Association between adiponectin gene polymorphisms and coronary artery disease across different populations

Objective

Many studies have suggested that adiponectin gene might be involved in the development of coronary artery disease (CAD). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to assess the associations of + 45T/G, + 276G/T and − 11377C/G polymorphisms in adiponectin gene with CAD susceptibility.

Methods

Published literature from PubMed and EMBASE databases were searched. Pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated using fixed- or random-effects model.

Results

Sixteen studies (4394 cases / 8187 controls) for + 45T/G polymorphism, fifteen studies (3569 cases / 7463 controls) for + 276G/T polymorphism, and thirteen studies (3531 cases / 7072 controls) for − 11377C/G polymorphism were included in the meta-analysis. The overall results showed that there was a statistically significant association between − 11377C/G polymorphism and CAD (G vs. C: OR = 1.15, 95%CI 1.07-1.24).Similar results were observed among European (G vs. C: OR = 1.11, 95%CI 1.02-1.20) and East Asian populations (G vs. C: OR = 1.27, 95%CI 1.11-1.45). However, no significant association was found for + 45T/G or + 276G/T polymorphism with CAD susceptibility.

Conclusions

The meta-analysis indicated the significant association of − 11377C/G polymorphism, but not + 45T/G or + 276G/T polymorphism, with CAD susceptibility. However, large-scale studies with the consideration of gene-gene and gene-environment interactions should be conducted to investigate the associations in future.     

A case-control study provides evidence of association for a common SNP rs974819 in PDGFD to coronary heart disease and suggests a sex-dependent effect

Introduction

Peden et al. have revealed a significant association between four new risk loci and coronary heart disease (CHD) in Europeans and South Asians. The goal of this study is to evaluate the contribution of these genetic loci to CHD risk in Han Chinese.

Methods

We recruited 161 CHD patients and 112 controls proved by angiography originated from Ningbo in the Eastern China, and performed a case-control association study of the four significant SNPs.

Results

Among the four tested SNPs, we found a significant association of rs974819 in PDGFD gene with CHD (allele p = 0.04; OR = 1.45, 95% CI = 1.02 - 2.08) and the allele A/G of rs974819 shows significant difference in females (allele p = 0.04; OR = 1.83, 95% CI = 1.01 - 3.31). A further meta-analysis showed that rs974819 of PDGFD gene was significantly associated with an increasing risk of CHD (OR = 1.08, 95% CI = 1.05 - 1.11) in both Europeans and South Asians including Han Chinese.

Conclusions

Our findings suggests that rs974819 of PDGFD is also a CHD risk factor in Han Chinese. In addition, it presents a sex-dependent genetic effect.     

The G894T polymorphism on endothelial nitric oxide synthase gene is associated with increased coronary heart disease among Asia population: evidence from a Meta analysis

Introduction

Growing studies have revealed the underlying association between eNOS 894 G/T (rs1799983) polymorphism and coronary heart disease (CHD) among Asia population. Results from these studies remained conflicting. We conducted this meta-analysis to estimate the overall CHD risk of eNOS 894 G/T polymorphism regarding Asia population.

Materials and methods

Up to October 2011, databases including PubMed, Embase and CNKI (China National Knowledge Infrastructure) were searched to access the relevant genetic association studies. Summary odds ratios and corresponding 95% confidence intervals (CIs) for eNOS 894 G/T polymorphism and CHD risk were estimated using fixed or random-effects models when appropriate.

Results

18 case-control studies with 2,994 cases and 3,130 controls were available for this study, including 13 studies of East-Asia descendents, 5 studies of Non East-Asian descendents. The mean T allele frequency was 0.111 in the East-Asia population and 0.147 in the Non East-Asia population, respectively. The summary OR for CHD associated with the T allele was 1.52 (95% confidence intervals (95%CI), 1.37-1.69) by random effects model. Similarly, significantly increased risks were observed in the East-Asia population (OR = 1.54; 95%CI = 1.35-1.76) and in the Non East-Asia population (OR = 1.48; 95%CI = 1.24-1.77), respectively.

