Association between mRNA 133b and Patients with Coronary Artery Ectasia and Acute Coronary Syndrome

Association between mRNA 133b and Patients with Coronary Artery Ectasia and 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 Association between mRNA 133b and Patients with Coronary Artery Ectasia and Acute Coronary Syndrome Jorge Alberto Vega-Gomez, Luis Fernando De los Ríos-Arce, Fausto Sánchez-Muñoz, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2921437/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Coronary artery ectasia (CAE) is an abnormal coronary dilatation that exceeds 1.5x the size of the adjacent coronary normal segments, considered a manifestation of atherosclerosis. However, information regarding its etiology and pathophysiology is scarce. MicroRNAs are small circulating proteins that regulate diverse biological processes and may be involved in tissue development, homeostasis, and cellular communication. We aimed to explore a signature of microRNAs in patients with acute coronary syndrome (ACS) and CAE. Methods a prospective case & control study including consecutive patients with ACS (STEMI and NSTEMI) with and without CAE. Plasma samples were obtained, and consequently, quantification of plasma levels of miR-208, miR-208b, miR-1, miR-133b, miR-21, miR-155, miR-126, and miR-16 was performed by qRT-PCR. For analytical purposes, patients were divided into two groups: patients with ACS and CAE and patients with ACS and obstructive CAD. We included 47 patients, 24 with CAE and 23 with obstructive coronary disease. Results Patients with CAE showed a higher incidence of obesity (50 vs 21.7%, p = 0.04) and a higher left ventricular ejection fraction (52 vs 41%, p = 0.01). The rest of the baseline clinical characteristics were well-balanced. Among the selected signatures of microRNAs, patients with ACS and CAE showed higher levels of miR-133b than those without CAE. All other analyzed miRNAs were similar among groups. Conclusions In patients with ACS and CAE, we found higher miR-133b. Future studies are required to expand the findings of this research work and propose using miR-133b. Trial Registration Protocol received approval by the institutional ethics and research committee with the number 21-1248. Acute Coronary Syndrome Coronary Artery Ectasia miRNA Figures Figure 1 Figure 2 Background Coronary artery ectasia (CAE), defined as a dilatation that exceeds the diameter of normal adjacent segments or the diameter of the largest coronary artery by a factor of 1.5x, is a coronary phenotype found in approximately 0.3–4.9% ( 1 , 2 – 7 ) of patients undergoing coronary angiography. CAE is considered a manifestation of atherosclerosis in up to 70% of the cases ( 8 ); other causes may include connective tissue diseases, coronary trauma including iatrogenic injury during percutaneous coronary intervention (PCI), infectious arteritis, Kawasaki syndrome and congenital ectasias ( 9 ). CAE may be present in up to 10.3% of patients with ACS ( 9 ), and longitudinal studies have suggested an increased risk of recurrent coronary and major cardiovascular events in patients with CAE. For all the above, CAE has been proposed to be different from obstructive coronary artery disease ( 10 ). Micro-RNAs (miRNAs) are endogenous single-stranded, non-coding RNAs, averaging 22 nucleotides in length ( 11 ). They are implicated in the post-transcriptional regulation of genes through degradation and interference of mRNA ( 12 ). Most miRNAs are located in the intracellular space, while some are found in plasma associated with proteins ( 13 , 14 ). Even more, the detection of freely circulating miRNAs in plasma has been demonstrated, obtained by ultracentrifugation, fractionation, and filtering peripheral blood samples ( 15 ). Different groups of miRNAs have been recognised as regulators of various biological processes, including (but not limited to) cell growth, proliferation, differentiation, senescence, angiogenesis, and apoptosis ( 16 ). Similarly, miRNA dysregulation has been studied in several disease states, including atherosclerosis, recurrent thromboembolism, and the broad spectrum of cardiovascular diseases ( 17 ). Nevertheless, to our knowledge, there are no studies of miRNA expression in patients with coronary ectasia. The present study aimed to evaluate the expression of various miRNAs associated with atherogenesis, thrombosis and inflammation in patients with acute coronary syndrome with and without CAE. Methods This was a prospective case & control study including patients admitted to the cardiovascular critical care department with the diagnosis of acute coronary syndrome between March 1st, 2022 and June 30 of 2022. We included adult patients (> 18 years old) with the diagnosis of acute coronary syndrome (either ST-elevation acute coronary syndrome or non-ST elevation acute Coronary syndrome). For analytical purposes, patients were divided in two groups: patients with ACS and CAE and patients with ACS and obstructive CAD. The study adheres to the ethical principles outlined in the Declaration of Helsinki, and the protocol received approval by the institutional ethics and research committee with the number 21-1248. Written informed consent was obtained from all subjects. The present analysis included seven cardiac-specific miRNAs up or downregulated in patients with CAD (Fig. 1 ). Candidate miRNAs included miR-1, expressed in vascular smooth muscle cells ( 18 ). Expression of miR-208 and miR-208b is upregulated in patients with CAD and has been used as a diagnostic biomarker ( 19 – 20 ). Meanwhile, miR-20b, mir-126, miR-133b and miR-155 are downregulated in patients with CAD ( 21 – 23 ). The diagnosis of ACS was based on current clinical practice guidelines ( 24 ). The definition of a CAE case was based on the opinion of two independent interventional cardiologists according to the currently accepted definition and the use of quantitative coronary angiography. In discordance between observers, a third interventional cardiologist gave the final opinion. Patients were treated following current clinical practice guidelines and, in most cases, received anticoagulants, dual antiplatelet therapy, a high-intensity statin, and anti-ischemic medication and underwent coronary angiography during the hospital stay. Blood samples were taken 24 hours after the diagnostic coronary angiography and no more than five days after ACS. MicroRNA quantification was performed as follows: RNA isolated from 200 µL of plasma was used with the microRNA isolation reagent miRNeasy serum/plasma using reagents and protocols for the TaqMan MicroRNA Reverse Transcription Kit and the TaqMan MicroRNA Assay (Applied Biosystems). RT-PCR reactions were performed with custom stem-loop primers (Applied Biosystems) specific for the corresponding mature sequence obtained from miRBase ( http://www.miRBase.org ). Amplification of cation reactions was performed using the CFX96 real-time PCR system (BIORAD). Quantitative RT-qPCR data were analysed using the comparative threshold cycle method (“Cycle threshold”, Ct), with miR-16 as the endogenous reference for plasma (“housekeeping”). The relative abundance of miRNAs was calculated by the arithmetic formula 2^-ΔΔCt, where Ct represents the point at which the fluorescence of the TaqMan assay reaction exceeded the threshold limit. ΔΔCt was a result of subtracting the Ct of each miRNA minus each