Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease
2019; Lippincott Williams & Wilkins; Volume: 141; Issue: 8 Linguagem: Inglês
10.1161/circulationaha.119.044235
ISSN1524-4539
AutoresC. David Mazer, Gregory M. T. Hare, Philip W. Connelly, Richard E. Gilbert, Nadine Shehata, Adrian Quan, Hwee Teoh, Lawrence A. Leiter, Bernard Zinman, Peter Jüni, Fei Zuo, Nikhil Mistry, Kevin E. Thorpe, Ronald Goldenberg, Andrew T. Yan, Kim A. Connelly, Subodh Verma,
Tópico(s)Diabetes, Cardiovascular Risks, and Lipoproteins
ResumoHomeCirculationVol. 141, No. 8Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEffect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease C. David Mazer, MD, Gregory M.T. Hare, MD, PhD, Philip W. Connelly, PhD, Richard E. Gilbert, MBBS, PhD, Nadine Shehata, MD, MSc, Adrian Quan, MPhil, Hwee Teoh, PhD, Lawrence A. Leiter, MD, Bernard Zinman, MD, Peter Jüni, MD, Fei Zuo, MPH, Nikhil Mistry, MSc, Kevin E. Thorpe, MMath, Ronald M. Goldenberg, MD, Andrew T. Yan, MD, Kim A. Connelly, MBBS, PhD and Subodh Verma, MD, PhD C. David MazerC. David Mazer C. David Mazer, MD, Department of Anesthesia, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. Email E-mail Address: [email protected] Department of Anesthesia (C.D.M., G.M.T.H., N.M.), Unity Health Toronto, Ontario, Canada. Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Anesthesia (C.D.M., G.M.T.H.), University of Toronto, Ontario, Canada. Department of Physiology (C.D.M., G.M.T.H., K.A.C.), University of Toronto, Ontario, Canada. , Gregory M.T. HareGregory M.T. Hare Department of Anesthesia (C.D.M., G.M.T.H., N.M.), Unity Health Toronto, Ontario, Canada. Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Anesthesia (C.D.M., G.M.T.H.), University of Toronto, Ontario, Canada. Department of Physiology (C.D.M., G.M.T.H., K.A.C.), University of Toronto, Ontario, Canada. , Philip W. ConnellyPhilip W. Connelly Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology (P.W.C., N.S.), University of Toronto, Ontario, Canada. , Richard E. GilbertRichard E. Gilbert Division of Endocrinology and Metabolism (R.E.G., H.T., L.A.L.), Unity Health Toronto, Ontario, Canada. Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. , Nadine ShehataNadine Shehata Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology (P.W.C., N.S.), University of Toronto, Ontario, Canada. Institute of Health Policy, Management and Evaluation (N.S., P.J.), University of Toronto, Ontario, Canada. Division of Hematology (N.S.), Toronto, Ontario, Canada. , Adrian QuanAdrian Quan Division of Cardiac Surgery (A.Q., H.T., S.V.), Unity Health Toronto, Ontario, Canada. Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. , Hwee TeohHwee Teoh Division of Endocrinology and Metabolism (R.E.G., H.T., L.A.L.), Unity Health Toronto, Ontario, Canada. Division of Cardiac Surgery (A.Q., H.T., S.V.), Unity Health Toronto, Ontario, Canada. Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. , Lawrence A. LeiterLawrence A. Leiter Division of Endocrinology and Metabolism (R.E.G., H.T., L.A.L.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. Department of Nutritional Sciences (L.A.L.), University of Toronto, Ontario, Canada. , Bernard ZinmanBernard Zinman Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.), Toronto, Ontario, Canada. , Peter JüniPeter Jüni Applied Health Research Centre (P.J., F.Z., K.E.T.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. Institute of Health Policy, Management and Evaluation (N.S., P.J.), University of Toronto, Ontario, Canada. , Fei ZuoFei Zuo Applied Health Research Centre (P.J., F.Z., K.E.T.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. , Nikhil MistryNikhil Mistry Department of Anesthesia (C.D.M., G.M.T.H., N.M.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. , Kevin E. ThorpeKevin E. Thorpe Applied Health Research Centre (P.J., F.Z., K.E.T.