Conclusions

This meta-analysis indicated that eNOS 894 G/T polymorphism may play an important role in CHD development among Asia population.     

Tumor necrosis factor-alpha G-308A gene polymorphism and coronary heart disease susceptibility: an updated meta-analysis

Purpose

Several studies have reported apparently conflicting findings for the effects of tumor necrosis factor-alpha (TNF-α) G-308A polymorphism on coronary heart disease (CHD) susceptibility. We undertook a systematic review and meta-analysis to investigate the association between this gene variant and CHD predisposition.

Methods

We systematically searched electronic databases (Medline, EMbase, Chinese BioMedical, BIOSIS, Global Health, PsycINFO, Allied and Complementary Medicine Database, Cochrane Library, HuGE Navigator, and British Nursing) for relevant studies published between 1947 and October, 2010. Summarized estimation of odds ratio (OR) and 95% confidence interval (CI) were calculated. Publication bias and heterogeneity among studies were explored.

Results

We identified 24 studies providing data for 9 921 cases and 7 944 controls. Pooled analysis based on ORs adjusted by CHD risk factors showed that carrying the TNF-α gene A variant conferred a 1.5-fold increased risk of developing CHD (AG + AA vs. GG, OR = 1.50, 95% CI: 1.23-1.77) in Caucasian population. No significant association between the gene polymorphism and CHD risk could be found in other ethnic groups.

Conclusions

It is probable that carrying the A variant is associated with CHD risk in Caucasians but not in Asians, Indians, or Africans. Further studies are merited to assess the association in greater details, especially in Asians, Indians and Africans.     

Interaction between homocysteine and lipoprotein(a) increases the prevalence of coronary artery disease/myocardial infarction in women: a case-control study

Introduction

Our aim was to investigate the association of elevated homocysteine (Hcy) and lipoprotein(a) Lp(a) with the prevalence of coronary artery disease (CAD) and myocardial infarction (MI) and to investigate their interaction in both genders.

Materials and methods

955 (male/female: 578/377) consecutive patients admitted for coronary angiography were enrolled in the study. Lp(a), Hcy, vitamin B12, folic acid, MTHFR C677T polymorphism and traditional risk factors were determined.

Results

619 patients had significant (≥ 50%) stenosis (CAD+) and 341 had MI (MI+). CAD-MI- cases (n = 302) were considered as controls. Adjusted Hcy levels were significantly elevated only in the female CAD + MI + group that was related to decreased vitamin B12 levels. Lp(a) was elevated in the CAD + MI + group of both genders. Folic acid levels and MTHFR T677 allele frequency did not show significant difference. Moderate hyperhomocysteinemia (Hcy > 15 μmol/L) or elevated Lp(a) (> 300 mg/L) increased the risk of CAD (OR 2.27, CI 1.36-3.80 and OR 1.64, CI 1.03-2.61, respectively) and MI (OR 2.52, CI 1.36-4.67 and OR 1.89, CI 1.06-3.38, respectively) only in women. Only simultaneous but not isolated elevation of Hcy and Lp(a) conferred a significant, 3.6-fold risk of CAD in females and even higher (11-fold) risk in young females, which suggested an interactive effect.

Conclusions

Moderate hyperhomocysteinemia or elevated Lp(a) level associated with a risk of CAD and MI only in women. While isolated elevation of one of the two parameters represented a mild risk of CAD, their combined elevation highly increased the risk in females. No such effect was observed in males.     

Thrombogenic potential of whole blood is higher in patients with acute coronary syndrome than in patients with stable coronary diseases

Introduction

Although thrombogenic potential of blood may play an important role for the onset of acute coronary syndrome (ACS), there is no established way to evaluate it by single parameter. We compared the thrombogenic potential of whole blood between patients with ACS and those with stable coronary diseases using single comprehensive parameter.

