Search

Although aspirin is effective in secondary prevention in coronary heart disease, new thromboembolic events in patients on aspirin are frequently seen. In trials on aspirin-treated patients, platelet function tests have revealed large variability in platelet aggregation. This phenomenon has been named aspirin resistance, aspirin non-responsiveness or high-on-aspirin residual platelet reactivity. The mechanism of aspirin antiplatelet effect is due to the inhibition of cyclooxygenase-1 enzyme in platelets. In some trials, almost all patients on aspirin have a very low level of serum thromboxane B2, indicating that the measured platelet reactivity in aspirin-treated patients might be due to platelet activation via other pathways, such as ADP or thrombin. The prevalence of real aspirin resistance seems to be very low, and probably the term "high-on-aspirin residual platelet reactivity" should be preferred to describe this phenomenon., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Mediators involved in atherosclerosis and plaque rupture may have importance as risk markers for coronary artery disease (CAD). We have investigated the influence of matrix metalloproteinase (MMP)-9 genetic variations on gene- and protein expression in stable CAD patients., Methods: The promoter -1562C/T and exon 6 R279Q A/G polymorphisms were determined in 1001 patients with angiographically verified stable CAD and in 204 healthy controls. Genotype and gene-expression were determined by real-time PCR. Serum levels of MMP-9 and its inhibitor TIMP-1were measured immunologically and by zymography (MMP-9 activity)., Results: None of the polymorphisms associated with the presence of CAD, myocardial infarction or type 2 diabetes, whereas the variant allele of the R279Q polymorphism associated with hypertension (adjusted p=0.015). The T- and G alleles associated with lower and higher mRNA levels, respectively (p<0.005 both), also shown in an experimental ex-vivo LPS stimulated model. T-allele carriers had higher concentrations of MMP-9 (adjusted p=0.032) and the GG genotype induced lower MMP-9 gelatinolytic activity (p=0.01). Higher MMP-9 gene-expression and TIMP-1 levels were observed in patients with previous myocardial infarction, the latter also was elevated in diabetics (<0.05, all)., Conclusion: The investigated MMP-9 polymorphisms influenced gene- and protein expression differently and the R279Q polymorphism associated significantly with hypertension., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Different platelet function tests can be used to evaluate the degree of achieved platelet inhibition in patients treated with clopidogrel. The presence of CYP 2C19*2 polymorphism can reduce the formation of the active metabolite of clopidogrel, resulting in less platelet inhibition., Patients and Methods: Patients with symptomatic coronary artery disease, all on chronic single aspirin treatment were randomized to continue on aspirin or change to clopidogrel. In 219 randomly selected clopidogrel treated patients, platelet reactivity was evaluated by VASP-PRI determination and by use of VerifyNow P2Y12-PRU. The CYP 2C19*2 G/A polymorphism was further determined., Results: The total frequency of clopidogrel resistance was 29.0% by VASP-PRI and 31.6% by VerifyNow-PRU. The number of patients being hetero- and homozygous combined for the CYP 2C19*2 polymorphism (GA/AA) was 64 (29%). Platelet reactivity was significantly higher in patients with the polymorphism compared to wild-type patients (GG). VASP-PRI was 50.9% (SD19) in patients having the polymorphism compared to 38.3% (SD21) in patients with the GG genotype (p = 0.001). Correspondingly, the mean PRU was 165 (SD67) compared to 124 (SD69) (p < 0.001). The frequency of clopidogrel resistance in patients with the polymorphism was 32% compared to 16% in wild-type patients when defined by VASP-PRI (p = 0.006). When defined by PRU (VerifyNow), the corresponding frequencies were 53% and 22% (p < 0.001)., Conclusions: Clopidogrel treated patients with the CYP 2C19*2 polymorphism have significantly increased platelet reactivity compared to patients with the wild-type, evaluated with the VASP determination, and even more pronounced with the VerifyNow P2Y12 method., Trial Registration: ClinicalTrials.gov: NCT00222261.

Background: Tissue factor (TF) and its inhibitor tissue factor pathway inhibitor (TFPI) are the main regulators of the initiation of the coagulation process, important in atherothrombosis. In this study we have investigated the frequency of six known TF and TFPI single nucleotide polymorphisms (SNPs) in CHD patients as compared to healthy individuals. These genotypes and the phenotypes (TF, TFPI free and total antigen) were evaluated with special reference to gender and diabetes in the CHD population., Methods: Patients with angiographically verified CHD (n = 1001; 22% women, 20% diabetics), and 204 healthy controls (28% women), were included. The investigated SNPs were: TF -1812C/T and TF -603A/G in the 5'upstream region, TF 5466A/G in intron 2, TFPI -399C/T and TFPI -287T/C in the 5'upstream region and the TFPI -33T/C in intron 7., Results: No significant differences in frequencies between the CHD population and the controls of any polymorphisms were observed. In the CHD population, the TF 5466 A/G SNP were significantly more frequent in women as compared to men (p < 0.001). The TF-1812C/T and the TF-603A/G SNPs were significantly more frequent in women without type-2 diabetes compared to those with diabetes (p < 0.018, both), and the heterozygous genotypes were associated with significantly lower TF plasma levels compared to the homozygous genotypes (p < 0.02, both).The TFPI-399C/T and the TFPI-33T/C SNPs were associated with lower and higher TFPI total antigen levels, respectively (p < 0.001, both)., Conclusion: Genetic variations in the TF and TFPI genes seem to be associated with gender and type-2 diabetes, partly affecting their respective phenotypes.

