WANG Xiao-lin, CHE Chi, CHEN Zhi-yong, HUANG Wan-qing, WANG Xing, LING Li, LIU Zhi-ming, LI Lin

1. Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China

2. Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China

Keywords:Heart failure Energy metabolism Glucose metabolism Fatty acid metabolism Traditional Chinese medicine

ABSTRACT Disorder of energy metabolism is a major pathological change in the progression of heart failure. This process leads to insufficient myocardial energy and further aggravates cardiac dysfunction. Disorders of metabolic substrate utilization, mainly glucose and fatty acids, play an important role in this process. Research over the years has shown that some traditional Chinese medicines or compound prescriptions whose main role is to replenish qi and warm yang have good effects in regulating energy metabolism disorders. It has been found that some active ingredients in traditional Chinese medicine can regulate the uptake and utilization of myocardial cell metabolic substrate, so that the metabolism of myocardial cells can be adjusted in a direction that is beneficial to the body under hypoxic conditions, increasing the overall energy supply of the myocardium and improving heart function. This article reviewed the research of traditional Chinese medicine intervention on glucose and lipid metabolism of heart failure myocardial cells, and preliminarily summarizes the law and mechanism of traditional Chinese medicine intervention in heart failure myocardial glucose and fatty acid metabolism,hoping to provide clues for energy metabolism therapy research from the perspective of traditional Chinese medicine.

1. Introduction

Heart failure (heartfailure, HF) is the end stage of the development of various cardiovascular diseases. At present, the treatment of HF is mainly to reduce myocardial oxygen consumption, which is mainly regulated by the neuroendocrine system. Previous studies have shown that the use of drugs to improve myocardial energy metabolism, such as trimetazidine, can significantly improve the prognosis of HF, but its effect on the prognosis of HF needs further study[1]. More and more researchers pay attention to the important influence of myocardial energy metabolism in the development of HF. The concept of "metabolic remodeling" was first put forward by MarcvanBilsen, et al. [2]. It is believed that in a failed heart,metabolic disorders of substrates such as glucose and fatty acids in cardiomyocytes lead to changes in cardiac energy metabolism pathways, resulting in abnormal myocardial structure and function.Metabolic group scholars believe that the development of HF is always accompanied by energy metabolism disorder, metabolic substrate utilization disorder, energy deficiency and oxidative stress are considered to be the basis of systolic dysfunction and disease progression [3]. Fatty acids and glucose are the main substrates of energy metabolism in cardiomyocytes [4]. At present, most studies believe that in cardiomyocytes with heart failure, energy metabolism changes from fatty acid metabolism to glucose metabolism. Thus meet the energy needs of the heart under the condition of hypoxia[5-7]. Therefore, regulating myocardial energy metabolism is expected to become a new strategy for the treatment of heart failure.According to traditional Chinese medicine, the basic pathogenesis of heart failure is "heart qi deficiency" [8]. It is believed that "qi"is the energy of human activity [9], and "qi" mainly comes from glucose and lipids consumed by the human body. as the Huangdi Internal Classic says: "drink into the stomach, swim over the essence, the spleen, the lungs, the channels, the bladder, the water essence, and the five meridians in parallel." Valley into the flavor,in order to spread in the lungs, five internal organs are to receive qi", diet grain into the stomach, spleen transport and get essence qi,essence qi spleen ascending clear, spread by the lungs, nourish the five internal organs. The heart governs the blood, and the heart qi is supported by water valley essence, so it can promote the continuous movement of the blood and transport fine substances to nourish the whole body, including the heart itself; while beware of losing the nourishment of essence and deficiency of heart qi, the heart beats and blood movement loses power, and the heart loses nourishment,which further aggravates the deficiency of heart qi. Many doctors believe that the energy metabolism disorder of the heart is closely related to "qi deficiency" and "yang deficiency". The method of warming yang and replenishing qi can improve myocardial energy metabolism [8, 12].

