The traditional Chinese medicine (TCM) theory of "treating heart and brain diseases with same methods (Nao Xin Tong Zhi: NXTZ)" has great significance to the treatment of cardiovascular and cerebrovascular diseases. It has been proven effective by a great deal of clinical researches. However, the underlying mechanism for this theory is still unclear. To provide insights into the potential mechanism of "NXTZ", this study attempts to deeply investigate the mechanism from two representative cardiovascular and cerebrovascular diseases, coronary heart disease (CHD) and cerebral apoplexy. First, various data resources were integrated to obtain different types of biomedical entities including drugs, targets, pathways and diseases. Then, three different approaches including text mining, biological network and enrichment analysis were utilized to recognize the potential common features between CHD and cerebral apoplexy, and the corresponding functions of drugs which could treat both diseases, thus unveiling the mechanism of NXTZ.
Brain ; drug effects ; Coronary Artery Disease ; drug therapy ; genetics ; metabolism ; Databases, Bibliographic ; Drugs, Chinese Herbal ; therapeutic use ; Heart ; drug effects ; Humans ; Stroke ; drug therapy ; genetics ; metabolism

Coronary heart disease (CHD) related genes and targets, as well as drug targets for preventing and treating CHD were taken as the study objects to build a CHD disease network and a drug action network preventing and treating CHD. Such topological characteristic parameters of the networks as degree distribution, characteristic path length, connectivity and heterogeneity were analyzed to verify the reliability of the networks. On that basis, the intersection calculation was conducted for both networks to analyze the drug action mechanism of their sub-networks. The disease network are composed of 15,221 nodes and 31,177 sides, while the drug action network preventing and treating CHD has 15,073 nodes and 32,376 sides. Both of their topological characteristic parameters showed scale-free small world structural characteristics. Two reaction pathways in the sub-networks-calcitonin gene-related peptide and IL-6 activated JAK/STAT were taken as examples to discuss the indirect action mechanism for preventing and treating CHD. The results showed that the biological network analysis method combining the disease network and the drug action network is helpful to further studies on the action mechanism of the drugs, and significant to the prevention and treatment of diseases.
Computational Biology ; Coronary Artery Disease ; drug therapy ; genetics ; pathology ; prevention & control ; Databases, Genetic ; Humans ; Molecular Targeted Therapy ; Signal Transduction ; drug effects

BACKGROUNDPremature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort.

METHODSWe performed a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis.

RESULTSAt the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 ± 5940 vs. 15,138 ± 7597 beats/d, P < 0.001) and the placebo group (10,592 ± 8009 vs. 14,529 ± 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantly greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%,P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%,P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC-related symptoms. No severe adverse effects attributable to Wenxin Keli were reported.

CONCLUSIONSWenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC-related symptoms in patients without structural heart diseases and had no severe side effects.

Coronary Artery Disease ; genetics ; prevention & control ; Double-Blind Method ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Humans ; MEF2 Transcription Factors ; genetics ; Mutation ; genetics ; Myocardial Infarction ; drug therapy ; genetics ; Randomized Controlled Trials as Topic ; Ventricular Premature Complexes ; drug therapy ; genetics

OBJECTIVETo investigate the association of rs72689236, a new functional single nucleotide polymorphism (SNP) of the gene encoding caspase-3 (CASP3), with the occurrence and development of Kawasaki disease by a meta analysis.

METHODSA literature search was performed using databases at home and abroad according to inclusion and exclusion criteria, to acquire studies on the relationship between rs72689236 and Kawasaki disease published up to November 2012, including case-control studies and transmission disequilibrium tests. An integrated meta analysis was performed using RevMan 5.1 software after the studies were screened and evaluated.

RESULTSSix studies were extracted for systematic review of the association between rs72689236 and Kawasaki disease. The frequency of allele A of the SNP was significantly higher in patients with Kawasaki disease than in the controls (OR=1.34, 95%CI=1.24-1.46, P<0.001); the risk for Kawasaki disease in children with allele A (AA+AG) increased by approximately 44% compared with children with GG (OR=1.44, 95%CI=1.27-1.65, P<0.001). The frequency of allele A of the SNP was significantly higher in Kawasaki disease patients with coronary artery lesions than in those without coronary artery lesions (OR=1.51, 95%CI=1.10-2.07, P= 0.01); the risk for coronary artery lesions in Kawasaki disease patients with allele A (AA+AG) increased by approximately 59% compared with Kawasaki disease patients with GG (OR=1.59, 95%CI= 1.00-2.53, P=0.05]. No association between this SNP and the therapeutic effect of intravenous immunoglobulin (IVIG) was found in patients with Kawasaki disease.