miR-16 Ct value of all samples, and for ΔΔCt, we used the NO CAE group mean ΔCt value as calibrator. Statistical Analysis Continuous variables are reported as mean ± standard deviation (SD), or median and interquartile range (IQR), according to their distribution. Categorical variables are reported as frequencies and percentages, and for their bivariate analysis, the Chi-square (χ2) or Fisher's exact test was used, depending on the number of events collected. A p-value of < 0.05 was considered significant. Results During the study period, a total of 47 patients were included, of whom 24 (51.0%) had CAE and 23 (49.0%) had obstructive coronary disease & no CAE; the mean age was 61 ± 11 years, 76% were male, and the prevalence of diabetes mellitus was 63.8%, dyslipidemia 29.7% and hypertension 63.8%. Patients with CAE showed a higher incidence of obesity (50 vs 21.7%, p = 0.04) and a higher left ventricular ejection fraction (52 vs 41%, p = 0.01). The rest of the baseline clinical characteristics were well-balanced among groups and are illustrated in Table 1 . Table 1 Baseline characteristics No CAE (n = 23) CAE (n = 24) p Value Male (%) 19 (82.6) 17 (70.8) 0.34 Age (± DE) 60 (12) 61 (11) 0.8 Cardiovascular risk factors Hypertension (%) 13 (56.5) 17 (70.8) 0.30 Diabetes type 2 (%) 16 (69.5) 11 (45.8) 0.1 Dyslipidemia (%) 9 (39.1) 5 (20.8) 0.17 Smoking (%) 9 (39.1) 15 (62.5) 0.10 Obesity (%) 5 (21.7) 12 (50) 0.04 Cardiovascular history Previous myocardial infarction (%) 4 (17.3) 2 (8.3) 0.35 Diagnosis at admission Acute coronary syndromes classification STEMI 16 (69.5) 15 (62.5) NSTEMi 7 (30.4) 7 (29.1) Unstable Angina 0 (0) 2 (8.33) Angiographic characteristics Affected arteries Left main 2 (8.7) 4 (16.6) 0.41 Anterior descendant 19 (82.6) 14 (58.3) 0.06 Circumflex 12 (52.1) 14 (58.3) 0.67 Right coronary artery 13 (56.5) 16 (66.6) 0.47 Markis classification 1 N/A 11 (47.8) N/A 2 N/A 2 (8.7) N/A 3 N/A 8 (34.7) N/A 4 N/A 2 (8.7) N/A Aneurysm N/A 2 (8.7) N/A Clinical characteristics LVEF %, (± DE) 41% (12) 52% (11) 0.01 SBP (IQR) 142 (116–160) 137 (113–149) 0.37 DBP(IQR) 80 (70–90) 79 (70–89) 0.97 Heart rate (IQR) 80 (70–97) 73.5 (64–93) 0.06 Respiratory rate (IQR) 18 (18–20) 18 (16–20) 0.14 Hemoglobin (IQR) 15 (12.7–16.1) 15.4 (14.6–17.4) 0.32 Platelets (IQR) 236 (200–274) 237 (192–275) 0.62 Leukocytes (IQR) 10.1 (8.1-13-3) 11.5 (8.3–12.9) 0.54 Creatinine (± DE) 1.09 (0.26) 1.15 (0.93) 0.43 BUN, median (IQR) 17.9 (12.5–25) 17.9 (12.5–25) 1.0 Glucose (IQR) 158 (144–291) 156 (118–190) 0.48 Troponin T (IQR) 1280 (235–4427) 633 (181–7565) 0.97 NTproBNP (IQR) 1668 (574–5079) 897 (175–3541) 0.24 PCR (IQR) 10.1 (2.2–48) 9.1 (3.7–64.5) 0.8 Hb A1c (IQR) 6.8 (6.1–8.8) 6.3 (5.9–7.5) 0.45 Albumin (± DE) 3.8 +-0.4 3.9 +-0.5 0.7 Total Cholesterol (IQR) 151 (125–191) 141 (123–164) 0.71 LDL Cholesterol (IQR) 94.3 (61–111) 84.1 (65.9–106) 0.63 Triglycerides (IQR) 137 (91–184) 126 (92.1–159) 0.5 Prognostic scales Killip y Kimball I 12 (52.1) 15 (62.5) II 9 (39.1) 9 (37.5) III 1 (4.35) 0 (0) IV 1 (4.35) 0 (0) Killip y Kimball ≥ 2 11 (47.8) 9 (37.5) 0.47 TIMI, mean (IQR) 4 (2–5) 3 (2–4) 0.51 GRACE (IQR) 105 (99–139) 114.5 (82.5–140) 0.33 SD, standard deviation; STEMI, ST-segment elevation myocardial infarction; NSTEMI, acute myocardial infarction to non-ST-segment elevation myocardium; LVEF, left ventricular ejection fraction; SBP; Systolic blood pressure; DBP, dyastolic blood pressure; BUN, blood urea nitrogen; NTproBNP, pro N-terminal brain natriuretic peptide; HbA1c, glycosylated hemoglobin; LDL, low-density lipoprotein; TIMI, Thrombolysis in Myocardial Infarction; GRACE, Global Registry on Acute Coronary Events. All miRNAs were detectable in plasma by means of the qPCR method, with the mean values from 24.8 for the most abundant miR-126 to 38.7 for the lowly-expressed miR-208b (Table 2 ). Table 2 Shows the graphical representation of the p obtained for Ct miR-133b Independent samples test Levene's test (equality of variances) t-test for equality of means F Sig. t gl Sig. (bilateral) Mean difference Standard error difference 95% confidence interval of the difference Inferior Superior 2^ −∆∆Ct miR-133b Equal variances are assumed 12.14 0.001 1.93 45 0.060 6.29 3.25 -0.26 12.84 Equal variances are not assumed 1.97 23.10 0.060 6.29 3.18 -0.29 12.87 We compared Ct values of the analyzed miRNAs between the study groups using the Mann–Whitney test and Student’s t-test for pairwise comparisons. An additional file demonstrates all miRNAs analyzed [see additional file1.] Among the analyzed miRNAs, miR-1, miR-21, miR 126, miR155, miR-208, and miR-208b showed similar distributions of Ct in the study groups. Meanwhile, the Ct for miR-133b was lower in patients with CAE, which can be slandered as a higher miR-133b expression in these patients, as seen for the 2^-ΔΔCt values (Fig. 2 ). The 133b microRNA target genes were searched with the interaction of the IL4, IL6, and IL2 genes related to etiology ( 25 , 26 ). Novel gene prediction was performed by miRNet and FunRich ( 27 , 28 ). miRNet and FunRich analysis revealed that the target genes of miR-133b-5p related to IL4, IL6, IL2 in CAE can interact with BCL2L1, BCL2L2, CNN2, CTGF, FGFR1, FOSL2, FOXC1, FOXL2, HAPLN1, MMP14 genes (Supplementary file). Reactome pathway analysis shows the participation of FGFR and EGFR pathways ( 29 – 31 ). Discussion To our knowledge, this is the first report of miRNAs in patients with ACS and CE. Much has been published about the role of miRNAs in CAD, but CE is perceived as a different disease than traditional obstructive CAD. miRNAs have emerged as stable blood-based biomarkers in numerous diseases, and they could help elucidate different phenotypic profiles among the broad spectrum of CAD, including CAE ( 32 ). Patients with obstructive CAD had a higher burden of diabetes and dyslipidemia. Furthermore, the level of triglycerides and LDL-C was higher in these patients. These findings could reflect a higher metabolic burden in patients with obstructive CAD. The mean age of our CAE population was 61 ± 11 years, and atherosclerosis-related CAE appears later in life compared to congenital CAE or those with an underlying inflammatory nature ( 12 ). In our study, miRNA expression was similar in both groups, except for miR-133b, which was upregulated in patients with CE. miR-133b is highly enriched in normal heart muscles, and it is downregulated in patients with ACS, particularly in ST-elevation myocardial infarction. It has also been associated with the number of diseased vessels. Even more, Kumar et al. found an altered expression of miR-133b in patients with ACS compared to patients with normal coronary arteries with an area under a ROC curve of 0.91. Fichtlscherer et al. and De Gonzalo-Calvo et al. found higher miR-133b levels in patients with CAD who have not developed ACS ( 33 , 34 ). This may be useful in patients who have been incidentally found to have coronary ectasia but without ACS. The measurement of the change in gene expression employing miRNA after treatment has been described in pathologies such as cancer and response to chemotherapy, cardiovascular pathologies in response to medical treatment, and after therapeutic interventions such as ablation of arrhythmias ( 35 – 37 ). For the above, miR-133b expression could be an additional biomarker in follow-up and in the guidance of medical therapy to prevent the development of ACS in patients with