Contribution of platelet-derived circFAM13B to the antiplatelet effectiveness of ticagrelor in patients with acute coronary syndrome

Contribution of platelet-derived circFAM13B to the antiplatelet effectiveness of ticagrelor in patients with acute coronary syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Contribution of platelet-derived circFAM13B to the antiplatelet effectiveness of ticagrelor in patients with acute coronary syndrome Yuting Zou, Yuyan Wang, Yanzhu Yao, Yangxun Wu, Chao Lv, Tong Yin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4242438/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Platelet is enriched with Circular RNAs (circRNAs), with circFAM13B rank among the 10 most abundant circRNAs in platelets. The aim of the present study was to evaluate the predictive value of platelet-derived circFAM13B for the antiplatelet responsiveness and efficacy of ticagrelor in patients with acute coronary syndrome (ACS). Methods: Consecutive ACS patients treated with ticagrelor were enrolled, and the antiplatelet responsiveness of 3 days of ticagrelor maintenance treatment was assessed by measuring the adenosine diphosphate (ADP)-induced platelet inhibition rate (ADP%) using thromboelastography. The expression of circFAM13B in the patients' platelets was analyzed by quantitative real-time polymerase chain reaction. The correlation between circFAM13B expression and ticagrelor antiplatelet responsiveness, as well as the independent contribution of circFAM13B to the composite of adverse ischemic events during a follow-up period of at least 12 months was evaluated. Results: A total of 129 eligible ACS patients treated with ticagrelor were enrolled in the study. A negative correlation was found between the expression of circFAM13B and the ADP% value (r = -0.41, P < 0.001). Patients with ADP% ≥ 76% had a significantly lower level of circFAM13B compared to those with ADP% 1.05 with clinical risk factors could effectively predict the risk of adverse ischemic events (AUC = 0.81, 95% CI: 0.69 to 0.92, P 1.05 had a significantly higher risk of adverse ischemic events compared to those with circFAM13B ≤ 1.05 (P = 0.003). Multivariate logistic hazard analysis identified circFAM13B > 1.05 as an independent risk factor for adverse ischemic events in in ticagrelor-treated ACS patients (adjusted OR: 5.60, 95% CI: 1.69–18.50; P = 0.005). Conclusions: Platelet-derived circFAM13B could be utilized for predicting the antiplatelet responsiveness and efficacy of ticagrelor in patients with ACS. platelet circFAM13B anti-platelet efficacy ticagrelor acute coronary syndrome Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Acute coronary syndrome (ACS) is the most prevalent and fatal clinical manifestation of cardiovascular disease. It is widely acknowledged that platelet aggregation plays an essential role in the pathogenesis of ACS. Dual antiplatelet therapy (DAPT) with a P2Y12 receptor inhibitor and aspirin is the standard treatment for patients with ACS. Ticagrelor, as the first reversible oral P2Y12 inhibitor with more potent antiplatelet effects than clopidogrel, is recommended for the treatment of patients with ACS [ 1 – 3 ]. Despite the widely recognized benefit of ticagrelor, there is still variation in anti-platelet responsiveness and residual risk of ischemic events in ACS patients treated with ticagrelor [ 4 – 7 ]. Therefore, how to predict the occurrence of adverse events in ticagrelor-treated patients is crucial for personalized antiplatelet therapy in patients with ACS. Platelets, as the main effectors of hemostasis and thrombosis, have been found to have an abundance of non-coding RNAs (ncRNAs) [ 8 , 9 ]. Compared to other hematopoietic cell types, platelets show a higher proportion of Circular RNAs (circRNAs), attributed to the general degradation of linear RNAs during the lifetime of platelets [ 10 ]. CircRNAs are generated through a unique mode of alternative splicing of pre-mRNAs, which are much more suitable as biomarkers due to the higher biological stability with the circular configuration and resistance to exoribonucleolytic degradation [ 10 – 12 ]. CircFAM13B was one of the 10 most abundant circRNAs predicted in platelets [ 11 ]. Previous studies have indicated that varying circFAM13B expression profiles in carcinomas suggest the potential value of circFAM13B as a biomarker for cancer treatment [ 13 – 15 ]. However, the predictive significance of platelet-derived circFAM13B in relation to the effectiveness of antiplatelet treatment has not been recognized. The aim of the present study was to evaluate the predictive value of platelet-derived circFAM13B in determining the antiplatelet efficacy of ticagrelor in patients with ACS. Material and methods Patient recruitment In the study, ticagrelor-treated patients with ACS were consecutively recruited from April 2020 to December 2021 in the Department of Cardiology, Chinese PLA General Hospital. All the enrolled patients received a maintenance dose of ticagrelor 90 mg twice daily after admission. Patients were excluded from the study if they were under 18 years old, had a history of hematologic diseases or a tendency to bleed within the last three months, a known contraindication to ticagrelor treatment, a history of serious surgery and deep puncture wounds, or severe hepatic and renal dysfunction with a life expectancy of less than 1 year. The study was approved by the institutional ethics committee of the Chinese PLA General Hospital and conducted in accordance with the declaration of Helsinki. All enrolled patients signed informed consent. Measurement of ticagrelor antiplatelet responsiveness The antiplatelet responsiveness of ticagrelor was measured for each patient using the Thromboelastography (TEG) Hemostasis Analyzer (Lepu Medical Technology, Beijing) with platelet mapping analysis. Blood samples were obtained via peripheral venipuncture after 3 days of maintenance treatment with ticagrelor, and were detected within 2 hours according to the manufacturer's instructions. The TEG system measures the maximum amplitude (MA), which is a direct parameter that reflects the maximum clot strength. The TEG system is capable of measuring thrombin-induced platelet fibrin clot strength (MA thrombin ) and ADP-induced platelet fibrin clot strength (MA ADP ), as well as MA generated by fibrin (MA fibrin ). The ticagrelor antiplatelet responsiveness was evaluated according to the calculation of the ADP-induced platelet inhibition rate (ADP%) as the following formula: ADP% = [1-(MA ADP –MA fibrin )/ (MA thrombin – MA fibrin )] × 100% [ 16 – 18 ]. The expression of circFAM13B in platelet Platelets were isolated from all enrolled patients. The expression of the circFAM13B was measured in platelets. The total RNA isolation was carried out using the high-purity total RNA isolation kit (# R1002, SinoGene, China) according to the manufacturer’s instructions. The RNA samples were then subjected to the preparation of cDNA samples using the Thermo First cDNA Synthesis Kit (# Q1010, SinoGene, China). With GAPDH serving as the internal reference, cDNA samples were used in qPCR to measure the relative expression levels of circFAM13B. RT-qPCRs were performed by 2×SG Green qPCR Mix (with ROX) (# Q1002, SinoGene, China) with the standard protocol on StepOnePLUS (Applied Biosystems, USA). All experiments were performed on three biological replicates. Ct thresholds were determined by the software. The expression of circFAM13B was normalized using the 2-ΔΔct method. Primer sequences were as follows: has-circ- 0001535 forward, 5′-CAATGAAGCTATGCAGCAAGA-3′ and reverse, 5′-CAAAAAGGTGCTGTTCCACA-3′; GADPH forward, 5′-GAAGGTGAAGGTCGGAGTC-3′ and reverse, 5′- GAAGATGGTGATGGGATTTC-3′. PCR thermal conditions were as follows: 10 min at 95°C and then 40 cycles of 20 s at 95°C and 30s at 60°C. Endpoints and follow-up The primary endpoint was the antiplatelet responsiveness of post 3 days of maintenance treatment of ticagrelor measured by TEG with the value of ADP% lower than 76%. The cut-off value was chosen as reflective of high on-treatment platelet reactivity (HTPR) under ticagrelor treatment and to predict adverse ischemic events [ 16 ]. The secondary endpoints were adverse ischemic events defined as all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, stent thrombosis and rehospitalization for unstable angina (UA). Patients were followed up for at least 12 months after discharge to identify the occurrence of adverse ischemic events. Statistical analysis Categorical variables are expressed as n (%) and were compared using the χ2 test. The Kolmogorov–Smirnov test was used to check for the normal distribution of continuous data. Continuous variables expressed as the mean ± standard deviation (SD) or median (interquartile range [IQR]) were compared using the t-test or Mann‒Whitney U test based on their distributions. The Pearson correlation test was utilized to evaluate