In patients with stable coronary heart disease (n = 1,001) we investigated the influence of tissue factor (TF) and TF pathway inhibitor (TFPI) polymorphisms on thrombin generation in vivo, measured by prothrombin fragment (F) 1 and 2, and the potential to generate thrombin ex vivo, measured by the calibrated automated thrombogram assay. Additionally, circulating levels of TF and TFPI were correlated to the different parameters of thrombin generation. The TF 5466 and TFPI -399 polymorphisms associated with higher thrombin generation in vivo, the latter also with a prolonged lag time of the thrombin generation ex vivo(p < 0.05 for all).The TF -1812 TT and the TF -603 GG genotypes were associated with lower peak thrombin and a decreased average net rate of thrombin activation during the propagation phases (p ≤ 0.05), and the TFPI -33 TC genotype with prolonged lag time (p < 0.05) and additionally time to peak (p = 0.06). Strong correlations between TFPI levels, prothrombin fragment 1 and 2 as well as calibrated automated thrombogram parameters were observed., (Copyright © 2011 S. Karger AG, Basel.)

Aspirin reduces several pro-inflammatory markers in patients with coronary heart disease (CHD), while limited data exists with clopidogrel. The aim of the present substudy of ASCET was to assess the influence of clopidogrel as compared to aspirin on selected circulating inflammatory markers in patients with stable angiographically verified CHD. Patients on treatment with aspirin 160 mg/day for at least seven days were randomized to either aspirin 160 mg/day (n = 105) or clopidogrel 75 mg/day (n = 101). Fasting blood samples were drawn at baseline and after one month and after one year for determination of high sensitivity C-reactive protein, tumor necrosis factor a (TNFa), interleukin 6, monocyte chemoattractant protein 1(MCP-1), CD40L, P-selectin, interleukin 10 and transforming growth factor. The groups were similar regarding demographic variables. There were no differences in any variables including changes from baseline to one month and one year between the groups. In the aspirin group we found significantly lower levels of TNFa and MCP-1 after one year; 1.00 versus 1.16 pg/ml (p < 0.001) and 245 versus 261 pg/ml (p < 0.001), respectively. Likewise, in the clopidogrel group the level of TNFa was significantly reduced after one year; 0.99 versus 1.19 pg/ml (p < 0.001). In patients with CHD we found no between-group differences in circulating markers of inflammation after one year treatment with clopidogrel 75 mg/day compared to aspirin 160 mg/day, but in both groups lower levels of TNFa were obtained. The present results indicate similar anti-inflammatory effects of the two drugs.

Background: Aspirin is widely used as an antiplatelet drug in patients with coronary heart disease. Despite documented clinical benefit, many patients on aspirin still experience severe cardiovascular events. Several laboratory reports have shown lack of platelet inhibition in 5-40% of aspirin-treated patients, and the term aspirin resistance has been introduced. The clinical relevance of these laboratory findings is, however, still unknown. New antiplatelet drugs have been developed, and the adenosin diphosphate (ADP) receptor inhibitor clopidogrel has at least the same efficacy as aspirin with an acceptable safety profile. Laboratory methods for determination of platelet reactivity and treatment efficacy have been complicated and time consuming. New methodologies, like the PFA-100 system, have made such analyses more suitable for clinical use., Design: In the ASCET study, 1000 patients with documented coronary heart disease will be randomized to either continued treatment with aspirin 160 mg/d or change to clopidogrel 75 mg/d after initial determination of their platelet reactivity while on aspirin treatment. Clinical endpoints will be recorded for at least 2 years and related to the initial aspirin response.

Background: Achieving reperfusion as soon as possible is essential in order to reduce myocardial infarction size and thus improve prognosis. An increasing number of patients with myocardial infarction are treated with primary percutaneous coronary intervention (PCI). Technetium 99m-tetrofosmin myocardial perfusion tomography (SPECT) is a valid test for assessing myocardium at risk and final infarct size expressed by a hypoperfusion index (HPI) of the left ventricular mass., Material and Methods: 20 patients with acute ST-elevation myocardial infarction were treated with primary percutaneous coronary intervention within six hours of onset of symptoms. Myocardium at risk and final infarct size were assessed by Technetium 99m-tetrofosmin immediately before and a few hours, one week and six weeks after., Results: The hypoperfusion index immediately before percutaneous coronary intervention was 31%, four to six hours after PCI 25%, one week later 16% and six weeks later 12%, i.e. a relative reduction of 60% (p < 0.01). Anterior wall infarctions had a higher level of myocardium at risk before primary PCI compared to inferior wall infarctions (36% vs. 24%), but anterior wall infarctions had a higher salvage index compared to inferior wall infarctions., Interpretation: This non-controlled study shows a marked reduction in final infarction size in patients with acute ST-elevation myocardial infarction treated with primary PCI.