Action and therapeutic targets of myosin light chain kinase, an important cardiovascular signaling mechanism.

The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is complex and not fully understood, and the physiological function of the heart is inextricably linked to well-regulated cardiac muscle movement. Myosin light chain kinase (MLCK) is essential for myocardial contraction and diastole, cardiac electrophysiological homeostasis, vasoconstriction of vascular nerves and blood pressure regulation. In this sense, MLCK appears to be an attractive therapeutic target for cardiac diseases. MLCK participates in myocardial cell movement and migration through diverse pathways, including regulation of calcium homeostasis, activation of myosin light chain phosphorylation, and stimulation of vascular smooth muscle cell contraction or relaxation. Recently, phosphorylation of myosin light chains has been shown to be closely associated with the activation of myocardial exercise signaling, and MLCK mediates systolic and diastolic functions of the heart through the interaction of myosin thick filaments and actin thin filaments. It works by upholding the integrity of the cytoskeleton, modifying the conformation of the myosin head, and modulating innervation. MLCK governs vasoconstriction and diastolic function and is associated with the activation of adrenergic and sympathetic nervous systems, extracellular transport, endothelial permeability, and the regulation of nitric oxide and angiotensin II. Additionally, MLCK plays a crucial role in the process of cardiac aging. Multiple natural products/phytochemicals and chemical compounds, such as quercetin, cyclosporin, and ML-7 hydrochloride, have been shown to regulate cardiomyocyte MLCK. The MLCK-modifying capacity of these compounds should be considered in designing novel therapeutic agents. This review summarizes the mechanism of action of MLCK in the cardiovascular system and the therapeutic potential of reported chemical compounds in cardiac diseases by modifying MLCK processes.

Effect of Tai Chi vs Aerobic Exercise on Blood Pressure in Patients With Prehypertension: A Randomized Clinical Trial.

Importance: Prehypertension increases the risk of developing hypertension and other cardiovascular diseases. Early and effective intervention for patients with prehypertension is highly important. Objective: To assess the efficacy of Tai Chi vs aerobic exercise in patients with prehypertension. Design, Setting, and Participants: This prospective, single-blinded randomized clinical trial was conducted between July 25, 2019, and January 24, 2022, at 2 tertiary public hospitals in China. Participants included 342 adults aged 18 to 65 years with prehypertension, defined as systolic blood pressure (SBP) of 120 to 139 mm Hg and/or diastolic BP (DBP) of 80 to 89 mm Hg. Interventions: Participants were randomized in a 1:1 ratio to a Tai Chi group (n = 173) or an aerobic exercise group (n = 169). Both groups performed four 60-minute supervised sessions per week for 12 months. Main Outcomes and Measures: The primary outcome was SBP at 12 months obtained in the office setting. Secondary outcomes included SBP at 6 months and DBP at 6 and 12 months obtained in the office setting and 24-hour ambulatory BP at 12 months. Results: Of the 1189 patients screened, 342 (mean [SD] age, 49.3 [11.9] years; 166 men [48.5%] and 176 women [51.5%]) were randomized to 1 of 2 intervention groups: 173 to Tai Chi and 169 to aerobic exercise. At 12 months, the change in office SBP was significantly different between groups by -2.40 (95% CI, -4.39 to -0.41) mm Hg (P = .02), with a mean (SD) change of -7.01 (10.12) mm Hg in the Tai Chi group vs -4.61 (8.47) mm Hg in the aerobic exercise group. The analysis of office SBP at 6 months yielded similar results (-2.31 [95% CI, -3.94 to -0.67] mm Hg; P = .006). Additionally, 24-hour ambulatory SBP (-2.16 [95% CI, -3.84 to -0.47] mm Hg; P = .01) and nighttime ambulatory SBP (-4.08 [95% CI, -6.59 to -1.57] mm Hg; P = .002) were significantly reduced in the Tai Chi group compared with the aerobic exercise group. Conclusions and Relevance: In this study including patients with prehypertension, a 12-month Tai Chi intervention was more effective than aerobic exercise in reducing SBP. These findings suggest that Tai Chi may help promote the prevention of cardiovascular disease in populations with prehypertension. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1900024368.