Materials and Methods

Consecutive patients with ACS (n = 146) and those with stable coronary heart diseases (control, n = 92) were prospectively examined. Thrombogenic potential of whole blood was evaluated by blood vulnerability index measured by Micro-Channel Array Flow Analyzer (MC-FAN).

Results

Blood vulnerability index was higher in ACS than in control patients (5099 ± 2278 vs. 2071 ± 389, p < 0.0001), higher in acute MI than in unstable angina patients (5693 ± 2146 vs. 3524 ± 1841, p < 0.0001), and higher in ACS patients with initial TIMI 0/1 flow grade than in those with TIMI 2/3 flow grade (6061 ± 1936 vs. 2560 ± 1301, p < 0.0001). Furthermore, blood vulnerability index decreased from acute to chronic stage in acute MI patients. Multivariate logistic regression analysis revealed that high blood vulnerability index, high LDL cholesterol, high CRP, no use of aspirin, and no use of β-blocker were the independent contributors for the onset of ACS.

Conclusion

High thrombogenic potential of whole blood evaluated by blood vulnerability index was significantly associated with ACS and was reduced from acute to chronic stage in acute MI.

Condensed Abstract

Thrombogenic potential of whole blood was evaluated by blood vulnerability index measured comprehensively by Micro-Channel Array Flow Analyzer (MC-FAN) in consecutive patients with ACS (n = 146) or stable coronary diseases (control, n = 92) prospectively. Blood vulnerability index was significantly higher in ACS patients, especially in acute MI and poor initial TIMI flow grade patients, compared with control patients; and blood vulnerability index was reduced from acute to chronic stage in acute MI patients.     

Reduced platelet response to aspirin in patients with coronary artery disease and type 2 diabetes mellitus

Introduction

Diabetes mellitus is complicated by accelerated atherosclerosis, resulting in an increased risk of coronary artery disease (CAD) and thrombosis. Despite the proven benefits of aspirin, previous studies indicate a reduced cardiovascular protection from aspirin in diabetic patients. We aimed to investigate whether diabetes mellitus influenced the platelet response to aspirin in patients with CAD.

Materials and Methods

Platelet aggregation and activation were evaluated during aspirin treatment in 85 diabetic and 92 non-diabetic patients with CAD. Adherence to aspirin was carefully controlled. All patients had CAD verified by coronary angiography and were taking 75 mg non-enteric coated aspirin daily.

Results

Diabetic patients showed significantly higher levels of platelet aggregation compared to non-diabetic patients evaluated by VerifyNow^® Aspirin (p = 0.03) and Multiplate^® aggregometry using arachidonic acid (AA) 0.5 mM (p = 0.005) and 1.0 mM (p = 0.009). In addition, platelet activation determined by soluble P-selectin was significantly higher in diabetics compared to non-diabetics (p = 0.005). The higher AA-induced aggregation was associated with higher levels of HbA_1c. Compliance was confirmed by low levels of serum thromboxane B₂ (below 7.2 ng/mL). Diabetics had significantly higher levels of serum thromboxane B₂ (p < 0.0001).

Conclusions

Diabetic patients with CAD had significantly higher levels of both platelet aggregation and activation compared to non-diabetic patients with CAD despite treatment with the same dosage of aspirin. These findings may partly explain the reduced cardiovascular protection from aspirin in diabetic patients.     

The influence of timing of polysomnography on diagnosis of obstructive sleep apnea in patients presenting with acute myocardial infarction and stable coronary artery disease

Background

We aimed to determine if timing of polysomnography (PSG) influences the diagnosis of obstructive sleep apnea (OSA) in acute myocardial infarction (AMI) or stable coronary artery disease (CAD).

Methods

A total of 160 patients admitted with AMI or stable CAD were consecutively recruited for either in-hospital (n = 80) or postdischarge (n = 80) PSG.

