| Background and objectivesAtherothrombosis is the first cause of death and disability globally. Antiplatelet agentssuch as aspirin and clopidogrel have been widely used in primary and secondary preventionof cardiovascular disease. The emergence of antiplatelet resistance challenges the currentantiplatelet guidelines. Poor adherence is a very common reason for antiplatelet-resistance.And it has been confirmed that antiplatelet resistance is associated with increased risk ofadverse events.How to treat antiplatelet resistance is the important concern in cardiovascular research.However, one-size-fits-all still seems to be the current principle regarding antiplatelettreatment in clinical cardiology, and the individual response to antiplatelet agents has beenignored for a long time. We are just entering a new era in personalized cardiovasculartherapies. Many therapeutic strategies have been proposed to decrease the risk of ischemiain patients with antiplatelet resistance. Such strategies that might serve as ways of tailoringantiplatelet therapy include the following:1) increasing the dose of original antiplateletagents,2) adding additional antiplatelet agents, and3) switching to other antiplatelet agentsor other methods of administration (e.g. switching from oral to intravenous administration).Currently, only a few randomized studies about the former three aspects mentioned above,have assessed the efficacy of tailored antiplatelet therapy on clinical adverse outcomes inantiplatelet-resistant patients. However, it remains controversial whetherantiplatelet-resistant patients benefit from a personalized strategy.Platelet activation plays an important role in the pathogenesis of acute coronarysyndrome (ACS). Despite receiving appropriate treatment, the risk of recurrent thromboembolic events in ACS patients remains high; this may be partly explained byantiplatelet resistance.Human apolipoprotein A-IV (apoA-IV) has a variety of physiological roles, whichinclude controlling food intake, regulating lipid metabolisms, anti-inflammation,anti-oxidation, anti-atherosclerosis, and so on. Moreover, in normal plasma clot theexpression of apoA-IV has been identified; there was an association between apoA-IV genepolymorphism and risk of thrombosis in people consuming low-fat meat rich in walnuts;two commonly used thrombolytic agents alteplase and tenecteplase can lower apoA-IVlevels. These evidence could give us a clue that apoA-IV may be related to plateletactivation and thrombus formation.In the study we aimed at:1) systematically evaluating in prospective studies theassociation between aspirin resistance in CHD patients with good compliance to aspirin andrisk of major adverse cardiovascular events, and in randomized studies the efficacy oftailored antiplatelet therapy in antiplatelet-resistant patients on clinical outcomes;2)investigating the apoA-IV plasma concentrations in ACS patients;3) studying the influenceof recombinant human apoA-IV in platelet activation, and exploring the possiblemechanisms. We expected to achieve a novel strategy for antiplatelet therapy.MethodsAn electronic literature search of PubMed, EMBASE, Web of Science and theCochrane Library as well as a hand search of bibliographies was conducted. Two groups ofstudies were included:1) they prospectively investigated the association of aspirinresistance with the risk of adverse cardiovascular events during follow-up in CHD patientswith confirmed compliance;2) they randomized assessed clinical efficacy of personalizedantiplatelet treatment in antiplatelet-resistant patients. The quality of included articles wasevaluated for qualitative and quantitative analysis, the former analysis including statisticsand analysis of clinical data, the latter one including heterogeneity, meta-analysis, subgroupanalysis, sensitivity analysis, and publication bias.In the next part,115ACS patients and68age-and sex-matched control individualswere included. Clinical data and blood samples were collected. Platelet count, routine bloodlipid profile (total cholesterol, triglycerides, low density lipoprotein cholesterol, highdensity lipoprotein cholesterol, apoA-I and apoB), coagulation profile (thrombin time, prothrombin time, activated partial thromboplastin time and fibrinogen) and plasmaapoA-IV levels were measured and compared.In the final part, PAC-1expression and fibrinogen binding in platelets were measuredafter recombinant apoA-IV treatment. CD62P release from α particle was studied by flowcytometry. For detecting the potential mechanism, we identified the acting targets ofapoA-IV on platelets using the co-immunoprecipitation, utilized GPIIb/IIIa transfectedCHO cells to confirm whether apoA-IV binded to GPIIb/IIIa, and detected cholesteroltransporters ABCA1, ABCG1and SRB1expression in platelets by western blotting.ResultsNine prospective studies with a total1,889CHD patients who were followed for1month to2.5years and study sample sizes ranging from86to496patients were identified.Overall,622out of the1,889CHD patients (33.0%) were classified as aspirin resistant withconfirmed aspirin adherence. Aspirin-resistant patients exhibited a significantly higher riskof adverse events compared with aspirin-sensitive patients [17.2%vs.9.1%; OR (95%CI)=2.44(1.81–3.30), p <0.00001].Data were combined across7randomized studies comprising12,048subjects, ofwhom3,738(31.0%) were found to be antiplatelet-resistant. Antiplatelet-resistant patientsprovided with tailored antiplatelet therapy showed less risk of death or stent thrombosisthan those assigned conventional antiplatelet treatment [0.5%vs.2.2%; OR (95%CI)=0.25(0.13–0.49), p <0.0001]. A significant benefit in terms of total adverse event riskreduction was observed during follow-up for tailored vs. conventional antiplatelet therapy[5.5%vs.10.0%; OR (95%CI)=0.40(0.20–0.77), p=0.006]. No statistical difference inbleeding complications was observed between these two groups (p=0.08).Plasma apoA-IV levels in ACS patients were significantly decreased compared to thelevels in control subjects (437.0±157.5μg/mL vs.590.2±183.7μg/mL, p <0.001). Anobvious decreasing trend of plasma apoA-IV levels from the control subjects, to patientswith unstable angina pectoris (UAP)(457.3±152.9μg/mL), to patients with acutemyocardial infarction (AMI)(311.7±127.8μg/mL), was observed. Moreover, plasmaapoA-IV level was negatively associated with New York Heart Association (NYHA)functional class. NYHA class II (467.2±142.1μg/mL, p <0.001) and class III/IV (368.1±170.8μg/mL, p <0.001) patients had statistically decreased levels of plasma apoA-IV when compared to the control subjects. A stepwise multivariate regression analysis identifiedtypes of ACS, NYHA classes, and plasma fibrinogen levels as the most importantdeterminants of plasma apoA-IV levels in ACS patients.Recombinant human apoA-IV significantly inhibited human platelet PAC-1expressionand fibrinogen binding, and decreased the release of CD62P from α particle in activatedplatelets. No targets of recombinant apoA-IV could be identified on platelets byco-immunoprecipitation. Recombinant apoA-IV did not competitively bind to GPIIb/IIIatransfected CHO cells on fibrinogen-coated surface. Significant expression of ABCG1andSRB1was confirmed in platelets by western blotting.ConclusionsIn CHD patients, on confirmed aspirin adherence, aspirin-resistant patients exhibit anincreased risk of MACEs compared with aspirin-sensitive patients. And personalizedantiplatelet treatment for antiplatelet resistance is associated with less occurrence of deathor stent thrombosis and the less risk of total clinical adverse events than conventionaltreatment, without increasing the risk of bleeding complications. Low plasma apoA-IVlevels are decreased in ACS patients, and recombinant human apoA-IV can inhibit humanplatelet activation in vitro. ApoA-IV as a cholesterol acceptor collects cholesterol fromplatelet surface by cholesterol transporters ABCG1and SRB1, thereby affecting plateletmembrane lipid structure, which could be the potential underlying mechanism. This helpsus to explore an effective antiplatelet agent, and a novel strategy for tailored antiplatelettreatment. |
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