Pharmacological Effects of Botanical Drugs on Myocardial Metabolism in Chronic Heart Failure.

Although there have been significant advances in the treatment of heart failure in recent years, chronic heart failure remains a leading cause of cardiovascular disease-related death. Many studies have found that targeted cardiac metabolic remodeling has good potential for the treatment of heart failure. However, most of the drugs that increase cardiac energy are still in the theoretical or testing stage. Some research has found that botanical drugs not only increase myocardial energy metabolism through multiple targets but also have the potential to restore the balance of myocardial substrate metabolism. In this review, we summarized the mechanisms by which botanical drugs (the active ingredients/formulas/Chinese patent medicines) improve substrate utilization and promote myocardial energy metabolism by activating AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs) and other related targets. At the same time, some potential protective effects of botanical drugs on myocardium, such as alleviating oxidative stress and dysbiosis signaling, caused by metabolic disorders, were briefly discussed.

Danhong Injection Up-regulates miR-125b in Endothelial Exosomes and Attenuates Apoptosis in Post-Infarction Myocardium.

OBJECTIVE: To investigate the involvement of endothelial cells (ECs)-derived exosomes in the anti-apoptotic effect of Danhong Injection (DHI) and the mechanism of DHI-induced exosomal protection against postinfarction myocardial apoptosis. METHODS: A mouse permanent myocardial infarction (MI) model was established, followed by a 14-day daily treatment with DHI, DHI plus GW4869 (an exosomal inhibitor), or saline. Phosphate-buffered saline (PBS)-induced ECs-derived exosomes were isolated, analyzed by miRNA microarray and validated by droplet digital polymerase chain reaction (ddPCR). The exosomes induced by DHI (DHI-exo), PBS (PBS-exo), or DHI+GW4869 (GW-exo) were isolated and injected into the peri-infarct zone following MI. The protective effects of DHI and DHI-exo on MI hearts were measured by echocardiography, Masson's trichrome staining, and TUNEL apoptosis assay. The Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to evaluate the expression levels of miR-125b/p53-mediated pathway components, including miR-125b, p53, Bak, Bax, and caspase-3 activities. RESULTS: DHI significantly improved cardiac function and reduced infarct size in MI mice (P<0.01), which was abolished by the GW4869 intervention. DHI promoted the exosomal secretion in ECs (P<0.01). According to the results of exosomal miRNA microarray assay, 30 differentially expressed miRNAs in the DHI-exo were identified (28 up-regulated miRNAs and 2 down-regulated miRNAs). Among them, DHI significantly elevated miR-125b level in DHI-exo and DHI-treated ECs, a recognized apoptotic inhibitor impeding p53 signaling (P<0.05). Remarkably, treatment with DHI and DHI-exo attenuated apoptosis, elevated miR-125b expression level, inhibited capsase-3 activity, and down-regulated the expression levels of proapoptotic effectors (p53, Bak, and Bax) in post-MI hearts, whereas these effects were blocked by GW4869 (P<0.05 or P<0.01). CONCLUSION: DHI and DHI-induced exosomes inhibited apoptosis, promoted the miR-125b expression level, and regulated the p53 apoptotic pathway in post-infarction myocardium.

Efficacy and safety of Tonifying Qi and activating blood Chinese herbal prescriptions for myocardial infarction: Study protocol for a multi-centered RCT.

