Depending on the pathophysiology of ACS disease, plasma or serum, is often used as a sample source for metabolomic studies, but it is unknown which source is better. Chacko et al. [10] in their study obtained coronary sinus and peripheral venous blood specimens to observe metabolic changes after acute myocardial ischemia. The same results were obtained from blood samples collected at both sites, confirming that these metabolic changes occur specifically in the myocardium. Urine metabolomics testing may also be an effective method to discover potential biomarkers of ACS and to explore the mechanisms of ACS [11]. Wang et al. [11] identified 9 metabolic pathways and 20 biomarkers of metabolites in urine samples, in which 11 metabolites were down-regulated in the urine of ACS patients, while the other 9 were up-regulated. Among these metabolic pathways, fatty acid metabolism, fatty acid $\beta$-oxidation metabolism, amino acid metabolism and tricarboxylic acid (TCA) cycle were closely associated with ACS (Table 1, Ref. [10, 11]).

In addition to being the main structural component of cells, lipids play an important role in cell signaling molecules and energy supply. Fatty acid metabolism is the main source of energy for the heart [11]. Myocardial ischemia may cause a significant increase in free fatty acid concentrations. Genomic studies and large randomized controlled trials have confirmed the relationship between dysregulated lipid metabolism and the progression of coronary heart disease [7]. Wang et al. [11] showed that lipid-related pathways, including fatty acid metabolism and fatty acid $\beta$-oxidation, also play an important role in the course of ACS. In summary, elucidating the composition of lipids at the molecular level is necessary to characterize the molecular basis of ACS, to reveal lipid alterations during the development of ACS, and to find new biomarkers for the early diagnosis of ACS. Lee et al. [12] studied 365 lipids and found increased levels of saturated lysophosphatidylcholine (LPC) species in the high-density lipoprotein (HDL) fraction (16:0 and 18:0) in the ACS group, suggesting an intermediate link between LPC and ACS progression. Sutter et al. [13, 14] demonstrated the effect of altered HDL lipidome on the severity of ACS disease. Garcia et al. [15] using targeted lipidomics showed that the HDL2 subclass is more enriched in oxidized fatty acids in ACS patients than in non-ACS patients, which may increase the risk of platelet-dependent thrombosis. Wang et al. [11] found that the expression of the long-chain free fatty acid palmitic acid was upregulated in ACS patients. The elevated palmitic acid content in the urine samples of the ACS group reinforced the concept of altered energy metabolism and fatty acid $\beta$-oxidation in ACS patients.

Lysophosphatidylcholines (LysoPCs) are proinflammatory factors that contribute to atherosclerosis and are major components of oxidized low-density lipoprotein (LDL) [16]. LysoPCs induce inflammation, activate T lymphocytes and macrophages, alter vascular smooth muscle cells, activate intracellular protein kinase C (PKC), promote vascular cellular adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expression, increase oxygen radical production, inhibit NO release from endothelial cells, and play an important role in the inflammatory response and remodeling of various cells in the vessel wall [17, 18]. Li et al. [19] found that increased levels of LysoPC were a marker for CHD in a model of myocardial ischemia. L-carnitine is an important cofactor for fatty acid B oxidation and plays an important role in promoting aerobic metabolism and scavenging toxic substances from energy metabolism [20, 21]. The content of L-carnitine and ATP in ischemic myocardium is significantly reduced, and free fatty acids are increased, leading to disturbances in myocardial cell energy metabolism [22]. Myocardial L-carnitine levels are significantly reduced, while blood L-carnitine levels are elevated, resulting from myocardial ischemia leading to partial release of L-carnitine into the blood or blocked transport of L-carnitine into cardiac myocytes [23]. Joanna et al. [24] using targeted analysis, demonstrated that ACS patients had the highest values for all 21 fatty acids on the day of onset of ACS, with values decreasing after 4 days and remaining at lower levels for 6 months.

Blood levels of trimethylamine oxide (TMAO) are an important marker for predicting ACS [25]. Lecithin, choline and carnitine can generate trimethylamine (TMA) through host gut microbes, which is subsequently released into the circulation to be oxidized by the liver to TMAO. This may promote the process of atherosclerosis by interfering with the reverse cholesterol transport. 3-dimethyl-1-butanol, on the other hand, can prevent ACS by interfering with TMA production in gut microbes and reducing circulating TMAO concentrations during ACS. Gut microbes are also thought to be key factors in regulating this process [25, 26]. Zhang et al. [27] performed a non-targeted analysis of metabolites in plasma in 2324 patients after coronary angiography, and quantitative analysis of N-acetylneuraminic acid using isotopic labeling, and also confirmed the role of N-acetylneuraminic acid in the pathophysiology of CHD (Table 2, Ref. [11, 12, 13, 14, 15, 19, 20, 24, 25, 27]).