the correlation between the expression level of circFAM13B and the ADP% measured by TEG. Univariate and multivariate logistic regression analysis was carried out to determine the independent predictive capability of the circFAM13B on the primary and secondary endpoints. Multivariate logistic regression analysis was adjusted for age, smoking, history of stroke, diabetes mellitus, prior percutaneous coronary intervention (PCI) and 3-vessel diseases of coronary artery. The role of circFAM13B in predicting adverse ischemic events was analyzed by performing ROC curve analysis. Kaplan–Meier estimates of adverse ischemic events were used to construct time-to-event curves according to the optimal cut-off level (relative expression of circFAM13B > 1.05). All statistical analysis was performed by the software of SPSS Statistics 22.0 (SPSS, Inc., Chicago, IL, USA), R (version 3.6.0) and GraphPad Prism 8. All p values were two-sided, with the P value < 0.05 as statistically significant. Results Patient characteristics The basic clinical characteristics of the consecutively recruited 129 ACS patients treated with ticagrelor enrolled for the study were summarized in Table 1 . It showed that the mean age of the enrolled patients was 60.76 ± 7.68 years old. According to the inclusion and exclusion criteria, 15 (11.63%) patients with STEMI, 15 (11.63%) patients with NSTEMI, and 99 (76.74%) patients with UA were finally included in the analysis. The proportion of ACS patients undergoing PCI was 97.67% in the whole study. Table 1 Baseline clinical characteristics of the patients with ACS Clinical characteristics Total (n = 129) Age, (mean ± SD) y 60.76 ± 7.68 Male, n (%) 104 (80.62) BMI, (mean ± SD) kg/m² 25.60 ± 3.25 Smoking, n (%) 61 (47.29) Drinking, n (%) 62 (48.06) Hypertension, n (%) 91 (70.54) Hyperlipidemia, n (%) 34 (26.36) Diabetes mellitus, n (%) 44 (34.11) Prior MI, n (%) 25 (19.38) Prior PCI, n (%) 44 (34.11) History of stroke, n (%) 15 (11.63) Clinical diagnosis STEMI, n (%) 15 (11.63) NSTEMI, n (%) 15 (11.63) UA, n (%) 99 (76.74) Undergoing PCI, n (%) 126 (97.67) Number of diseased vessels for PCI 1-vessel, n (%) 21 (16.28) 2-vessel, n (%) 42 (32.56) 3-vessel, n (%) 61 (47.29) LVEF, median (IQR) % 61 (56,64) ACEI/ARB, n (%) 55 (42.64) β-Blockers, n (%) 81 (62.79) CCB, n (%) 38 (29.46) PPI, n (%) 81(62.79) Statins, n (%) 124 (96.12) Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; BMI, body mass index; BUN, blood urea nitrogen; CCB, calcium channel blockers; MI, myocardial infarction; NSTEMI, Non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PPI, proton pump inhibitors; STEMI, ST-segment elevation myocardial infarction, UA, unstable angina. The ADP-induced platelet inhibition rate measured by TEG The majority of ACS patients have great responsiveness to 3 days of treatment with ticagrelor, with ADP% values measured by TEG skewed towards higher. The value of ADP% was 80.11% ± 17.17% on average (ranging from 10.60–99.80%) in all study patients. According to the cut-off value of ADP% < 76% which defines the patients with HTPR under ticagrelor treatment, 45 patients (34.88%) had ADP% <76% and 84 patients (65.12%) had ADP% ≥76% in all enrolled patients. The expression of platelet-derived circFAM13B To investigate the differential expression of circFAM13B in ACS patients treated with ticagrelor, platelet samples were obtained after ticagrelor treatment. The distribution of circFAM13B expression levels was measured by qRT-PCR, with an average expression level of 0.94 ± 0.88. The expression of circFAM13B derived from platelets was significantly higher in patients with ADP% < 76% who were treated with ticagrelor for ACS (1.27 ± 1.10 vs. 0.77 ± 0.67, P = 0.001). Association between the platelet-derived circFAM13B and ticagrelor antiplatelet responsiveness There is a negative correlation between circFAM13B levels and ADP% measured by TEG (r = -0.41, P < 0.001) (Fig. 1 ), and the expression of circFAM13B revealed a trend toward decline with increasing ADP% (Fig. 2 ). Compared to the patients with ADP% < 76%, those with ADP% ≥ 76% had significantly lower circFAM13B levels. In logistic regression analysis, we found that the platelet-derived circFAM13B was independently associated with ticagrelor antiplatelet responsiveness in ACS patients with the adjustment of clinical factors (including smoking, history of stroke, diabetes mellitus, prior PCI and 3-vessel diseases of the coronary arteries) (P = 0.009, Fig. 3 ). Contribution of the platelet-derived circFAM13B to the prediction of adverse ischemic events Follow-up was available at a median of 20 months (interquartile range: 19 to 36 months). A total of 20 (15.50%) patients had adverse ischemic events that occurred in our study. The all-cause mortality was found in 2 patients (1.55%), nonfatal MI in 2 patients (1.55%), nonfatal stroke in 3 patients (2.32%), and rehospitalization for UA in 13 patients (10.08%). A ROC analysis showed that the expression levels of circFAM13B could distinguish adverse ischemic events (AUC = 0.68, 95% CI: 0.55 to 0.81, P = 0.01) (Fig. 4 ). Overall, the relative expression of circFAM13B > 1.05 was identified as the optimal cut-off to predict the occurrence of adverse ischemic events. We found that the cut-off value was an independent risk factor for adverse ischemic events in both the univariate (unadjusted OR: 3.71, 95% CI: 1.39–9.91; P = 0.009) and the multivariate logistic regression analysis (adjusted OR: 5.60, 95% CI: 1.69–18.50; P = 0.005) (Table 2 ). Moreover, combining the cut-off value (relative expression of circFAM13B > 1.05) with clinical risk factors, including smoking, history of stroke, diabetes mellitus, prior PCI, and 3-vessel diseases of the coronary artery, improved the ability to predict the occurrence of adverse ischemic events (AUC = 0.81, 95% CI: 0.69 to 0.92, P < 0.001) (Fig. 4 ) compared to clinical risk factors alone (AUC = 0.74, 95% CI: 0.63 to 0.84, P = 0.001) (Fig. 4 ). The Kaplan–Meier analysis for the adverse ischemic events based on circFAM13B ≤ 1.05 or circFAM13B > 1.05 in our study was shown in Fig. 5 . It was indicated that with the expression of circFAM13B > 1.05, the survival rates decreased (p = 0.003) (Figure. 5). Table 2. Association of the platelet derived expression of circFAM13B and clinical risk factors with adverse ischemic events in ticagrelor treated patients with ACS Variable Univariate analysis Multivariate analysis OR (95% CI) P Value OR (95% CI) P Value Relative expression of circFAM13B>1.05 3.71 (1.39-9.91) 0.009 5.60 (1.69-18.50) 0.005 Age 1.05 (0.98-1.12) 0.159 1.09 (1.01-1.18) 0.033 Smoking 1.14 (0.44-2.95) 0.792 2.20 (0.68-7.08) 0.186 History of stroke 0.82 (0.17-3.95) 0.805 0.51 (0.09-3.04) 0.459 Diabetes mellitus 2.21 (0.84-5.79) 0.108 3.64 (1.18-11.22) 0.024 Prior PCI 0.29 (0.08-1.06) 0.061 0.22 (0.05-0.94) 0.041 3-vessel diseases of coronary artery 0.70 (0.27-1.86) 0.479 0.77 (0.26-2.26) 0.636 Multivariate analysis was adjusted by age, smoking, history of stroke, diabetes mellitus, prior PCI and 3-vessel diseases of coronary artery. ACS, acute coronary syndrome; PCI, percutaneous coronary intervention. Adverse ischemic events defined as all-cause death, nonfatal myocardial infarction, nonfatal stroke, stent thrombosis and rehospitalization for unstable angina. Discussion The present study found that platelet-derived circFAM13B was correlated with the antiplatelet responsiveness and the occurrence of adverse ischemic events in ticagrelor treated patients with ACS. Therefore, circFAM13B might improve the ability to predict the occurrence of adverse ischemic events and could serve as one of the indicators to monitor antiplatelet treatment in patients with ACS. As far as we know, this is the first study to identify that platelet-derived circRNA could be informative for personalized antiplatelet therapy in patients with ACS. Consistent with previous study [ 19 ], the variability of ADP-induced platelet aggregation could be observed in ACS patients receiving the ticagrelor treatment. A prospective study demonstrated that 46.2% of patients with ST-segment elevation myocardial infarction displayed HTPR after a 2-hour loading dose of ticagrelor [ 20 ]. The relatively lower incidence of HTPR in the present study might be primarily due to the different timing of the test measurements. Ischemic events occurred in ACS patients treated with ticagrelor, with the incidence rate ranging from 3.6 to 10.3 [ 6 , 21 – 25 ]. The relatively higher incidence rate of ischemic events (15.5%) in the present study might be attributed to the inclusion of the rehospitalization for unstable angina. Our study aimed to explore whether platelet derived circFAM13B could affect the efficacy of the potent antithrombotic therapy of ticagrelor. As a 331bp circular RNA localized to chromosome 5, circFAM13B is highly expressed in the testis, endometrium, as well as testis, endometrium, and blood platelet [ 26 ]. Recent studies found the dysregulation of circFAM13B expression in bladder cancer [ 13 ], ovarian cancer [ 27 ] or hepatocellular carcinoma [ 14 ]. However, as one of the highly abundant circRNAs in human platelets [ 28 , 29 ], no study has investigated the role of circFAM13B in the platelets. In the present study, we discovered that independent of the traditional clinical risk factors, platelet-derived circFAM13B was associated with antiplatelet efficacy of ticagrelor, with higher expression of circFAM13B in ticagrelor treated patients with HTPR. Moreover, the increased expression of circFAM13B in the present cohort conferred a 5-fold higher risk of clinical ischemic events. Therefore, it suggested that circFAM13B might improve the predictability for the occurrence of adverse ischemic events in ACS patients treated with ticagrelor. Several limitations should be mentioned. Firstly, the present study as a single-center with a relatively small sample size, may require further large-scale and multicenter studies to verify the association of circFAM13B with platelet reactivity and adverse ischemic events in ticagrelor treated patients with ACS. Secondly, we did not investigate the mechanism of circFAM13B affects the platelet reactivity. However, using a bioinformatics prediction analysis tool, we found that circFAM13B has the potential binding sites on miR-126 ( http://mirwalk.umm.uni-heidelberg.de/ ) (data not shown). As a highly expressed platelet miRNA, miR-126 has been discovered to be associated with platelet reactivity as well as the efficacy of antithrombotic therapy [ 28 ] [ 30 ]. Therefore, we hypothesized that platelet-derived circFAM13B might interact with miR-126 to influence the antiplatelet reactivity of ticagrelor. Further basic research should be warranted to explore the potential mechanism. Thirdly, the study population in the present study was restricted to ACS patients treated with ticagrelor. Following studies required to encompass ACS patients treated with other P2Y12 receptor inhibitors (such as clopidogrel and prasugrel). Conclusion Platelets-derived circFAM13B is associated with platelet reactivity and the occurrence of ischemic events in ACS patients treated with ticagrelor. Further research should be conducted to verify the mechanism of circFAM13B in the regulation of platelet reactivity and the antiplatelet responsiveness. Abbreviations Abbreviations Full Name ACS acute coronary syndrome ADP adenosine diphosphate ADP% ADP-induced platelet inhibition rate AUC area under the curve CircRNAs circular RNAs DAPT dual antiplatelet therapy HTPR high on-treatment platelet reactivity IQR interquartile range MA maximum amplitude MA ADP ADP-induced platelet-fibrin clot strength MA fibrin Fibrin-induced clot strength MA Thrombin thrombin-induced clot strength MI myocardial infarction NcRNA non-coding RNA NSTEMI Non-ST segment elevation myocardial infarction PCI percutaneous coronary intervention ROC receiver operating characteristic curve STEMI ST-segment elevation myocardial infarction TEG Thromboelastography UA unstable angina Declarations Ethical Approval and Consent to participate The studies involving human participants were reviewed and approved by the institutional ethics committee of the Chinese PLA General Hospital. The patients/participants provided their written informed consent to participate in this study. Consent for publication Yes Availability of supporting data The data used to support the findings of this study are available from the corresponding author ( [email protected] ) upon request. Competing interests None Funding This work was supported by grants from the National Natural Science Foundation of China (No. 8217130415). Authors' contributions Study concept and design: Tong Yin, Yuting Zou, Yuyan Wang Acquisition of data: Yuting Zou, Yuyan Wang, Yanzhu Yao, Yangxun Wu, Chao Lv, Analysis and interpretation of data: Yuting Zou, Yuyan Wang, Tong Yin Drafting of the manuscript: Yuting Zou, Yanzhu Yao, Yangxun Wu, Chao Lv, Tong Yin Critical revision of the manuscript for important intellectual content: Tong Yin, Yuting Zou Acknowledgements The authors gratefully thank all study participants and all dedicated co-workers who helped to succeed this trial. Authors' information (optional) Authors: 1,2 Yuting Zou, 1 Yuyan Wang, 1 Yanzhu Yao, 1 Yangxun Wu, 1 Chao Lv, 1* Tong Yin Authors affiliations : 1 Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China 2 Senior Department of Cardiology, the 6th Medical Center, Chinese PLA General Hospital, Beijing, China Correspondence : * Tong Yin, MD, PhD Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Medical School of Chinese PLA and Chinese PLA General Hospital No.28 Fu Xing Road, Beijing 100853, China E-mail: [email protected] Email address: Yuting Zou: [email protected] Yuyan Wang: [email protected] Yanzhu Yao: [email protected] Yangxun Wu: [email protected] Chao Lv: [email protected] Tong Yin: [email protected] References Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, Claeys MJ, Dan GA, Dweck MR, Galbraith M, et al: 2023 ESC Guidelines for the management of acute coronary syndromes. 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Neu CT, Gutschner T, Haemmerle M: Post-Transcriptional Expression Control in Platelet Biogenesis and Function. Int J Mol Sci 2020, 21. Czajka P, Fitas A, Jakubik D, Eyileten C, Gasecka A, Wicik Z, Siller-Matula JM, Filipiak KJ, Postula M: MicroRNA as potential biomarkers of platelet function on antiplatelet therapy: A Review. Front Physiol 2021, 12:652579. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 29 Apr, 2024 Reviews received at journal 28 Apr, 2024 Reviewers agreed at journal 28 Apr, 2024 Reviews received at journal 13 Apr, 2024 Reviewers agreed at journal 11 Apr, 2024 Reviewers invited by journal 11 Apr, 2024 Editor assigned by journal 11 Apr, 2024 Submission checks completed at journal 10 Apr, 2024 First submitted to journal 09 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4242438","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290896115,"identity":"3fd5b644-fca4-41ff-a1e6-dee3b48e91de","order_by":0,"name":"Yuting Zou","email":"","orcid":"","institution":"Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center,Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuting","middleName":"","lastName":"Zou","suffix":""},{"id":290896117,"identity":"dec27976-665e-4bb7-81dd-b833ba5fc4d8","order_by":1,"name":"Yuyan Wang","email":"","orcid":"","institution":"Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center,Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuyan","middleName":"","lastName":"Wang","suffix":""},{"id":290896119,"identity":"d818bd2b-54c9-4f4d-bfb1-8e43014aa2e6","order_by":2,"name":"Yanzhu Yao","email":"","orcid":"","institution":"Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center,Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanzhu","middleName":"","lastName":"Yao","suffix":""},{"id":290896120,"identity":"3a60ddff-567b-4570-bce2-0af3d5cc9f6d","order_by":3,"name":"Yangxun Wu","email":"","orcid":"","institution":"Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center,Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yangxun","middleName":"","lastName":"Wu","suffix":""},{"id":290896121,"identity":"01e93e4c-9366-4a4f-9f04-dd5eb9d20876","order_by":4,"name":"Chao Lv","email":"","orcid":"","institution":"Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center,Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Lv","suffix":""},{"id":290896122,"identity":"1f455580-80be-4b62-a581-38d205fe233e","order_by":5,"name":"Tong Yin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYDACZghlx8bMfODAhx/EaWFsAFLJ/OxsiQdn9hBnD1gL48x+HuPDHGxEqDc4znv8wccdtcwGh3k+HGbgYZDnFztAQMthvsTGmWeO8xkc5t1wuMCCwXDm7ARCWngMm3nbjjGDtczgYUgwuE2kFsYNh3keHOZhI15LDePMZh4G4rRIArXMnNl2IJmfmc0AGMgShP3Cd/6MwYePbXV2bPyHH3/48MNGnl+agBaFA2DqMIwvgV85CMg3gKk6wipHwSgYBaNg5AIAEAxHIKEWXX8AAAAASUVORK5CYII=","orcid":"","institution":"Institute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center,Chinese PLA General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tong","middleName":"","lastName":"Yin","suffix":""}],"badges":[],"createdAt":"2024-04-09 13:57:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4242438/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4242438/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54930038,"identity":"6140ba5e-f249-4ae5-a1cd-daa660f5eb76","added_by":"auto","created_at":"2024-04-18 18:01:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21062,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between the relative expression of platelet derived circFAM13B and ADP% measured by TEG in ticagrelor-treated patients with ACS.\u003c/strong\u003e ADP%, adenosine diphosphate (ADP)-induced platelet inhibition rate; TEG, thromboelastography; ACS, acute coronary syndrome.