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High Asymmetric Dimethylarginine (ADMA) levels are associated with increased platelet activity, elevated blood pressure, vasoconstriction and impaired vascular relaxation. We hypothesized that the myocardial infarction morning peak of occurrence is closely related to a morning peak of ADMA levels. We performed a cross-sectional study among patients with documented myocardial infarction who had been enrolled in the prospective MISSION! Intervention Study. In total, serum ADMA levels were measured in their acute setting of myocardial infarction in 120 patients. The frequency of myocardial infarction onset of symptoms and emergency coronary catheterization and the ADMA levels displayed a similar daily pattern with a morning peak between 06:00-11:59 h. The absolute ADMA levels peak was between 06:00-07:59 h with a median (interquartile range) peak value of 1.01 (0.84-1.21) μmol/L for the n=9 patients vs. 0.75 (0.61-0.89) μmol/L for the remaining 111 patients admitted throughout the rest of the 24-hour interval (p=0.003 for between groups comparison). The amplitude (95% 0.08 μmol/L (0.004-0.16) with p=0.042 for statistic model significance. In conclusion, ADMA levels display a 24-hour variation with a significant morning peak in patients with acute myocardial infarction. These findings may relate ADMA levels to the acute onset of thrombotic cardiovascular events. [ABSTRACT FROM AUTHOR]

PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with greater circadian variation of PAI-1 levels. We hypothesized that the 24 h variation of cardiac risk is more pronounced among persons with the 4G4G genotype than among ones with 4G5G and 5G5G genotypes. We assessed the time of onset of symptoms in 623 consecutive patients with acute myocardial infarction (AMI) enrolled in the MISSION! Study between February 1, 2004, and October 29, 2006. All of the patients were genotyped for the PAI-1 4G/5G polymorphism. We quantified the amplitude of the 24 h variation of AMI with a generalized linear model with Poisson distribution. A morning peak, between 06:00-11:59 h (n = 197; 32% of all cases), in the onset of symptoms of AMI was observed. The group composed of patients with the 4G4G genotype did not have a more pronounced morning peak than the groups composed of other genotypes; the 24 h variation was 38% (95% confidence interval 12-70%) in the group of 4G4G patients and 34% (14-58%) and 56% (20-100%) in the 4G5G and 5G5G groups of patients, respectively. Our findings show that 24 h variation of cardiac risk is not more pronounced among the 4G4G genotype of PAI-1. (Author correspondence: j.g.vanderbom@lumc.nl) [ABSTRACT FROM AUTHOR]

Abstract: Background: Antiplatelet drug resistance is a well-known problem, causing recurrent cardiovascular events. Multiple genetic polymorphisms have been related to antiplatelet resistance by several large trials, however data from common clinical practice is limited. We examined the influence of previously described polymorphisms, related to aspirin and clopidogrel resistance, on treatment outcome in a real life unselected population of patients presenting with ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention. Methods and results: This cohort study consisted of 1327 patients with STEMI. Patients were treated according to a standardized guideline-based protocol. Nine polymorphisms, COX1 (?842A>G), P2Y1 (893C>T), GPIa (807C>T), GPIIIa (PlA1/A2), CYP2C19 (*2, *3 and *17), ABCB1 (3435T>C) and PON1 (576A>G), were genotyped. During 1year of follow up the primary endpoint, a composite of cardiac death or recurrent myocardial infarction, was reached in 86 patients. The COX1 and CYP2C19*2 polymorphisms were associated with the primary endpoint, HR 2.55 (95% CI 1.48–4.40), P=0.001 and HR 2.03 (1.34–3.09) P=0.001, respectively. The combined analysis demonstrated a 2.5-fold increased risk for individuals with ?2 risk alleles, P=6.9×10–9. The association of COX1 was driven by mortality related events whereas that of CYP2C19*2 was mainly attributed to myocardial infarction and stent thrombosis. Conclusion: In this unselected, real life population of STEMI patient on dual-antiplatelet therapy, the polymorphisms COX1 –842A>G and CYP2C19*2 were determinants of thrombotic complications during follow-up. We show that in a clinical setting, testing for these polymorphisms could be of value in the identification of STEMI patients at risk for recurrent cardiovascular events. [Copyright &y& Elsevier]

Abstract: As chemokines are considered instrumental in thrombotic plaque rupture and erosion as well as in ischemia-reperfusion injury processes, we aimed to identify previously unknown chemokines associated with acute coronary syndromes. Plasma of 44 patients with acute myocardial infarction (AMI) and 22 controls were profiled for a panel of chemokines by multiplex analysis. Levels of CCL3 were prospectively verified in 54 patients with unstable angina pectoris (UAP). An AMI mouse model was used to assess the relationship between differentially expressed chemokines and myocardial ischemia. CCL3 levels were significantly elevated in AMI vs. controls (P =0.02) albeit, that adjustment for confounding factors attenuated this association. In support of a direct association with cardiac ischemia CCL3 levels were also seen to be elevated in patients with UAP at baseline and significantly down-regulated after 180 days (P <0.001). Importantly, baseline upper quartile levels were strongly correlated with future acute coronary syndromes (Likelihood Ratio 11.5; P <0.01). Furthermore circulating levels of CCL3 were significantly enhanced after AMI in mice (P =0.02), while CCR5+ T-cell numbers were increased as well, suggestive of CCL3 driven T-cell homing towards the ischemic area. CCL3 levels are elevated during ACS and released upon ischemia. Since CCL3 specifically predicts future cardiovascular events, it may serve as a predictive biomarker. [Copyright &y& Elsevier]

