Lipids play a crucial role in the human body by serving as a primary energy source and forming essential components such as cytomembranes, hormones, and other important biomolecules. Lipid metabolism assumes a critical function, acting as the primary fuel for mediating the oxidative metabolism of the myocardium, thus attributed to driving exacerbation of myocardial injury [
16]. Consequently, the exacerbation of MINS can be attributed to the involvement of lipids in this process.
When the myocardial injury occurred, fatty acid uptake and metabolism surged to meet the requirement of the urgent need for energy and metabolic adjustment [
17]. In this study, it was observed that Tetranor-12(S)-HETE (hydroxyeicosatetraenoic acid) was markedly upregulated in MINS patients. Previous research has shown that 12(S)-HETE is associated with various cardiovascular biological activities. Ma et al. discovered that the catalytic process of converting arachidonic acid to 12-hydroperoxyeicosatetraenoic acid, facilitated by platelet-type 12-lipoxygenase, was reduced through diverse mechanisms to produce 12(S)-HETE. It has been discovered that small renal arteries are constricted by 12(S)-HETE [
18]. Furthermore, 12(S)-HETE significantly impacts angiotensin II-dependent hypertension [
19]. Nadler and Satio et al. concluded that angiotensin II-induced aldosterone secretion [
20], as well as intracellular calcium transients, was modulated by 12 (S)-HETE [
21]. Additionally, research on patients with essential hypertension revealed an elevated level of 12(S)-HETE due to urinary excretion and platelet production [
22]. The impact of Tetranor-12(S)-HETE in MINS has remained unclear thus far, but it is a metabolite that warrants further investigation.
Elevated levels of 4-Hydroxybutyric acid (GHB) and arachidonic acid (AA) were observed in the samples obtained from patients with MINS. GHB, an endogenous short-chain fatty acid, is naturally found in the central nervous system and shares structural similarities with γ-aminobutyric acid (GABA), a key inhibitory neurotransmitter [
23]. Previous studies have indicated the presence of GHB binding sites in cardiac tissue [
24]. Additionally, the enzyme gamma-aminobutyrate transaminase, which plays a crucial role in GABA catabolism, may contribute to cardiac protection by preserving mitochondrial function rather than its GABA catabolic capacity [
25]. This suggests potential associations between inhibitory neurotransmitters and myocardial injury.
A non-targeted metabolomics analysis conducted on plasma samples from patients who underwent percutaneous coronary intervention 6 hours post-surgery revealed that the AA metabolism exhibited the most significant alterations among all the metabolites [
26]. This discovery emphasizes the significance of investigating AA metabolism in the context of MINS. Numerous studies have indicated that the activation of AA metabolism signals during ischemia-reperfusion directly triggered progressive cardiomyocyte-inflammatory and apoptosis, extensive inflammatory cell infiltration and subsequent cardiac dysfunction [
26,
27]. The prostanoids and other biologically active lipids, known as eicosanoids, are synthesized from AA. Zhang et al. conducted studies that suggested prostanoid biosynthesis in cardiomyocytes and the vascular system may serve as a protective mechanism against acute myocardial ischemia-reperfusion injury [
28]. Our research identified elevated levels of prostaglandin G2, prostaglandin K2, prostaglandin E1, and tetranor-PGFM (prostaglandin F 2alpha metabolite) in the MI group, which aligns with findings from previous studies.
Glycerophospholipids (GPLs), which are the primary component of cytomembrane and important bioactive lipids such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE), have been found to be associated with clinical outcomes of myocardial injury [
29,
30]. In this study, metabolic analyses revealed an upregulation of PC (20:5e/16:4), PC (7:0/13:1), PC (4:0/16:3), and PE (18:2e/20:3) in the MINS group. It was confirmed that pharmacologically increasing bioactive phosphosphingolipids following acute myocardial injury had a beneficial effect on improving physiological function after myocardial infarction [
31]. Sphingomyelin (SM), being the principal phosphosphingolipids and a crucial component of cytomembranes, plays a pivotal role in regulating mechanical stability, signaling, and sorting. This research identified upregulated levels of SM (d14:0/14:0), SM (d14:1/22:0), SM (d14:1/14:0), SM (d14:2/24:1), and SM (d26:2/18:2) in the MINS group.
The KEGG analysis revealed that cholesterol metabolism exhibited the most significant alterations. Cholesterol homeostasis is required to maintain proper cellular and systemic functions, and disturbances in cholesterol metabolism have been implicated as a causative factor in cardiovascular disease [
32]. Specifically, cholesterol level is a strong risk factor for atherosclerosis and cardiovascular disease. Additionally, cholesterol crystals have been observed predominantly in thrombi originating from plaque rupture of patients who suffered myocardial infarction, although the precise role of cholesterol crystals in thrombi remains to be thoroughly investigated [
33]. The primary pathway for cholesterol metabolism involves its conversion into bile acids. Williamson et al. observed that the contraction of cardiomyocytes and the maintenance of intracellular calcium balance were influenced by the primary bile acid taurocholate [
34]. Zhang et al. discovered that an abnormal elevation in serum total bile acid levels tends to higher the risk of developing coronary plaques in asymptomatic patients, suggesting that serum bile acid levels could serve as a reliable indicator of acute myocardial injury [
35]. These findings suggest a strong association between abnormal bile acid metabolism and the occurrence and progression of myocardial injury [
36]. The KEGG analysis revealed that primary bile acid biosynthesis was a pathway that exhibited significant changes, with an observed increase in glycocholic acid, taurocholic acid, and taurochenodeoxycholic acid.
