| Background:Antiplatelet therapy is the cornerstone of antithrombotic treatment ofcardiovascular disease. Now dual antiplatelet therapy, with aspirin and clopidogrel,is the guidelines recommended standard program for patients with acute coronarysyndrome (ACS) and patients who accepted percutaneous coronaryintervention therapy (PCI). However, some patients can not benefit from itbecause of individual differences. Following aspirin resistance (AR),clopidogrel resistance (CR) has also been reported frequently. Metabolicdifferences and other factors (such as hyperglucose) may be the causes ofweakening antithrombotic effect, which likely lead to coronary events andintra-stent thromboses or even maybe important factors to stimulate intimalhyperplasia and atherosclerosis progress. Accordingly, identifying their resistancemechanism is good for clinicians to promptly adjust their antiplatelet prescriptionaccording to each individual to reduce or avoid the occurrence of adverse events.Therefore, it would promote the development of antithrombotic individualizedtreatment.Objective:To study the potential mechanism of clopidogrel resistance in cardiovascularpatients complicated with abnormal glucose metabolism.Methods:1. To confirm the impact which glucose affected clopidogrel reactivity fromclinical data. About122patients (male95; female27) with coronary arterydisease (CAD) accompanying hypertension (HPT) admitted to Department ofCardiology, Chinese PLA General Hospital, from October2010to April2011,were randomly analyzed. The patients were divided into low-response group (LRG) and response group (RG) according to the inhibition of their platelet(through the way of ADP inhibition rate in mTEG). Compared risk factors ofgender, age, body mass index, smoking (current smoking and quitting smokingless than2years), drinking (alcohol32g/d and above), glucose metabolismabnormality or not and blood indicators of tow groups to find significant riskfactors and independent risk factors. All data were analyzed by SPSS17.0statistical software. Measurement data were expressed as mean±SD, andStudent’s t-test was used to compare the difference between different groups. Theratio and percentage was used to express count data and compared by thechi-square test. The risk factors for CR were analyzed by univariate analysis andmultivariate stepwise logistic regression analysis. p<0.05was accepted asstatistical difference.2. To find the potential mechanism by detection of molecular markers in the angleof platelet energy metabolism. Randomly selected45patients from the enrolled122cases, there were19cases (group A with male12cases and female6cases)with abnormal glucose metabolism and20normal cases (group B with male12cases and female8cases). Fresh platelets were isolated for ATP and mitochondrialmembrane potential (Δψm) analysis. ATP contents were determinated byluciferin/luciferase luminometric method, and the flow cytometry technique wasadopted to evaluate Δψm. In all participants correlation between platelet ATPcontent, Δψmand other variables was analyzed by a multivariable stepwiseregression.Result:1.①Of the122patients,49were low responsive to clopidogrel, accounting for40.2%.②Univariate analysis showed that3variables (drinking, abnormal glucosemetabolism and fasting plasma glucose) could influence the response of patientswith CAD accompanying HPT to clopidogrel.③Multivariate stepwise logisticregression analysis revealed that FPG was an independent factor for CR in thesepatients (β=0.193; P=0.033) and alcohol drinking might be a protective factor for CR (β=－1.175; P=0.051).2.①Platelet ATP contents were significantly higher in group A (4.369±2.174nmol/mg) than in the control group (group B;1.628±0.452nmol/mg), P<0.001.Interestingly, Δψmwas markedly decreased in patients of group A (0.484±0.118)compared with group B (2.381±0.194); P<0.001.②For whole subjects, a linerstepwise regression showed that plasma glycated hemoglobin A1c (HbA1c) levelpositively correlated to platelet ATP content (β=1.235; P=0.000), and negativelycorrelated to Δψm(β=－0.54; P=0.000). Although, the ages of the patients wereinvolved in the regression equation, but significantly correlation (β=0.03; P=0.006)was found between Δψmand HbAlc instead of Age.Conclusion:1. FPG is closely related with CR and therefore it should actively controlled inpatients with cardiovascular diseases on clopidogrel therapy.2. Hyperglucose leads platelet to produce more ATP, which is positively correlatedwith the concentration of HbAlc. This shows that the plasma glucose is directlyresulting in increased platelet activity, and reasoning for the susceptibility of CRin patients with cardiovascular disease accompanying hyperglucose.Simultaneously, the reduction of Δψmshows their platelets early enteringapoptosis. Does this imply that bone marrow compensatory production of platelets,further exacerbating the occurrence of CR?... |
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