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4242438/v1/2c70bb8fa845c143bba587a1.png"},{"id":54930039,"identity":"808c7b98-7687-433f-bd8f-48c10d1a382c","added_by":"auto","created_at":"2024-04-18 18:01:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":28924,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBar charts summarized the average relative expression of circFAM13B presenting with ADP%\u003c/strong\u003e \u003cstrong\u003edistribution in ticagrelor-treated patients with ACS.\u003c/strong\u003e ADP%, adenosine diphosphate (ADP)-induced platelet inhibition rate; ACS, acute coronary syndrome.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4242438/v1/d4ada1be498be83e861f3202.png"},{"id":54930030,"identity":"db1ba0d9-12cf-45c7-b7ba-3dc1ca092c30","added_by":"auto","created_at":"2024-04-18 18:01:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":27806,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe expression of the platelet derived circFAM13B was presented relative to GAPDH based on double calculations of 2\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e−ΔΔCt\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e. The relative expression of platelet derived circFAM13B in ADP% value \u0026lt; 76% and ≥ 76% in ticagrelor treated patients with ACS . \u003c/strong\u003e\u003csup\u003e*\u003c/sup\u003eAdjusted by the covariates of age, smoking, history of stroke, 3-vessel diseases of coronary artery, diabetes mellitus and prior PCI. ADP%, adenosine diphosphate (ADP) induced platelet inhibition rate measured by thrombelastography.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4242438/v1/6cc8776c595ddf0f4def5a2a.png"},{"id":54930037,"identity":"11f3934f-8927-46aa-b218-0c5ce406652c","added_by":"auto","created_at":"2024-04-18 18:01:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":23585,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReceiver-operating characteristic curve for the prediction of adverse ischemic events in ticagrelor-treated patients with ACS according to the platelet derived circFAM13B with the relative expression level \u0026gt;1.05 (dot line), clinical risk factors (solid and dot line), and the combination of circFAM13B and clinical risk factors (solid line).\u003c/strong\u003e The clinical risk factors include age, smoking, history of stroke, 3-vessel diseases of coronary artery, diabetes mellitus, and prior PCI. AUC, area under the curve.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4242438/v1/2b0b9437abe06740e65d2319.png"},{"id":54930033,"identity":"96d35bec-c6a4-4018-bce2-02b5aea20775","added_by":"auto","created_at":"2024-04-18 18:01:28","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":34082,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier survival curves for the adverse ischemic events within a follow-up of a median of 20 months in ticagrelor treated patients with ACS grouped according to the relative expression of platelet derived circFAM13B with the threshold of 1.05. \u003c/strong\u003eACS, acute coronary syndrome.\u003c/p\u003e","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4242438/v1/c72c00e3f985d4eeaa937737.png"},{"id":54930080,"identity":"27468a04-d2a9-40e0-a53a-bfdc72b306ca","added_by":"auto","created_at":"2024-04-18 18:01:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":896598,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4242438/v1/b298bf65-26b4-4888-bce5-1aa67316b5cd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Contribution of platelet-derived circFAM13B to the antiplatelet effectiveness of ticagrelor in patients with acute coronary syndrome","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute coronary syndrome (ACS) is the most prevalent and fatal clinical manifestation of cardiovascular disease. It is widely acknowledged that platelet aggregation plays an essential role in the pathogenesis of ACS. Dual antiplatelet therapy (DAPT) with a P2Y12 receptor inhibitor and aspirin is the standard treatment for patients with ACS. Ticagrelor, as the first reversible oral P2Y12 inhibitor with more potent antiplatelet effects than clopidogrel, is recommended for the treatment of patients with ACS [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite the widely recognized benefit of ticagrelor, there is still variation in anti-platelet responsiveness and residual risk of ischemic events in ACS patients treated with ticagrelor [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, how to predict the occurrence of adverse events in ticagrelor-treated patients is crucial for personalized antiplatelet therapy in patients with ACS.\u003c/p\u003e \u003cp\u003ePlatelets, as the main effectors of hemostasis and thrombosis, have been found to have an abundance of non-coding RNAs (ncRNAs) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Compared to other hematopoietic cell types, platelets show a higher proportion of Circular RNAs (circRNAs), attributed to the general degradation of linear RNAs during the lifetime of platelets [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. CircRNAs are generated through a unique mode of alternative splicing of pre-mRNAs, which are much more suitable as biomarkers due to the higher biological stability with the circular configuration and resistance to exoribonucleolytic degradation [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. CircFAM13B was one of the 10 most abundant circRNAs predicted in platelets [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Previous studies have indicated that varying circFAM13B expression profiles in carcinomas suggest the potential value of circFAM13B as a biomarker for cancer treatment [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the predictive significance of platelet-derived circFAM13B in relation to the effectiveness of antiplatelet treatment has not been recognized.\u003c/p\u003e \u003cp\u003eThe aim of the present study was to evaluate the predictive value of platelet-derived circFAM13B in determining the antiplatelet efficacy of ticagrelor in patients with ACS.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient recruitment\u003c/h2\u003e \u003cp\u003eIn the study, ticagrelor-treated patients with ACS were consecutively recruited from April 2020 to December 2021 in the Department of Cardiology, Chinese PLA General Hospital. All the enrolled patients received a maintenance dose of ticagrelor 90 mg twice daily after admission. Patients were excluded from the study if they were under 18 years old, had a history of hematologic diseases or a tendency to bleed within the last three months, a known contraindication to ticagrelor treatment, a history of serious surgery and deep puncture wounds, or severe hepatic and renal dysfunction with a life expectancy of less than 1 year. The study was approved by the institutional ethics committee of the Chinese PLA General Hospital and conducted in accordance with the declaration of Helsinki. All enrolled patients signed informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMeasurement of ticagrelor antiplatelet responsiveness\u003c/h2\u003e \u003cp\u003eThe antiplatelet responsiveness of ticagrelor was measured for each patient using the Thromboelastography (TEG) Hemostasis Analyzer (Lepu Medical Technology, Beijing) with platelet mapping analysis. Blood samples were obtained via peripheral venipuncture after 3 days of maintenance treatment with ticagrelor, and were detected within 2 hours according to the manufacturer's instructions. The TEG system measures the maximum amplitude (MA), which is a direct parameter that reflects the maximum clot strength. The TEG system is capable of measuring thrombin-induced platelet fibrin clot strength (MA\u003csub\u003ethrombin\u003c/sub\u003e) and ADP-induced platelet fibrin clot strength (MA\u003csub\u003eADP\u003c/sub\u003e), as well as MA generated by fibrin (MA\u003csub\u003efibrin\u003c/sub\u003e). The ticagrelor antiplatelet responsiveness was evaluated according to the calculation of the ADP-induced platelet inhibition rate (ADP%) as the following formula: ADP% = [1-(MA\u003csub\u003eADP\u003c/sub\u003e\u0026ndash;MA\u003csub\u003efibrin\u003c/sub\u003e)/ (MA\u003csub\u003ethrombin\u003c/sub\u003e\u0026ndash; MA \u003csub\u003efibrin\u003c/sub\u003e)] \u0026times; 100% [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eThe expression of circFAM13B in platelet\u003c/h2\u003e \u003cp\u003ePlatelets were isolated from all enrolled patients. The expression of the circFAM13B was measured in platelets. The total RNA isolation was carried out using the high-purity total RNA isolation kit (# R1002, SinoGene, China) according to the manufacturer\u0026rsquo;s instructions. The RNA samples were then subjected to the preparation of cDNA samples using the Thermo First cDNA Synthesis Kit (# Q1010, SinoGene, China). With GAPDH serving as the internal reference, cDNA samples were used in qPCR to measure the relative expression levels of circFAM13B. RT-qPCRs were performed by 2\u0026times;SG Green qPCR Mix (with ROX) (# Q1002, SinoGene, China) with the standard protocol on StepOnePLUS (Applied Biosystems, USA). All experiments were performed on three biological replicates. Ct thresholds were determined by the software. The expression of circFAM13B was normalized using the 2-ΔΔct method. Primer sequences were as follows: has-circ- 0001535 forward, 5\u0026prime;-CAATGAAGCTATGCAGCAAGA-3\u0026prime; and reverse, 5\u0026prime;-CAAAAAGGTGCTGTTCCACA-3\u0026prime;; GADPH forward, 5\u0026prime;-GAAGGTGAAGGTCGGAGTC-3\u0026prime; and reverse, 5\u0026prime;- GAAGATGGTGATGGGATTTC-3\u0026prime;. PCR thermal conditions were as follows: 10 min at 95\u0026deg;C and then 40 cycles of 20 s at 95\u0026deg;C and 30s at 60\u0026deg;C.