The dependence of the normal heart on amino acids as a source of ATP is relatively small, but in patients with ACS, amino acids become an important source of energy and play an important role in ACS as precursors of energy metabolism [28]. Glutamate and glutamic acid can be phosphorylated at the substrate level to produce guanosine triphosphate. Yang et al. [29] suggested that branched-chain amino acids (BCAAs) predicted the risk for ACS. An increase in the concentration of BCAAs caused a significant increase in the risk of ACS development. Bernini et al. [30] also found that lower concentrations of threonine and creatinine anhydride reduced the risk of developing ACS. The essential amino acid tryptophan also plays an important role in human physiological and biochemical processes. Studies have shown that plasma choline levels are associated with an increased risk of cardiovascular disease [30, 31]. Yingfeng et al. [11] found that the upregulation of tryptophan in the urine of ACS patients was associated with a decrease in tryptophan catabolism, and that 5-hydroxytryptophan and 5-methoxytryptophan, the downstream metabolites of tryptophan, were also affected by changes in tryptophan content. Tryptophan can be converted to niacin, and its catabolic products, nicotinic acid and cucurbitacin, can affect choline metabolism. The study also demonstrated an upregulation of S-adenosyl-L-homocysteine expression. This suggests that the metabolic pathways of niacin and niacinamide were disrupted in the ACS patients, and that homocysteine is a potential marker in the progression of atherosclerosis (Table 3, Ref. [29, 30, 31]).

Myocardial ischemia and hypoxia occur in the acute coronary syndrome. Ischemia decreases aerobic oxidation of fatty acids, increases anaerobic respiration of glucose for ATP synthesis, and decreases aerobic metabolism of glucose while anaerobic glycolysis is enhanced [10]. Sabatine et al. [32] found that following an exercise stress test, there were significant changes in circulating levels of various metabolites such as lactate in ischemic myocardium. The pathway analysis suggested that the TCA cycle plays an important role in the process of myocardial ischemia. Li Jia et al. [33] found that succinate levels were abnormally elevated in the blood of ACS patients, and that ischemia and hypoxia can cause intracellular and extracellular succinate accumulation in the myocardium. Accumulation of intracellularly succinate inhibits pyruvate dehydrogenase (PDH) in a hypoxia-inducible factor -1$\alpha$ (HIF-1$\alpha$)-dependent pathway, and extracellularly accumulated succinate activates its specific receptor G-protein-coupled receptor 91 (GPR91), which promotes downstream PKC$\delta$ activation and translocation to the mitochondria, impairing PDH activity, which affects the production of the TCA intermediate acetyl coenzyme A. Succinate-mediated blockade of glucose oxidation also exacerbates ischemia-reperfusion injury in cardiac myocytes. Another study [34] found that elevated levels of caffeine and paraxanthine caused coronary artery spasm leading to myocardial ischemia (Table 4, Ref. [32, 33, 34]).

Myocardial reperfusion injury caused by the sudden reintroduction of oxygen and nutrients during reperfusion in STEMI patients can exacerbate myocardial cell death. A sudden increase in available oxygen occurs after ischemia-reperfusion, resulting in a dramatic burst of mitochondrial reactive oxygen species that causes cellular dysfunction through modification of intracellular molecules. Ischemia-reperfusion also restores physiological pH, which inhibits the opening of the mitochondrial permeability transition space. Reperfusion can lead to intracellular calcium overload due to sarcoplasmic reticulum dysfunction, and increase endoplasmic reticulum stress which exerts a pro-inflammatory response [7] and activates pro-thrombotic pathways in ischemic tissues [7]. Even with rapid and successful reperfusion, the mortality rate after acute myocardial infarction (AMI) is still close to 10% [35]. Chouchani et al. [36] studied metabolomic assays in a mouse model of ischemia/reperfusion (I/R) injury and showed that succinate accumulation, an intermediate product of the TCA cycle during ischemia, and succinate oxidation during reperfusion, increased mitochondrial reactive oxygen species (ROS) and reperfusion injury. Kohlhauer et al. [37] using a targeted LC/MS approach to plasma metabolite analysis in STEMI patients treated with percutaneous coronary intervention (PCI), identified myocardial succinate accumulation as an early marker of I/R injury in humans. Li et al. [38] also showed that impaired BCAA catabolism inhibited glucose uptake and exacerbated I/R injury. Surendran et al. [7] found that pentadecanoic acid, 18:2 carnitine and, 18:2 lysophosphatidylcholine levels could determine the extent of I/R injury after PCI in STEMI patients. Jia et al. [33] found that ginsenosides could reduce succinate accumulation, restore PDH viability, and improve ischemia-reperfusion injury in cardiac myocytes. However, there are limited clinical treatment options for I/R injury [7]. Therefore, metabolomics will be used to find new methods to prevent and treat I/R injury (Table 5, Ref. [35, 36, 37, 38]).