2. Glucose and Lipid Metabolism in normal Myocardium

60%-90% of the energy needed for normal myocardial activity is provided by fatty acid (FA) metabolism, and another 10%-40% is provided by oxidation of carbohydrates such as glucose. Glucose and lipid metabolism is the main source of ATP produced by the heart. Therefore, the research on the substrate of cardiac energy metabolism is mainly focused on glucose and fatty acids.

2.1 Glucose Metabolism

The extracellular glucose uptake of cardiomyocytes occurs along the glucose concentration gradient. Due to the hydrophilicity of glucose, the transmembrane glucose transporter GLUT4 (major) and GLUT1 must be transported into the cell, and then phosphorylated to glucose 6-phosphate (G6P) under the catalysis of glycokinase (HK).G6P produces pyruvate (PA) through glycolysis. When oxygen is sufficient, PA is oxidized and decarboxylated to acetyl coenzyme A (acetylCoA), acetyl CoA enters the tricarboxylic acid cycle to produce a large amount of ATP;. When cells are anoxic, PA produces lactic acid (LA), through glycolysis in the cytoplasm and produces a small amount of ATP, to provide energy for myocardial activity [13].

2.2 Fatty acid metabolism

The FA consumed by myocardial metabolism is mainly fatty acid synthase (FAs), released by free fatty acid (FFA) and triglyceride(Tag). They enter cardiomyocytes under the mediation of fatty acid transporter (FAT/CD36), membrane-bound fatty acid binding protein(FABPpm) and fatty acid transporter 1 (FATP1/6) and are converted to acyl CoA under the catalysis of acyl CoA synthetase. Fatty acyl CoA synthesizes stearyl carnitine with carnitine under the catalysis of mitochondrial outer membrane carnitine acyltransferase-1 (CPT-1).After entering the mitochondria, the latter enters the mitochondria through fatty acid β-oxidation (FAO) to produce acetyl coenzyme CoA, acetyl CoA and into the tricarboxylic acid cycle to produce a large amount of ATP, to maintain normal myocardial activity.

2.3 Interaction between glucose and fatty acid metabolism

The interaction between glucose and fatty acid metabolism is mainly realized by "Randle cycle" [15], also known as "glucose-fatty acid cycle". In this metabolic process, FFA acts as a ligand to activate peroxisome proliferator-activated receptor (PPAR), which in turn upregulates the expression of pyruvate dehydrogenase kinase (PDK),while PDK phosphorylation inactivates pyruvate dehydrogenase(PDH), preventing pyruvate from entering mitochondria, thus inhibiting glucose oxidation. In addition, acetyl CoA and reduced coenzyme 1 (NADH) produced during FAO can also up-regulate the expression of PDK and further inhibit glucose oxidation. On the contrary, acetyl CoA produced during glucose oxidation can inhibit 3-KAT (3-keto acyl-CoA thioenzyme), while 3-KAT has inhibitory feedback on NADH. When the current one is inhibited, the level of the latter increases, while the accumulated NADH can inhibit fatty acid oxidation [7].

3. Changes of myocardial metabolic substrate in patients with heart failure

The heart is the organ with the most internal energy consumption.Because the storage concentration of ATP in the heart itself is very low, it is necessary to continuously produce ATP to maintain the normal activity of the heart. HF is accompanied by the disorder of energy metabolism, which leads to the further deterioration of heart function. There are three basic steps of energy metabolism disorder during HF: disorder of substrate uptake and utilization, oxidative phosphorylation disorder (mainly mitochondrial dysfunction),and abnormal energy transfer through phosphate transfer system[3]. During the development of HF, the increase of cardiac preload and preload increases the myocardial energy consumption, but due to cardiac dysfunction, the oxygen supply of cardiomyocytes decreases, which impairs the function of mitochondrial oxidative metabolism. In order to meet the energy needed for myocardial activity, the metabolic substrate of myocardial metabolism changes from fatty acids to glucose, because under the premise of the same oxygen consumption, glucose oxidizes the release of excess glucose from ATP [5,14]. However, at the end of heart failure, severe hypoxia leads to myocardial insulin resistance (insulinresistance,IR) [16]and decreased myocardial glucose uptake; at the same time, due to the weakening of myocardial FAO capacity, the production of ATP is further reduced, and excessive fatty acid uptake will lead to myocardial fatty acid accumulation poisoning, trigger oxidative stress reaction, produce free radicals to attack mitochondria, and induce mitochondrial structural damage. These factors aggravate the progress of HF [17].