INTRODUCTION: Acute myocardial infarction (AMI) is a common cause of death worldwide and heart failure (HF) is the main complication. Although the increase in percutaneous coronary intervention and drug treatment can reduce in-hospital mortality after AMI, the incidence of HF after AMI and the resulting risk of death are still rising, which causes difficulties in the rehabilitation of AMI patients after reperfusion. METHODS: In this prospective, multicenter, randomized, double-blind, double-dummy, placebo-controlled trial, we will assigned 673 eligible patients with AMI after reperfusion into 4 groups: receiving Nao-Xin-Tong capsule (NXT), Bu-Yang-Huan-Wu (BYHW) granule (BYHW), Yang-Yin-Tong-Nao granule (YYTN), or placebo. The course of treatment will be 3 months. The primary outcome is HF incidence within 180 days. Nao-Xin-Tong capsule, BYHW granule, and Yang-Yin-Tong-Nao granule are different traditional Chinese medicines used for tonifying Qi and activating blood (TQAB). RESULTS: Three months of TQAB combined with Western medicine may reduce the incidence of HF after reperfusion of AMI and improve patients' quality of life. DISCUSSION: This study will provide an important basis for the application of traditional Chinese medicine in patients with AMI after reperfusion and provide an evidence-based basis for the prevention and treatment strategy of HF after AMI.

Danhong Injection Alleviates Cardiac Fibrosis via Preventing the Hypermethylation of Rasal1 and Rassf1 in TAC Mice.

BACKGROUND/AIM: Danhong injection (DHI) is a Chinese patent drug used for relieving cardiovascular diseases. Recent studies have suggested that DNA methylation plays a pivotal role in the maintenance of cardiac fibrosis (CF) in cardiovascular diseases. This study was aimed at identifying the effect and the underlying mechanism of DHI on CF, especially the DNA methylation. METHODS: A CF murine model was established by thoracic aortic constriction (TAC). A 28-day daily treatment with or without DHI via intraperitoneal injection was carried out immediately following TAC surgery. The changes in cardiac function, pathology, and fibrosis following TAC were measured by echocardiography and immunostaining. We used methyl-seq analysis to assess the DNA methylation changes in whole genes and identified the methylation changes of two Ras signaling-related genes in TAC mice, including Ras protein activator like-1 (Rasal1) and Ras-association domain family 1 (Rassf1). Next, the methylation status and expression levels of Rasal1 and Rassf1 genes were consolidated by bisulfite sequencing, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and Western blotting, respectively. To determine the underlying molecular mechanism, the expressions of DNA methyltransferases (DNMTs), Tet methylcytosine dioxygenase 3 (TET3), fibrosis-related genes, and the activity of Ras/ERK were measured by RT-qPCR and Western blotting. RESULTS: DHI treatment alleviated CF and significantly improved cardiac function on day 28 of TAC. The methyl-seq analysis identified 42,606 differential methylated sites (DMSs), including 19,618 hypermethylated DMSs and 22,988 hypomethylated DMSs between TAC and sham-operated mice. The enrichment analysis of these DMSs suggested that the methylated regulation of Ras signal transduction and focal adhesion-related genes would be involved in the TAC-induced CF development. The results of bisulfite sequencing revealed that the TAC-induced methylation affected the CpG site in both of Rasal1 and Rassf1 genes, and DHI treatment remarkably downregulated the promoter methylation of Rasal1 and Rassf1 in CF hearts. Furthermore, DHI treatment upregulated the expressions of Rasal1 and Rassf1, inhibited the hyperactivity of Ras/ERK, and decreased the expressions of fibrosis-related genes. Notably, we found that DHI treatment markedly downregulated the expression of DNMT3B in CF hearts, while it did not affect the expressions of DNMT1, DNMT3A, and TET3. CONCLUSION: Aberrant DNA methylation of Rasal1 and Rassf1 genes was involved in the CF development. DHI treatment alleviated CF, prevented the hypermethylation of Rasal1 and Rassf1, and downregulated DNMT3B expression in CF hearts.

Danhong injection enhances angiogenesis after myocardial infarction by activating MiR-126/ERK/VEGF pathway.