CONCLUSIONSThe allele A of functional SNP rs72689236 of CASP3 increases the risk for Kawasaki disease, and it may be used as the genetic marker for susceptibility to coronary artery lesions as a complication of Kawasaki disease. Currently, there is still no sufficient evidence that this SNP has an impact on the therapeutic effect of IVIG in patients with Kawasaki disease, and more studies are needed to investigate the feasibility of its application in individualized treatment.

Caspase 3 ; genetics ; Coronary Artery Disease ; etiology ; Genotype ; Humans ; Immunoglobulins, Intravenous ; therapeutic use ; Mucocutaneous Lymph Node Syndrome ; drug therapy ; etiology ; genetics ; Polymorphism, Single Nucleotide

BACKGROUNDDual anti-platelet treatment with aspirin and clopidogrel is established foundation for patients undergoing percutaneous coronary intervention (PCI) to prevent thrombotic events. The present study was conducted to examine whether the CYP2C19 681G > A polymorphism and cigarette smoking had independent or interactive effect on response to clopidogrel.

METHODSAmong 722 Chinese Han patients undergoing elective coronary stent placement due to stable angina pectoris, a loading dose of 300 mg clopidogrel was given to all patients and a daily maintenance dose of 75 mg for a minimum of 12 months. CYP2C19 681G > A polymorphism was genotyped. The platelet reactivity was measured by light transmittance aggregometry (LTA) with 5 µmol/L adenosine diphosphate (ADP) induced. The poor response was defined as 10% or less absolute difference between aggregation at baseline and 24 hours after loading dose of clopidogrel.

RESULTSThe results showed that the poor-response to clopidogrel was presented in 105 patients (14.5%). Overall, the genotype GA/AA carriers were likely to be poor-responsive cases (19.6% vs. 11.0%, P = 0.001) with odds ratio (OR) of 1.971 (95%CI: 1.296 - 2.998, P = 0.002), compared with the GG homozygotes. Meanwhile, compared with nonsmokers, the smokers showed lower rate of poor-response (10.9% vs. 17.3%, P = 0.015) with OR of 0.582 (95%CI: 0.374 - 0.904, P = 0.016). The smokers with GG genotype had the lowest risk with OR of 0.487 (95%CI: 0.246 - 0.961, P = 0.038) while nonsmokers with GA/AA genotype had the highest risk of poor-response with OR of 1.823 (95%CI: 1.083 - 3.068, P = 0.024), compared with nonsmokers with GG genotype. However, there was no significant interaction between genotype and smoking.

CONCLUSIONOur study indicated that both CYP2C19 polymorphism and smoking independently affected response to clopidogrel.

Aged ; Angioplasty, Balloon, Coronary ; Aryl Hydrocarbon Hydroxylases ; genetics ; Coronary Artery Disease ; genetics ; therapy ; Cytochrome P-450 CYP2C19 ; Drug-Eluting Stents ; Female ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors ; therapeutic use ; Polymorphism, Genetic ; genetics ; Ticlopidine ; analogs & derivatives ; therapeutic use

OBJECTIVETo investigate the relation of clopidogrel resistance to polymorphism of adenosine diphosphate receptor (P2Y12).

METHODSThree hundred and seventy patients with coronary atherosclerotic heart disease, who were admitted in hospital from May 2011 to November 2012 and underwent percutaneous coronary intervention, were enrolled in the study. All patients received antiplatelet therapy (oral aspirin 100 mg per night and clopidogrel 75 mg per day for >7 d). The gene polymorphisms of C34T and G52T P2Y12 receptor were detected by using DNA sequencing technique. The relationship of gene polymorphism with the incidence of clopidogrel resistance and clinical outcomes were analyzed.

RESULTSAmong 370 patients, clopidogrel resistance developed in 100 cases, including 36 males (36%) and 64 females (64%). In the C34T locus, 212 cases were of CC genotype and 158 were of CT+TT genotype; the incidence of clopidogrel resistance in CC genotype was significantly lower than that in CT+TT genotype (P<0.05). In the G52T locus, 218 cases were of GG genotype and 152 cases were of GT+TT genotype; the incidence of clopidogrel resistance in GT+TT genotype were significantly higher than that in GG genotype (P<0.05). After 1-year follow-up, patients with CC genotype had lower incidence of angina recurrence than patients with CT+TT genotype did (13.2% vs 19.6%, Χ2=4.956, P<0.05), and patients with GG genotype had lower incidence of emergency revascularization, angina, and cardiovascular composite endpoint events than patients with GT+TT genotype did (Χ2=4.135,6.823,5.916, Ps<0.05).