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints and follow-up\u003c/h2\u003e \u003cp\u003eThe primary endpoint was the antiplatelet responsiveness of post 3 days of maintenance treatment of ticagrelor measured by TEG with the value of ADP% lower than 76%. The cut-off value was chosen as reflective of high on-treatment platelet reactivity (HTPR) under ticagrelor treatment and to predict adverse ischemic events [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The secondary endpoints were adverse ischemic events defined as all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, stent thrombosis and rehospitalization for unstable angina (UA). Patients were followed up for at least 12 months after discharge to identify the occurrence of adverse ischemic events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables are expressed as n (%) and were compared using the χ2 test. The Kolmogorov\u0026ndash;Smirnov test was used to check for the normal distribution of continuous data. Continuous variables expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (interquartile range [IQR]) were compared using the t-test or Mann‒Whitney U test based on their distributions. The Pearson correlation test was utilized to evaluate the correlation between the expression level of circFAM13B and the ADP% measured by TEG. Univariate and multivariate logistic regression analysis was carried out to determine the independent predictive capability of the circFAM13B on the primary and secondary endpoints. Multivariate logistic regression analysis was adjusted for age, smoking, history of stroke, diabetes mellitus, prior percutaneous coronary intervention (PCI) and 3-vessel diseases of coronary artery. The role of circFAM13B in predicting adverse ischemic events was analyzed by performing ROC curve analysis. Kaplan\u0026ndash;Meier estimates of adverse ischemic events were used to construct time-to-event curves according to the optimal cut-off level (relative expression of circFAM13B\u0026thinsp;\u0026gt;\u0026thinsp;1.05). All statistical analysis was performed by the software of SPSS Statistics 22.0 (SPSS, Inc., Chicago, IL, USA), R (version 3.6.0) and GraphPad Prism 8. All p values were two-sided, with the P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 as statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eThe basic clinical characteristics of the consecutively recruited 129 ACS patients treated with ticagrelor enrolled for the study were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. It showed that the mean age of the enrolled patients was 60.76\u0026thinsp;\u0026plusmn;\u0026thinsp;7.68 years old. According to the inclusion and exclusion criteria, 15 (11.63%) patients with STEMI, 15 (11.63%) patients with NSTEMI, and 99 (76.74%) patients with UA were finally included in the analysis. The proportion of ACS patients undergoing PCI was 97.67% in the whole study.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline clinical characteristics of the patients with ACS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eClinical characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;129)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD) y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.76\u0026thinsp;\u0026plusmn;\u0026thinsp;7.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104 (80.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBMI, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD) kg/m\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.60\u0026thinsp;\u0026plusmn;\u0026thinsp;3.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSmoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (47.29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDrinking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (48.06)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHypertension, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91 (70.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHyperlipidemia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (26.36)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDiabetes mellitus, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (34.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrior MI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (19.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrior PCI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (34.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHistory of stroke, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (11.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eClinical diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSTEMI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (11.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNSTEMI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (11.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eUA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99 (76.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eUndergoing PCI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e126 (97.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eNumber of diseased vessels for PCI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e1-vessel, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (16.28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e2-vessel, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (32.56)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3-vessel, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e61 (47.29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLVEF, median (IQR) %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (56,64)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eACEI/ARB, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (42.64)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eβ-Blockers, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 (62.79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCCB, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (29.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePPI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81(62.79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStatins, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124 (96.12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; BMI, body mass index; BUN, blood urea nitrogen; CCB, calcium channel blockers; MI, myocardial infarction; NSTEMI, Non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PPI, proton pump inhibitors; STEMI, ST-segment elevation myocardial infarction, UA, unstable angina.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eThe ADP-induced platelet inhibition rate measured by TEG\u003c/h2\u003e \u003cp\u003eThe majority of ACS patients have great responsiveness to 3 days of treatment with ticagrelor, with ADP% values measured by TEG skewed towards higher. The value of ADP% was 80.11% \u0026plusmn; 17.17% on average (ranging from 10.60\u0026ndash;99.80%) in all study patients. According to the cut-off value of ADP% \u0026lt; 76% which defines the patients with HTPR under ticagrelor treatment, 45 patients (34.88%) had ADP% \u0026lt;76% and 84 patients (65.12%) had ADP% \u0026ge;76% in all enrolled patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eThe expression of platelet-derived circFAM13B\u003c/h2\u003e \u003cp\u003eTo investigate the differential expression of circFAM13B in ACS patients treated with ticagrelor, platelet samples were obtained after ticagrelor treatment. The distribution of circFAM13B expression levels was measured by qRT-PCR, with an average expression level of 0.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88. The expression of circFAM13B derived from platelets was significantly higher in patients with ADP% \u0026lt; 76% who were treated with ticagrelor for ACS (1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10 vs. 0.