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Background The pathophysiological mechanism behind adverse outcomes associated with ischemia-inducing epicardial coronary stenoses and microcirculatory dysfunction remains unclear. Wall shear stress (WSS) plays an important role in atherosclerotic plaque progression and vulnerability. We aimed to evaluate the relationship between WSS, functionally significant epicardial coronary stenoses, and microcirculatory dysfunction. Methods and Results Patients undergoing invasive coronary physiology testing were included. Fractional flow reserve, instantaneous wave-free ratio, and the index of microcirculatory resistance were measured. Quantitative coronary angiography was used to obtain the lesion percentage diameter stenosis. Computational fluid dynamics analysis was performed to calculate WSS parameters. Multiple regression analysis was performed to calculate the standardized regression coefficient (β) for the coronary physiology indices. A total of 107 vessels from 88 patients were included. Fractional flow reserve independently predicted the total area of low WSS (β=-0.44; 95% CI, -0.62 to -0.25; P <0.001) and maximum lesion WSS (β=-0.53; 95% CI, -0.70 to -0.36; P <0.001) after adjusting for percentage diameter stenosis and index of microcirculatory resistance. Similarly, instantaneous wave-free ratio also independently predicted the total area of low WSS (β=-0.45; 95% CI, -0.62 to -0.28; P <0.001) and maximum lesion WSS (β=-0.58; 95% CI, -0.73 to -0.43; P <0.001). The index of microcirculatory resistance did not predict either low or high WSS. Conclusions Fractional flow reserve and instantaneous wave-free ratio independently predicted the total burden of low WSS and maximum lesion WSS in coronary arteries. No relationship was found between microcirculatory dysfunction and WSS.

Background: Brief nonharmful ischemia, remote ischemic preconditioning (RIPC) has been proposed to confer benefit to patients with coronary artery disease via unknown mechanisms., Objectives: We aimed to investigate the effect of RIPC on circulating levels of extracellular vesicles (EVs) and global coagulation and fibrinolytic factors in patients with coronary disease., Patients/methods: Blood samples were taken from 60 patients presenting for coronary angiography enrolled in a randomized, controlled trial before and after RIPC (3 × 5 min administration of 200 mmHg sphygmomanometer on the arm, n = 31) or sham (n = 29) treatment. Most patients (n = 48) had significant coronary artery disease and all were taking at least one antiplatelet agent., Results: Remote ischemic preconditioning significantly decreased circulating levels of EVs expressing platelet markers CD41 and CD61 detected by flow cytometry in plasma, whereas no such effect was found on EVs expressing phosphatidylserine, CD62P, CD45, CD11b, CD144, CD31 + /CD41 - , or CD235a. RIPC had no effect on the overall hemostatic potential assay or circulating antigen levels of tissue plasminogen activator, urokinase, plasminogen activator inhibitor-1, or plasminogen. Sham treatment had no effect on any studied parameter. Statin use inhibited the effect of RIPC on CD61 + EVs, diabetes modified the effect of RIPC on CD45 + and CD11b + EVs, and hypertension modified the effect of RIPC on CD235a + EVs., Conclusions: Remote ischemic preconditioning decreased circulating levels of platelet-derived EVs in patients with coronary disease taking conventional antiplatelet therapy. This may reflect increased EV clearance/uptake or change in production. Clinical variables may alter the effectiveness of RIPC., (© 2021 International Society on Thrombosis and Haemostasis.)

Objectives: We investigated whether remote ischemic preconditioning (RIPC) inhibits agonist-induced conformational activation of platelet α IIb β 3 in patients with coronary artery disease already receiving conventional antiplatelet therapy., Patients/methods: Consecutive patients with angiographically confirmed coronary artery disease were randomized to RIPC or sham treatment. Venous blood was collected before and immediately after RIPC/sham. Platelet aggregometry (ADP, arachidonic acid) and whole blood platelet flow cytometry was performed for CD62P, CD63, active α IIb β 3 (PAC-1 binding) before and after stimulation with ADP, thrombin ± collagen, or PAR-1 thrombin receptor agonist., Results: Patients (25 RIPC, 23 sham) were well matched, 83% male, age (mean ± standard deviation) 63.3 ± 13.2 years, 95% aspirin, 81% P2Y 12 inhibitor. RIPC did not affect platelet aggregation, nor agonist-induced expression of CD62P, but selectively and significantly decreased α IIb β 3 activation after stimulation with either PAR-1 agonist peptide or the combination of thrombin + collagen, but not after ADP nor thrombin alone. The effect of RIPC on platelet α IIb β 3 activation was evident in patients receiving both aspirin and P2Y 12 inhibitor, and was not associated with an increase in vasodilator-stimulated phosphoprotein phosphorylation., Conclusions: Remote ischemic preconditioning inhibits conformational activation of platelet α IIb β 3 in response to exposure to thrombin and collagen in patients with coronary artery disease receiving dual antiplatelet therapy. These findings indicate agonist-specific inhibition of platelet activation by RIPC in coronary artery disease that is not obviated by the prior use of P2Y 12 inhibitors., (© 2020 International Society on Thrombosis and Haemostasis.)