Screening of an FDA-approved compound library identifies apigenin for the treatment of myocardial injury.

Apigenin is the active ingredient in Ludangshen. Although previous studies reported the cardioprotective actions of apigenin against doxorubicin (Dox)-induced cardiomyopathy, the underlying mechanisms remain incompletely understood. Since apigenin beneficially regulates various aspects of mitochondrial function and dynamics, we asked whether apigenin improves heart function in mice with Dox-induced cardiomyopathy by regulating the mitochondrial unfolded protein response (UPRmt). Co-administration of apigenin significantly restored heart function, reduced myocardial swelling, inhibited cardiac inflammation, increased cardiac transcription of UPRmt-related genes, and promoted cardiomyocyte survival in Dox-treated mice. In turn, blockade of UPRmt abolished the mito- and cytoprotective effects of apigenin, evidenced by decreased ATP production, suppressed mitochondrial antioxidant capacity, and increased apoptosis, in Dox-treated, cultured HL-1 cardiomyocytes. Furthermore, apigenin treatment prevented Dox-induced downregulation of Sirt1 and Atf5 expression, and the beneficial effects of apigenin were completely nullified in Sirt1 knockout (KO) mice or after siRNA-mediated Sirt1 knockdown in vitro. We thus provide novel evidence for a promotive effect of apigenin on UPRmt via regulation of the Sirt1/Atf5 pathway. Our findings uncover that apigenin seems to be an effective therapeutic agent to alleviate Dox-mediated cardiotoxicity.

Impact of the COVID-19 pandemic lockdown on hospitalizations for cerebrovascular disease and related in-hospital mortality in China: A nationwide observational study.

BACKGROUND AND PURPOSE: The aim of this nationwide study was to assess the impact of the COVID-19 pandemic on cerebrovascular disease hospitalization rates, out-of-pocket rates, and in-hospital case fatality rates. METHODS: All hospitalizations for cerebrovascular disease from 1599 hospitals from 2019 to 2020 were selected using the International Classification of Diseases, 10th revision, in the Hospital Quality Monitoring System (HQMS). We defined 2019 as the pre-pandemic group and 2020 as the post-pandemic group. Multivariate analyses were done to assess the association between the pandemic and patient outcomes and out-of-pocket rate with odds ratios (OR) and 95% CIs presented. RESULTS: In total, 9 640 788 patients with the cerebrovascular disease were recruited (mean age was 65.7[SE.0.004] years, and 55.7% were male), and data is available for 5145358 patients in 2019 (pre-epidemic) and 4495430 patients in 2020(post-pandemic), indicating a 12.6% decrease. Out-of-pocket rate increase of 9.3% (2020 vs 2019: 34.1%% vs 31.2% [absolute difference, 2.9% {95% CI, 1.3% to 4.5%}, odd ratio {OR}, 1.1{95% CI, 1.0 to 1.1}]. The epidemic has led to an 18.0% increase in in-hospital mortality (2020 vs 2019: 1.1%% vs 0.9% [absolute difference, 0.2% {95% CI, 0.1% to 0.2%}, odd ratio {OR}, 1.1{95% CI, 1.1 to 1.2}]. The epidemic has led to significantly increased in-hospital mortality for patients with stroke but had no significant impact on other cerebrovascular diseases. CONCLUSIONS: During the COVID-19 pandemic lockdown, patients hospitalized for stroke fell by 12.6%, and there were substantial increases in out-of-pocket rates (9.3%) and in-hospital case fatality rates (18.0%).

Huoxue Qingre decoction used for treatment of coronary heart disease network analysis and metabolomic evaluation.

