Efficacy and safety of Shexiang Baoxin pill (MUSKARDIA) in patients with stable coronary artery disease: a multicenter, double-blind, placebo-controlled phase IV randomized clinical trial.

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.

May Measurement Month 2017: an analysis of blood pressure screening results in China-East Asia.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. In China, several hypertension screening programmes are undertaken in the elderly in the community and in youths at university entrance and graduation. However, most people, especially the middle-aged working population, do not often have their BP measured. The current awareness (46.9%), treatment (40.7%), and control rates (15.3%) of hypertension remain low, while the proportion of screenees with hypertension is high in adult Chinese (23.2%). An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. About 125 236 individuals were screened. After multiple imputation, with 124 623 as denominator, 32 089 (25.7%) had hypertension. Of the 103 981 individuals not on antihypertensive medication, 11 447 (11.0%) were hypertensive. Of the 20 547 individuals on antihypertensive medication, 7392 (36.0%) had uncontrolled BP (≥140/90 mmHg). An opportunistic screening may effectively identify those with high BP regardless of the use of antihypertensive medication and shows similar information on BP as a survey in a randomly selected population sample.

Effect of Shexiang Tongxin Dropping Pills () on the Immediate Blood Flow of Patients with Coronary Slow Flow.

OBJECTIVE: To observe the immediate effect and safety of Shexiang Tongxin dropping pills (, STDP) on patients with coronary slow flow (CSF), and furthermore, to explore new evidence for the use of Chinese medicine in treating ischemic chest pain. METHODS: Coronary angiography (CAG) with corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) was applied (collected at 30 frames/s). The treatment group included 22 CSF patients, while the control group included 22 individuals with normal coronary flow. CSF patients were given 4 STDP through sublingual administration, and CAG was performed 5 min after the medication. The immediate blood flow frame count, blood pressure, and heart rate of patients before and after the use of STDP were compared. The liver and kidney functions of patients were examined before and after treatments. RESULTS: There was a significant difference in CTFC between groups (P<0.05). The average CTFC values of the vessels with slow blood flow in CSF patients were, respectively, 49.98 ± 10.01 and 40.42 ± 11.33 before and after the treatment with STDP, a 19.13% improvement. The CTFC values (frame/s) measured before and after treatment at the left anterior descending coronary artery, left circumflex artery, and right coronary artery were, respectively, 48.00 ± 13.32 and 41.80 ± 15.38, 59.00 ± 4.69 and 50.00 ± 9.04, and 51.90 ± 8.40 and 40.09 ± 10.46, giving 12.92%, 15.25%, and 22.76% improvements, respectively. The CTFC values of vessels with slow flow before treatment were significantly decreased after treatment (P<0.05). There were no apparent changes in the heart rate, blood pressure, or liver or kidney function of CSF patients after treatment with STDP (all P>0.05). CONCLUSIONS: The immediate effect of STDP in treating CSF patients was apparent. This medication could significantly improve coronary flow without affecting blood pressure or heart rate. Our findings support the potential of Chinese medicine to treat ischemic chest pain.

Neat1 regulates oxidized low-density lipoprotein-induced inflammation and lipid uptake in macrophages via paraspeckle formation.

Oxidized low-density lipoprotein (oxLDL) indu-ces macrophage inflammation and lipid uptake, and serves important roles in the development of atherosclerosis. The long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (neat1) has two isoforms; the longer isoform, neat1_2, mediates the formation of subnuclear structures called paraspeckles. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR), western blotting and RNA protein immunoprecipitation (RIP), revealed that oxLDL induced paraspeckle formation in the THP­1 cell line. Additionally, the nuclear factor­κB and p38 pathways were observed to be involved in neat1 transcription. To investigate the role of paraspeckles in oxLDL­induced macrophage inflammation and lipid uptake, macrophages were transfected with small interfering RNAs against NEAT1, NEAT1_2, non­POU domain-containing octamer-binding (NONO) and splicing factor proline and glutamine rich prior to oxLDL incubation. In addition, inflammation­associated pathways and scavenger receptors were analyzed by performing western blotting and RT­qPCR. p65 phosphorylation and cluster of differentiation 36 (CD36) were demonstrated to serve roles in paraspeckle­mediated inflammation and lipid uptake, respectively. To determine the underlying mechanism, RIP was preformed, which revealed that NONO binds CD36 mRNA to decrease its expression. In conclusion, oxLDL induced neat1_2­mediated paraspeckle formation. Paraspeckles participate in oxLDL­induced macrophage inflammation and lipid uptake by regulating p65 phosphorylation and CD36 mRNA.

Imbalanced response of ATP-binding cassette transporter A1 and CD36 expression to increased oxidized low-density lipoprotein loading contributes to the development of THP-1 derived foam cells.

