S1) and different ASCVD phenotypes in two studies, the population-based Leipzig Research Center for Civilization Diseases (LIFE)-Adult study and LIFEHeart—a study of patients with suspected or confirmed coronary artery disease (CAD)
Considering 145 probes of 91 genes involved in the pathways “fatty acid catabolic process” (GO:0009062) and “cellular ketone body metabolic process” (GO:0046950), we found 18 significant associations, 17 with NT-proBNP and one with ankle brachial index (ABI)-PAD with peripheral blood mononuclear cell (PBMC) gene expression in LIFE-Heart
Summary
The human heart hydrolyzes a total of 6 kg of adenosine tri-phosphate (ATP) per day to maintain contractile function [1]. Energy production needs to be tightly linked to energy expenditure. This high energy demand is primarily met from mitochondrial fatty acid oxidation (FAO), but the myocardium is characterized as highly flexible in its substrate choice and is able to utilize a variety of substrates, such as lactate, ketone bodies, glucose and amino acids [3]. Under hypertrophy, a decrease in FAO and an increase in glycolysis have been frequently observed [1]. This remodeling is a complex process that leads to a maladaptive spiral and eventually ATP depletion by affecting a multitude of metabolic pathways such as Ca2+ homeostasis, creation of reactive oxygen species (ROS) and inflammation [2]. The precise characterization of these disturbances is difficult, with descriptions of the failing heart reaching from “an engine out of fuel” to “an engine flooded with fuel” [3,4]
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