Background: The Shexiang Baoxin Pill (MUSKARDIA) has been used for treating coronary artery disease (CAD) and angina for more than 30 years in China. Nevertheless, methodologically sound trials on the use of MUSKARDIA in CAD patients are scarce. The aim of the study is to determine the effects of MUSKARDIA as an add-on to optimal medical therapy (OMT) in patients with stable CAD. Methods: A total of 2674 participants with stable CAD from 97 hospitals in China were randomized 1:1 to a MUSKARDIA or placebo group for 24 months. Both groups received OMT according to local tertiary hospital protocols. The primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary outcomes included all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or heart failure, peripheral revascularization, angina stability and angina frequency. Results: In all, 99.7% of the patients were treated with aspirin and 93.0% with statin. After 2 years of treatment, the occurrence of MACEs was reduced by 26.9% in the MUSKARDIA group (MUSKARDIA: 1.9% vs. placebo: 2.6%; odds ratio = 0.80; 95% confidence interval: 0.45–1.07; P  = 0.2869). Angina frequency was significantly reduced in the MUSKARDIA group at 18 months (P = 0.0362). Other secondary endpoints were similar between the two groups. The rates of adverse events were also similar between the two groups (MUSKARDIA: 17.7% vs. placebo: 17.4%, P = 0.8785). Conclusions: As an add-on to OMT, MUSKARDIA is safe and significantly reduces angina frequency in patients with stable CAD. Moreover, the use of MUSKARDIA is associated with a trend toward reduced MACEs in patients with stable CAD. The results suggest that MUSKARDIA can be used to manage patients with CAD. Trial registration chictr.org.cn, No. ChiCTR-TRC-12003513

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We identify 3 novel loci associated with CAD and show that 2 genes, and, make functional contributions to atherosclerosis. How rs852787 and its host gene are linked to CAD needs further studies.

Oxidized low density lipoprotein (ox-LDL)-induced macrophage apoptosis contributes to the formation of atherosclerosis. Metformin, an antidiabetic drug, has been reported to attenuate lipid accumulation in macrophages. In this study, the effects of metformin on ox-LDL-induced macrophage apoptosis were investigated and the mechanisms involved in this process were examined. By performing flow cytometry analysis, it was demonstrated that metformin inhibited ox-LDL-induced macrophage apoptosis. Increased expression of endoplasmic reticulum (ER) stress marker proteins, including C/EBP-homologous protein, eukaryotic translation initiation factor 2A, and glucose-regulated protein 78 kDa, induced by ox-LDL was also reversed by metformin. Furthermore, ox-LDL-induced cytochrome c (cyto-c) release and mitochondrial membrane potential loss were inhibited by metformin. As lipid uptake in macrophages contributed to ER stress, cyto-c release and mitochondrial membrane potential loss, the mechanisms involved in metformin-inhibited macrophage lipid uptake were investigated. Expression of scavenger receptors, including scavenger receptor A, cluster of differentiation 36 and lectin-type oxidized LDL receptor 1 was examined in the presence or absence of metformin with ox-LDL treatment. Additionally, the upstream regulatory mechanism of scavenger receptors by metformin was also analyzed. In conclusion, metformin protects against ox-LDL-induced macrophage apoptosis and inhibits macrophage lipid uptake.