Statins are a class IA indication for secondary prevention in patients with CHD. Previous studies and clinical practice have demonstrated that the application of statin therapy is strongly associated with a reduced incidence of plaque rupture and improved prognosis for patients with ACS [39]. Hu et al. [39] found that patients on chronic statin therapy had fewer adverse events than those who had not received statins. This study used beta diversity analysis to find significant differences in microbial composition between the ACS and control groups. The BugBase database predicted that the ACS group was enriched in potentially pathogenic bacteria, while the ACS-statin group was relatively depleted, thus inferring that statins may be the driving force behind the shift of intestinal flora in ACS patients to a healthy population. This finding suggests that statins may reduce potentially pathogenic bacteria and increase probiotic bacteria such as bifidobacteria by modulating the intestinal flora of ACS patients. It also predicted that statins may be associated with fatty acid and isoprenoid pathways (Table 6, Ref. [39]).

The relationship between coronary atheromatous dilatation (CAE) and CHD is unclear. Coronary artery dilatation can lead to AMI and a poor prognosis. Swayze et al. [40] suggested that CAE may be a variant of CHD. Both diseases share similar risk factors, and both may also share a pathological process, one of the pathophysiological factors being the immune response to endothelial cell injury. Unfortunately, however, there are no studies on the metabolomics of CAE.

Metabolomics has now made great progress in prognostic prediction [41]. Metabolomics has also been used to predict adverse cardiovascular events in patients with ACS. A study by Mehta et al. [42] using a non-targeted LC/MS approach, showed that six metabolic pathways, including the urea cycle, tyrosine, lysine, tryptophan, asparagine/aspartate and carnitine shuttle metabolism, were associated with increased mortality in CAD patients. Du et al. [43] performed LC/MS analysis of 26 amino acids in 138 patients with acute heart failure with an STEMI and found that elevated plasma BCAA levels at admission were associated with adverse cardiovascular events. Vignoli et al. [44] studied 2-year mortality in 978 patients with AMI using nuclear magnetic resonance spectroscopy methods and showed that elevated amino acid levels were strongly associated with mortality after an AMI. Chorell et al. [45] showed that the lysophospholipid ratio (lysophosphatidylcholine: lysophosphatidylethanolamine, LPC: LPE) was significantly associated with the risk for future cardiovascular adverse events in patients with STEMI and NSTEMI.

Plasma ceramides have been found to be predictive for the risk of ACS. Cheng et al. [46] studied lipids and 1-year clinical outcomes in 581 patients with ACS and stable CAD and showed that plasma ceramide (d18:1/16:0) was strongly associated with 1-year major adverse cardiac events (MACE) and plaque instability. Arterial and myocardial tissue ceramide levels were also associated with MACE in patients with an AMI. Carvalho et al. [47] further confirmed these results by performing a lipidomic analysis on paired tissue plasma samples in human and animal models. In a study with a mean follow-up of 3.1 years in 2023 patients with coronary angiography, they found a strong association between the dicarboxylation product acylcarnitine and the occurrence of death or MI, with an independent association with mortality [48]. A study on patients with coronary artery bypass grafts also suggested an association between short- to medium-chain dicarboxylated acylcarnitine and adverse cardiovascular events [49].

The value of metabolomics in predicting risk in patients with in-stent restenosis (ISR) has also been demonstrated. Cui et al. [50] studied the sensitivity and specificity of metabolites of phospholipids and sphingolipids for risk prediction in ISR patients, which were 91% and 90%, respectively. Cui et al. [51] also found that the metabolites arachidonic acid, sphingolipids and acylcarnitine predicted the recurrence of angina.

Jieying Luo et al. [52] studied the ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS) platform approach to identify retinol metabolism as the best way to screen for early ventricular fibrillation (VF) after STEMI. 9-cis-retinoic acid (9cRA) was the most important biomarker to identify VF after STEMI (Table 7, Ref. [42, 43, 44, 45, 46, 47, 48, 50, 51, 52]).