Objective: Network pharmacology provides new methods and references for the research of traditional Chinese medicine, but some problems remain, such as single evaluation components and index methods, imperfect relevant databases, unscientific prediction results, and lack of verification of results. Herein, we used a modified network pharmacology research method to explore the potential network analysis mechanism of Huoxue Qingre decoction in the treatment of coronary heart disease and utilized clinical trials for assessment. Methods: Based on literature research, the targets corresponding to the drug were obtained with the assistance of the TCMSP database and Swiss Target Prediction, and the target proteins were corrected using the UniProt database. The targets related to coronary heart disease was obtained through the GeneCards database. A protein-protein interaction network diagram was constructed, and a "component-intersection target" network diagram was drawn based on Cytoscape 3.6.2 software. The mapped targets were imported into the DAVID bioinformatics platform, which underwent Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and the network pharmacology prediction results were evaluated through clinical trials. Results: We obtained 151 compounds related to Huoxue Qingre decoction, 286 genes after evaluation and deduplication, and 426 genes related to coronary heart disease. Finally, 81 common target genes were obtained with 32 pathways according to the KEGG pathway enrichment analysis. The validation results of the clinical trials showed that a total of 98 differential metabolites were found in the treatment of coronary heart disease with Huoxue Qingre decoction, involving a total of 16 metabolic pathways. Compared with the network pharmacology prediction results, it was found that only the pathways in cancer (hsa05200) were the common pathways in the top 32 signaling pathways predicted by network pharmacology. The expanded network pharmacology prediction results revealed that the sphingolipid signaling pathway (hsa04071) and prostate cancer pathway (hsa05215) matched the predicted metabolic pathways, with differential metabolites of N-oleoyl-D-sphingomyelin and 1-methyl-6-phenyl-1h-imidazole[4,5-b]pyridine-2-amine. Conclusion: Through the network analysis and metabolomic evaluation, there may be three signaling pathways that involve the Huoxue Qingre decoction in the treatment of coronary heart disease: pathways in cancer (hsa05200), sphingolipid signaling pathway (hsa04071), and prostate cancer pathway (hsa05215).

Pharmacological properties of total flavonoids in Scutellaria baicalensis for the treatment of cardiovascular diseases.

BACKGROUND: Scutellaria baicalensis, a medicinal herb belonging to the Lamiaceae family, has been recorded in the Chinese, European, and British Pharmacopoeias. The medicinal properties of this plant are attributed to the total flavonoids of Scutellaria baicalensis (TFSB), particularly the main component, baicalin. This study provides a systematic and comprehensive list of the identified TFSB components and their chemical structures. The quality control process, pharmacokinetics, clinical application, and safety of Scutellaria baicalensis are discussed, and its pharmacological effect on cardiovascular diseases (CVDs) is detailed. Finally, the future research trends and prospects of this medicinal plant are provided. METHODS: The Chinese and English papers related to TFSB were collected from the PubMed and CNKI databases using the relevant keywords. To highlight the pharmacological mechanism, clinical application, and safety of TFSB, the collected articles were screened and classified based on their research content. RESULTS: TFSB contains at least 100 different kinds of flavonoids, of which baicalin, baicalein, wogonin, wogonoside, scutellarin, and scutellarein are the main active ingredients. The preparation process of TFSB is relatively well established, and the extraction rate can be significantly increased by enzymatic pretreatment and ultrasonication. The low oral availability of TFSB may be effectively enhanced using nanoformulations. The available pharmacokinetic data show that flavonoid glycosides and aglycones with the same parent nucleus may be converted to structures that are conducive to absorption in vivo. Moreover, TFSB can protect against CVDs by inhibiting apoptosis, regulating oxidative stress response, participating in inflammatory response, protecting against myocardial fibrosis, inhibiting myocardial hypertrophy, and regulating blood vessels. In terms of clinical application and animal safety, the available studies show that TFSB can be applied in a wide range of clinical treatments and is safe to use is animals. CONCLUSION: This article systematically reviews the therapeutic effect and underlying pharmacological mechanism of TFSB against CVDs. The available studies clearly suggest that TFSB has great potential for the treatment of CVDs and is worthy of in-depth research and development.

Relevance of Ferroptosis to Cardiotoxicity Caused by Anthracyclines: Mechanisms to Target Treatments.

