Objective: To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS) patients undergoing percutaneous coronary intervention(PCI). Methods: This study was a retrospective cohort study. ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited. The inhibition rate of adenosine diphosphate(ADP) was monitored by thromboelastography. All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results. CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR. Patients were divided into slow, medium and fast metabolic group, according to the CYP2C19 genotype. After 12 months of follow-up, the end points included all-cause death, cardiac death, angina, myocardial infarction, stent thrombosis, ischemic stroke and hemorrhage were collected. Combined thrombotic events were defined as a composite of angina, myocardial infarction, stent thrombosis and ischemic stroke. The differences of the incidence of clinical events between groups were compared. Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events, cardiac death and hemorrhage. Results: A total of 1 696 patients were included, and the age was (59.4±9.6) years, with 1 280(75.5%) males. There were 471 cases(27.8%) in clopidogrel resistance group, and 1 225 cases(72.2%) in clopidogrel non-resistance group. There were 218 patients(12.9%) were in slow metabolic group, 668(39.4%) in medium metabolic group, and 810 (47.8%) in fast metabolic group. The median follow-up time was 13.3 months, and 131 cases were lost to follow-up, with a loss follow-up rate of 7.7%. Compared with the clopidogrel non-resistance group, the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471) vs. 5.1%(62/1 225), P=0.041), a lower incidence of hemorrhage (13.2%(62/471) vs. 17.9%(219/1 225), P=0.020) and minor hemorrhage(11.5%(54/471) vs. 15.8% (194/1 225), P=0.022). There were no statistically significant difference in all-cause death, cardiac death, angina, stent thrombosis, ischemic stroke and severe bleeding between clopidogrel resistance and non-resistance group(all P>0.05). There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes (all P>0.05). Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events (OR=2.334, 95%CI 1.215-4.443, P=0.016) and bleeding events (OR=0.481, 95%CI 0.174-0.901, P=0.023). While CYP2C19 genotype was not independent factor for combined thrombotic events, cardiac death and hemorrhage (all P>0.05). Conclusion: For ACS patients after PCI, clopidogrel resistance can increase the risk of combined thrombotic events, but also reduce the risk of bleeding; while CYP2C19 genotype is not an independent factor for clinical prognosis.
Acute Coronary Syndrome/genetics* ; Clopidogrel/therapeutic use* ; Cytochrome P-450 CYP2C19/genetics* ; Genotype ; Humans ; Male ; Percutaneous Coronary Intervention ; Platelet Aggregation Inhibitors/therapeutic use* ; Prognosis ; Retrospective Studies ; Treatment Outcome

OBJECTIVETo investigate the relationship between plasma cytochrome P450 3A4 (CYP3A4) 894C>T gene polymorphism and the risk of recurrence of adverse cardiac events after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS).

METHODSA total of 275 patients with ACS received standard dual antiplatelet therapy and PCI. Platelet aggregation rate (PAR) was detected in each patient before and 7 days after administration of the anti-platelet drugs. Single nucleotide polymorphism of CYP3A4 gene 894C>T was detected with PCR and microarray technique. The number of coronary artery lesions was determined by PCI and the Gensini score was calculated. The patients were followed up for 3-12 months after discharge.

RESULTSNo significant difference was found in CYP3A4 gene polymorphism between patients with clopidogrel resistance (CR group) and those without CR (NCR group) (P>0.05). Multivariate logistic regression analysis showed that CYP3A4 gene 894C>T polymorphism was not correlated with CR in patients with ACS (OR 1.359, P>0.05). During the follow-up, the incidence of cardiovascular events was significantly higher in CR group than in NCR group (P<0.05), but this difference was not related to the mutation type of 894C>T locus of CYP3A4 gene.

CONCLUSIONThe CYP3A4 gene 894C>T polymorphism is not associated with the effect of anti-platelet therapy and the risk of cardiovascular event in patients with ACS following PCI.

Acute Coronary Syndrome ; therapy ; Alleles ; Blood Platelets ; Cytochrome P-450 CYP3A ; genetics ; Humans ; Percutaneous Coronary Intervention ; Platelet Aggregation ; Platelet Aggregation Inhibitors ; therapeutic use ; Platelet Function Tests ; Polymorphism, Single Nucleotide ; Ticlopidine ; analogs & derivatives ; therapeutic use

BACKGROUNDTo investigate the contributions of CYP2C19 polymorphisms to the various clopidogrel responses tested by thrombelastography (TEG) in Chinese patients with the acute coronary syndrome (ACS).

METHODSPatients were screened prospectively with ACS diagnose and were treated with clopidogrel and aspirin dual antiplatelet therapy. CYP2C19 loss of function (LOF) and gain of function (GOF) genotype, adenosine 5'-diphosphate (ADP)-channel platelet inhibition rate (PIR) tested by TEG and the occurrence of 3-month major adverse cardiovascular events and ischemic events were assessed in 116 patients.