CONCLUSIONT-34, -52 mutations on P2Y12 receptor gene may be a risk factor for clopidogrel resistance and adverse cardiovascular events.

Adolescent ; Adult ; Aged ; Coronary Artery Disease ; drug therapy ; genetics ; Drug Resistance ; genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Polymorphism, Genetic ; Prognosis ; Receptors, Purinergic P2Y12 ; genetics ; Ticlopidine ; analogs & derivatives ; pharmacology ; Young Adult

We investigated the persistence of viable Orientia tsutsugamushi in patients who had recovered from scrub typhus. Blood specimens were available from six patients with scrub typhus who were at 1 to 18 months after the onset of the illness. The EDTA-treated blood specimens were inoculated into ECV304 cells, and cultures were maintained for 7 months. Sequencing of the 56-kDa type-specific antigen gene of O. tsutsugamushi was performed to ascertain the homology of isolates. O. tsutsugamushi was isolated from all six patients, and nucleotide sequences of isolates serially collected from each patient were identical in all five patients in whom nucleotide sequences were compared. One patient relapsed 2 days after completion of antibiotic therapy; two patients complained of weakness for 1 to 2.5 months after the illness; one patient underwent coronary angioplasty 6 months later; and one patient suffered from a transient ischemic attack 8 months later. This finding suggests that O. tsutsugamushi causes chronic latent infection, which may be associated with certain clinical illnesses, preceded by scrub typhus. Antibiotic therapy abates the symptoms of scrub typhus, but does not eradicate O. tsutsugamushi from the human body.
Adult ; Aged ; Aged, 80 and over ; Antigens, Bacterial/genetics ; Bacterial Proteins/genetics ; Base Sequence ; Case-Control Studies ; Chronic Disease ; Coronary Artery Disease/etiology ; DNA, Bacterial/genetics/isolation & purification ; Female ; Genes, Bacterial ; Humans ; Ischemic Attack, Transient/etiology ; Male ; Membrane Proteins/genetics ; Middle Aged ; Muscle Weakness/etiology ; Orientia tsutsugamushi/genetics/immunology/*isolation & purification ; Recurrence ; Scrub Typhus/complications/drug therapy/*microbiology ; Time Factors

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.
Anticoagulants/therapeutic use ; Antidepressive Agents/therapeutic use ; Antimetabolites, Antineoplastic/therapeutic use ; Antitubercular Agents/therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Coronary Artery Disease/drug therapy/genetics ; Cytochrome P-450 CYP2C19/genetics ; Cytochrome P-450 CYP2C9/genetics ; Cytochrome P-450 CYP2D6/genetics ; Depressive Disorder/drug therapy/genetics ; Genotype ; Isoniazid/therapeutic use ; Laboratories, Hospital/standards ; Methyltransferases/genetics ; Pharmacogenomic Testing/*methods/standards ; Platelet Aggregation Inhibitors/therapeutic use ; Pulmonary Embolism/drug therapy/genetics ; Ticlopidine/analogs & derivatives/therapeutic use ; Tuberculosis/drug therapy/genetics ; Vitamin K Epoxide Reductases/genetics ; Warfarin/therapeutic use

OBJECTIVETo study the relationships of blood stasis syndrome (BSS), CYP2C19 gene polymorphism with clopidogrel resistance (CR) and post-PCI prognosis.

METHODSMaterials of 415 patients (Han nationality) with coronary atherosclerotic heart disease (CAHD) hospitalized between January 2008 and July 2009 were collected. The CYP2C19*2 gene distribution in patients with different degrees of BBS was observed, and the relationships of BSS, CYP2C19*2 with the laboratory CR [LCR, percentage of patients with ADP-induced maximal platelet aggregation (MPA) rate reduced for < or = 10% after a 10-day clopidogrel treatment] were analyzed. Besides, an assay on the relations of maximal platelet aggregation suppressive rate (MPAS), LCR, recurrent cardiovascular events (RCEs) with BSS and CYP2C19*2 gene mutation was performed in a 7-month (in median) follow-up study on 180 post-PCI patients who received conventional treatment by clopidogrel and aspirin.