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.67, P\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAssociation between the platelet-derived circFAM13B and ticagrelor antiplatelet responsiveness\u003c/h2\u003e \u003cp\u003eThere is a negative correlation between circFAM13B levels and ADP% measured by TEG (r = -0.41, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and the expression of circFAM13B revealed a trend toward decline with increasing ADP% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Compared to the patients with ADP% \u0026lt; 76%, those with ADP% \u0026ge; 76% had significantly lower circFAM13B levels. In logistic regression analysis, we found that the platelet-derived circFAM13B was independently associated with ticagrelor antiplatelet responsiveness in ACS patients with the adjustment of clinical factors (including smoking, history of stroke, diabetes mellitus, prior PCI and 3-vessel diseases of the coronary arteries) (P\u0026thinsp;=\u0026thinsp;0.009, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eContribution of the platelet-derived circFAM13B to the prediction of adverse ischemic events\u003c/h2\u003e \u003cp\u003eFollow-up was available at a median of 20 months (interquartile range: 19 to 36 months). A total of 20 (15.50%) patients had adverse ischemic events that occurred in our study. The all-cause mortality was found in 2 patients (1.55%), nonfatal MI in 2 patients (1.55%), nonfatal stroke in 3 patients (2.32%), and rehospitalization for UA in 13 patients (10.08%). A ROC analysis showed that the expression levels of circFAM13B could distinguish adverse ischemic events (AUC\u0026thinsp;=\u0026thinsp;0.68, 95% CI: 0.55 to 0.81, P\u0026thinsp;=\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Overall, the relative expression of circFAM13B\u0026thinsp;\u0026gt;\u0026thinsp;1.05 was identified as the optimal cut-off to predict the occurrence of adverse ischemic events. We found that the cut-off value was an independent risk factor for adverse ischemic events in both the univariate (unadjusted OR: 3.71, 95% CI: 1.39\u0026ndash;9.91; P\u0026thinsp;=\u0026thinsp;0.009) and the multivariate logistic regression analysis (adjusted OR: 5.60, 95% CI: 1.69\u0026ndash;18.50; P\u0026thinsp;=\u0026thinsp;0.005) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Moreover, combining the cut-off value (relative expression of circFAM13B\u0026thinsp;\u0026gt;\u0026thinsp;1.05) with clinical risk factors, including smoking, history of stroke, diabetes mellitus, prior PCI, and 3-vessel diseases of the coronary artery, improved the ability to predict the occurrence of adverse ischemic events (AUC\u0026thinsp;=\u0026thinsp;0.81, 95% CI: 0.69 to 0.92, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) compared to clinical risk factors alone (AUC\u0026thinsp;=\u0026thinsp;0.74, 95% CI: 0.63 to 0.84, P\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The Kaplan\u0026ndash;Meier analysis for the adverse ischemic events based on circFAM13B\u0026thinsp;\u0026le;\u0026thinsp;1.05 or circFAM13B\u0026thinsp;\u0026gt;\u0026thinsp;1.05 in our study was shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. It was indicated that with the expression of circFAM13B\u0026thinsp;\u0026gt;\u0026thinsp;1.05, the survival rates decreased (p\u0026thinsp;=\u0026thinsp;0.003) (Figure. 5).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 2. Association of the platelet derived expression of circFAM13B and clinical risk factors with adverse ischemic events in ticagrelor treated patients with ACS\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.32490974729242%\" colspan=\"2\" valign=\"top\" style=\"width: 30.0165%;\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.37906137184115%\" colspan=\"2\" valign=\"top\" style=\"width: 35.102%;\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003eP Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003eP Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003eRelative expression of circFAM13B\u0026gt;1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003e3.71 (1.39-9.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003e5.60 (1.69-18.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003e1.05\u0026nbsp;(0.98-1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003e1.09 (1.01-1.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003e1.14 (0.44-2.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003e0.792\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003e2.20 (0.68-7.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003eHistory of stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003e0.82 (0.17-3.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003e0.805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003e0.51 (0.09-3.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003e0.459\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003e2.21\u0026nbsp;(0.84-5.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003e0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003e3.64 (1.18-11.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003ePrior PCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003e0.29 (0.08-1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003e0.22 (0.05-0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.041\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.79783393501805%\" valign=\"top\" style=\"width: 27.5358%;\"\u003e\n \u003cp\u003e3-vessel diseases of coronary\u0026nbsp;artery\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.216606498194945%\" valign=\"top\" style=\"width: 20.0937%;\"\u003e\n \u003cp\u003e0.70 (0.27-1.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.108303249097473%\" valign=\"top\" style=\"width: 10.0469%;\"\u003e\n \u003cp\u003e0.479\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48014440433213%\" valign=\"top\" style=\"width: 21.3341%;\"\u003e\n \u003cp\u003e0.77 (0.26-2.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.898916967509026%\" valign=\"top\" style=\"width: 13.7679%;\"\u003e\n \u003cp\u003e0.636\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMultivariate analysis was adjusted by age, smoking, history of stroke, diabetes mellitus, prior PCI and 3-vessel diseases of coronary artery. ACS, acute coronary syndrome; PCI, percutaneous coronary intervention. Adverse ischemic events defined as all-cause death, nonfatal myocardial infarction, nonfatal stroke, stent thrombosis and rehospitalization for unstable angina.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study found that platelet-derived circFAM13B was correlated with the antiplatelet responsiveness and the occurrence of adverse ischemic events in ticagrelor treated patients with ACS. Therefore, circFAM13B might improve the ability to predict the occurrence of adverse ischemic events and could serve as one of the indicators to monitor antiplatelet treatment in patients with ACS. As far as we know, this is the first study to identify that platelet-derived circRNA could be informative for personalized antiplatelet therapy in patients with ACS.\u003c/p\u003e \u003cp\u003eConsistent with previous study [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], the variability of ADP-induced platelet aggregation could be observed in ACS patients receiving the ticagrelor treatment. A prospective study demonstrated that 46.2% of patients with ST-segment elevation myocardial infarction displayed HTPR after a 2-hour loading dose of ticagrelor [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The relatively lower incidence of HTPR in the present study might be primarily due to the different timing of the test measurements. Ischemic events occurred in ACS patients treated with ticagrelor, with the incidence rate ranging from 3.6 to 10.3 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The relatively higher incidence rate of ischemic events (15.5%) in the present study might be attributed to the inclusion of the rehospitalization for unstable angina. Our study aimed to explore whether platelet derived circFAM13B could affect the efficacy of the potent antithrombotic therapy of ticagrelor. As a 331bp circular RNA localized to chromosome 5, circFAM13B is highly expressed in the testis, endometrium, as well as testis, endometrium, and blood platelet [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Recent studies found the dysregulation of circFAM13B expression in bladder cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], ovarian cancer [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] or hepatocellular carcinoma [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, as one of the highly abundant circRNAs in human platelets [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], no study has investigated the role of circFAM13B in the platelets. In the present study, we discovered that independent of the traditional clinical risk factors, platelet-derived circFAM13B was associated with antiplatelet efficacy of ticagrelor, with higher expression of circFAM13B in ticagrelor treated patients with HTPR. Moreover, the increased expression of circFAM13B in the present cohort conferred a 5-fold higher risk of clinical ischemic events. Therefore, it suggested that circFAM13B might improve the predictability for the occurrence of adverse ischemic events in ACS patients treated with ticagrelor.