RESULTSHigh on-treatment platelet reactivity (HTPR) prevalence defined by PIR <30% by TEG in ADP-channel was 32.76% (38/116). With respect to the normal wild type, CYP2C19*2, and *3 LOF alleles, and *17 GOF alleles, patients were classified into three metabolism phenotypes: 41.38% were extensive metabolizers (EMs), 56.90% were intermediate metabolizers (IMs), and 1.72% were poor metabolizers (PMs). Of the enrolled patients, 31.47%, 5.17%, and 0.43%, respectively, were carriers of *2, *3, and *17 alleles. The HTPR incidence differed significantly according to CYP2C19 genotypes, accounting for 18.75%, 41.54%, and 100.00% in EMs, IMs, and PMs, respectively. Eighteen (17.24%) ischemic events occurred during the 3-month follow-up, and there was a significant difference in ischemic events between HTPR group and nonhigh on-treatment platelet reactivity group.

CONCLUSIONSGenetic CYP2C19 polymorphisms are relative to the inferior, the antiplatelet activity after clopidogrel admission and may increase the incidence of ischemic events in patients with ACS.

Acute Coronary Syndrome ; genetics ; physiopathology ; Aged ; Alleles ; Asian Continental Ancestry Group ; Blood Platelets ; drug effects ; Cytochrome P-450 CYP2C19 ; genetics ; Female ; Genetic Variation ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors ; pharmacology ; Polymorphism, Genetic ; Prospective Studies ; Thrombelastography ; Ticlopidine ; analogs & derivatives ; pharmacology

Depression is prevalent in patients with physical disorders, particularly in those with severe disorders such as cancer, stroke, and acute coronary syndrome. Depression has an adverse impact on the courses of these diseases that includes poor quality of life, more functional impairments, and a higher mortality rate. Patients with physical disorders are at higher risk of depression. This is particularly true for patients with genetic and epigenetic predictors, environmental vulnerabilities such as past depression, higher disability, and stressful life events. Such patients should be monitored closely. To appropriately manage depression in these patients, comprehensive and integrative care that includes antidepressant treatment (with considerations for adverse effects and drug interactions), treatment of the physical disorder, and collaborative care that consists of disease education, cognitive reframing, and modification of coping style should be provided. The objective of the present review was to present and summarize the prevalence, risk factors, clinical correlates, current pathophysiological aspects including genetics, and treatments for depression comorbid with physical disorders. In particular, we tried to focus on severe physical disorders with high mortality rates, such as cancer, stroke, and acute coronary syndrome, which are highly comorbid with depression. This review will enhance our current understanding of the association between depression and serious medical conditions, which will allow clinicians to develop more advanced and personalized treatment options for these patients in routine clinical practice.
Acute Coronary Syndrome ; Comorbidity ; Depression ; Education ; Epigenomics ; Genetics ; Humans ; Mortality ; Prevalence ; Prognosis ; Quality of Life ; Risk Factors ; Stroke

OBJECTIVETo investigate the association between CD147 expression and its untranslated regions 3'UTR rs8259 T/A polymorphism and acute coronary syndrome (ACS).

METHODSThe genotypes of CD147 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods in 182 ACS patients and 328 healthy controls. The plasma level of CD147 was determined by enzyme-linked immunosorbent assay (ELISA). CD147 mRNA and protein expression was detected by real-time fluorescent quantitative PCR (RT-qPCR) and Western blot.

RESULTSThe plasma CD147 level obtained from radial artery in ACS patients ((3.63 ± 0.70) pg/L) was significantly higher than in control ((2.45 ± 0.27) pg/L, P < 0.05), and highest in plasma obtained from the coronary artery ((4.28 ± 1.03) pg/L, P < 0.05) in ACS patients. Furthermore, the plasma CD147 level was higher in the ACS patients with rs8259 AA genotype than in the ACS patients with rs8259 TT genotype ((4.08 ± 0.41) pg/L vs. (3.05 ± 0.79) pg/L in radial artery and (5.29 ± 0.62) pg/L vs. (3.13 ± 0.52) pg/L in coronary artery, both P < 0.05). There are an enhanced expression of CD147 mRNA (2.45 times higher than control) and protein (3.66 ± 1.56 vs. 1.81 ± 1.29) in PBMCs from ACS patients than that from controls (both P < 0.05). The PBMCs CD147 mRNA and protein expression level were significantly higher in ACS patients with rs8259 AA genotype (mRNA:2.45 ± 0.35, protein:1.63 ± 0.16) compared to ACS patients with rs8259 TT genotype (mRNA:1.69 ± 0.15, protein: 0.88 ± 0.16, both P < 0.05). Multiple logistic analysis showed that CD147 T allele (AT+TT) was a protective factor to ACS (OR = 0.667, 95% CI 0.507-0.879, P < 0.05).