Aims: The optimal drug-eluting stent (DES) in ST-elevation myocardial infarction (STEMI) patients remains unclear. We sought to compare the long-term performance of everolimus-eluting stents (EES) and Endeavor zotarolimus-eluting stents (E-ZES) in STEMI., Methods and Results: The current analysis of a prospective registry included consecutive patients treated with EES or E-ZES for STEMI. Adjustment for measured confounders was done using Cox regression. In total, 931 patients met the inclusion criteria (412 EES and 519 E-ZES). Baseline characteristics were balanced, apart from a lower rate of renal insufficiency in EES. Median follow-up duration was 2.4 years (IQR 1.6-3.1). Mortality outcomes were similar. Up to three-year follow-up, the composite endpoint of cardiac death, target vessel-related myocardial infarction and target lesion revascularisation (TLR) was lower in EES; 9.7% vs. 13.7% in E-ZES (HR 0.64, 95% CI: 0.42-0.99), primarily driven by reduced TLR rates; 3.4% in EES vs. 7.3% in E-ZES (HR 0.46, 95% CI: 0.23-0.92). Definite stent thrombosis rates were low and similar between groups (1.1% in EES vs. 1.9% in E-ZES, p=0.190)., Conclusions: Use of EES led to lower rates of the composite endpoint, driven by reduced TLR. This suggests that EES are more efficacious than Endeavor ZES in STEMI. Definite ST rates were low, and the strategy of second-generation DES implantation and the administration of upfront GP IIb/IIIa inhibitors appear to be safe in STEMI.

Aims: To evaluate the clinical outcomes of sirolimus-eluting stent (SES) versus bare metal stent (BMS) implantation in patients with ST-segment elevation myocardial infarction (STEMI) at long-term follow-up., Methods and Results: After five years, 310 STEMI patients randomly assigned to implantation of either SES or BMS, were compared. Survival rates were comparable between groups (SES 94.3% vs. BMS 92.8%, p=0.57), as were the rates of reinfarction (10.6% vs. 13.7%, p=0.40), freedom of death/re-MI (84.4% vs. 79.8%, p=0.29) and target vessel failure (14.9% vs. 21.7%, p=0.11). Likewise, rates of overall stent thrombosis (ST) (5.4% vs. 2.7%, p=0.28) and very late ST (4.1% vs. 0.7%, p=0.07) did not significantly differ between the SES- and BMS-group. In 184 patients with IVUS data, definite and definite/probable VLST was more common in those with late stent malapposition versus those without late stent malapposition (4.3% and 6.6% vs. no events [p=0.018 and p=0.004], respectively). The cumulative incidences of target vessel and target lesion revascularisation (TVR and TLR) were not significantly lower in the SES-group (11.2% vs. 17.9%, p=0.09 and 7.2% vs. 12.9%, p=0.08), as was the rate of clinically driven TLR (6.6% vs. 9.5%, p=0.30)., Conclusions: SES implantation was neither associated with increased rates of major adverse cardiac events, nor with a reduction in re-intervention, compared to implantation of a BMS in patients with STEMI after five years. However, a trend of more very late stent thrombosis was observed after SES implantation (ISRCTN62825862).

Aims: To evaluate effects of sirolimus-eluting stents (SES) compared to bare-metal stents (BMS) at stent edges in patients with acute myocardial infarction (AMI)., Methods and Results: Clinical, angiographic, intravascular ultrasound (lVUS) and virtual histology (VH)-IVUS results were obtained and analysed in 20 SES and 20 BMS AMI patients at the index procedure and at nine months follow-up. Quantitative angiography and IVUS showed a trend toward decreases in mean lumen diameter, vessel volume, minimum lumen area and mean lumen area at both stent edges of BMS, and at the proximal edge of SES. At the distal stent edge, a significant difference between BMS and SES treated patients in mean lumen area was found (D-0.8+/-1.6 mm2 versus D0.2+/-0.8 mm2 respectively, p=0.04). Furthermore, in-stent SES had a larger lumen volume (SES: 167.7+/-59.2 mm3 versus BMS: 125.1+/-43.8 mm3; p=0.02) and less neointima volume (7.3+/-9.1 mm3 versus 53.2+/-35.1 mm3; p<0.001). Neither SES nor BMS demonstrated a significant effect on plaque composition at follow-up VH-IVUS analysis., Conclusions: A significant difference between SES and BMS treated patients was observed with respect to mean lumen diameter distal to the stented segment which suggests a downstream effect of sirolimus elution.