At present, some studies have found that, in addition to glucose and fatty acids, metabolic changes of ketones and branched-chain amino acids in cardiomyocytes may also affect the severity of HF through cellular signals, but these "fuels" have a limited effect on total energy production and have little effect on the progress of HF [18, 19].

4. Study on the intervention of traditional Chinese Medicine on Myocardial glucose and Lipid Metabolism

More and more studies have confirmed that traditional Chinese medicine can play an important role in the metabolic remodeling of HF cardiomyocytes. Using traditional Chinese medicine to interfere with the metabolic remodeling of HF cardiomyocytes has certain advantages and characteristics. Some components of traditional Chinese medicine can correct the disorder of HF energy metabolism and show a good effect in regulating the uptake and utilization of metabolic substrates.

4.1 Study on single traditional Chinese medicine or traditional Chinese medicine extract

ZhangJ et al. [20] found that high dose of astragaloside could reduce the content of FFA in the myocardium of HF rats and significantly enhance the oxidation of fatty acid β in cardiomyocytes. It is speculated that astragaloside can stimulate the metabolism of cardiomyocytes from glycolysis to fatty acid oxidation through PPAR α. Astragaloside IV can enhance the oxidative utilization of fatty acids in myocardium, increase the energy supply of excitationcontraction coupling, reduce the production of LA, and improve the function of mitochondria. Wang Yuming [21] studied the intervention mechanism of total astragalus extract, astragaloside IV and astragalus polysaccharide on myocardial energy metabolism induced by doxorubicin in HF rats from the aspects of substrate transporter and metabolic key enzymes. The results showed that total astragalus extract and effective components of astragalus could improve the transport efficiency of FFAs, promote the metabolism of FFAs, and inhibit the uptake and utilization of glucose. Another study based on humoral metabonomics method [22] found that serum lipid, pyruvate,glycerol and other biomarkers increased significantly, while β-glucose and creatine decreased significantly in HF rats after intervention with astragalus, which further proved that astragalus could rectify the uptake of metabolic substrates.

ZhengX et al. [23] by observing the effects of ginsenoside Rb1 on myocardial mitochondrial metabolism and remodeling in HF rats,it was found that ginsenoside Rb1 may increase glucose uptake by promoting GLUT4 translocation to the plasma membrane through Akt pathway, and ginsenoside Rb1 can alleviate HFinduced mitochondrial dysfunction and inhibit ERK pathway to reduce myocardial hypertrophy and fibrosis, thus protecting cardiac remodeling. One experiment [24] found that ginsenoside Rb3 could up-regulate the expression of cardiac carnitine palmitoyltransferase-1 α (CPT-1α), acyl-CoA dehydrogenase long-chain (ACADL) and mitochondrial major dehydrogenase sirtuin3 (Sirt3) in HF rats,thus promoting fatty acid uptake and oxidation. It can be seen that Radix Astragali and Ginseng play a significant role in regulating the metabolic substrate of HF, which may explain the therapeutic mechanism of Qi-invigorating method on Qi-deficiency HF from the point of view of metabolism.