Anthracyclines (ANTs) are a class of anticancer drugs widely used in oncology. However, the clinical application of ANTs is limited by their cardiotoxicity. The mechanisms underlying ANTs-induced cardiotoxicity (AIC) are complicated and involve oxidative stress, inflammation, topoisomerase 2ß inhibition, pyroptosis, immunometabolism, autophagy, apoptosis, ferroptosis, etc. Ferroptosis is a new form of regulated cell death (RCD) proposed in 2012, characterized by iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation. An increasing number of studies have found that ferroptosis plays a vital role in the development of AIC. Therefore, we aimed to elaborate on ferroptosis in AIC, especially by doxorubicin (DOX). We first summarize the mechanisms of ferroptosis in terms of oxidation and anti-oxidation systems. Then, we discuss the mechanisms related to ferroptosis caused by DOX, particularly from the perspective of iron metabolism of cardiomyocytes. We also present our research on the prevention and treatment of AIC based on ferroptosis. Finally, we enumerate our views on the development of drugs targeting ferroptosis in this emerging field.

Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury and Application of Natural Plant Products.

Ischemic heart disease (IHD) is currently one of the leading causes of death among cardiovascular diseases worldwide. In addition, blood reflow and reperfusion paradoxically also lead to further death of cardiomyocytes and increase the infarct size. Multiple evidences indicated that mitochondrial function and structural disorders were the basic driving force of IHD. We summed up the latest evidence of the basic associations and underlying mechanisms of mitochondrial damage in the event of ischemia/reperfusion (I/R) injury. This review then reviewed natural plant products (NPPs) which have been demonstrated to mitochondria-targeted therapeutic effects during I/R injury and the potential pathways involved. We realized that NPPs mainly maintained the integrality of mitochondria membrane and ameliorated dysfunction, such as improving abnormal mitochondrial calcium handling and inhibiting oxidative stress, so as to protect cardiomyocytes during I/R injury. This information will improve our knowledge of mitochondrial biology and I/R-induced injury's pathogenesis and exhibit that NPPs hold promise for translation into potential therapies that target mitochondria.

Protective effects of natural products against myocardial ischemia/reperfusion: Mitochondria-targeted therapeutics.

Patients with ischemic heart disease receiving reperfusion therapy still need to face left ventricular remodeling and heart failure after myocardial infarction. Reperfusion itself paradoxically leads to further cardiomyocyte death and systolic dysfunction. Ischemia/reperfusion (I/R) injury can eliminate the benefits of reperfusion therapy in patients and causes secondary myocardial injury. Mitochondrial dysfunction and structural disorder are the basic driving force of I/R injury. We summarized the basic relationship and potential mechanisms of mitochondrial injury in the development of I/R injury. Subsequently, this review summarized the natural products (NPs) that have been proven to targeting mitochondrial therapeutic effects during I/R injury in recent years and related cellular signal transduction pathways. We found that these NPs mainly protected the structural integrity of mitochondria and improve dysfunction, such as reducing mitochondrial division and fusion abnormalities, improving mitochondrial Ca2+ overload and inhibiting reactive oxygen species overproduction, thereby playing a role in protecting cardiomyocytes during I/R injury. This data would deepen the understanding of I/R-induced mitochondrial pathological process and suggested that NPs are expected to be transformed into potential therapies targeting mitochondria.

Epac, a positive or negative signaling molecule in cardiovascular diseases.

Cardiovascular disease (CVD) is one of the leading causes of death and disability, and has always been a hotspot in clinical and scientific research. The illness brings a heavy economic burden and causes psychological pressure on society and families. The pathogenesis of CVD is complex and has not yet been fully elucidated. Mitochondria provide energy for cardiovascular function. cAMP signaling is closely related to the mechanism of action of mitochondria. Epac, an important effector of cAMP, is involved in a variety of physiopathological mechanisms of CVD. Epac acts on a variety of pathways, including ion level regulation, cardiac hypertrophy, cardiac fibrosis, cardiomyocyte apoptosis, and angiogenesis. In this article, we systematically discuss the mechanism of action of Epac in CVDs to provide (i) ideas for the treatment of CVDs such as arrhythmia and heart failure and (ii) a basis for studying biological pathways and carrying out targeted drug research. Although some of the studied mechanisms are inconsistent, they also illustrate the complexity and importance of the effects of Epac.