Results

The median time from admission to PSG for the in-hospital and postdischarge groups was 1 day and 17 days, respectively (P < .001). Overall, 59 patients (36.9%) were diagnosed with OSA (apnea–hypopnea index [AHI] ?15), and they were more likely to have diabetes mellitus (DM), hypertension, hyperlipidemia, chronic renal failure, and a greater body mass index (BMI) (P < .05 for all). The diagnosis of OSA was significantly higher (P = .037) in patients who had a PSG performed as an inpatient than those who had a PSG as an outpatient. There was a significant interaction between clinical presentation and the effect of PSG timing on the diagnosis of OSA (P = .003). For the patients presenting with AMI but not those with stable CAD, in-hospital PSG was an independent predictor of OSA (adjusted odds ratio, 3.84 [95% confidence interval, 1.42–10.41]; P = .008).

Conclusion

The timing of PSG influenced the diagnosis of OSA in patients who presented with AMI but not in those who presented with stable CAD.     

G-455A polymorphism of β-fibrinogen gene and the risk of premature myocardial infarction in Greece

Introduction

There are limited and controversial data regarding the impact of G-455A polymorphism of β-fibrinogen gene in the pathogenesis of premature myocardial infarction (MI). We examined whether the G-455A polymorphism of β-fibrinogen gene is associated with the development of MI ≤ 35 years of age.

Methods

We recruited 181 consecutive patients who had survived their first acute MI ≤ 35 years of age (mean age = 32.2 ± 3.4 years). The control group consisted of 129 healthy individuals matched with cases for age and sex, without a family history of premature coronary heart disease. G-455A polymorphism of β-fibrinogen was tested with polymerase chain reaction and reverse hybridization.

Results

There was a higher prevalence of carriers of the A allele (GA+AA genotype) in controls than in patients (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.36 to 0.91, p = 0.02). G-455A polymorphism of β-fibrinogen gene was associated with lower risk for acute MI (OR 0.46, 95% CI 0.25 to 0.83, p = 0.01) after adjusting for major cardiovascular risk factors. Fibrinogen levels were higher in patients compared to controls [332 (292-385) vs. 311 (262-373) mg/dL, p = 0.01], but the adjusted for classical risk factors fibrinogen levels did not differ (OR 1.003, 95% CI 0.99 to 1.01, p = 0.37). Patients possessing the A allele did not differ in their fibrinogen and lipid levels compared to patients with the -455GG genotype.

Conclusions

Our data indicate that the presence of the G-455A polymorphism of β-fibrinogen gene has a “protective effect” against the development of non-fatal acute MI ≤ 35 years of age in Greece.     

ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a meta-analysis

Introduction

The ABCB1 C3435T polymorphism limits oral bioavailability of clopidogrel and may influence prognosis of patients treated with clopidogrel. Several studies have examined the association between the C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients, but the results were inconsistent. To assess the role of the C3435T polymorphism in the impact on clinical outcomes, a meta-analysis was conducted.

Methods

6 studies with 10,153 subjects were included in this meta-analysis. Fixed- or random-effects model was chosen according to heterogeneity. Publication bias was evaluated by fail-safe numbers.

Results

The association of the C3435T polymorphism with risk of overall recurrent ischemic events in clopidogrel treated patients was not statistically significant for all genetic models (OR = 1.13, 95%CI: 0.78-1.64, P = 0.51; OR = 1.15, 95%CI: 0.99-1.33, P = 0.07; OR = 1.19, 95%CI: 0.81-1.76, P = 0.37). Significant association was identified between the C3435T polymorphism and risk of short-term recurrent ischemic events (OR = 1.55, 95% CI: 1.09-2.20, P = 0.01; OR = 1.41, 95% CI: 1.06-1.87, P = 0.02; OR = 1.77, 95% CI: 1.19-2.63, P = 0.005). No statistically significant association between the C3435T polymorphism and stent thrombosis (OR = 0.79, 95% CI: 0.47-1.32, P = 0.37) or bleeding (OR = 0.98, 95% CI: 0.79-1.21, P = 0.82) was identified. The results may be affected by publication bias.

Conclusions

This meta-analysis failed to show an association between the ABCB1 C3435T polymorphism and risk of overall recurrent ischemic events, stent thrombosis or bleeding in clopidogrel treated patients. However, the association between TT homozygotes of the C3435T polymorphism and risk of short-term recurrent ischemic events may exist, but needs more studies to confirm.     