CE. Additionally, the study by Cipollone et al. associated the expression of miR-133b with unstable atherosclerotic plaques ( 38 ). Therefore, a higher expression of miR-133b in patients with CAE could represent a coronary inflammatory milieu similar to the unstable plaque phenotype. Troponin and NT-proBNP levels were analyzed as exploratory variables to look for a significant difference between both groups, which was not found in our study. In addition, CRP measurement was added as a surrogate for inflammation in these patients, and no significant difference was found between both groups. Previous studies have reported higher inflammatory markers in patients with CAE. It has been seen that fibroblast growth factor-2 (FGF-2) signaling contributes significantly to smooth muscle cell hyperplasia and disease progression in humans and rats. Besides, the autocrine release of endothelial-derived FGF-2 also contributed to acquiring and maintaining an abnormal endothelial cell phenotype, enhancing proliferation, and decreasing apoptosis ( 30 ). FGF-1 and FGF-2 mediate their biological effects by binding to a family of selective high-affinity cell-surface receptors with protein tyrosine kinase activity. High levels of FGF-1 and its type-1 receptor (FGFR-1) are expressed in human atherosclerotic lesions and accelerated coronary atherosclerosis in cardiac transplants characterized by coronary intimal hyperplasia. These studies predict an important role for FGF ligands and FGFR-1 in neointima formation after vascular injury ( 29 ). The epidermal growth factor receptor (EGFR) is mainly known for its role in tumorigenesis. Still, it has also been associated with AngII-mediated regulation of vascular tone and blood pressure, vascular remodeling, fibrosis, cell migration, and cardiac hypertrophy. Also, it can be stimulated by AngII ( 31 ). Our study had several limitations: the small sample size (derived from the low prevalence of CAE) and the limited number of studied miRNAs are the most important. The number of miRNA markers analyzed using qPCR in this study was limited by study funding. Including other miRNAs linked with atherosclerosis, inflammation, and venous thrombosis would have been helpful for further characterization of these allegedly different populations (CAE and obstructive CAD). These results should stimulate further investigations on miRNAs profile in patients with CE. Conclusions In patients suffering from acute coronary syndrome and coronary artery ectasia, an increased expression of miR-133b was found compared to patients without coronary ectasia. This finding may suggest that coronary artery ectasia is related to atherosclerotic burden and “unstable plaque” phenotype, which may have implications for treatment. Future studies are required to expand the findings of this research work and propose using miR-133b as a prognostic and follow-up marker in patients with ACS and coronary artery ectasia. Declarations Ethics Approval and Consent to Participate: The study adheres to the ethical principles outlined in the Declaration of Helsinki, and the protocol received approval by the institutional ethics and research committee (Comité de Investigación y Ética del Instituto Nacional de Cardiología Ignacio Chávez) with the number 21-1248. Written informed consent was obtained from all subjects and/or their legal guardian(s). Consent for Publication: Not applicable. Availability of Data and Materials: The data that support the findings of this study are available from Instituto Nacional de Cardiología “Ignacio Chávez”, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request to the corresponding author and with permission of Instituto Nacional de Cardiología “Ignacio Chávez.” Competing Interests: Araiza-Garaygordobil has received institutional research grants from Novartis and reports speaking fees from Boehringer Ingelheim, Novartis, AstraZeneca, Servier & Abbott. Dr A.S. Arias-Mendoza has served on the advisory board of Roche Diagnostics and reports speaking fees from Novo Nordisk, Novartis, Roche Diagnostics, and Sanofi Aventis. All other authors declare no relevant conflicts of interest. Funding: No funding was received Author Contributions: JG conceived and designed the research and drafted the original manuscript. DA designed the research and is responsible for the work. FD drafted the manuscript. MR analyzed and interpreted data. FS, MP and LJ received and analyzed blood samples. NB, VS, MR, AN, AA, GS were responsible for obtaining data and drafting manuscript. JG obtained data and designed the central image. RG, DS and HG were responsible for revising the manuscript critically for important intellectual content. AA had the duty of managing the project, overseeing it, and ensuring the accuracy and validity of the study. Acknowledgements: Not applicable Authors’ information: Not applicable References Swaye PS, Fisher LD, Litwin P, Vignola PA, et al. Aneurysmal coronary artery disease. Circulation. 1983;67:134–138. Hartnell GG, Parnell BM, Pridie RB. Coronary artery ectasia: its prevalence and clinical significance in 4993 patients. Br Heart J . 1985;54:392–5. 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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-2921437","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":201241864,"identity":"675f8c38-a1cc-4f4e-b574-29884fd62319","order_by":0,"name":"Jorge Alberto Vega-Gomez","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jorge","middleName":"Alberto","lastName":"Vega-Gomez","suffix":""},{"id":201241865,"identity":"99d8ddd8-8b44-4e2f-a73f-34fe3ff90977","order_by":1,"name":"Luis Fernando De los 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Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Arturo","middleName":"Maximiliano","lastName":"Ruiz-Beltrán","suffix":""},{"id":201241868,"identity":"f304124a-ec66-44e1-b1d4-b27cc96312c3","order_by":4,"name":"Nayeli Belderrain-Morales","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nayeli","middleName":"","lastName":"Belderrain-Morales","suffix":""},{"id":201241869,"identity":"6738682d-c10d-4d36-b4b6-30c1210c6a84","order_by":5,"name":"Vianney Sarabia-Chao","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vianney","middleName":"","lastName":"Sarabia-Chao","suffix":""},{"id":201241870,"identity":"1274e100-0474-414a-8444-fe5cb2f0e57f","order_by":6,"name":"Mario Peña-Peña","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mario","middleName":"","lastName":"Peña-Peña","suffix":""},{"id":201241871,"identity":"871b2690-de8d-4f55-872b-5da9d56fcdbb","order_by":7,"name":"Leonor Jacobo-Albavera","email":"","orcid":"","institution":"National Institute of Genomic Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Leonor","middleName":"","lastName":"Jacobo-Albavera","suffix":""},{"id":201241872,"identity":"c74bc3ef-6d33-4318-856b-505aef792c36","order_by":8,"name":"Robles-Ledesma Mariana","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Robles-Ledesma","middleName":"","lastName":"Mariana","suffix":""},{"id":201241876,"identity":"7a8b9c93-3727-4135-9823-f1c1a76ee131","order_by":9,"name":"Nitzha Andrea Najera-Rojas","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nitzha","middleName":"Andrea","lastName":"Najera-Rojas","suffix":""},{"id":201241878,"identity":"917976c5-9dd3-4057-8404-f3b2f54041a9","order_by":10,"name":"Alma Paola