| Background:Cardiac remote ischemic preconditioning (RIPC) by means of skeletal muscle ischemia and reperfusion (I/R) is a promising strategy for myocardial protection. However, transient and repeated interruption of blood flow will influence the biochemical milieu of skeletal muscle, and may give rise to systemic impact on platelet aggregation.Objective:This work was aimed to determine whether this novel method has clinically relevant impact on platelet aggregability, and was designed to investigate potential factors that involved in this process.Method:We enrolled 31 healthy volunteers in Pingjin Hospital,Medical College of Chinese People's Armed Police Forces during Jun 16,2009 to Jul 26,2009.The research protocol was approved by the ethical committee of Pingjin Hospital.All participants provided written informed consent. We used a standard skeletal muscle I/R protocol (three 5-min cycles of unilateral upper arm I/R by blood pressure at 200 mmHg),and serially measured adenosine diphosphate (ADP)-induced platelet aggregation, and related biochemical changes at baseline,60min after skeletal muscle I/R, and 24 hours after skeletal muscle I/R. Platelet aggregation was performed by light transmission aggregometry. Plasma levels of high-sensitivity C reactive protein (hsCRP),tissue factor (TF),myoglobin and plasminogen activator inhibitor-1 (PAI-1) levels were measured using commercially available ELISA kits.Result:According to the criteria for volunteer Eligibility, data from 24 healthy subjects,including 8 women and 16 men (mean age 30.7±1.4 years;mean waist to hip ratio 0.84±0.1;mean body mass index 22.1±0.5 Kg/m2),were entered for final analysis.All participants finished the research protocol and thrice blood samplings. There was no significant changes of plasma potassium and PAI-1 levels across time (potassium:4.5±0.1 mmol/L,4.5±0.1 mmol/L and 4.4±0.1 mmol/L,for three different time points respectively, P=0.568 for trend; and PAI-1:14.6±0.2 ng/mL,14.6±0.3 ng/mL and 14.5±0.2 ng/mL, for three different time points respectively,P=0.848 for trend).And no significant change of platelet aggregation was observed in all participants across time. There is an inter-individual variability of platelet aggregation to transient limb I/R. To explore potential clinical parameters associated with this inter-individual heterogenicity, all participants were dichotomized according to their responsiveness. An individual's platelet reactivity to transient limb I/R, defined as an absolute change of aggregation (AA), was calculated by aggregation (after ischemia) minus aggregation (before ischemia).IfΔA≥10%, the individual was categorized as "hyper-responder", otherwise classified as "non/hypo-responder".After I/R, and 24h later, hsCRP levels and AhsCRP in non/hypo-responders were significantly higher than those of hyper-responders.There was no significant change of plasma hsCRP levels at any time points in hyper-responders (P=0.450).On the contrary, hsCRP levels in non/hypo-responders exhibited a significant increase immediately after I/R, and this trend persisted till 24h later (P=0.047).In addition, AA was negatively correlated with AhsCRP(r=-0.411,P=0.046)Conclusion:In summary, in the present work we investigated the potential safety considerations after a three 5-min cycles limb I/R procedure in healthy volunteers.In general,this procedure is well-tolerated, and has no obvious impact on ADP-induced platelet aggregation, except for a transient elevation of circulating TF.However, the individual's response of platelet aggregability to limb I/R is differential,and is associated with change of plasma CRP level.These observations underscore the necessity of dissecting clinical characteristics and screening for genetic candidates and/or biomarkers underlying these phenotypes that aim to reduce potential thromboembolic events in conjunction with efforts to enhance myocardial protection by means of cardiac RIPC.
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