\u003c/p\u003e \u003cp\u003eSeveral limitations should be mentioned. Firstly, the present study as a single-center with a relatively small sample size, may require further large-scale and multicenter studies to verify the association of circFAM13B with platelet reactivity and adverse ischemic events in ticagrelor treated patients with ACS. Secondly, we did not investigate the mechanism of circFAM13B affects the platelet reactivity. However, using a bioinformatics prediction analysis tool, we found that circFAM13B has the potential binding sites on miR-126 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://mirwalk.umm.uni-heidelberg.de/\u003c/span\u003e\u003cspan address=\"http://mirwalk.umm.uni-heidelberg.de/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (data not shown). As a highly expressed platelet miRNA, miR-126 has been discovered to be associated with platelet reactivity as well as the efficacy of antithrombotic therapy [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Therefore, we hypothesized that platelet-derived circFAM13B might interact with miR-126 to influence the antiplatelet reactivity of ticagrelor. Further basic research should be warranted to explore the potential mechanism. Thirdly, the study population in the present study was restricted to ACS patients treated with ticagrelor. Following studies required to encompass ACS patients treated with other P2Y12 receptor inhibitors (such as clopidogrel and prasugrel).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePlatelets-derived circFAM13B is associated with platelet reactivity and the occurrence of ischemic events in ACS patients treated with ticagrelor. Further research should be conducted to verify the mechanism of circFAM13B in the regulation of platelet reactivity and the antiplatelet responsiveness.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eAbbreviations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eFull Name\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eACS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eacute coronary syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eADP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eadenosine diphosphate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eADP%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eADP-induced platelet inhibition rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eAUC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003earea under the curve\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eCircRNAs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003ecircular RNAs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eDAPT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003edual antiplatelet therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eHTPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003ehigh on-treatment platelet reactivity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eIQR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003einterquartile range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003emaximum amplitude\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eMA\u003csub\u003eADP\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eADP-induced platelet-fibrin clot strength\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eMA \u003csub\u003efibrin\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eFibrin-induced clot strength\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eMA\u003csub\u003eThrombin\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003ethrombin-induced clot strength\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003emyocardial infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eNcRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003enon-coding RNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eNSTEMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eNon-ST segment elevation myocardial infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003ePCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003epercutaneous coronary intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eROC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003ereceiver operating characteristic curve\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eSTEMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eST-segment elevation myocardial infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eTEG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eThromboelastography\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.942133815551536%\" valign=\"top\"\u003e\n \u003cp\u003eUA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.057866184448464%\" valign=\"top\"\u003e\n \u003cp\u003eunstable angina\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the institutional ethics committee of the Chinese PLA General Hospital. The patients/participants provided their written informed consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used to support the findings of this study are available from the corresponding author ([email protected]) upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the National Natural Science Foundation of China (No. 8217130415).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy concept and design: Tong Yin, Yuting Zou, Yuyan Wang\u003c/p\u003e\n\u003cp\u003eAcquisition of data: Yuting Zou, Yuyan Wang, Yanzhu Yao, Yangxun Wu, Chao Lv,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of data: Yuting Zou, Yuyan Wang, Tong Yin\u003c/p\u003e\n\u003cp\u003eDrafting of the manuscript: Yuting Zou, Yanzhu Yao, Yangxun Wu, Chao Lv, Tong Yin\u003c/p\u003e\n\u003cp\u003eCritical revision of the manuscript for important intellectual content: Tong Yin, Yuting Zou\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors gratefully thank all study participants and all dedicated co-workers who helped to succeed this trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information (optional)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1,2\u003c/sup\u003eYuting Zou, \u003csup\u003e1\u003c/sup\u003eYuyan Wang, \u003csup\u003e1\u003c/sup\u003eYanzhu Yao,\u003csup\u003e1\u003c/sup\u003eYangxun Wu, \u003csup\u003e1\u003c/sup\u003eChao Lv, \u003csup\u003e1*\u003c/sup\u003e Tong Yin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors affiliations\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eInstitute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eSenior Department of Cardiology, the 6th Medical Center, Chinese PLA General Hospital, Beijing, China\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eTong Yin, MD, PhD\u003c/p\u003e\n\u003cp\u003eInstitute of Geriatrics, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Medical School of Chinese PLA and Chinese PLA General Hospital\u003c/p\u003e\n\u003cp\u003eNo.28 Fu Xing Road, Beijing 100853, China\u003c/p\u003e\n\u003cp\u003eE-mail: [email protected]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEmail address:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYuting Zou: [email protected]\u003c/p\u003e\n\u003cp\u003eYuyan Wang: [email protected]\u003c/p\u003e\n\u003cp\u003eYanzhu Yao: [email protected]\u003c/p\u003e\n\u003cp\u003eYangxun Wu: [email protected]\u003c/p\u003e\n\u003cp\u003eChao Lv: [email protected]\u003c/p\u003e\n\u003cp\u003eTong Yin: [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eByrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, Claeys MJ, Dan GA, Dweck MR, Galbraith M, et al: 2023 ESC Guidelines for the management of acute coronary syndromes. \u003cem\u003eEur Heart J \u003c/em\u003e2023, 44:3720-3826.\u003c/li\u003e\n\u003cli\u003eSanderson NC, Parker WAE, Storey RF: Ticagrelor: clinical 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Chem \u003c/em\u003e2022, 29:3420-3444.\u003c/li\u003e\n\u003cli\u003eAlhasan AA, Izuogu OG, Al-Balool HH, Steyn JS, Evans A, Colzani M, Ghevaert C, Mountford JC, Marenah L, Elliott DJ, et al: Circular RNA enrichment in platelets is a signature of transcriptome degradation. \u003cem\u003eBlood \u003c/em\u003e2016, 127:e1-e11.\u003c/li\u003e\n\u003cli\u003ePreu\u0026szlig;er C, Hung LH, Schneider T, Schreiner S, Hardt M, Moebus A, Santoso S, Bindereif A: Selective release of circRNAs in platelet-derived extracellular vesicles. \u003cem\u003eJ Extracell Vesicles \u003c/em\u003e2018, 7:1424473.\u003c/li\u003e\n\u003cli\u003eLi X, Yang L, Chen LL: The Biogenesis, Functions, and Challenges of Circular RNAs. \u003cem\u003eMol Cell \u003c/em\u003e2018, 71:428-442.\u003c/li\u003e\n\u003cli\u003eLv J, Li K, Yu H, Han J, Zhuang J, Yu R, Cheng Y, Song Q, Bai K, Cao Q, et al: HNRNPL induced circFAM13B increased bladder cancer immunotherapy sensitivity via inhibiting glycolysis through IGF2BP1/PKM2 pathway. \u003cem\u003eJ Exp Clin Cancer Res \u003c/em\u003e2023, 42:41.