Alonso-Bringas","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alma","middleName":"Paola","lastName":"Alonso-Bringas","suffix":""},{"id":201241879,"identity":"65c70de3-f67e-4351-9796-7e5dc010eb2d","order_by":11,"name":"Giovanna Sanchez-Leony","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Giovanna","middleName":"","lastName":"Sanchez-Leony","suffix":""},{"id":201241881,"identity":"89f54658-d645-4982-9545-d14b4d615caa","order_by":12,"name":"Jimena Gonzalez-Salido","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jimena","middleName":"","lastName":"Gonzalez-Salido","suffix":""},{"id":201241883,"identity":"1dbf02c9-6d48-452b-a742-991394152cbf","order_by":13,"name":"Rodrigo Gopar-Nieto","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"","lastName":"Gopar-Nieto","suffix":""},{"id":201241884,"identity":"f6bfadd6-8942-4068-8e5a-157c31858722","order_by":14,"name":"Daniel Sierra-Lara Martinez","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"Sierra-Lara","lastName":"Martinez","suffix":""},{"id":201241887,"identity":"a2515613-4f33-4740-b9c9-213c6a71b8da","order_by":15,"name":"Hector Gonzalez-Pacheco","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hector","middleName":"","lastName":"Gonzalez-Pacheco","suffix":""},{"id":201241889,"identity":"0e62a05b-90ee-41b2-b920-b71302a6dfda","order_by":16,"name":"Diego Araiza Garaygordobil","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYDCCA1CaH0QkFJCiRbIBpMWAFC0GYAYxWviOn3384uceu8TN51cnfnhgwCDPL3YAvxbJM+lmlj3PkhO33Xi7WQLoMMOZsxPwazE4kMZmwHOAGajl7AaQlgSD24S0nH/GZvjnQH3i5hlnN/8gTsuNNObHPAcOJ27g791GnC2SN56xMcscOG484wbvNosEAwnCfuE7n8b88c2Batn+/rObb/6osJHnlyagBQjYJICEY4MEWKUEQeUgwPwBSNgz8B8gSvUoGAWjYBSMQAAAUspMVmplv/sAAAAASUVORK5CYII=","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Diego","middleName":"Araiza","lastName":"Garaygordobil","suffix":""},{"id":201241891,"identity":"ebce54f7-2b7e-495c-aaa1-c140781757f0","order_by":17,"name":"Alexandra Arias-Mendoza","email":"","orcid":"","institution":"National Institute of Cardiology “Ignacio Chavez''","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Arias-Mendoza","suffix":""}],"badges":[],"createdAt":"2023-05-11 18:59:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2921437/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2921437/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":37260640,"identity":"b9654018-8e11-4bb7-b5ac-92b2b1a24bc8","added_by":"auto","created_at":"2023-05-19 21:18:16","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1142792,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentation of the principal roles of each MicroRNA in the diverse physiopathological process in cardiovascular disease.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2921437/v1/1c20858169498d7af16d7034.jpg"},{"id":37259806,"identity":"7965954a-c75d-4f02-9488-c1220dc1013d","added_by":"auto","created_at":"2023-05-19 21:10:16","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":238458,"visible":true,"origin":"","legend":"\u003cp\u003eLeft panel shows miR-133b Ct value and the right panel 2^-ΔΔCt values normalized to miR-16, two tailed p-values were calculated by t- student test. No CAE n= 23; CAE = 24\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2921437/v1/e62b15ffe521bcc09ce86dc0.jpg"},{"id":39955159,"identity":"24ff3e42-e401-45fc-9fbd-185538fc5e25","added_by":"auto","created_at":"2023-07-13 07:14:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":460279,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2921437/v1/351282a1-1a50-4631-852a-314612976479.pdf"},{"id":37259808,"identity":"7c50966d-9e97-440f-af70-37c17eadba75","added_by":"auto","created_at":"2023-05-19 21:10:16","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":683792,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2921437/v1/8b7f8afe0595434a01ce8791.docx"}],"financialInterests":"Competing interest reported. Araiza-Garaygordobil has received institutional research grants from Novartis and reports speaking fees from Boehringer Ingelheim, Novartis, AstraZeneca, Servier \u0026 Abbott. Dr A.S. Arias-Mendoza has served on the advisory board of Roche Diagnostics and reports speaking fees from Novo Nordisk, Novartis, Roche Diagnostics, and Sanofi Aventis. All other authors declare no relevant conflicts of interest.","formattedTitle":"Association between mRNA 133b and Patients with Coronary Artery Ectasia and Acute Coronary Syndrome","fulltext":[{"header":"Background","content":"\u003cp\u003eCoronary artery ectasia (CAE), defined as a dilatation that exceeds the diameter of normal adjacent segments or the diameter of the largest coronary artery by a factor of 1.5x, is a coronary phenotype found in approximately 0.3\u0026ndash;4.9% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) of patients undergoing coronary angiography. CAE is considered a manifestation of atherosclerosis in up to 70% of the cases (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e); other causes may include connective tissue diseases, coronary trauma including iatrogenic injury during percutaneous coronary intervention (PCI), infectious arteritis, Kawasaki syndrome and congenital ectasias (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). CAE may be present in up to 10.3% of patients with ACS (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), and longitudinal studies have suggested an increased risk of recurrent coronary and major cardiovascular events in patients with CAE. For all the above, CAE has been proposed to be different from obstructive coronary artery disease (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMicro-RNAs (miRNAs) are endogenous single-stranded, non-coding RNAs, averaging 22 nucleotides in length (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). They are implicated in the post-transcriptional regulation of genes through degradation and interference of mRNA (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Most miRNAs are located in the intracellular space, while some are found in plasma associated with proteins (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Even more, the detection of freely circulating miRNAs in plasma has been demonstrated, obtained by ultracentrifugation, fractionation, and filtering peripheral blood samples (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDifferent groups of miRNAs have been recognised as regulators of various biological processes, including (but not limited to) cell growth, proliferation, differentiation, senescence, angiogenesis, and apoptosis (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Similarly, miRNA dysregulation has been studied in several disease states, including atherosclerosis, recurrent thromboembolism, and the broad spectrum of cardiovascular diseases (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Nevertheless, to our knowledge, there are no studies of miRNA expression in patients with coronary ectasia.\u003c/p\u003e \u003cp\u003eThe present study aimed to evaluate the expression of various miRNAs associated with atherogenesis, thrombosis and inflammation in patients with acute coronary syndrome with and without CAE.