Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro.

Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of CYP2J2 and its impact on drug catalytic activity, especially in the Chinese Han population. In this study, we sequenced the promoter and exon regions of CYP2J2 in 1,163 unrelated healthy Chinese Han individuals using the multiplex PCR amplicon sequencing method. Then, the catalytic activities of the detected CYP2J2 variants were evaluated after recombinant expression in S. cerevisiae microsomes. As a result, CYP2J2*7, CYP2J2*8, 13 variations in the promoter region and 15 CYP2J2 nonsynonymous variants were detected, of which V15A, G24R, V68A, L166F and A391T were novel missense variations. Immunoblotting results showed that 11 of 15 CYP2J2 variants exhibited lower protein expression than wild-type CYP2J2.1. In vitro functional analysis results revealed that the amino acid changes of 14 variants could significantly influence the drug metabolic activity of CYP2J2 toward ebastine or terfenadine. Specifically, 4 variants with relatively higher allele frequencies, CYP2J2.8, 173_173del, K267fs and R446W, exhibited extremely low protein expression and defective catalytic activities for both substrates. Our results indicated that a high genetic polymorphism of CYP2J2 could be detected in the Chinese Han population, and most genetic variations in CYP2J2 could influence the expression and catalytic activity of CYP2J2. Our data significantly enrich the knowledge of genetic polymorphisms in CYP2J2 and provide new theoretical information for corresponding individualized medication in Chinese and other Asian populations.

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.

Structural changes in exon 11 of MEF2A are not related to sporadic coronary artery disease in Han Chinese population.

BACKGROUND: A mutation in MEF2A (myocyte enhancer factor-2A) had been reported to be the first gene linked directly to coronary artery disease (CAD). However, an opposing opinion was proposed recently that MEF2A mutations are not a common cause of sporadic CAD. In this study, we screened exon 11 of the MEF2A gene in people of the Han nationality in China and finished some functional analysis of found variations. MATERIALS AND METHODS: A gene structural investigation of MEF2A in 257 CAD patients and 154 control individuals were developed in this study. Subsequently, typical MEF2A variations were cloned and expressed in HeLa or 293T cell line to illustrate whether found structure changes could influence the main biological functions of these proteins. At last, another set of gene structural screen was initialized to get more reliable conclusions. RESULTS: Totally 16 different variations were detected in exon 11 of this gene in the first set of gene structural screen. By cloning and expressing typical MEF2A proteins in cultured cells, all the acquired MEF2A variations had transcriptional activation capabilities and subcellular localization patterns similar to those of the wild-type protein. Further larger scale genetic screening also revealed that the reported genetic variations of MEF2A did not differ significantly between CAD patients and healthy controls. CONCLUSIONS: Our results reveal that structural changes of exon 11 in MEF2A are not involved in sporadic CAD in the Han population of China.

Coronary artery aneurysm formation after drug-coated balloon treatment of de novo lesions: Two case reports.

RATIONALE: The safety and efficacy of drug-coated balloon (DCB) technology have primarily been proven in the treatment of coronary in-stent restenosis. Whereas increasing evidences show that DCB use was feasible in certain de novo coronary lesions. In 2012, Vassilev reported the 1st case in which a coronary aneurysm formed after a DCB was used to treat drug-eluting stent (DES) restenosis. To date, limited information has been reported on coronary artery aneurysm (CAA) development following DCB treatment of de novo lesions. PATIENT CONCERNS: A 42-year-old male underwent delayed coronary angiography due to extensive anterior wall myocardial infarction. After balloon predilation in the mid-left anterior descending (LAD) artery, the residual 30% stenosis without major dissection was treated with a DCB. Angiographic follow-up at 6 and 12 months revealed an aneurysm in the treated area of the LAD artery, with positive vascular remodeling behind this aneurysm. A 54-year-old male with nonstent thrombosis elevation myocardial infarction underwent elective catheterization. Coronary angiography revealed critical stenosis in the LAD and significant narrowing at the distal segments of both the left circumflex artery (LCX) and the nondominant right coronary artery. After predilation of the lesion in the LCX, the residual 30% stenosis was treated with a DCB. The lesion in the LAD was treated with a DCB either. Angiography follow-up at 6 months revealed good results in the LAD; however, an aneurysm was observed in the DCB-treated area of the LCX. DIAGNOSIS: The CAA formation after DCB treatment of de novo lesions. INTERVENTIONS AND OUTCOMES: Because the 2 patients were asymptomatic upon diagnosis, the aneurysms were left untreated. Long-term dual antiplatelet therapy and intense follow-up were recommended. LESSONS: Our cases raise questions regarding the safety of DCB treatment for de novo lesions in real-world contexts. There might be a need to clarify the appropriate doses for drugs coated on DCBs. Although indications for DCB treatment for de novo coronary lesions should not be overly aggressively broadened, the potential role of such treatment in this context merits additional elucidation in future studies.

Comparison of (99)mTc-methoxyisobutylisonitrile myocardial single-photon emission computed tomography and electron beam computed tomography for detecting coronary artery disease in patients with no myocardial infarction.

BACKGROUND: Previous studies have compared single-photon emission computed tomography (SPECT) and electron beam computed tomography (EBCT) in detection of coronary artery disease (CAD) in patients with myocardial infarction (MI). The purpose of this study was to compare SPECT with EBCT in detection of CAD in patients with no MI. METHODS: One hundred and forty-seven patients with suspected CAD underwent stress-rest (99)mTc-methoxyisobutylisonitrile ((99)mTc-MIBI) myocardial SPECT, cardiac EBCT and coronary angiography (CAG) within one month. Of them, 73 patients (aged 52.6 +/- 10.6 years old) with no history of MI were included in this study. Coronary artery calcium (CAC) was defined as a CT value >or= 130 HU within the boundary of coronary artery on EBCT. RESULTS: There were 35 and 38 patients with or without CAD according to CAG. Ninety-six percent of the patients with abnormal SPECT and CAC had a coronary arteries stenosis >or= 50%, and 90.9% patients with normal SPECT and EBCT showed no CAD. The sensitivity of SPECT and EBCT in detection of CAD was comparable, and the specificity of SPECT (92.1%) was significantly higher than that of EBCT (55.3%) (P < 0.005). For the detection of individual coronary artery stenosis, both sensitivity and specificity of SPECT (75.0% and 93.7%) were significantly higher than those of EBCT (53.3% and 76.7%) (P < 0.025 and P < 0.005, respectively). In patients without chest pain, the sensitivity and specificity of SPECT (76.9% and 91.4%) were significantly higher than those of EBCT (23.1% and 69.0%) in detection of a coronary artery stenosis of >or= 50% (P < 0.01 and P < 0.005, respectively). However, in patients with chest pain, both sensitivity and specificity of SPECT were comparable to those of EBCT. In patients or= 50% (P < 0.005), and the specificity of SPECT was comparable to that of EBCT. In patients > 45 years old, the specificity of SPECT (94.3%) was significantly higher than that of EBCT (70.5%) (P < 0.005), and the sensitivity of SPECT was comparable to that of EBCT. CONCLUSION: (99)mTc-MIBI myocardial perfusion SPECT has higher accuracy than that of EBCT in detection of CAD in patients without MI.