ATP-binding cassette transporter A1 (ABCA1) and CD36, type B scavenger receptor, function as the key mediators of macrophages cholesterol efflux and intake, respectively. However, their contribution to development of foam cells still remains uncertain. We here examined the effects of increased oxidized low-density lipoprotein (oxLDL) loading on the ABCA1 and CD36 expression, and lipid accumulation in THP-1 macrophages. The cultured THP-1 macrophages were treated with different copper-oxLDL concentrations. The intracellular lipid contents and cholesterol efflux were measured, and the ABCA1 and CD36 expression were assessed. We found that expression of ABCA1 and CD36 were coordinately induced upon low to moderate doses of oxLDL loading. However, higher doses of oxLDL stimulation resulted in the imbalanced expression of ABCA1 and CD36 proteins with more preferentially suppressed ABCA1 protein, attenuated cholesterol efflux and development of THP-1 derived foam cells. The PPAR-γ expression was remarkably induced, and PPAR-γ agonist, pioglitazone, significantly promoted the ABCA1 and CD36 expression. Additionally, ABCA1 and CD36 proteins were strong colocalized in THP-1 macrophages membrane. In conclusion, the more preferentially suppressed ABCA1 expression as compared with CD36 at higher doses of oxLDL stimulation may be the initiator for the formation of macrophage-derived foam cells.

[Evaluation of myocardial perfusion in patients with coronary slow flow by myocardial contrast echocardiography].

OBJECTIVE: To explore myocardial perfusion of patients with coronary slow flow (CSF) using myocardial contrast echocardiography. METHODS: Myocardial contrast echocardiography was performed in coronary artery angiography diagnosed CSF patients (n = 20) and control patients (n = 20). The images at baseline and after low dose dobutamine stress test were analyzed by automatic tracking software and the maximal amplitude score A, the mean ascending slope of the curve ß and the product of A×ß were measured. The reserve of A×ß was also calculated. Electrocardiogram at rest and at each stage of dobutamine stress test was obtained simultaneously. RESULTS: At baseline, the A [(6.85 ± 2.99) dB vs. (7.01 ± 3.49) dB], ß[(0.59 ± 0.33)/s vs. (0.61 ± 0.38)/s] and A×ß [(3.48 ± 1.46) dB/s vs. (3.31 ± 0.96) dB/s] values were similar between CSF group and control group (all P > 0.05). After dobutamine stress test, both ß and A×ß were significantly increased in two groups. The ß [(0.89 ± 0.42)/s vs. (1.31 ± 0.54)/s, P < 0.01] and A×ß [(5.82 ± 2.69) dB/s vs. (8.07 ± 2.76)dB/s, P < 0.05] in CSF group were significantly lower than in control group. Electrocardiogram of all the subjects was normal at rest, but the electrocardiogram positive rate was significantly higher in CSF group than in control group after dobutamine stress test (12% vs. 2%, 60% vs. 10%, P < 0.01). CONCLUSIONS: Dobutamine stress test could induce myocardial perfusion abnormalities in patients with coronary slow flow phenomenon.

[Clinical application of VerifyNow-P2Y12 assay in evaluation of platelet inhibition efficacy of clopidogrel].

OBJECTIVE: To evaluate the platelet inhibition efficacy in patients under regular maintenance dose of clopidogrel by VerifyNow-P2Y12 assay and explore the clinical characteristics of clopidogrel non-responders and related predicting factors. METHODS: A total of 99 patients underwent percutaneous coronary intervention procedure and receiving clopidogrel in regular maintenance dose for at least 1 week were enrolled. Platelet reactivity, including baseline, P2Y12 reaction unit (PRU), and platelet inhibition rate were measured with VeifyNow-P2Y12 assay. The dosage of anti-platelet drugs, combination with any other drugs, clinical characters in baseline of all enrolled patients were analyzed. PRU ≤ 240 was used as cut-off to identify clopidogrel responder and clopidogrel non-responder. In the non-responder group, patients were further separated into 3 sub-groups (types) according to the baseline and platelet inhibition rate: type I with high baseline, high inhibition rate, representing false non-responder; type II with low inhibition rate, representing true non-responder and type III mixed type. RESULTS: In this study, 48 of 99 patients were found to be clopidogrel non-responder (48.5%). The ratio of type I, type II and type III in the non-responder group was 9.1% (n = 9), 27.3% (n = 27), and 12.1% (n = 12), respectively. Baseline platelet value in female patients was significantly higher than in males (P < 0.01), number of females with high PRU also is higher than males (P < 0.01), female gender was a predict factor for type I non-responder (OR = 6.5, 95%CI 2.295 - 18.407, P < 0.01). BMI > 24 kg/m(2) was a risk factor for clopidogrel non-responder (P < 0.05), and may be regarded as a predict factor for type II non-responder (OR = 3.207, 95%CI 1.375 - 7.485, P < 0.01). Age, hypertension, diabetics, smoking, hyperlipidemia, CRP and pantoprazole use do not show significant correlation with baseline and platelet inhibition rate. CONCLUSIONS: Clopidogrel responses could be reliably detected by VerifyNow-P2Y12 assay. Female gender and high body weight are independent risk factors for clopidogrel non-responses.