RESULTS(1) The frequency of 681G>A mutation in patients with severe BSS and in those who received PCI was higher than that in those with mild BSS (P<0.01); (2) After clopidogrel treatment, LCR was 45.06% (187/415) in total patients, 61.63% (143/232) in patients with severe BSS, 53.24% (115/216) in patients carrying 681A allele; (3) The MPA was less decreased and the LCR was higher in patients with severe BSS than in those with mild BSS (P<0.01); (4) After clopidogrel treatment, the MPA was less decreased and the LCR was higher in carrying CYP2C19 681A allele than in those carrying 681 GG type gene (P<0.01); (5) Follow-up study showed that not only the MPA suppressive rate was lower, LCR was higher in patients with severe BSS or those carrying CYP2C19 681A allele, but a higher RCEs was also shown in them (P<0.01). Moreover, after the various risk factors had been adjusted, the RCEs in patients with severe BSS or carrying CYP2C19 681A allele was higher than in those with mild BSS (OR: 4.01; 95% CI: 1.79-8.99) or carrying GG type gene (OR: 6.89; 95% CI: 2.97-15.97).

CONCLUSIONSevere BSS and CYP2C19*2 gene mutation are associated with LCR, and could increase the risk of post-PCI cardiovascular events recurrence in patients with CAHD.

Aged ; Aryl Hydrocarbon Hydroxylases ; genetics ; Coronary Artery Disease ; therapy ; Cytochrome P-450 CYP2C19 ; Diagnosis, Differential ; Drug Resistance ; Female ; Humans ; Male ; Medicine, Chinese Traditional ; Middle Aged ; Percutaneous Coronary Intervention ; Platelet Aggregation Inhibitors ; pharmacology ; therapeutic use ; Polymorphism, Genetic ; Prognosis ; Ticlopidine ; analogs & derivatives ; pharmacology ; therapeutic use

BACKGROUNDAspirin is widely used in the secondary prevention of coronary artery diseases, including myocardial infarction, stroke, and vascular related deaths. However, the antiplatelet effect of aspirin appears to be variable and aspirin resistance (AR) is currently still controversial for Chinese patients. The aim of this study was to describe the prevalence of AR, and identify possible risk factors associated with a lack of response to aspirin treatments in patients with unstable coronary artery disease.

METHODSPlatelet function tests with arachidonic acid (ARA) and urinary 11-dehydro-thromboxane B2 (11-DH-TXB2) concentrations were performed in 262 patients with unstable coronary artery disease who had not been taking aspirin before admission. ARA induced platelet aggregation and 11-DH-TXB2 were detected to evaluate the functional and biochemical responses to aspirin before and on days 1, 4, and 10 after aspirin administration. Six-month follow-up was completed in patients who developed AR to evaluate the effect of aspirin in a long-term treatment. GP1Bα (C1018T), Pl (A1/A2), P2Y1 (A1622G), TBXA2R (T924C) were also detected to evaluate the influence of genetic variant on aspirin responsiveness.

RESULTSA total of 8.8% of patients were indentified as AR at the first day after aspirin treatment. The level of urine 11-DH-TXB2 in the AR group was higher compared to non-AR group (P < 0.05). There was no relationship between ARA induced platelet aggregation and urinary 11-DH-TXB2 levels (r = 0.038, P = 0.412). The results of DNA sequencing showed that TBXA2R-924TT homozygotes had a significantly high rate of AR. Logistic regression demonstrated that diabetes was an independent risk factor of AR.

CONCLUSIONSIn the beginning period of administration, aspirin was not a sufficient factor that inhibits platelet aggregation. TBXA2R-924T allele was involved in AR. Diabetes was an independent risk factor of AR.

Aged ; Aged, 80 and over ; Arachidonic Acid ; pharmacology ; Aspirin ; therapeutic use ; Coronary Artery Disease ; drug therapy ; genetics ; Diabetes Mellitus, Type 2 ; Female ; Genotype ; Humans ; Male ; Membrane Glycoproteins ; genetics ; Middle Aged ; Platelet Aggregation ; drug effects ; Platelet Aggregation Inhibitors ; therapeutic use ; Platelet Function Tests ; Platelet Glycoprotein GPIb-IX Complex ; Polymerase Chain Reaction ; Polymorphism, Genetic ; genetics ; Receptors, Purinergic P2Y1 ; genetics ; Receptors, Thromboxane A2, Prostaglandin H2 ; genetics ; Thromboxane B2 ; analogs & derivatives ; urine