Interpretation of amino acid metabolisms in MINS
In addition to lipids, amino acids serve as an essential source of energy for cardiovascular adjustments. Specifically, branched-chain amino acids (BCAA), a crucial group of amino acids, act as substrates for oxidation in myocardial tissues [
37]. The findings of the studies indicated that the utilization of fatty acids in adult cardiac myocytes could be enhanced through the use of BCAA [
38]. Specifically, the level of 3-methyl-2-oxobutanoic acid was upgraded in our experimental results. The observed reduction in 3-methyl-2-oxobutanoic acid levels resulted in impaired BCAA transformation, potentially compromising the utilization of fatty acids, and weakening the myocardial injury protection mechanism [
39].
The metabolism of phenylalanine has been identified as a potential profile associated with myocardial injury. The findings of our study revealed that L-phenylalanine, L-tyrosine, and hippuric acid were found to be elevated. Previous research has also demonstrated a correlation between increased levels of serum phenylalanine and coronary failure [
40]. Additionally, the process of C4-hydroxylation of phenylalanine into tyrosine, which serves as a precursor for catecholamines that are upregulated in senescence and heart failure, is catalyzed by phenylalanine hydroxylase [
41]. Furthermore, another study indicated that alterations in phenylalanine levels might be associated with the incidence of acute rejection in rat heart transplantation [
42]. The metabolic pathways of cysteine and methionine have been found to be extensively linked to the occurrence and development of cardiovascular diseases [
43], which is consistent with the findings of the KEGG result. The upgraded L-homocystine and downgraded S-adenosylhomocysteine were observed in MINS patients.
The role of hormone metabolism in cardiovascular diseases has been focused over the last several years. The physiological state of steroid hormones, regulated by nongenomic pathways affecting calcium homeostasis, can potentially modify cardiac repolarization [
44]. Among all the related hormones, aldosterone and testosterone contribute the most to cardiovascular diseases, especially myocardial injury [
45,
46]. The adverse effect of the increase in aldosterone levels has been thoroughly validated in individuals experiencing the acute phase of myocardial injury [
45]. Multiple studies have demonstrated that decreased serum testosterone levels can be applied to predicting the mortality of patients with heart failure [
46]. Both aldosterone and testosterone appear to play crucial roles in acute myocardial injury. Our findings suggest that aldosterone synthesis and secretion is a significantly enriched pathway in differential metabolites. AA also plays a role in this metabolic pathway. This finding indicated an increase in AA levels, while methyltestosterone levels decreased in patients with MINS.
Additionally, our study observed an elevation in L-pyroglutamic acid and pyridoxamine. Pyroglutamic acid is derived from glutathione degradation, and there is a comprehensive understanding of the involvement of the glutathione cycle in the cellular response to heart function [
47]. Pyridoxamine, a natural form of vitamin B6, was identified as a protective factor in cases of cardiac dysfunction resulting from aging or myocardial infarction [
48,
49]. These associations suggest potential predictive capabilities for MINS.
Generalizability
MINS stands as one of the most critical post-surgery complications, significantly linked to postoperative mortality and adverse cardiovascular outcomes. Despite its gravity, the distinctive pathophysiological changes underlying MINS remain elusive, presenting a considerable challenge in timely diagnosis. Our study endeavors to address this gap by shedding light on the metabolomic features of MINS and presenting potential biomarkers. The novel contributions could be summarized as: (1) contextualization of metabolism and biomarkers in MINS: the development and onset of myocardial injury during the perioperative period differ from those in traditional coronary heart disease, influenced by factors such as anesthesia, surgery, and pain. Our focus on the context of MINS allowed us to delineate the specific relevance of the identified molecules in a distinct clinical scenario. By identifying their correlations with MINS, we highlight their potential as specific biomarkers, paving the way for a more tailored diagnostic and prognostic approach for MINS patients; (2) propose a novel strategy for biomarker discovery and potential intervention targets: our study goes beyond the mere identification of biomarkers by integrating bioinformatic analyses subsequent to MS-spectrum analysis. This approach allowed us to unravel intricate relationships between these molecules and additional pathways, revealing potential mechanisms underlying their involvement in MINS. The interconnectedness of these biomarkers with various other molecular pathways sheds new light on the complex molecular landscape of MINS. While these molecules have been implicated in cardiovascular diseases, our study provides a foundation for potential targeted interventions specific to prevent or treat MINS. This holds the promise of yielding a positive impact on patient care and outcomes.