[Diagnostic value of 320-slice computed tomography coronary angiography to assess in-stent restenosis].

OBJECTIVE: To evaluate the diagnostic accuracy of 320-slice CT coronary angiography (CTA) in the evaluation of in-stent restenosis (ISR, ≥50% luminal narrowing) in comparison with quantitative coronary angiography (CAG). METHODS: A total of 69 patients with previous stent implantation who underwent both CTA and CAG were prospectively included. We assessed diagnostic valve for ISR with CTA in comparison with CAG. RESULTS: A total of 110 stents were implanted in these patients.CAG identified 14 ISR. CTA correctly identified 13 ISR and misdiagnosed 5 ISR in stents without ISR. Besides, 6 stents could not be evaluated by CTA due to unsatisfied image quality. Accordingly, sensitivity, specificity, positive and negative predictive value of CTA for diagnosing ISR were 93%, 89%, 54% and 99%, respectively. The image quality of CTA was significantly better in larger stents (percentages of good and moderate stent image of ≥3.0 mm and <3.0 mm: 56% vs. 27%, 25% vs. 49%) and which was linked with better diagnostic coincidence rate (95% vs. 78%) for larger stents. The image quality of CTA was significantly better in stents with thinner stent strut thickness (percentages of poor CTA stent image quality of stent strut thickness<140 µm and ≥140 µm: 12% vs. 45%, P<0.01) and which was associated with better diagnostic coincidence rate for stents with thinner stent strut thickness (94% vs. 76%, P<0.05). The image quality of CTA was also significantly better in single stent (percentages of poor CTA stent image quality of single stent vs. overlap and dedicated stent: 17% vs. 36%, P<0.05). However, heart rate (≥65 beats/min vs. <65 beats/min) during CTA acquisition was not associated with image quality and the diagnostic coincidence rate (all P>0.05). CONCLUSIONS: Our results indicate that 320-slice CTA allows accurate noninvasive assessment of significant in-stent restenosis in selected patients. Stents with a large diameter and thin struts are associated with better image quality and higher diagnostic accuracy.

[Geographical characteristics of single nucleotide polymorphism of candidate genes associated with coronary artery disease in Chinese Han population].