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis was a prospective case \u0026amp; control study including patients admitted to the cardiovascular critical care department with the diagnosis of acute coronary syndrome between March 1st, 2022 and June 30 of 2022. We included adult patients (\u0026gt;\u0026thinsp;18 years old) with the diagnosis of acute coronary syndrome (either ST-elevation acute coronary syndrome or non-ST elevation acute Coronary syndrome). For analytical purposes, patients were divided in two groups: patients with ACS and CAE and patients with ACS and obstructive CAD. The study adheres to the ethical principles outlined in the Declaration of Helsinki, and the protocol received approval by the institutional ethics and research committee with the number 21-1248. Written informed consent was obtained from all subjects.\u003c/p\u003e \u003cp\u003eThe present analysis included seven cardiac-specific miRNAs up or downregulated in patients with CAD (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Candidate miRNAs included miR-1, expressed in vascular smooth muscle cells (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Expression of miR-208 and miR-208b is upregulated in patients with CAD and has been used as a diagnostic biomarker (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Meanwhile, miR-20b, mir-126, miR-133b and miR-155 are downregulated in patients with CAD (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe diagnosis of ACS was based on current clinical practice guidelines (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The definition of a CAE case was based on the opinion of two independent interventional cardiologists according to the currently accepted definition and the use of quantitative coronary angiography. In discordance between observers, a third interventional cardiologist gave the final opinion. Patients were treated following current clinical practice guidelines and, in most cases, received anticoagulants, dual antiplatelet therapy, a high-intensity statin, and anti-ischemic medication and underwent coronary angiography during the hospital stay.\u003c/p\u003e \u003cp\u003eBlood samples were taken 24 hours after the diagnostic coronary angiography and no more than five days after ACS. MicroRNA quantification was performed as follows: RNA isolated from 200 \u0026micro;L of plasma was used with the microRNA isolation reagent miRNeasy serum/plasma using reagents and protocols for the TaqMan MicroRNA Reverse Transcription Kit and the TaqMan MicroRNA Assay (Applied Biosystems). RT-PCR reactions were performed with custom stem-loop primers (Applied Biosystems) specific for the corresponding mature sequence obtained from miRBase (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.miRBase.org\u003c/span\u003e\u003cspan address=\"http://www.miRBase.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmplification of cation reactions was performed using the CFX96 real-time PCR system (BIORAD). Quantitative RT-qPCR data were analysed using the comparative threshold cycle method (\u0026ldquo;Cycle threshold\u0026rdquo;, Ct), with miR-16 as the endogenous reference for plasma (\u0026ldquo;housekeeping\u0026rdquo;). The relative abundance of miRNAs was calculated by the arithmetic formula 2^-ΔΔCt, where Ct represents the point at which the fluorescence of the TaqMan assay reaction exceeded the threshold limit. ΔΔCt was a result of subtracting the Ct of each miRNA minus each miR-16 Ct value of all samples, and for ΔΔCt, we used the NO CAE group mean ΔCt value as calibrator.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStatistical Analysis\u003c/strong\u003e \u003cp\u003eContinuous variables are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), or median and interquartile range (IQR), according to their distribution. Categorical variables are reported as frequencies and percentages, and for their bivariate analysis, the Chi-square (χ2) or Fisher's exact test was used, depending on the number of events collected. A p-value of \u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period, a total of 47 patients were included, of whom 24 (51.0%) had CAE and 23 (49.0%) had obstructive coronary disease \u0026amp; no CAE; the mean age was 61\u0026thinsp;\u0026plusmn;\u0026thinsp;11 years, 76% were male, and the prevalence of diabetes mellitus was 63.8%, dyslipidemia 29.7% and hypertension 63.8%. Patients with CAE showed a higher incidence of obesity (50 vs 21.7%, p\u0026thinsp;=\u0026thinsp;0.04) and a higher left ventricular ejection fraction (52 vs 41%, p\u0026thinsp;=\u0026thinsp;0.01). The rest of the baseline clinical characteristics were well-balanced among groups and are illustrated in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo CAE (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCAE (n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep Value\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (82.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (70.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (\u0026plusmn;\u0026thinsp;DE)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCardiovascular risk factors\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (56.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (70.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes type 2 (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (69.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (45.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDyslipidemia (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (39.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.17\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSmoking (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (39.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (62.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eObesity (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (21.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCardiovascular history\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrevious myocardial infarction (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (17.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis at admission\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eAcute coronary syndromes classification\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSTEMI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (69.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (62.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNSTEMi\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (30.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (29.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnstable Angina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAngiographic characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eAffected arteries\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLeft main\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (16.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnterior descendant\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (82.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (58.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCircumflex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (52.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (58.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRight coronary artery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (56.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (66.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eMarkis classification\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (47.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (34.