Platelet activation and microvascular injury in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Dual antiplatelet therapy reduces the risk of thrombotic complications after primary percutaneous coronary intervention (PCI). AIM: To assess whether inhibition of platelet function attenuates microvascular damage in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We studied 83 STEMI patients treated with primary PCI. Platelet aggregation was measured on admission (ADM) and 4 days later (D4) by light transmission aggregometry after stimulation with 0.5 mM of arachidonic acid and after stimulation with 5 and 20 µM of adenosine diphosphate (ADP) on treatment with dual antiplatelet therapy with aspirin and clopidogrel. Platelet-neutrophil aggregate (PNA) and platelet-monocyte aggregate (PMA) were analysed by flow cytometry. Contrast-enhanced magnetic resonance imaging was performed 2-4 days after STEMI to detect the area of perfusion defect at rest and to determine the size of microvascular obstruction. Microvascular obstruction was expressed as a percentage of infarct area. RESULTS: Perfusion defect at rest was found in 56 (67.5%) patients whereas microvascular obstruction in 63 (75.9%) patients. Patients with perfusion defect at rest had on admission a significantly higher level of both PMA (7.0 vs. 4.5%, p = 0.004) and PNA (4.1 vs. 2.2%, p = 0.016), however there were no significant differences at D4. Platelet aggregation after stimulation with 5 µM of ADP on ADM was correlated (r = 0.37, p = 0.004) with microvascular obstruction area. Moreover, the higher the concentration of PMA(ADM) (r = 0.31, p = 0.016), PNA(ADM) (r = 0.34, p = 0.006) and PM(AD4) (r = 0.35, p = 0.005) the larger the size of microvascular obstruction. Infarct size (ß = 0.43, 95% CI 0.19 to 0.67, p 〈 0.0001), TIMI < 3 after PCI (ß = -0.27, 95% CI -1.90 to -0.11, p = 0.015) and PMA(D4) (ß = 0.21, 95% CI 0.13 to 1.86, p = 0.032) independently influenced the size of microvascular obstruction (R2 = 0.60, p 〈 0.0001). CONCLUSIONS: Excessive platelet activation during reperfusion in STEMI patients despite dual antiplatelet therapy is associated with greater microvascular impairment.

Polyunsaturated omega-3 fatty acids improve responsiveness to clopidogrel after percutaneous coronary intervention in patients with cytochrome P450 2C19 loss-of-function polymorphism.

BACKGROUND: Antiplatelet properties of omega-3 polyunsaturated fatty acids (PUFA) have been demonstrated in patients with coronary artery disease (CAD). It is unknown whether omega-3 PUFA can enhance platelet inhibition on standard aspirin and clopidogrel treatment in the setting of CYP2C19 loss-of-function polymorphism. AIM: To investigate whether omega-3 PUFA are able to modify platelet responsiveness to clopidogrel therapy in patients with CYP2C19 loss-of-function polymorphism undergoing percutaneous coronary intervention (PCI). METHODS: 63 patients with stable CAD undergoing PCI (48 males, mean age 63.2 ± 9.6 years) were enrolled into an investigator- initiated, prospective, single-centre, double-blind, placebo-controlled, randomised study. Patients on standard dual antiplatelet therapy (aspirin 75 mg daily and clopidogrel 600 mg loading dose followed by 75 mg daily) were assigned to receive the addition of 1 g of omega-3 ethyl esters (n = 33) or placebo (n = 30) for 1 month. Platelet function was measured serially by light transmittance aggregometry in response to 5 and 20 µmol/L ADP at baseline, 12 h, 3-5 days and 30 days after randomisation. CYP2C19*2 was genotyped at baseline. RESULTS: No significant differences were found in baseline variables, including the frequency of CYP2C19 genetic variants. At least one loss-of-function variant of CYP2C19*2 was found in 19 (30.2%) patients. In patients with CYP2C19*1/*2 and *2/*2 variants, maximal platelet aggregation induced by 5 and 20 µmol/L ADP was reduced by 21.4% (p = 0.006) and 14.3% (p = 0.041), respectively, after 1 month of treatment with omega-3 PUFA as compared to placebo. The beneficial effect of omega-3 PUFA was demonstrated in carriers of CYP2C19 loss-of-function polymorphism, whereas no differences in platelet aggregation between the omega-3 PUFA and placebo groups were found in patients with the 1*/1* variant. CONCLUSIONS: The addition of omega-3 ethyl esters significantly potentiates platelet response to clopidogrel after PCI mostly in patients with CYP2C19 loss-of-function polymorphism.