BACKGROUND/AIM: Danhong injection (DHI) is a Chinese drug used for relieving cardiovascular diseases. This study aimed to identify the effect and mechanism of action of DHI on post-infarct angiogenesis, especially the epigenetic regulation of angiogenesis. METHODS: A myocardial infarction (MI) mouse model was induced by ligating the left anterior descending coronary artery. A 4-week daily treatment with or without DHI via intraperitoneal injection was started immediately following MI. The changes in cardiac function, pathology, and angiogenesis following MI were measured by echocardiography and immunostaining. Matrigel tube formation and scratch wound assays were used to evaluate the effect of DHI on the proliferation and migration of hypoxic human umbilical vein endothelial cells (HUVECs). The expression of miR-126, Spred-1, and angiogenesis-related mRNAs was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of related proteins and the phosphorylated levels of extracellular signal-regulated kinase (ERK) and protein kinase B were detected by Western blot analysis. The loss-of-function study was performed using antagomir-126. RESULTS: The DHI-treated mice had significantly reduced infarct area, improved ejection fraction, and increased capillary density 4 weeks after MI. Also, DHI promoted the proliferation and migration of hypoxic HUVECs. The qRT-PCR and Western blot analysis revealed that DHI intervention upregulated miR-126, suppressed Spred-1 expression, and activated the ERK pathway, but not the Akt pathway. The loss-of-function study showed the blockade of the pro-angiogenic effect of DHI by antagomir-126 involving the ERK/vascular endothelial growth factor (VEGF) pathway. CONCLUSION: DHI enhanced post-infarct angiogenesis after MI by activating the miR-126/ERK/VEGF pathway.

[Therapy for replenishing qi, nourishing yin and promoting blood circulation in patients with acute myocardial infarction undergoing percutaneous coronary intervention: a randomized controlled trial].

BACKGROUND: No-reflow phenomenon after reperfusion treatment of acute myocardial infarction (AMI) is becoming more recognized today. The effective treatment for no-reflow has not been reported. OBJECTIVE: To observe the effects of traditional Chinese medicine (TCM) therapy for replenishing qi, nourishing yin, and promoting blood circulation on AMI patients undergoing percutaneous coronary intervention (PCI). DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This study was conducted from January 2005 to March 2006 using a double-blinded, randomized method. Thirty-five AMI patients (Killip I-II) were first diagnosed as ST segment elevation AMI and obtained primary PCI. They were recruited from People's Hospital, Peking University. All patients' symptoms accorded with qi-yin deficiency syndrome and blood stasis syndrome. They were randomly and double blindly divided into control group (18 cases) and treatment group (17 cases). The patients in the control group received Western medicine treatment, and the patients in the treatment group were treated with Western medicine plus American ginseng and Salviae miltiorrhizae preparations. They were all treated for 3 months. MAIN OUTCOME MEASURES: Before and after 3-month treatment, the TCM symptoms were observed and scored. At the state of baseline and dobutamine stress, left ventricular ejection fraction (LVEF), wall motion score (WMS), WMS index and normal cardiac muscle percentage (NCMP), and the myocardial contrast echocardiography index k, which reflects myocardium microcirculation perfusion, were detected. RESULTS: After 3-month treatment, the TCM symptoms in the treatment group were improved as compared with the control group (X(2)=4.118, P=0.042). At the state of dobutamine stress, LVEF in the treatment group after treatment was higher than those in the control group (t=2.130, P=0.041) and before treatment (t=2.345, P=0.032). Although the number of the segments with increased k value was more than that in the control group, there was no significant difference. CONCLUSION: TCM therapy for replenishing qi, nourishing yin and promoting blood circulation can improve the clinical symptoms and quality of life of the AMI patients undergoing PCI, and is beneficial to myocardium microcirculation. Thus, it may be an alternative cardioprotective treatment strategy for successful myocardial microcirculation in AMI patients after reperfusion.

[Effect of Chinese herbal medicine for benefiting qi and nourishing yin to promote blood circulation on ventricular wall motion of AMI patients after revascularization].