Background Remote ischemic preconditioning (RIPC) attenuates myocardial damage during elective and primary percutaneous coronary intervention. Recent studies suggest that coronary microcirculatory function is an important determinant of clinical outcome. The aim of this study was to assess the effect of RIPC on markers of microcirculatory function. Methods and Results Patients referred for cardiac catheterization and fractional flow reserve measurement were randomized to RIPC or sham. Operators and patients were blinded to treatment allocation. Comprehensive physiological assessments were performed before and after RIPC/sham including the index of microcirculatory resistance and coronary flow reserve after intracoronary glyceryl trinitrate and during the infusion of intravenous adenosine. Thirty patients were included (87% male; mean age: 63.1±10.0 years). RIPC and sham groups were similar with respect to baseline characteristics. RIPC decreased the calculated index of microcirculatory resistance (median, before RIPC: 22.6 [interquartile range [IQR]: 17.9-25.6]; after RIPC: 17.5 [IQR: 14.5-21.3]; P=0.007) and increased coronary flow reserve (2.6±0.9 versus 3.8±1.7, P=0.001). These RIPC-mediated changes were associated with a reduction in hyperemic transit time (median: 0.33 [IQR: 0.26-0.40] versus 0.25 [IQR: 0.20-0.30]; P=0.010). RIPC resulted in a significant decrease in the calculated index of microcirculatory resistance compared with sham (relative change with treatment [mean±SD] was -18.1±24.8% versus +6.1±37.5; P=0.047) and a significant increase in coronary flow reserve (+41.2% [IQR: 20.0-61.7] versus -7.8% [IQR: -19.1 to 10.3]; P<0.001). Conclusions The index of microcirculatory resistance and coronary flow reserve are acutely improved by remote ischemic preconditioning. This raises the possibility that RIPC confers cardioprotection during percutaneous coronary intervention as a result of an improvement in coronary microcirculatory function. Clinical Trial Registration URL: www.anzctr.org.au/ . Unique identifier: CTRN12616000486426.

Essentials Procoagulant platelets can be detected using GSAO in human whole blood. Stable coronary artery disease is associated with a heightened procoagulant platelet response. Agonist-induced procoagulant platelet response is not inhibited by aspirin alone. Collagen plus thrombin induced procoagulant platelet response is partially resistant to clopidogrel., Summary: Background Procoagulant platelets are a subset of highly activated platelets with a critical role in thrombin generation. Evaluation of their clinical utility in thrombotic disorders, such as coronary artery disease (CAD), has been thwarted by the lack of a sensitive and specific whole blood assay. Objectives We developed a novel assay, utilizing the cell death marker, GSAO [(4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid], and the platelet activation marker, P-selectin, to identify procoagulant platelets in whole blood by flow cytometry. Patients/Methods Using this assay, we characterized the procoagulant platelet population in healthy controls and a cohort of patients undergoing elective coronary angiography. Results In patients with CAD, compared with patients without CAD, there was a heightened procoagulant platelet response to thrombin (25.2% vs. 12.2%), adenosine diphosphate (ADP) (7.8% vs. 2.7%) and thrombin plus collagen (27.2% vs. 18.3%). The heightened procoagulant platelet potential in CAD patients was not associated with other markers of platelet function, including aggregation, dense granule release and activation of α 2b β 3 integrin. Although dual antiplatelet therapy (DAPT) was associated with partial suppression of procoagulant platelets, this inhibitory effect on a patient level could not be predicted by aggregation response to ADP and was not fully suppressed by clopidogrel. Conclusions We report for the first time that procoagulant platelets can be efficiently detected in a few microliters of whole blood using the cell death marker, GSAO, and the platelet activation marker, P-selectin. A heightened procoagulant platelet response may provide insight into the thrombotic risk of CAD and help identify a novel target for antiplatelet therapies in CAD., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)