CONCLUSIONSThe over-expression of CD147 is involved in the pathogenesis of ACS. The CD147 3'UTR rs8259 T allele may be a protective factor for ACS, its polymorphism can affect the CD147 protein expression in ACS patients.

Acute Coronary Syndrome ; genetics ; Alleles ; Basigin ; biosynthesis ; genetics ; Case-Control Studies ; Genotype ; Humans ; Leukocytes, Mononuclear ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length

OBJECTIVETo investigate the expression of myeloid-related protein complex (MRP-8/14) in children with acute Kawasaki Disease (KD).

METHODSA total of 41 children with acute KD and 40 age- and sex-matched control children with upper respiratory tract infection were recruited. Serum levels of MRP-8/MRP-14 complex were measured by ELISA, messenger ribonucleic acid (mRNA) abundance of MRP-8 and MRP-14 in circulating granulocytes and monocytes was determined by RT-PCR, and the number of circulating endothelial cells was determined by flow cytometry.

RESULTSWhen the analysis was stratified according to the presence or absence of coronary artery ectasia in the KD patient group, serum levels of MRP-8/MRP-14 complex, MRP-8 and MRP-14 mRNA abundance in granulocytes, and the number of circulating endothelial cells were all significantly higher in KD patients with coronary artery ectasia than in KD patients without coronary artery ectasia (P<0.05). Serum levels of MRP-8/MRP-14 complex were positively correlated with the number of endothelial cells in the circulation (r=0.69, P<0.05).

CONCLUSIONSSerum levels of MRP-8/MRP-14 complex are elevated in a positive association with the number of circulating endothelial cells in KD children with coronary artery ectasia, suggesting a causative role in the development of coronary artery lesions.

Acute Disease ; Calgranulin A ; blood ; genetics ; physiology ; Calgranulin B ; blood ; genetics ; physiology ; Child, Preschool ; Coronary Artery Disease ; etiology ; Endothelial Cells ; pathology ; Female ; Humans ; Infant ; Male ; Mucocutaneous Lymph Node Syndrome ; blood ; complications ; pathology ; RNA, Messenger ; analysis

BACKGROUNDThe CYP2C19 G681A single polymorphism has been proven to affect clopidogrel responsiveness. However, the effect of coexisting polymorphisms of other genes has not yet been reported in the Chinese population. This study investigated the effect of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and adverse clinical events in Chinese patients.

METHODSIn 577 Han Chinese patients undergoing stent placement because of acute coronary syndrome had platelet reactivity assessed by thromboelastography, and the CYP2C19 G681A and P2Y12 C34T polymorphisms were detected by the ligase detection reaction. Primary clinical endpoints included cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis. The secondary clinical endpoints were thrombolysis in myocardial infarction bleeding. The follow-up period was 12 months.

RESULTSGenotyping revealed 194 carriers of the wild type GG genotype of CYP2C19 and the wild type CC genotype of P2Y12 (group 1), 102 carriers of the wild type GG genotype of CYP2C19 and the mutational T allele of P2Y12 (group 2), 163 carriers of the mutational A allele of CYP2C19 and the wild type CC genotype of P2Y12 (group 3), and 118 carriers of the mutational A allele of CYP2C19 and the mutational T allele of P2Y12 (group 4). Group 4 had the lowest ADP-inhibition (49.74 ± 32.61) and the highest prevalence of clopidogrel low response (29.7%) of the four groups. The rate of the composite of primary clinical endpoints increased more in group 4 (8.5%) than in the other three groups; the rate of composite primary endpoints in group 2 (2.9%) and group 3 (3.7%) were not significantly different than that of group 1 (1.5%).

CONCLUSIONCoexisting polymorphisms of different genes affected clopidogrel responsiveness and clinical outcome more than single polymorphism in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Acute Coronary Syndrome ; drug therapy ; genetics ; Aged ; Alleles ; Aryl Hydrocarbon Hydroxylases ; genetics ; Cytochrome P-450 CYP2C19 ; Genotype ; Humans ; Middle Aged ; Mutation ; Polymorphism, Genetic ; genetics ; Receptors, Purinergic P2Y12 ; genetics ; Ticlopidine ; analogs & derivatives ; therapeutic use

OBJECTIVETo assess the association between single nucleotide polymorphism rs501120 and progress of unstable coronary atherosclerotic plaque in diabetes mellitus complicated with acute coronary syndrome (ACS).

