The Risk Factors Investigation Of Aspirin Resistance And The Experimental Study For The Prevention And Treatment Of Aspirin Resistance

Objective:The purpose of the present study was to evaluate the related risk factors for aspirin resistance in elderly patients with cardiovascular disease (CVD). We performed some animal experiments for the prevention and treatment of aspirin resistance. We investigated the effect of the combination of aspirin, simvastatin or ramipril on platelet function in diabetic rat and spontaneous hypertensive rat.Methods:Clinical study Four hundred and fifty-four elderly patients (age,73.91±8.12 years) receiving daily aspirin therapy (≥75 mg) over 1 month were recruited. Platelet aggregation was measured by light transmission aggregometry (LTA) and thrombelastography platelet mapping assay (TEG). Platelet activation was determined by platelet surface expression of PAC-1 and CD62P after natural activation using flow cytometry. The definitions of aspirin resistance wer≥20% arachidonic acid (AA)-and >70% adenosine diphosphate (ADP)-induced aggregation by LTA. Aspirin semi-responders were defined as meeting one (but not both) of these criteria. Aspirin resistance by TEG was defined as≥50% aggregation induced by AA. Experimental study Diabetic rats, spontaneous hypertensive rats, Wistar rats and Wistar Kyoto rats were given aspirin, simvastatin, ramipril, combination of aspirin and simvastatin or ramipril for 8 weeks. The platelet function was evaluated by whole blood aggregation, TEG and the expression of CD62P. The changes of nitric oxide (NO) endothelin (ET), prostacyclin (PGI2), adiponectin (APN), thromboxane B2 (TXB2), super oxide dismutase (SOD), malondialdehyde (MDA) were detected in blood. The endothelial function was assessed by the vascular reactivity of the thoracic aorta in vitro experiment. The expression of heme oxygenase-1 (HO-1), heme oxygenase-2 (HO-2), endothelial nitric oxide synthase (eNOS), phosphorylated endothelial nitric oxide synthase (p-eNOS), Bcl-2, cyclooxygenases-2 (COX-2) in thoracic aorta were evaluated by Western Blot. Results:Clinical study By LTA,38 (8.4%) of elderly patients were found to be resistant to aspirin therapy; 166 (36.6%) patients were semi-responders. By TEG,111 patients (24.4%) were aspirin-resistant. Of the 111 patients who were aspirin-resistant by TEG,33 were aspirin-resistant by LTA. Forty of 166 semi-responders by LTA were aspirin-resistant by TEG. The kappa statistic between these two methods was 0.364 (95% confidence interval (CI),0.265-0.454). In the multivariate logistic regression analysis, Fasting serum glucose levels(odds ratio (OR)=1.211,95% CI:1.047-1.402, p=0.010), CD62P levels (OR=1.010,95% CI:1.002-1.019, p=0.019), the administrations of ACEIs/ARBs (OR=0.524,95% CI:0.309-0.890,p=0.017) and nitrate (OR=0.638,95% CI: 0.414-0.983, p=0.042) were correlated with aspirin resistance. The incidence of cardiovascular related events was higher in patients with aspirin resistance or aspirin semi-responders than aspirin-sensitive patients by LTA(9.3% vs 9.2%). By TEG, aspirin-resistant patients had a more cardiovascular events than aspirin-sensitive patients (9.9% vs 9.0%). Experimental study Compared with control rats, diabetic rats and spontaneous hypertensive rats had high levels of platelet aggregation and activation (p<0.05), which could not be relieved by aspirin (p<0.05). The combination of medication resulted in a greater inhibitory effect on platelet aggregation and activation than control animals by upregulation fo HO-1, eNOS, p-eNOS, Bcl-2, APN levels and downregulation of COX-2. The combination therapy improved endothelial function through the balance of TXA2/PGI2 levels, increasing NO levels, which resulted in a great potential antiplatelet effect.Conclusion:The prevalence of aspirin resistance in elderly patients with CVD is high, which is considerably higher in patients with a higher Fasting serum glucose levels, CD62P levels, and in patients without certain medication. The incidence of cardiovascular related events is higher in patients with aspirin resistance or aspirin semi-responders than aspirin-sensitive patients. Experimental study suggests that simvastatin or ramipril may improve the aspirin anti-platelet effect in diabetic rat and spontaneous hypertensive rat.