OBJECTIVE: To investigate the effect of Chinese herbal medicine for benefiting qi and nourishing yin to promote the blood circulation (abbr. as CHM) in promoting ventricular wall motion and myocardial contraction in acute myocardial infarction (AMI) patients after revascularization. METHODS: Subjects were 80 AMI patients after revascularization, of those, the 40 patients in the TCM group were treated with Xinyue Capsule and compound Tanshinon Tablet upon the basic conventional Western medical treatment and the other 40 in the control group were given conventional Western medicine alone, the course for them all was 3 months. Cardiac function indexes, including left ventricular ejection fraction (LVEF), wall motion indices, normal myocardial percentage (NMP), longitudinal systolic peak strain (LSPS) and rate (LSPSR), were observed by Doppler ultrasound under dobutamine stress at the 14 days after revascularization and the end of 3-month treatment. RESULTS: Except the 5 cases (3 in the TCM group and 2 in the control group) dropped out in the observation period, the trial was completed in 75 patients totally. LVEF, NMP, minus LSPS of left ventricular anterior apex and inferior basement, minus LSPSR of anterior apex, middle, basement, and minus LSPSR of inferior middle, basement were more significantly increased in Chinese medicinal treatment group than those in the control group at 14-day after revascularization (P < 0.01). The treatment group, minus LSPS and minus LSPSR of the left ventricular anterior apex and the inferior basement were at markedly higher levels compared with the controls at 3-month after revascularization (P < 0.05). Minus LSPSR of the left ventricular anterior apex and the inferior basement in the treatment group at 3-month was higher than that at 14-day after revascularization (P < 0.05). CONCLUSION: CHM combining with conventional Western medicine treatment could improve the left ventricular contractive function and wall motion in AMI patients after revascularization.

Effect of Chinese drugs for supplementing Qi, nourishing Yin and activating blood circulation on myocardial perfusion in patients with acute myocardial infarction after revascularization.

OBJECTIVE: To observe the effects of Chinese drugs for supplementing qi, nourishing yin and activating blood circulation on the myocardial perfusion in acute myocardial infarction (AMI) patients after revascularization. METHODS: Eighty patients with anterior or inferior ventricular wall AMI, who had received revascularization by intravenous thrombolysis or coronary bypass, were randomized into the treated group and the control group equally, both treated with conventional Western medical treatment, but combined, respectively, with Xinyue Capsule (, XYC) plus Composite Salvia Tablet (CST) and placebo for 3 months. Dobutamine stress echocardiography (DSE) was performed 14 days and 3 months after revascularization, respectively on every patient to observe blood perfusion extent (b value), myocardial perfusion velocity (k value) and local blood fl ow volume (k x b) in left ventricular infarction-related vascular segments under stressed state. RESULTS: With 5 cases dropping out in the observation period (3 in the treated group and 2 in the control group), the trial was completed in 75 patients in total. The 14-day DSE shows that the b value and k x b value of left anterior ventricular wall mid segment and apex segment, and the k value of apex segment in patients with anterior wall AMI, as well as the b value and k x b of basal segment in patients with inferior wall AMI in the treated group were significantly higher than those in the control group (P<0.05 or P<0.01). The 3-month DSE shows that the b value of apex segment, k x b value of basal segment, mid segment and apex segment of left anterior ventricular wall in patients with anterior wall AMI as well as the b value and k x b value of basal segment of left inferior ventricular wall in patients with inferior wall AMI were all higher in the treated group than those in the control group, respectively (P<0.05). The comparison between 14-day DSE and 3-month DSE in the treated group showed that the b value of apex segment of left anterior ventricular wall in patients with anterior wall AMI and the k x b value of apex segment and mid segment of left inferior ventricular wall in patients with inferior wall AMI significantly increased along with the on-going treatment (P<0.05). CONCLUSION: Therapy with Chinese drugs for supplementing qi, nourishing yin and activating blood circulation in combination with conventional Western medical treatment could obviously improve the blood perfusion at the myocardial tissue level in infarction-related vascular segments.