METHODSNine hundred and two patients with diabetes complicated with acute coronary syndrome were enrolled. The genotype of rs501120 was determined with TaqMan-MGB probes. Two hundred and five cases of TT genotype, 205 age-and sex-frequency-matched cases of TC genotype and 205 age- and sex-frequency-matched cases of CC genotype were chosen and followed up for 3 years. Clinical data and re-occurrences of ACS were recorded.

RESULTSPatients with TT genotype had a significantly higher incidence of recurrence of ACS than those with CC genotype (TT vs. CC: OR 1.7, 95%CI 1.1-2.7, P= 0.02). And the significance has remained even after adjusting for conventional risk factors by logistic regression (OR 1.6, 95% CI1.05-3.6, P= 0.03). Patients with TT genotype had a significantly higher incidence of myocardial infarction than those with CC genotype(TT vs. CC: OR 1.9, 95% CI 1.2-3.2, P= 0.007).

CONCLUSIONOur results has suggested an association between the rs501120 polymorphism and progress of unstable coronary atherosclerotic plaque.

Acute Coronary Syndrome ; genetics ; Aged ; Coronary Artery Disease ; genetics ; Diabetes Complications ; genetics ; Disease Progression ; Female ; Genotype ; Humans ; Logistic Models ; Male ; Middle Aged ; Plaque, Atherosclerotic ; genetics

BACKGROUND: Clopidogrel has been widely used to prevent recurrent ischemia in patients with acute coronary syndrome (ACS). However, inter-individual variability in response to clopidogrel has been a problem in the clinical setting. The aim of the present study was to investigate the frequency of clopidogrel resistance and to determine the clinical, pharmacokinetic, and pharmacogenetic factors for clopidogrel resistance in Korean patients with ACS. METHODS: Clinical information, such as the underlying diseases and concurrent medications, of 114 patients with ACS who received clopidogrel therapy was studied. The degree of inhibition of platelets was assessed using the VerifyNow assay (Accumetrics, USA). The patients who showed less than 20% inhibition of platelets were defined as non-responders to clopidogrel treatment. Steady state plasma concentrations of clopidogrel were measured using HPLC/tandem mass spectrometry. CYP2C19 genotyping was also performed. RESULTS: A wide inter-individual variability was observed in platelet inhibition (0-76%); 56 patients (49%) showed less than 20% inhibition. There were no differences between the patients' history of diabetes mellitus and concurrent medications as well as the plasma concentrations of clopidogrel of the responders and non-responders. CYP2C19 variants, including CYP2C19*2 and CYP2C19*3, were more commonly observed in the non-responders than in the responders (P value<0.0001). CONCLUSIONS: The response to clopidogrel was highly variable in Korean patients with ACS. The results of the present study confirmed that the genetic polymorphism of CYP2C19 could be important in clopidogrel response. However, further studies are required to investigate other likely factors involved in clopidogrel resistance.
Acute Coronary Syndrome/complications/*drug therapy/genetics ; Adult ; Aged ; Aged, 80 and over ; Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors/genetics/metabolism ; Asian Continental Ancestry Group/*genetics ; Diabetes Complications ; Drug Resistance ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors/blood/pharmacokinetics/*therapeutic use ; Polymorphism, Genetic ; Republic of Korea ; Ticlopidine/*analogs & derivatives/blood/pharmacokinetics/therapeutic use

OBJECTIVETo assess the value of serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) levels and LOX-1 mRNA expression in peripheral blood mononuclear cells in early diagnosis of acute coronary syndrome (ACS).

METHODSEnzyme-linked immunosorbent assay was used to detect the levels of plasma ox-LDL and LOX-1 in 95 patients with ACS, 60 with stable angina pectoris (SAP) and 40 normal control subjects. The expression of LOX-1 mRNA in peripheral blood mononuclear cells was detected by RT-PCR in the 3 groups.

RESULTSThe levels of ox-LDL, LOX-1 and LOX-1 mRNA in the peripheral blood mononuclear cells were significantly higher in ACS patients than in SAP patients and normal control subjects (P<0.05). In ACS group, the level of plasma ox-LDL was significantly correlated to serum LOX-1 and LOX-1 mRNA expression in peripheral mononuclear cells.

CONCLUSIONThe level of plasma soluble LOX-1 and LOX-1 mRNA in peripheral mononuclear cells are significantly increased in ACS, and when combined, they provide a useful means for detecting ACS in the prophase.

Acute Coronary Syndrome ; blood ; diagnosis ; Aged ; Early Diagnosis ; Female ; Humans ; Leukocytes, Mononuclear ; metabolism ; Male ; Middle Aged ; RNA, Messenger ; genetics ; Scavenger Receptors, Class E ; blood