4.2 Study on compound prescription of traditional Chinese Medicine

Wang Yi et al. [25] used Yiqi Huoxue recipe to interfere with the regulation of PGC-1α pathway on myocardial energy metabolism remodeling in HF rats. it was found that Yiqi Huoxue recipe could enhance the expression of PGC-1α protein and gene, while some studies [26] confirmed that PGC-1α pathway played an important role in myocardial energy metabolism. The activation of this pathway could positively regulate the expression of CPT-1 and GLUT4,thus increasing the uptake of glucose and FA by cardiomyocytes.Furthermore, it can improve the lipid deposition and insufficient glucose uptake caused by the disturbance of lipid metabolism. XuW et al. [27] using serum metabonomics and network analysis, it was found that Lingguizhugan decoction could inhibit the activity of phospholipase A2 (PLA2), while the increase of PLA2 activity led to the rapid production and accumulation of free fatty acids including arachidonic acid, which led to myocardial lipotoxicity. In a study on glucose and lipid metabolism of neonatal rat cardiomyocytes injured by hypoxia / reoxygenation [28], it was found that Qi-Xue Bingzhi recipe could activate AMPK pathway, up-regulate the expression of GLUT4 and PFK2, increase the utilization of glucose in myocardium, promote the transport of fatty acids regulated by FAT/CD36, and relieve the inhibition of fatty acid oxidation by ACC2, so as to improve the utilization of fatty acids in myocardium.Wan Huansong et al. [29] studied the effect of Sijunzi decoction on myocardial protein expression in CHF rats by proteomic method.After screening and integrated analysis of 16 significant protein spots, it was found that the expression of pyruvate dehydrogenase complex (Pdhx) decreased significantly. It is speculated that the mechanism may be that Sijunzi decoction changes myocardial oxygen or energy supply substrates, promotes fatty acid oxidation,inhibits glycolysis and strengthens the aerobic oxidation of glucose.Improve myocardial energy metabolism. Shengzhen decoction can increase the content of L-carnitine in myocardium. The important function of L-carnitine is to transport FA, between cytoplasm and mitochondria, and acetyl-L-carnitine (one of L-carnitine) is also involved in controlling the proportion of peroxidase isozymes of acetyl CoA and fatty acids in mitochondria. It is speculated that Shengzhen decoction can improve the disorder of CHF metabolism by promoting fatty acid metabolism[30].

Shenqi Yixin decoction can reduce the content of FFA in cardiomyocytes, inhibit the oxidation of FA, increase the synthesis of myocardial ATP and inhibit the remodeling of myocardial metabolism, and its regulation of myocardial glucose and lipid metabolism is significantly better than that of trimetazidine [31].Inhibiting fatty acid metabolism and promoting glucose metabolism,increasing the efficiency of ATP production while reducing oxygen consumption and a large number of myocardial toxic substances may be the mechanism of Shenqi Yixin recipe in the treatment of HF.

4.3 Research on proprietary Chinese medicine

Qili Qiangxin capsule can up-regulate the expression of GLUT4 in AMPK/PGC1-α axis, regulate the expression of key enzymes HK2, PDK4 and CS in glucose oxidation, increase the utilization of glucose and oxidative phosphorylation in myocardium, so as to improve the left ventricular diastolic function of spontaneously hypertensive (SHR) model rats [32]. Under the condition of HF,cholesterol synthesis is overactivated and lipid synthesis increases,which can easily lead to lipotoxicity caused by myocardial lipid accumulation. Qili Qiangxin capsule can inhibit lipid synthesis by down-regulating the expression of 8 iso PGF2α and 3 NT, which can promote the transport, uptake and utilization of fatty acids and reduce lipid accumulation [33]. In addition, studies have found that Qili Qiangxin capsule can protect myocardial mitochondria and improve the efficiency of glucose and lipid metabolism[34]. Other scholars carried out studies from different infarcted myocardium, and found that Qiliqiangxin capsule could promote the transformation from glucose oxidation to glycolysis in the marginal zone of infarcted myocardium (adjacent scar) by enhancing the expression of phosphopyruvate dehydrogenase (p-PDH), pyruvate dehydrogenase kinase 4 (PDK4) and lactate dehydrogenase A(LDHA). Simultaneously up-regulate the expression of FAT/CD36 and CPT-1 to restore the uptake and oxidation of FA in the remote area (distal scar) [35]. Thus it can be seen that Qiliqiangxin capsule can regulate the infarcted myocardium regionally and select different metabolic substrates according to the local hypoxia environment, so as to improve the substrate utilization rate. Qili Qiangxin capsule can promote fatty acid and glucose metabolism at the same time.