Efficacy and safety of Chinese herbal medicine Wen Xin granules for the treatment of unstable angina pectoris with Yang deficiency and blood stasis syndrome: study protocol for a randomized controlled trial.

INTRODUCTION: Unstable angina pectoris (UAP) is the common type of coronary heart disease with the risk of developing into acute myocardial infarction (AMI). Currently, there are still numerous patients suffering from recurrent angina after revascularization or conventional medication due to the microvascular lesions, endothelial dysfunction, chronic inflammation, in-stent restenosis, and other factors. As an important part of China's medical and health care system, traditional Chinese medicine (TCM) has rich clinical experience in the treatment of UAP. According to the theory of TCM, Yang deficiency and blood stasis syndrome is a common type of UAP. Wen Xin decoction, as a type of Chinese herbal medicine, has been used in the clinic for years and shown great efficacy in the treatment of UAP with Yang deficiency and blood stasis syndrome. This study aims to evaluate the efficacy and safety of Wen Xin granular in patients with UAP. METHODS AND ANALYSIS: This is a double-blinded, randomized, placebo-controlled clinical trial. A total of 502 participants will be randomly allocated to the intervention group and the placebo group. Based on conventional medication, the intervention group will be treated with Wen Xin granular and the placebo group will be treated with Wen Xin granular placebo. The primary outcomes are major adverse cardiovascular events (MACE). Assessments will be performed 1 year after the treatment. The secondary outcomes include TCM symptom scale score, Seattle angina questionnaire, and thromboelastography. Assessments will be performed at baseline (before randomization) and 4 and 8 weeks after randomization. DISCUSSION: This trial will provide high-quality data on the benefits and risks of Wen Xin granular in patients with UAP. TRIAL REGISTRATION: ClinicalTrials.gov NCT04661709 . Registered on 30 November 2020.

Cardioprotective effect of saffron total glycoside tablets in patients with breast cancer receiving anthracycline-based chemotherapy: study protocol for a multicentre, randomised, parallel, double-blind, placebo-controlled clinical trial.

BACKGROUND: Breast cancer is the most common cancer worldwide. Anthracyclines, alone or in combination with other chemotherapeutic agents, are the most effective chemotherapy agents against breast cancer. However, the dose-dependent cardiotoxicity of anthracyclines is a serious drawback in clinical treatment. Considerable efforts have been made to establish suggestions to avoid anthracycline-induced cardiotoxicity. Crocin extracted from saffron has potential cardioprotective effects against anthracycline-induced cardiotoxicity. The aim of this study was to estimate the cardioprotective effects and safety of saffron total glycoside tablets relative to placebo in patients with breast cancer undergoing anthracycline-based chemotherapy. METHODS: This is a multicentre, randomised, double-blind, placebo-controlled clinical trial. A sample of 200 participants (100 per group) with breast cancer will be randomly assigned to receive either saffron total glycoside tablet or placebo (four tablets each time, three times each day) for 6 months. Each participant will be interviewed three times: baseline (visit 1), after 3 months (visit 2), and after 6 months (visit 3). The primary outcome is to confirm if administration of saffron total glycoside tablets reduces the rate of cardiotoxicity relative to that with placebo. Secondary outcomes include new arrhythmic events, and cardiac troponin I and N-terminal pro-B-type natriuretic peptide levels. The quantity, quality, and severity of the adverse events will be carefully documented. DISCUSSION: We look forward to obtaining high-quality evidence that can be used to formulate clinical practice guidelines. Thus, the findings of this study are expected to help fill the current gap in cardiotoxicity prevention drugs. TRIAL REGISTRATION: This trial was published in the Chinese Clinical Trial Registry (No. ChiCTR2000041134, registered on 19th December 2020).

[Analysis on disease burden and direct medical cost of Xueshuan Xinmaining Tablets in patients with cerebral infarction and coronary heart disease].