\u003c/li\u003e\n\u003cli\u003eXie Y, Hang X, Xu W, Gu J, Zhang Y, Wang J, Zhang X, Cao X, Zhan J, Wang J, Gan J: CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway. \u003cem\u003eCancer Cell Int \u003c/em\u003e2021, 21:410.\u003c/li\u003e\n\u003cli\u003eHan Y, Zheng Y, You J, Han Y, Lu X, Wang X, Shi C, Zhu W: Hsa_circ_0001535 inhibits the proliferation and migration of ovarian cancer by sponging miR-593-3p, upregulating PTEN expression. \u003cem\u003eClin Transl Oncol \u003c/em\u003e2023, 25:2901-2910.\u003c/li\u003e\n\u003cli\u003eZou Y, Wang Y, Wu Y, Zhang S, Liu H, Yin T: Prediction of residual ischemic risk in ticagrelor-treated patients with acute coronary syndrome. \u003cem\u003eThromb J \u003c/em\u003e2022, 20:21.\u003c/li\u003e\n\u003cli\u003eGurbel PA, Bliden KP, Navickas IA, Mahla E, Dichiara J, Suarez TA, Antonino MJ, Tantry US, Cohen E: Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events. \u003cem\u003eAm Heart J \u003c/em\u003e2010, 160:346-354.\u003c/li\u003e\n\u003cli\u003eBliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA: Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2007, 49:657-666.\u003c/li\u003e\n\u003cli\u003eSiller-Matula JM, Akca B, Neunteufl T, Maurer G, Lang IM, Kreiner G, Berger R, Delle-Karth G: Inter-patient variability of platelet reactivity in patients treated with prasugrel and ticagrelor. \u003cem\u003ePlatelets \u003c/em\u003e2016, 27:373-377.\u003c/li\u003e\n\u003cli\u003eAlexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G: Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. \u003cem\u003eCirc Cardiovasc Interv \u003c/em\u003e2012, 5:797-804.\u003c/li\u003e\n\u003cli\u003eSch\u0026uuml;pke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, W\u0026ouml;hrle J, Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, et al: Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. \u003cem\u003eN Engl J Med \u003c/em\u003e2019, 381:1524-1534.\u003c/li\u003e\n\u003cli\u003eTurgeon RD, Koshman SL, Youngson E, Har B, Wilton SB, James MT, Graham MM: Association of ticagrelor vs clopidogrel with major adverse coronary events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. \u003cem\u003eJAMA Intern Med \u003c/em\u003e2020, 180:420-428.\u003c/li\u003e\n\u003cli\u003eLarmore C, Effron MB, Molife C, DeKoven M, Zhu Y, Lu J, Karkare S, Lieu HD, Lee WC, Vetrovec GW: \u0026quot;Real-World\u0026quot; comparison of prasugrel with ticagrelor in patients with acute coronary syndrome treated with percutaneous coronary intervention in the United States. \u003cem\u003eCatheter Cardiovasc Interv \u003c/em\u003e2016, 88:535-544.\u003c/li\u003e\n\u003cli\u003eEffron MB, Nair KV, Molife C, Keller SY, Page RL, 2nd, Simeone JC, Murphy B, Nordstrom BL, Zhu Y, McCollam PL, Vetrovec GW: one-year clinical effectiveness comparison of prasugrel with ticagrelor: results from a retrospective observational study using an integrated claims database. \u003cem\u003eAm J Cardiovasc Drugs \u003c/em\u003e2018, 18:129-141.\u003c/li\u003e\n\u003cli\u003eHan Y, Claessen BE, Chen SL, Chunguang Q, Zhou Y, Xu Y, Hailong L, Chen J, Qiang W, Zhang R, et al: ticagrelor with or without aspirin in chinese patients undergoing percutaneous coronary intervention: a twilight china substudy. \u003cem\u003eCirc Cardiovasc Interv \u003c/em\u003e2022, 15:e009495.\u003c/li\u003e\n\u003cli\u003eThe database is freely accessible through the web server at http://circinteractome.nia.nih.gov.Accessed 11 Nov. 2023.\u003c/li\u003e\n\u003cli\u003eNing L, Long B, Zhang W, Yu M, Wang S, Cao D, Yang J, Shen K, Huang Y, Lang J: Circular RNA profiling reveals circEXOC6B and circN4BP2L2 as novel prognostic biomarkers in epithelial ovarian cancer. \u003cem\u003eInt J Oncol \u003c/em\u003e2018, 53:2637-2646.\u003c/li\u003e\n\u003cli\u003eJansen F, Yang X, Proebsting S, Hoelscher M, Przybilla D, Baumann K, Schmitz T, Dolf A, Endl E, Franklin BS, et al: MicroRNA expression in circulating microvesicles predicts cardiovascular events in patients with coronary artery disease. \u003cem\u003eJ Am Heart Assoc \u003c/em\u003e2014, 3:e001249.\u003c/li\u003e\n\u003cli\u003eNeu CT, Gutschner T, Haemmerle M: Post-Transcriptional Expression Control in Platelet Biogenesis and Function. \u003cem\u003eInt J Mol Sci \u003c/em\u003e2020, 21.\u003c/li\u003e\n\u003cli\u003eCzajka P, Fitas A, Jakubik D, Eyileten C, Gasecka A, Wicik Z, Siller-Matula JM, Filipiak KJ, Postula M: MicroRNA as potential biomarkers of platelet function on antiplatelet therapy: A Review. \u003cem\u003eFront Physiol \u003c/em\u003e2021, 12:652579.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"platelet, circFAM13B, anti-platelet efficacy, ticagrelor, acute coronary syndrome","lastPublishedDoi":"10.21203/rs.3.rs-4242438/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4242438/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003ePlatelet is enriched with Circular RNAs (circRNAs), with circFAM13B rank among the 10 most abundant circRNAs in platelets. The aim of the present study was to evaluate the predictive value of platelet-derived circFAM13B for the antiplatelet responsiveness and efficacy of ticagrelor in patients with acute coronary syndrome (ACS).\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eConsecutive ACS patients treated with ticagrelor were enrolled, and the antiplatelet responsiveness of 3 days of ticagrelor maintenance treatment was assessed by measuring the adenosine diphosphate (ADP)-induced platelet inhibition rate (ADP%) using thromboelastography. The expression of circFAM13B in the patients' platelets was analyzed by quantitative real-time polymerase chain reaction. The correlation between circFAM13B expression and ticagrelor antiplatelet responsiveness, as well as the independent contribution of circFAM13B to the composite of adverse ischemic events during a follow-up period of at least 12 months was evaluated.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eA total of 129 eligible ACS patients treated with ticagrelor were enrolled in the study. A negative correlation was found between the expression of circFAM13B and the ADP% value (r = -0.41, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with ADP% \u0026ge; 76% had a significantly lower level of circFAM13B compared to those with ADP% \u0026lt; 76% (adjusted P\u0026thinsp;=\u0026thinsp;0.009). Receiver operating characteristic curve analysis demonstrated that combining circFAM13B expression\u0026thinsp;\u0026gt;\u0026thinsp;1.05 with clinical risk factors could effectively predict the risk of adverse ischemic events (AUC\u0026thinsp;=\u0026thinsp;0.81, 95% CI: 0.69 to 0.92, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Kaplan-Meier survival analysis showed that patients with circFAM13B\u0026thinsp;\u0026gt;\u0026thinsp;1.05 had a significantly higher risk of adverse ischemic events compared to those with circFAM13B\u0026thinsp;\u0026le;\u0026thinsp;1.05 (P\u0026thinsp;=\u0026thinsp;0.003). Multivariate logistic hazard analysis identified circFAM13B\u0026thinsp;\u0026gt;\u0026thinsp;1.05 as an independent risk factor for adverse ischemic events in in ticagrelor-treated ACS patients (adjusted OR: 5.60, 95% CI: 1.69\u0026ndash;18.50; P\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003ePlatelet-derived circFAM13B could be utilized for predicting the antiplatelet responsiveness and efficacy of ticagrelor in patients with ACS.\u003c/p\u003e","manuscriptTitle":"Contribution of platelet-derived circFAM13B to the antiplatelet effectiveness of ticagrelor in patients with acute coronary syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-18 18:00:37","doi":"10.21203/rs.3.rs-4242438/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-29T04:57:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-29T02:45:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72610093391144332033419593355535591463","date":"2024-04-28T05:32:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-13T12:50:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12c553ea-c969-439b-8294-dfa1b17b865f","date":"2024-04-12T00:01:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-11T23:48:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-11T08:41:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-10T13:33:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thrombosis Journal","date":"2024-04-09T13:56:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8deec779-afcf-4226-8659-da5abefdefd7","owner":[],"postedDate":"April 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-10T00:53:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-18 18:00:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4242438","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4242438","identity":"rs-4242438","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}