Wang Liyun et al. [36] using gas chromatography-mass spectrometry(GC-MS), it was found that Xinfukang oral liquid could increase the level of plasma endogenous metabolite octadecenoic acid (oleic acid) in HF rats. It is speculated that Xinfukang oral liquid may increase myocardial lipid decomposition during HF, inhibit the oxidation and utilization of FA, and reduce myocardial oxygen consumption. On the other hand, cardiac rehabilitation can also promote glucose metabolism, and its mechanism is that the effective components of cardiac rehabilitation can promote the expression of GLUT4 and GLUT1 in cardiomyocytes, increase the efficiency of glucose transport, and improve glucose metabolism, and its effect is positively correlated with intervention time [37] and dose [38].GaoK et al. [39] after interfering with HF with Qishen granule, it was found that proteins related to FA uptake, transport and β-oxidation(FAT/CD36, CPT1A, ACADL, ACADM, ACAA2 and SCP2) and upstream transcriptional regulators (PPARα, RXRα, RXRβ and RXRγ) were up-regulated, while in glucose metabolism,glycolysis was inhibited by reducing LDHA and glucose oxidation was promoted by reducing PDK4. Shenfu Yixin granule can improve the inhibition of AMPK and PDH in cardiomyocytes induced by hypoxia, increase the expression of GLUT-4, FAT, CPT-1, CK and other proteins, and reduce mitochondrial damage [40]. Danqi tablets can up-regulate the expression of PPAR γ in the upstream pathway of glucose and lipid metabolism, which can increase the transcription and expression of fatty acid transporters FATP and FAT/CD36 in lipid metabolism, up-regulate the levels of key enzymes such as ACADL and SCP2 in glucose and lipid metabolism, and enhance fatty acid β-oxidation. Further study on the cardiomyocyte model of H9C2 injury showed that Danqi tablet could increase the expression of GLUT4 and PFK in myocardium and down-regulate the expression of GSK-3 β, promote the dephosphorylation of glycogen synthase (GS), promote glycogen synthesis, and finally correct the disorder of myocardial glucose and lipid metabolism [41].The double substrate regulation effect of Xinfukang, Qishen granule,Shenfu Yixin granule and Danqi tablet can significantly improve the disturbance of myocardial energy metabolism.

Qiangxinkang granule can also interfere with the substrate metabolism of HF. Middle and high dose Qiangxinkang can significantly increase the content of PGC-1α mRNA in cardiomyocytes. The activation of PGC-1α pathway may be the mechanism of Qiangxinkang granule in the treatment of HF by improving myocardial energy metabolism [42]. Li Rui et al. [43]found in the clinical study that the addition of Wenshen Huoxue capsule to the basic treatment of anti-heart failure can reduce the level of serum FFA and reduce the myocardial toxicity caused by lipid accumulation. WuR et al. [44] found that Yangxinshi tablet can reduce myocardial oxygen consumption, promote the expression of AMPK/PGC1 α signal pathway, and up-regulate transporter GLUT4,to improve the utilization of glucose under hypoxia.

4.4 Study on traditional Chinese Medicine injection

A single-blind controlled study [45] found that after 7 days of routine treatment of HF plus Shenmai injection night, the contents of FFA, PA and LA in serum decreased significantly, and the effect was more significant than that of trimetazidine group and routine treatment group. Shenmai injection can optimize the utilization of metabolic substrates in circulatory system and improve cardiac function in patients with HF. Ma Chen et al. [46] found in the ischemia-reperfusion experiment of isolated rat heart that Salvia miltiorrhiza injection does not directly act on glucose oxidation, but improves the efficiency of energy metabolism, reduces myocardial oxygen consumption and protects myocardium by inhibiting fatty acid oxidation. Another experiment on Danshensu, the effective component of Salvia miltiorrhiza injection, found that Danshensu could reduce the ratio of AcCoA/CoA, which could be regarded as the inhibition of fatty acid oxidation, the increase of glucose metabolism and the increase of myocardial oxidation metabolism,but its effect was not as good as that of ranolazine. It can be seen that the regulatory effect of Salvia miltiorrhiza injection on myocardial energy metabolism may have the best effect under the joint action of various active components, but the effect of single Danshensu on the improvement of myocardial energy metabolism in HF is limited.