The increasing burden of cardiovascular disease in China has become a major public health problem, and the prevention and treatment of cardiovascular disease is in urgent need. For the reality of integrated Chinese and Western medicine in the Chinese health care system, we can consider the service ability of traditional Chinese medicine. Xueshuan Xinmaining Tablet is a kind of Chinese patent medicine commonly used in the treatment of recovery stage of ischemic stroke and angina pectoris of coronary heart disease. Based on the data of hospitalized patients covered by national urban basic medical insurance of China Medical Insurance Research Association in 2013, this study evaluated the treatment cost and detailed composition of the cost for the patients with cerebral infarction and coronary heart disease treated by Xueshuan Xinmaining Tablets. At the same time, the differences in disease burden and direct medical expenses among Xueshuan Xinmaining Tablets group, Western medicine group and another commonly used Chinese patent medicine group were analyzed. Among the three groups of patients with cerebral infarction and coronary heart disease, the hospitalization rates caused by various causes(44.4% and 29.6%) and diseases(20.8% and 5.2%) in Xueshuan Xinmaining Tablets group were the lowest(all P<0.01), and the number of hospitalization times in half a year was highest in the common Chinese patent medicine group(all P<0.01). In patients with cerebral infarction, the median annual total outpatient expenses were 7 476.8, 7 601.8, 15 650.1 yuan respectively in Western medicine group, Xueshuan Xinmaining Tablets group and the common Chinese patent medicine group(P<0.01), and the median hospitalization expenses were 11 620.2, 14 988.9, 13 325.6 yuan respectively(P=0.058). In patients with coronary heart disease, the total outpatient expenses of the three groups were 6 831.4, 10 228.6, 13 132.4 yuan respectively(P<0.01), and the total hospitalization expenses were 13 354.7, 14 911.5, 15 725.3 yuan respectively(P=0.134). The results showed that in patients with cerebral infarction and coronary heart disease, the hospitalization rate was lowest in Xueshuan Xinmaining Tablets group, beneficial to the turnover of hospital beds and full use of hospital medical resources. The total annual outpatient cost of Xueshuan Xinmaining Tablets group was lower than that of common Chinese patent medicine group, beneficial to reduce the burden of disease.

Effects of Danlou tablet for the treatment of stable angina pectoris: A study protocol of a randomized, double-blind, and placebo-controlled clinical trial.

INTRODUCTION: Stable angina pectoris has a high prevalence and causes serious harm. Revascularization therapy can relieve angina pectoris to some extent, but it is not widely accepted in China due to the cost and secondary events. The Chinese proprietary medicine Danlou tablet has been widely used to treat angina pectoris, but previous trials had inadequate methodologies. In this study, we aim to conduct a randomized controlled trial to evaluate its efficacy and safety on stable angina. METHODS AND ANALYSIS: This study is a WeChat-based randomized, double-blind, and placebo-controlled clinical trial in China. Eligible participants are adults (aged 30-75 years) with CT-confirmed stable angina and traditional Chinese medicine-diagnosed intermingled phlegm and blood stasis syndrome. A total of 76 participants will be randomly allocated in a 1:1 ratio to the oral Danlou tablet group (1.5 mg a time, 3 times daily for 28 days) or the placebo group. Patients are permitted concomitant use of routine medications during these 28 days. The primary outcome is angina frequency per week. The secondary outcomes include angina severity, angina duration, traditional Chinese medicine efficacy, the withdrawal rate of emergency medications, blood lipids, and electrocardiograph efficacy. The WeChat app will be used to remind patients to take their medicines and fill out the forms. All data will be recorded in case report forms and analyzed by Statistical Analysis System software. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences in Beijing, China (No. 2019-225-KY). TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, ID: ChiCTR1900028068.

Cardiac CaMKIIδ and Wenxin Keli Prevents Ang II-Induced Cardiomyocyte Hypertrophy by Modulating CnA-NFATc4 and Inflammatory Signaling Pathways in H9c2 Cells.