Eosinophil count predicts mortality following percutaneous coronary intervention

Introduction

Several inflammatory markers have been shown to be independent predictors for both the development of clinically significant atherosclerosis and for adverse outcome in patients with symptomatic coronary artery disease (CAD). We investigated the prognostic role of eosinophil count in low to intermediate risk patients with CAD.

Methods

We studied 909 patients admitted for elective or urgent percutaneous coronary intervention (PCI) from April 2002 to December 2004, and measured pre-procedural total and differential white blood cell (WBC) counts. Inter-tertile WBC differences in short (6 months) and long term (up to 74 months) mortality were analysed after adjusting for differences in baseline characteristics.

Results

Over a median period of 54 months (inter-quartile range 47-65), a total of 138 deaths (15.2%) occurred, of which 24 were in the first 6 months of follow-up. Cox regression analysis showed that high pre-procedural eosinophil count (top tertile) was associated with improved outcome within the first 6 months (OR = 0.23 [0.06-0.84]; p = 0.03) but after this period there was an increased risk of mortality (OR = 2.21, [1.26-3.88]; p = 0.006).

Conclusions

Eosinophil count is a novel biomarker for risk stratification of CAD patients, which was associated initially with reduced mortality, but after 6 months with increased mortality.     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: A meta-analysis

Introduction

The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies.

Materials and Methods

A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6^th 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0.

Results

A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR = 1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR = 1.60, 95%CI: 1.24-2.06, P = 0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR = 2.08, 95%CI: 1.29-3.35, P = 0.003) and Caucasians (dominant model: OR = 1.31, 95%CI: 1.10-1.56, P = 0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR = 1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery.

Conclusion

Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders.     

Baseline platelet size is increased in patients with acute coronary syndromes developing early stent thrombosis and predicts future residual platelet reactivity. A case-control study

Introduction

Pre-procedural predictors of early stent thrombosis (ST) and future response to platelet inhibitors are in demand. We sought to evaluate the impact of baseline platelet indices on the occurrence of early ST and future residual platelet reactivity.

Materials and methods

Hundred and eight patients with acute coronary syndromes (ACS) in whom stents were implanted were included: 36 consecutive ST cases and 72 matched controls. Platelet indices assessed with flow cytometry before stent implantation were retrieved from the department's data base. Residual platelet reactivity specific to aspirin (aspirin reaction units-ARU) and clopidogrel (P2Y12 reaction units-PRU) was assessed prospectively with VerifyNow^® under dual antiplatelet treatment.

Results

Platelet size reported as mean platelet volume (MPV) or proportion of large platelets (LPLT) was significantly higher in ST cases compared with controls (10.4, 95% confidence intervals [CI], 10.1-10.8 vs. 9.7, CI, 9.5-9.9, P = 0.0004 and 35.8, CI, 34.2-37.3 vs. 33.3, CI, 32.2-34.3, P = 0.007, respectively). Dual aspirin and clopidogrel poor-responsiveness was diagnosed significantly more often in ST cases than in controls (19.6% vs. 1.4%, P = 0.004), whereas no difference was observed for single aspirin or clopidogrel poor-responsiveness. A strong correlation was found between MPV and both, ARU (r = 0.66, P < 0.0001) and PRU (r = 0.55, P < 0.0001). Similarly, higher LPLT was associated with higher ARU (r = 0.47, P < 0.0001) and PRU (r = 0.38, P = 0.0001).

Conclusions

Baseline platelet size is increased in patients with ACS developing early ST and correlates with future residual platelet reactivity under aspirin and clopidogrel therapy. Dual but not isolated aspirin or clopidogrel poor-responsiveness appears to be associated with early ST.     