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAneurysm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLVEF %, (\u0026plusmn;\u0026thinsp;DE)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41% (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52% (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSBP (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e142 (116\u0026ndash;160)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137 (113\u0026ndash;149)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.37\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDBP(IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (70\u0026ndash;90)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79 (70\u0026ndash;89)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHeart rate (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (70\u0026ndash;97)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.5 (64\u0026ndash;93)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRespiratory rate (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (18\u0026ndash;20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (16\u0026ndash;20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHemoglobin (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (12.7\u0026ndash;16.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.4 (14.6\u0026ndash;17.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.32\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlatelets (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e236 (200\u0026ndash;274)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e237 (192\u0026ndash;275)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLeukocytes (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.1 (8.1-13-3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.5 (8.3\u0026ndash;12.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.54\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCreatinine (\u0026plusmn;\u0026thinsp;DE)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.09 (0.26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.15 (0.93)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBUN, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.9 (12.5\u0026ndash;25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.9 (12.5\u0026ndash;25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGlucose (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e158 (144\u0026ndash;291)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e156 (118\u0026ndash;190)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.48\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTroponin T (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1280 (235\u0026ndash;4427)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e633 (181\u0026ndash;7565)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNTproBNP (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1668 (574\u0026ndash;5079)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e897 (175\u0026ndash;3541)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePCR (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.1 (2.2\u0026ndash;48)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.1 (3.7\u0026ndash;64.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb A1c (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.8 (6.1\u0026ndash;8.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.3 (5.9\u0026ndash;7.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlbumin (\u0026plusmn;\u0026thinsp;DE)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.8 +-0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.9 +-0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal Cholesterol (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e151 (125\u0026ndash;191)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e141 (123\u0026ndash;164)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.71\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLDL Cholesterol (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e94.3 (61\u0026ndash;111)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e84.1 (65.9\u0026ndash;106)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.63\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTriglycerides (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137 (91\u0026ndash;184)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e126 (92.1\u0026ndash;159)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic scales\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eKillip y Kimball\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (52.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (62.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eII\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (39.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (37.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIII\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4.35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4.35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKillip y Kimball\u0026thinsp;\u0026ge;\u0026thinsp;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (47.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (37.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTIMI, mean (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (2\u0026ndash;4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGRACE (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105 (99\u0026ndash;139)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114.5 (82.5\u0026ndash;140)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eSD, standard deviation; STEMI, ST-segment elevation myocardial infarction; NSTEMI, acute myocardial infarction to non-ST-segment elevation myocardium; LVEF, left ventricular ejection fraction; SBP; Systolic blood pressure; DBP, dyastolic blood pressure; BUN, blood urea nitrogen; NTproBNP, pro N-terminal brain natriuretic peptide; HbA1c, glycosylated hemoglobin; LDL, low-density lipoprotein; TIMI, Thrombolysis in Myocardial Infarction; GRACE, Global Registry on Acute Coronary Events.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll miRNAs were detectable in plasma by means of the qPCR method, with the mean values from 24.8 for the most abundant miR-126 to 38.7 for the lowly-expressed miR-208b (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eShows the graphical representation of the \u003cem\u003ep\u003c/em\u003e obtained for \u003cem\u003eCt\u003c/em\u003e miR-133b\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"11\" align=\"left\"\u003e\n\u003cp\u003eIndependent samples test\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" rowspan=\"3\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eLevene's test (equality of variances)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003et-test for equality of means\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eSig.