Previous studies have demonstrated that calcium-/calmodulin-dependent protein kinase II (CaMKII) and calcineurin A-nuclear factor of activated T-cell (CnA-NFAT) signaling pathways play key roles in cardiac hypertrophy (CH). However, the interaction between CaMKII and CnA-NFAT signaling remains unclear. H9c2 cells were cultured and treated with angiotensin II (Ang II) with or without silenced CaMKIIδ (siCaMKII) and cyclosporine A (CsA, a calcineurin inhibitor) and subsequently treated with Wenxin Keli (WXKL). Patch clamp recording was conducted to assess L-type Ca2+ current (ICa-L), and the expression of proteins involved in signaling pathways was measured by western blotting. Myocardial cytoskeletal protein and nuclear translocation of target proteins were assessed by immunofluorescence. The results indicated that siCaMKII suppressed Ang II-induced CH, as evidenced by reduced cell surface area and ICa-L. Notably, siCaMKII inhibited Ang II-induced activation of CnA and NFATc4 nuclear transfer. Inflammatory signaling was inhibited by siCaMKII and WXKL. Interestingly, CsA inhibited CnA-NFAT pathway expression but activated CaMKII signaling. In conclusion, siCaMKII may improve CH, possibly by blocking CnA-NFAT and MyD88 signaling, and WXKL has a similar effect. These data suggest that inhibiting CaMKII, but not CnA, may be a promising approach to attenuate CH and arrhythmia progression.

Huoxue Huatan Decoction Ameliorates Myocardial Ischemia/Reperfusion Injury in Hyperlipidemic Rats via PGC-1α-PPARα and PGC-1α-NRF1-mtTFA Pathways.

OBJECTIVE: The aim of this study was to eluc\idate the preventive and therapeutic effects and the underlying mechanisms of Huoxue Huatan Decoction (HXHT) on myocardial ischemia/reperfusion (I/R) injury in hyperlipidemic rats. METHODS: An I/R model was established in hyperlipidemic Wistar rats. After 4-8 weeks of HXHT treatment, the physical signs of rats were observed. Lipid metabolism, myocardial enzyme spectrum, cardiac function, myocardial histomorphology, and mitochondrial biosynthesis were investigated by a biochemical method, ultrasonography, electron microscopy, pathological examination, real-time PCR, and Western blot. RESULTS: HXHT can affect lipid metabolism at different time points and significantly reduce the levels of cholesterol (CHO), triglyceride (TG), high-density lipid-cholesterol (HDL-C), and low-density lipid-cholesterol (LDL-C) in hyperlipidemic rats (P < 0.05 or P < 0.01); it can significantly reduce the levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), reduce the myocardial infarct size and myocardial ischemic area, and improve cardiac function. The results of myocardial histomorphology showed that HXHT could protect myocardial cells, relieve swelling, reduce the number of cardiac lipid droplets, and improve myocardial mitochondrial function. HXHT could significantly increase the levels of total superoxide dismutase (T-SOD) and succinate dehydrogenase (SDH) (P < 0.05 or P < 0.01), increase CuZn-superoxide dismutase (CuZn-SOD) and glutathione-peroxidase (GSH-Px) levels, and decrease the levels of malondialdehyde (MDA) (P < 0.05); it could increase the mRNA and protein expression levels of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (mtTFA) (P < 0.05 or P < 0.01), and increase the synthesis of mitochondrial DNA (mtDNA) (P < 0.01). CONCLUSION: HXHT can reduce myocardial I/R injury in hyperlipidemic rats. The protective mechanisms may involve a reduction in blood lipids, enhancement of PGC-1α-PPARα pathway activity, and, subsequently, an increase in fatty acid ß-oxidation, which may provide the required input for mitochondrial energy metabolism. HXHT can additionally enhance PGC-1α-NRF1-mtTFA pathway activity and, subsequently, increase the antioxidant capacity, promote mtDNA synthesis, and reduce mitochondrial damage. The two pathways use PGC-1α as the intersection point to protect mitochondrial structure and function, reduce I/R-induced injury, and improve cardiac function.

Astragaloside IV: An Effective Drug for the Treatment of Cardiovascular Diseases.