Prevalence of silent myocardial ischemia in single and multiple lacunar infarcts and large vessel disease stroke

Background and purpose

The relationships between single (SLI) and multiple lacunar infarcts (MLI) and occult coronary artery disease (CAD) have not yet been sufficiently evaluated. We aimed to investigate the prevalence of silent CAD in patients with SLI, MLI and large vessel disease (LVD) stroke, and to identify factors associated with its presence.

Methods

We enrolled 125 patients who had suffered their first non-cardioembolic ischemic stroke but had no documented history of CAD. According to their pathologies, these patients were assigned to one of three groups: MLI (n = 21), SLI (n = 50) or LVD (n = 54). Asymptomatic CAD was detected by myocardial perfusion SPECT imaging.

Results

Silent CAD was detected in 40 patients (32% of the total); of those that experienced CAD, 15 (30%) were from the SLI group, 7 (33%) had MLI, and 18 (33%) had an LVD stroke. Differences between the groups were not significant. During a median follow-up of 48 months, the overall stroke recurrence was 8.8%; the stroke recurrence rates for each subgroup were 6% in patients with SLI, 7% in LVD and 19% in MLI. Mortality was higher in patients from the MLI and LVD groups (26% and 14%, respectively) than in those from the SLI group (6%; p = 0.02). We found no relationships between the various risk factors and silent CAD.

Conclusions

In this exploratory study, SPECT imaging results revealed that the prevalence of abnormal myocardial perfusion was similar in patients with either single or multiple lacunar infarcts and those that had experienced large vessel disease stroke.     

Pharmacodynamic assessment of a novel P2Y12 receptor antagonist in Japanese patients with coronary artery disease undergoing elective percutaneous coronary intervention

Introduction

Numerous reports have shown that prasugrel shows a rapid and consistent antiplatelet effect among European and US patients. Previous studies suggest that prasugrel might be expected to achieve an adequate antiplatelet effect in healthy Asian subjects, even at lower doses than those assessed in the TRITON-TIMI 38 study. In this study, the antiplatelet effect of prasugrel was evaluated in Japanese coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI).

Methods and results

Eighty-four patients were randomized into four treatment groups: prasugrel 10/2.5 mg (loading dose [LD]/maintenance dose [MD]), 15/3.75 mg or 20/5 mg, and clopidogrel 300/75 mg. The LD of each regimen was administered the day before PCI, followed by 28-day MD on aspirin background therapy (81-100 mg). Antiplatelet effects were evaluated by light transmission aggregometry and VASP assay.The mean inhibition of platelet aggregation (IPA) induced by 20 μM of adenosine diphosphate at 4 hours after LD was higher among the prasugrel 10/2.5 mg, 15/3.75 mg and 20/5 mg groups compared with the clopidogrel group (12.3%, 20.9%, 29.8% vs. 8.4%, respectively). The proportion of subjects with an IPA of < 10% on Day 28 was lower among the prasugrel 15/3.75 mg, and 20/5 mg groups than in the clopidogrel group (0%, 6.3% vs. 15.8%, respectively). No “major” or “clinically relevant non-major” bleeding was observed.

Conclusions

Prasugrel 15 mg LD/3.75 mg MD or higher doses was well tolerated and achieved a more rapid, higher and consistent antiplatelet effect than clopidogrel in Japanese CAD patients undergoing PCI.     

Relationship Between ABCB1 Polymorphisms,Thromboelastography and Risk of Bleeding Events in Clopidogrel-Treated Patients With ST-Elevation Myocardial Infarction

Introduction

This study sought to investigate the relationship of polymorphisms in ABCB1 and the predictive value of thromboelastography (TEG) on bleeding risk in clopidogrel-treated patients with ST-elevation myocardial infarction (STEMI).

Methods

467 consecutive patients with STEMI undergoing percutaneous coronary intervention (PCI) were enrolled. Twenty tag single nucleotide polymorphisms (SNPs) selected from ABCB1 gene and CYP2C19*2, *3, *17 were detected by the ligase detection reaction. Platelet reactivity was assessed by TEG. The follow-up period was 12 months.