OBJECTIVE: To investigate the geographical characteristics of single nucleotide polymorphism (SNP) of candidate genes associated with coronary artery disease in Chinese Han population. METHODS: Study population were Chinese Han nationality recruited from Xi'an, Shiyan and Ningbo districts. Patients with coronary artery disease were defined by coronary angiography with stenosis >or= 50% and control subjects with stenosis < 10%, respectively. The DNA was extracted from peripheral white blood cell by approach comprised proteinase K digestion, phenol and chloroform extraction as well as isopropanol precipitation. The SNP of ATP-binding cassette transporter (ABCA1)-G596A, cholesteryl ester transfer protein (CETP)-Taq1B, Lipoprotein lipase (LPL)-Hind III and LPL-Pvu II were genotyped by PCR-RFLPs, and verified by gene sequencing. RESULTS: A Total of 615 patients undertaken coronary angiography were recruited from cardiac center in Xi'an (220), Ningbo (209) and Shiyan district (186), China (mean age 60 +/- 10 years, 75.9% males). Diabetes mellitus was more prevalent in Xi'an Cohort population than Shiyan and Ningbo cohort (P < 0.01). Plasma total cholesterol, LDL cholesterol and triglyceride levels in Xi'an Cohort population were significantly higher, and HDL-C siginificantly lower than in Shiyan and Ningbo cohort population [HDL-C: (1.17 +/- 0.48) mmol/L vs. (1.25 +/- 0.33) mmol/L and (1.29 +/- 0.44) mmol/L, P < 0.05]. Distribution differences for ABCA1-G596A and CETP-Taq1B genotypes were found in Xi'an Cohort population compared to Ningbo and Shiyan cohorts (for ABCA1, Xi'an: 0.24, 0.53, 0.23 and Shiyan: 0.17, 0.62, 0.21 and Ningbo: 0.34, 0.37, 0.29, for GG, AG, AA, respectively, P < 0.01; and for CETP, Xi'an: 0.29, 0.54, 0.17 and Shiyan: 0.38, 0.40, 0.22 and Ningbo: 0.39, 0.49, 0.12 for B1B1, B1B2, B2B2, respectively, P < 0.01), but not for LPL variants. ABCA1-G596A variant predicted HDL-C [Xi'an: (1.2 +/- 0.3) mmol/L, (1.3 +/- 0.2) mmol/L and (1.4 +/- 0.4) mmol/L, P = 0.01; Shiyan: (1.1 +/- 0.4) mmol/L: (1.2 +/- 0.3) mmol/L and (1.3 +/- 0.4) mmol/L, P = 0.03; Ningbo, (1.2 +/- 0.3) mmol/L, (1.3 +/- 0.4) mmol/L and (1.4 +/- 0.3) mmol/L, across GG, GA to AA genotype, respectively, P = 0.01] and TG levels [Xi'an: (2.4 +/- 1.3) mmol/L, (1.9 +/- 0.9) mmol/L and (1.6 +/- 0.8) mmol/L, P < 0.01; Shiyan: (2.1 +/- 1.0) mmol/L, (1.9 +/- 0.8) mmol/L and (1.8 +/- 0.7) mmol/L, P = 0.03; Ningbo: (1.9 +/- 1.1) mmol/L, (1.8 +/- 0.9) mmol/L and (1.6 +/- 0.7) mmol/L, across GG, GA to AA genotype, P = 0.05] with dose-dependent relationship. LPL-Hind III (+) carriers had higher triglycerides in three cohort population [Xi'an: (2.2 +/- 1.0) mmol/L, (1.8 +/- 0.9) mmol/L, (1.6 +/- 0.7) mmol/L, P = 0.01; Shiyan: (2.1 +/- 0.7) mmol/L, (1.9 +/- 1.0) mmol/L, (1.7 +/- 0.6) mmol/L, P = 0.01; Ningbo: (1.8 +/- 1.0) mmol/L, (1.6 +/- 0.6) mmol/L and (1.4 +/- 0.5) mmol/L, for +/+, +/- and -/- genotypes, respectively, P = 0.001]. SNP of CETP-Taq1B, LPL-Hind III and LPL-Pvu II predicted HDL-C and/or TG levels in different cohort population with different manners. All these SNP were not significantly associated with the development of coronary artery disease (all P > 0.05). CONCLUSION: A geographical heterogeneity of environmental and genetic risk factors related to the development of coronary artery disease exists in Chinese Han population. Irrespective of the different geographical cohort of Chinese Han population, the SNP of candidate genes can partly predict the differences in risk-related plasma HDL-C and/or TG levels rather than angiographic coronary artery disease.

Modified classic risk factors for coronary artery disease in Chinese Han population.

OBJECTIVE: To investigate the levels of cardiovascular disease risk factors and their relations to clinical phenotype associated with coronary artery disease (CAD). METHODS: The subjects were recruited from five independent cardiovascular centers. Coronary angiography was employed to define the CAD with stenosis in each major vessel > or = 70% and control with stenosis < 10% in every lesion. The classic risk factors including family history, body mass index, smoking habits, hypertension, diabetes mellitus, and serum lipid levels were surveyed according to established criteria. Associations between risk levels and clinical phenotypes were assessed by case control and correlation analysis. RESULTS: A total of 762 individuals were collected, including 481 men and 281 women, aged from 17 to 81 (mean 60 +/- 10) years. The patients with CAD accounted for 55.5% of all participants, and controls 44.5%, respectively. Compared with the pattern in published data, our study showed that mean serum high density lipoprotein cholesterol (HDL-C) level was significantly lower (P < 0.001) and triglycerides was significantly higher (P < 0.001), while total cholesterol (TC) and low density lipoprotein cholesterol levels were comparative (both P > 0.05). The prevalence of low HDL-C (< 40 g/L) and hypertriglyceridemia (> 150 g/L) were 27.2% and 41.4%, respectively. Mean serum levels of HDL-C and apolipoprotein A1 were significantly higher in female subjects than in male (P < 0.001). Lower HDL-C functioned as an independent risk factor for CAD only in men (RR = 2.8, 95% CI: 1.5-4. 2, P < 0.001), yet increased non-HDL cholesterol combined with diabetes mellitus and obesity seemed to play a key role in the development of CAD in women. Similarity in risk association with CAD was found for hypertension and TC/HDL ratio in male and female subjects, while family history had no relationship with the presence of CAD. CONCLUSION: It is remarkable that emphasis of intervention in future should be given on the prevalent low serum HDL-C and its strong risk correlation with the presence of CAD in male subjects of Chinese Han population.