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003et\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003egl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eSig. (bilateral)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMean difference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eStandard error difference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e95% confidence interval of the difference\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInferior\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSuperior\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e2^\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;∆∆Ct\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003emiR-133b\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEqual variances are assumed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.060\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.84\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEqual variances are not assumed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.060\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.87\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe compared \u003cem\u003eCt\u003c/em\u003e values of the analyzed miRNAs between the study groups using the Mann\u0026ndash;Whitney test and Student\u0026rsquo;s t-test for pairwise comparisons. An additional file demonstrates all miRNAs analyzed [see additional file1.] Among the analyzed miRNAs, miR-1, miR-21, miR 126, miR155, miR-208, and miR-208b showed similar distributions of \u003cem\u003eCt\u003c/em\u003e in the study groups. Meanwhile, the \u003cem\u003eCt\u003c/em\u003e for miR-133b was lower in patients with CAE, which can be slandered as a higher miR-133b expression in these patients, as seen for the 2^-\u0026Delta;\u0026Delta;Ct values (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe 133b microRNA target genes were searched with the interaction of the IL4, IL6, and IL2 genes related to etiology (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e). Novel gene prediction was performed by miRNet and FunRich (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e). miRNet and FunRich analysis revealed that the target genes of miR-133b-5p related to IL4, IL6, IL2 in CAE can interact with BCL2L1, BCL2L2, CNN2, CTGF, FGFR1, FOSL2, FOXC1, FOXL2, HAPLN1, MMP14 genes (Supplementary file). Reactome pathway analysis shows the participation of FGFR and EGFR pathways (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first report of miRNAs in patients with ACS and CE. Much has been published about the role of miRNAs in CAD, but CE is perceived as a different disease than traditional obstructive CAD. miRNAs have emerged as stable blood-based biomarkers in numerous diseases, and they could help elucidate different phenotypic profiles among the broad spectrum of CAD, including CAE (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Patients with obstructive CAD had a higher burden of diabetes and dyslipidemia.\u003c/p\u003e \u003cp\u003eFurthermore, the level of triglycerides and LDL-C was higher in these patients. These findings could reflect a higher metabolic burden in patients with obstructive CAD. The mean age of our CAE population was 61\u0026thinsp;\u0026plusmn;\u0026thinsp;11 years, and atherosclerosis-related CAE appears later in life compared to congenital CAE or those with an underlying inflammatory nature (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, miRNA expression was similar in both groups, except for miR-133b, which was upregulated in patients with CE. miR-133b is highly enriched in normal heart muscles, and it is downregulated in patients with ACS, particularly in ST-elevation myocardial infarction. It has also been associated with the number of diseased vessels. Even more, Kumar et al. found an altered expression of miR-133b in patients with ACS compared to patients with normal coronary arteries with an area under a ROC curve of 0.91. Fichtlscherer et al. and De Gonzalo-Calvo et al. found higher miR-133b levels in patients with CAD who have not developed ACS (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). This may be useful in patients who have been incidentally found to have coronary ectasia but without ACS. The measurement of the change in gene expression employing miRNA after treatment has been described in pathologies such as cancer and response to chemotherapy, cardiovascular pathologies in response to medical treatment, and after therapeutic interventions such as ablation of arrhythmias (\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). For the above, miR-133b expression could be an additional biomarker in follow-up and in the guidance of medical therapy to prevent the development of ACS in patients with CE.\u003c/p\u003e \u003cp\u003eAdditionally, the study by Cipollone et al. associated the expression of miR-133b with unstable atherosclerotic plaques (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Therefore, a higher expression of miR-133b in patients with CAE could represent a coronary inflammatory milieu similar to the unstable plaque phenotype. Troponin and NT-proBNP levels were analyzed as exploratory variables to look for a significant difference between both groups, which was not found in our study. In addition, CRP measurement was added as a surrogate for inflammation in these patients, and no significant difference was found between both groups. Previous studies have reported higher inflammatory markers in patients with CAE.\u003c/p\u003e \u003cp\u003eIt has been seen that fibroblast growth factor-2 (FGF-2) signaling contributes significantly to smooth muscle cell hyperplasia and disease progression in humans and rats. Besides, the autocrine release of endothelial-derived FGF-2 also contributed to acquiring and maintaining an abnormal endothelial cell phenotype, enhancing proliferation, and decreasing apoptosis (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). FGF-1 and FGF-2 mediate their biological effects by binding to a family of selective high-affinity cell-surface receptors with protein tyrosine kinase activity. High levels of FGF-1 and its type-1 receptor (FGFR-1) are expressed in human atherosclerotic lesions and accelerated coronary atherosclerosis in cardiac transplants characterized by coronary intimal hyperplasia. These studies predict an important role for FGF ligands and FGFR-1 in neointima formation after vascular injury (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). The epidermal growth factor receptor (EGFR) is mainly known for its role in tumorigenesis. Still, it has also been associated with AngII-mediated regulation of vascular tone and blood pressure, vascular remodeling, fibrosis, cell migration, and cardiac hypertrophy. Also, it can be stimulated by AngII (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur study had several limitations: the small sample size (derived from the low prevalence of CAE) and the limited number of studied miRNAs are the most important. The number of miRNA markers analyzed using qPCR in this study was limited by study funding. Including other miRNAs linked with atherosclerosis, inflammation, and venous thrombosis would have been helpful for further characterization of these allegedly different populations (CAE and obstructive CAD). These results should stimulate further investigations on miRNAs profile in patients with CE.