5. Summary

HF belongs to the category of "palpitation", "heart water" and"asthma syndrome" in traditional Chinese medicine. its basic pathogenesis is deficiency of qi-yang, stagnation of blood stasis,basic treatment of replenishing qi and activating blood circulation,warming yang and promoting diuresis, commonly used Shenfu decoction, Zhenwu decoction and so on. A large number of studies have shown that traditional Chinese medicine can regulate HF neuroendocrine factors, reduce myocardial fibrosis, inhibit ventricular remodeling, improve metabolic remodeling, and improve cardiac function. By reviewing the research in recent years,it is found that traditional Chinese medicine mostly uses single traditional Chinese medicine or compound proprietary medicine of replenishing qi and warming yang, such as ginseng, astragalus and Qiliqiangxin capsule in interfering with HF metabolism. Some traditional Chinese medicines can not only regulate the metabolism of glucose or fatty acids, but also regulate double substrates, and even improve the function of mitochondria. Compared with western medicine, traditional Chinese medicine has the advantage of multi-target and multi-link coordination on the metabolism of HF.Traditional Chinese medicine can carry out dynamic intervention and comprehensive regulation of the metabolic disorder of HF,such as substrate uptake, mitochondrial function, key enzyme activity, energy metabolism signal regulation pathway and so on.However, in the selection of metabolic substrates, some researchers believe that glucose and fatty acid uptake and oxidation should be promoted at the same time, while others believe that glucose metabolism should be promoted and fatty acid uptake should be inhibited to reduce lipotoxicity and oxygen consumption. Some researchers believe that fatty acid metabolism should be promoted alone to improve productivity efficiency. We believe that the cause of this phenomenon may be related to the development stage of the disease, the "Randle cycle" of glucose and lipid metabolism,insulin resistance and etiology. With the development of HF, the choice of glucose and lipids in myocardium is dynamic, and even different parts of myocardium have different choices for substrates.In fact, during the metabolic treatment of HF, there is no consensus on whether myocardial substrate uptake is to promote fatty acid or glucose, and whether to inhibit or promote fatty acid metabolism.Some experts have proposed that regulating the flexibility of myocardial metabolism, making different parts of myocardium choose appropriate substrates for metabolism according to their exposed environment, and increasing the overall energy supply of myocardium is an effective means of treatment[35,48].

For traditional Chinese medicine, it is necessary to give full play to the advantages of systematic treatment of traditional Chinese medicine and pay attention to the improvement of metabolic ability rather than the selection of metabolic substrates, because it is difficult to achieve ideal results by unidirectional regulation of a certain metabolic substrate. The intervention of traditional Chinese medicine may make myocardial metabolism adjustment beneficial to the body under different pathological changes, reduce the harm caused by oxygen deficiency and poison accumulation, and improve the utilization rate of myocardial metabolic substrates. Make the metabolic state reach a steady-state balance conducive to disease control and improve energy deficiency. This may be the research direction of traditional Chinese medicine in the treatment of heart failure in the future, and it is also expected to provide new ideas for the treatment of other diseases related to energy metabolism disorders. Metabonomics has the characteristics of panoramic and holistic. By studying the metabolism of drugs and the changes of endogenous metabolites caused by drugs, that is, selecting the corresponding metabolic markers for metabolic pathway analysis,we can comprehensively evaluate the effect of traditional Chinese medicine in the treatment of HF, clarify its mechanism, and provide new ideas and approaches for the treatment of HF with the combination of traditional Chinese and western medicine. At present,there are few studies on traditional Chinese medicine intervention metabonomics based on syndrome differentiation of human body,and there is a lack of research means corresponding to prescription and syndrome, so it is difficult to do the research of one disease and multiple syndrome from the perspective of energy metabolism,which may be an urgent problem to be solved in the future research of traditional Chinese medicine.