Results

By receiver operating characteristic curve analysis, the TEG platelet mapping assay value of ADP inhibition had the best predictive value of bleeding academic research consortium definition (BARC) ≥ 3b bleedings, yielding an area under the curve (AUC) of 0.707 (95% CI 0.662-0.749, p = 0.009; cut-off value > 93.4%). ADP inhibition can also predict BARC ≥ 3 bleedings with an AUC of 0.594 (95% CI 0.546-0.640, p = 0.05; cut-off value > 92.5%). After adjustment for established risk factors of bleeding including the gain of function CYP2C19*17 allele, age, female gender, renal function, the multivariable logistic regression model demonstrated that ADP inhibition > 92.5% (OR 2.247, 95%CI 1.082-4.665, P = 0.03), carriage of rs1045642 (OR 2.943, 95%CI 1.195-7.247, P = 0.019) and rs7779562 (OR 0.453, 95%CI 0.219-0.936, P = 0.032) were independent predictors of BARC ≥ 3 bleedings. These associations were validated in a second cohort of 504 STEMI patients.

Conclusions

In STEMI patients treated with clopidogrel after PCI, the ABCB1 tag SNP rs1045642 is associated with higher risk of bleedings while rs7779562 is associated with lower bleeding risk, and ADP inhibition in TEG has a predictive value of bleedings.     

Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease

Objective

To assess serum brain derived neurotrophic factor (BDNF) concentrations as a correlate of cardiopulmonary fitness and as a predictor of cognitive performance in subjects with coronary artery disease (CAD).

Methods

Serum BDNF concentrations were assayed by ELISA and fitness was assessed using a standardized exercise stress test. The Mini Mental Status Examination (MMSE), California Verbal Learning Test 2nd Ed., Stroop, Trail Making Test B and the Digit Symbol-Coding task were administered. The val66met BDNF genotype and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were determined as potential confounders.

Results

In subjects with CAD (n = 88; 85.2% male, mean age 62.8 ± 10.5 yr), cardiopulmonary fitness was associated with higher serum BDNF concentrations (β = .305, p = .013). Higher serum BDNF concentrations were associated with higher MMSE scores (F(1, 87) = 15.406, p < .0005) and better performance on the Digit Symbol-Coding task (F(1, 87) = 9.620, p = .003). IL-6, TNF-α and the val66met genotype did not influence these results.

Conclusion

Serum BDNF concentrations were associated with cardiopulmonary fitness, psychomotor processing speed and overall cognition in subjects with CAD.     

Association of tissue plasminogen activator and plasminogen activator inhibitor polymorphism with myocardial infarction: A meta-analysis

Introduction

To investigate whether t-PA Alu repeat insertion/deletion (I/D) and PAI-1 4 G/5 G genetic variations are associated with the risk of MI.

Methods

We conducted a meta-analysis to assess the association between the t-PA I/D and PAI-1 4 G/5 G polymorphisms and risk of MI. We also performed subgroup analyses based on ethnicity (Caucasian, Asian, and African), gender and age. Forty one eligible studies including 12,461 cases and 14,993 controls were identified to evaluate the impact of PAI-1 4 G/5 G polymorphism on MI. Seven studies investigated the relationship between t-PA I/D and MI.

Results

This meta-analysis revealed that the PAI-1 4 G allele (4 G/4 G and 4 G/5 G genotype) was associated with an increased risk of MI compared with the 5 G allele in the overall population (OR = 1.094, 95% CI = 1.021 - 1.172, p = 0.011). The relative risks of MI for 4 G/4 G genotype was increased when compared to 5 G/5 G genotype and 5 G allele, with odds ratio at 1.157 (95% CI 1.015 - 1.320, p = 0.029) and 1.126 (95% CI = 1.015 - 1.249, p = 0.025). However, the results show that the 4 G/5 G polymorphism risk for MI was not associated with ethnicity stratification as Caucasian, Asian or African population. No substantial differences in the genotype distributions were observed in the MI group and control group along the lines of gender and age. After multivariable analysis t-PA I/D polymorphism showed no consistent association with MI.