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn patients suffering from acute coronary syndrome and coronary artery ectasia, an increased expression of miR-133b was found compared to patients without coronary ectasia. This finding may suggest that coronary artery ectasia is related to atherosclerotic burden and \u0026ldquo;unstable plaque\u0026rdquo; phenotype, which may have implications for treatment. Future studies are required to expand the findings of this research work and propose using miR-133b as a prognostic and follow-up marker in patients with ACS and coronary artery ectasia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics Approval and Consent to Participate:\u0026nbsp;\u003c/em\u003eThe study adheres to the ethical principles outlined in the Declaration of Helsinki, and the protocol received approval by the institutional ethics and research committee (Comit\u0026eacute; de Investigaci\u0026oacute;n y \u0026Eacute;tica del Instituto Nacional de Cardiolog\u0026iacute;a Ignacio Ch\u0026aacute;vez) with the number 21-1248. Written informed consent was obtained from all subjects and/or their legal guardian(s).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for Publication:\u0026nbsp;\u003c/em\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of Data and Materials:\u003c/em\u003e The data that support the findings of this study are available from Instituto Nacional de Cardiolog\u0026iacute;a \u0026ldquo;Ignacio Ch\u0026aacute;vez\u0026rdquo;, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request to the corresponding author and with permission of Instituto Nacional de Cardiolog\u0026iacute;a \u0026ldquo;Ignacio Ch\u0026aacute;vez.\u0026rdquo;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting Interests:\u0026nbsp;\u003c/em\u003e Araiza-Garaygordobil has received institutional research grants from Novartis and reports speaking fees from Boehringer Ingelheim, Novartis, AstraZeneca, Servier \u0026amp; Abbott. Dr A.S. Arias-Mendoza has served on the advisory board of Roche Diagnostics and reports speaking fees from Novo Nordisk, Novartis, Roche Diagnostics, and Sanofi Aventis. All other authors declare no relevant conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding:\u0026nbsp;\u003c/em\u003eNo funding was received\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthor Contributions:\u0026nbsp;\u003c/em\u003eJG conceived and designed the research and drafted the original manuscript. DA designed the research and is responsible for the work. FD drafted the manuscript. MR analyzed and interpreted data. FS, MP and LJ received and analyzed blood samples. NB, VS, MR, AN, AA, GS were responsible for obtaining data and drafting manuscript. JG obtained data and designed the central image. RG, DS and HG were responsible for revising the manuscript critically for important intellectual content. AA had the duty of managing the project, overseeing it, and ensuring the accuracy and validity of the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements:\u003c/em\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; information:\u0026nbsp;\u003c/em\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSwaye PS, Fisher LD, Litwin P, Vignola PA, et al. 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MicroRNA in cardiovascular biology and disease. \u003cem\u003eAdvances in Clinical and Experimental Medicine. \u003c/em\u003e2017;26:868-874.\u003c/li\u003e\n\u003cli\u003eFichtlscherer S, De Rosa S, Fox H, et al. \u003cem\u003eCirculating microRNAs in patients with coronary artery disease.\u003c/em\u003e Circ Res. 2010;107:677\u0026ndash;684.\u003c/li\u003e\n\u003cli\u003eDe Gonzalo-Calvo D, Iglesias-Guti\u0026eacute;rrez E, Llorente-Cort\u0026eacute;s V. \u003cem\u003eE\u003c/em\u003epigenetic Biomarkers and Cardiovascular Disease: Circulating MicroRNAs\u003cem\u003e.\u003c/em\u003e \u003cem\u003eRevista Espa\u0026ntilde;ola de Cardiolog\u0026iacute;a \u003c/em\u003e(English Edition). 2017;70:763-769.\u003c/li\u003e\n\u003cli\u003eLindholm E, Ragle Aure M, Haugen M, Kleivi Sahlberg K, Kristensen V, Nebdal D et al. miRNA expression changes during the course of neoadjuvant bevacizumab and chemotherapy treatment in breast cancer. \u003cem\u003eMolecular Oncology. \u003c/em\u003e2019;13:2278-2296.\u003c/li\u003e\n\u003cli\u003eSardu C, Santamaria M, Paolisso G, Marfella R. microRNA expression changes after atrial fibrillation catheter ablation. \u003cem\u003ePharmacogenomics. \u003c/em\u003e2015;16:1863-187\u003c/li\u003e\n\u003cli\u003eWeber M, Baker M, Patel R, Quyyumi A, Bao G, Searles C. MicroRNA Expression Profile in CAD Patients and the Impact of ACEI/ARB. \u003cem\u003eCardiology Research and Practice. \u003c/em\u003e2011;2011:1-5.\u003c/li\u003e\n\u003cli\u003eCipollone F, Felicioni L, Sarzani R, Ucchino S, Spigonardo F, Mandolini C, et al. A Unique MicroRNA Signature Associated with Plaque Instability in Humans.\u003cem\u003e Stroke. \u003c/em\u003e2011;42: 2556\u0026ndash;2563. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acute Coronary Syndrome, Coronary Artery Ectasia, miRNA","lastPublishedDoi":"10.21203/rs.3.rs-2921437/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2921437/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCoronary artery ectasia (CAE) is an abnormal coronary dilatation that exceeds 1.5x the size of the adjacent coronary normal segments, considered a manifestation of atherosclerosis. However, information regarding its etiology and pathophysiology is scarce. MicroRNAs are small circulating proteins that regulate diverse biological processes and may be involved in tissue development, homeostasis, and cellular communication. We aimed to explore a signature of microRNAs in patients with acute coronary syndrome (ACS) and CAE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea prospective case \u0026amp; control study including consecutive patients with ACS (STEMI and NSTEMI) with and without CAE. Plasma samples were obtained, and consequently, quantification of plasma levels of miR-208, miR-208b, miR-1, miR-133b, miR-21, miR-155, miR-126, and miR-16 was performed by qRT-PCR. For analytical purposes, patients were divided into two groups: patients with ACS and CAE and patients with ACS and obstructive CAD. We included 47 patients, 24 with CAE and 23 with obstructive coronary disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with CAE showed a higher incidence of obesity (50 vs 21.7%, p = 0.04) and a higher left ventricular ejection fraction (52 vs 41%, p = 0.01). The rest of the baseline clinical characteristics were well-balanced. Among the selected signatures of microRNAs, patients with ACS and CAE showed higher levels of miR-133b than those without CAE. All other analyzed miRNAs were similar among groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn patients with ACS and CAE, we found higher miR-133b. Future studies are required to expand the findings of this research work and propose using miR-133b.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProtocol received approval by the institutional ethics and research committee with the number 21-1248.\u003c/p\u003e","manuscriptTitle":"Association between mRNA 133b and Patients with Coronary Artery Ectasia and Acute Coronary Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-19 21:10:11","doi":"10.21203/rs.3.rs-2921437/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7c7164f6-ef5c-4bc7-9e5b-bd34e4375adc","owner":[],"postedDate":"May 19th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-07-13T07:14:12+00:00","versionOfRecord":[],"versionCreatedAt":"2023-05-19 21:10:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2921437","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2921437","identity":"rs-2921437","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}