Cardiovascular disease (CVD), the number one cause of death worldwide, has always been the focus of clinical and scientific research. Due to the high number of deaths each year, it is essential to find alternative therapies that are safe and effective with minimal side effects. Traditional Chinese medicine (TCM) has a long history of significant impact on the treatment of CVDs. The mode of action of natural active ingredients of drugs and the development of new drugs are currently hot topics in research on TCM. Astragalus membranaceus is a commonly used Chinese medicinal herb. Previous studies have shown that Astragalus membranaceus has anti-tumor properties and can regulate metabolism, enhance immunity, and strengthen the heart. Astragaloside IV (AS-IV) is the active ingredient of Astragalus membranaceus, which has a prominent role in cardiovascular diseases. AS-IV can protect against ischemic and hypoxic myocardial cell injury, inhibit myocardial hypertrophy and myocardial fibrosis, enhance myocardial contractility, improve diastolic dysfunction, alleviate vascular endothelial dysfunction, and promote angiogenesis. It can also regulate blood glucose and blood lipid levels and reduce the risk of cardiovascular diseases. In this paper, the mechanism of AS-IV intervention in cardiovascular diseases in recent years is reviewed in order to provide a reference for future research and new drug development.

Efficacy and safety of traditional Chinese medicine injections in the treatment of acute myocardial infarction: A protocol for systematic review and network meta-analysis.

BACKGROUND: As one of the common cardiovascular diseases, acute myocardial infarction (AMI) is characterized by a high mortality rate, frequent complications, and a serious threat to human health and quality of life. Traditional Chinese medicine injection (TCMI) has been used clinically to treat AMI; however, there is no uniform standard for clinical treatment of AMI. The purpose of this study is to evaluate the efficacy and safety of different TCMI by using systematic review and network meta-analysis. METHODS: According to the strategy, the authors will retrieve both 4 Chinese databases and 3 English databases by June 30, 2020. After a series of screening, randomized controlled trials will be included related to TCMI for AMI. Two researchers will use Aggregate Data Drug Information System and STATA 15.0 to analyze the data. Finally, the evidence grade of the results will be evaluated. RESULTS: This study will provide a reliable evidence for the selection of TCMI therapies for AMI. CONCLUSION: The results of this study will provide references for evaluating the influence of different TCMI therapies for AMI, and provide decision-making references for clinical research. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/FYGBT.

Efficacy, Chemical Constituents, and Pharmacological Actions of Radix Paeoniae Rubra and Radix Paeoniae Alba.

Radix Paeoniae Rubra and Radix Paeoniae Alba are the different characteristic forms of Paeonia lactiflora Pall. They are widely used as traditional Chinese medicines in clinical practices. This study analyzes the development history, efficacy, chemical compositions, and pharmacological effects of Radix Paeoniae Rubra and Radix Paeoniae Alba, and explores the causes of the similarities and differences of these two amalgams. It provides a basis for the clinical application of these two Chinese medicinal materials, and lays a foundation for further study of the pharmacological effects and the quality identification of Paeonia lactiflora Pall as it applies to traditional Chinese medicine.

Traditional Chinese medicine on treating dilated cardiomyopathy: A protocol for systematic review and meta analysis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a type of complex cardiomyopathy characterized by enlargement and contractile dysfunction of the left ventricle, right ventricle, or double ventricle. Modern studies have shown that the pathogenesis of DCM is closely related to factors such as heredity, gene mutation, autoimmunity, and viral infection. The etiology is complex and the mortality rate is high. Many clinical trials have proved that traditional Chinese medicine has a great therapeutic effect on DCM. In this systematic review, we aim to evaluate the effectiveness and safety of traditional Chinese medicine for DCM. METHODS: The databases of Pubmed, The Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (WANFANG Data), Weipu Information Chinese Periodical Service Platform (VIP), and China Biomedical Literature Service System (SinoMed) will be searched online to collect randomized controlled trials related to the treatment of DCM with Traditional Chinese medicine The time is limited from the construction of the library to December 2019. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata 13.0 software so as to systematically review the effectiveness of Traditional Chinese medicine for DCM. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of traditional Chinese medicine for DCM. Because all data used in this systematic review and meta-analysis have been published, this review does not require ethical approval. In addition, all data will be analyzed anonymously during the review process. TRIAL REGISTRATION NUMBER: PROSPERO CRD42020163332.