Conclusions

This study suggests that the 4 G/5 G polymorphism of PAI-1 may be a risk factor for MI in overall populations.     

CYP2C19*2 and other genetic variants affecting platelet response to clopidogrel in patients undergoing percutaneous coronary intervention

Introduction

Information regarding any possible additional effect of genetic variants other than CYP2C19*2 on platelet reactivity in patients undergoing percutaneous coronary intervention (PCI), while on dual antiplatelet therapy, is sparse.

Materials and Methods

Genotyping for CYP2C19*2, CYP2C19*17, CYP2C9*3, CYP2B6*5, ABCB1 and P2RY12 (c.-217 + 2739 T > C) variants was performed in 146 consecutive PCI patients receiving clopidogrel. Platelet reactivity was assessed by the Verify Now P2Y12 point-of-care assay and high on-treatment platelet reactivity (HTPR) was defined as a Platelet Reactivity Unit (PRU) ≥ 235.

Results

We identified 65(44.5%) patients with HTPR and 38(26%) carriers of at least one CYP2C19*2 allele, which had higher platelet reactivity compared to non-carriers [least square (LS) mean difference 44.5, 95%CI 15.8-77.3, p = 0.003]. In the entire study population, the presence of at least one CYP2C19*2 or P2RY12 allelic variant was independently associated with HTPR (OR = 3.02, 95%CI 1.16-7.86, p = 0.023 and OR = 3.11, 95%CI 1.03-9.39, p = 0.05 respectively). In CYP2C19*2 non-carriers, carriers of at least one CYP2B6*5 allelic variant had higher platelet reactivity compared to the remainders (LS mean difference 35.6, 95%CI 3.7-67.6, p = 0.03) and the presence of at least one CYP2B6*5 or P2RY12 allelic variant was independently associated with HTPR (OR = 3.26, 95%CI 1.08-9.86, p = 0.04 and OR = 4.27, 95%CI 1.11-16.4, p = 0.04 respectively).

Conclusions

Apart from the CYP2C19*2, other genetic variants involved in clopidogrel metabolism and action like CYP2B6*5 and P2RY12 seem to have an important association with HTPR.     

Chronic kidney disease status modifies the association of CYP2C19 polymorphism in predicting clinical outcomes following coronary stent implantation

Introduction

There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients with dual antiplatelet therapy. Chronic kidney disease (CKD) is associated with increased risk of cardiovascular event, but the association between the possession of CYP2C19 loss-of-function (LOF) alleles and clinical outcome according to the presence of CKD is poorly understood. The aim of this study was to investigate whether CKD status modifies the association of CYP2C19 polymorphism in predicting outcomes in a prospective cohort study.

Material and Methods

We enrolled 331 patients following coronary stent implantation. Patients were divided into two groups: CKD (n = 154) and non-CKD (n = 177). Platelet reactivity and CYP2C19 polymorphism were examined. The subjects were further divided into two groups according to the possession of CYP2C19 LOF alleles: carriers and non-carriers. Patients were followed up and clinical events were evaluated according to CKD and carrier status.

Results

The proportion of high platelet reactivity was significantly higher in carriers than in non-carriers in both CKD (42.4% versus 21.7%; P = 0.016) and non-CKD groups (34.3% versus 3.7%; P < 0.001). In the non-CKD group alone, the incidence of cardiovascular events was significantly higher in carriers than in non-carriers (13.7% versus 1.7%; P = 0.013). Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers than in non-carriers in the non-CKD group (log-rank test: P = 0.013) and there was no significant difference in the CKD group (log-rank test: P = 0.591). Multivariate analysis identified carriers as an independent predictor of cardiovascular events only in the non-CKD group alone (hazard ratio: 8.048; 95% confidence interval: 1.066 to 60.757; P = 0.043).

Conclusions

CYP2C19 polymorphism significantly correlates with clinical outcome in non-CKD patients, and CKD status modifies the association of CYP2C19 polymorphism in predicting clinical outcomes following coronary stent implantation.