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. and Dalla Lana School of Public Health (K.E.T.), University of Toronto, Ontario, Canada. , Ronald M. GoldenbergRonald M. Goldenberg LMC Diabetes & Endocrinology, Concord, Ontario, Canada (R.M.G.). , Andrew T. YanAndrew T. Yan Division of Cardiology (A.T.Y., K.A.C.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. , Kim A. ConnellyKim A. Connelly Division of Cardiology (A.T.Y., K.A.C.), Unity Health Toronto, Ontario, Canada. Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Physiology (C.D.M., G.M.T.H., K.A.C.), University of Toronto, Ontario, Canada. Department of Medicine (P.W.C., R.E.G., N.S., L.A.L., B.Z., P.J., A.T.Y., K.A.C.), University of Toronto, Ontario, Canada. and Subodh VermaSubodh Verma Division of Cardiac Surgery (A.Q., H.T., S.V.), Unity Health Toronto, Ontario, Canada. Keenan Research Centre for Biomedical Science (C.D.M., G.M.T.H., P.W.C., R.E.G., A.Q., H.T., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Li Ka Shing Knowledge Institute of St Michael's Hospital (C.D.M., G.M.T.H., R.E.G., A.Q., H.T., L.A.L., P.J., F.Z., N.M., K.E.T., A.T.Y., K.A.C., S.V.), Unity Health Toronto, Ontario, Canada. Department of Surgery (S.V.), University of Toronto, Ontario, Canada. Department of Pharmacology and Toxicology (S.V.), University of Toronto, Ontario, Canada. Originally published11 Nov 2019https://doi.org/10.1161/CIRCULATIONAHA.119.044235Circulation. 2020;141:704–707Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 11, 2019: Ahead of Print Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes, including hospitalization for heart failure and mortality, in people with and without diabetes mellitus.1,2 The mechanisms underlying this benefit remain unclear.Although several hypotheses have been suggested (including SGLT2 inhibitor–mediated diuresis and natriuresis, reduction in blood pressure and afterload, direct effects on myocardial sodium and calcium handling, alterations in myocardial energetics, reduction in left ventricular mass, and improved progenitor cell response),3 a mediation analysis from the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) suggests that an increase in hematocrit may account for more than half of the mortality benefit observed. The consistent observation of an increase in hematocrit, even in those without diabetes mellitus, has led to the hypothesis that SGLT2 inhibitors may increase erythropoiesis via enhanced erythropoietin secretion by the kidney.4 This SGLT2 inhibitor–mediated increase in erythropoietin production (and resultant rise in hematocrit) could lead to systemic organ protection by virtue of its capacity as a circulating pleiotropic cytokine, known to favorably influence cardiomyocyte mitochondrial function, angiogenesis, cell proliferation, and inflammation. In addition, an increase in erythropoietin-induced hematocrit may improve myocardial function by directly enhancing myocardial and systemic tissue oxygen delivery.In this substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes) CardioLink-6 randomized clinical trial in which 6 months of empagliflozin treatment was associated with significant reduction in left ventricular mass index,5 we measured erythropoietin levels, red blood cell (RBC) morphology, and indices of iron stores in individuals with type 2 diabetes mellitus and stable coronary artery disease who were randomized to either empagliflozin 10 mg daily or placebo for 6 months. The St Michael's Hospital Research Ethics Board approved the study, and all subjects gave informed consent. Blood samples were collected at baseline, after 1 month of treatment, and at the end of the study (6 months). Erythropoietin levels were measured from frozen sera with a 2-site immunoenzymatic chemiluminescent assay, and the data were analyzed with a linear mixed-effects model that included treatment group, visit, and treatment-by-visit interaction, and baseline values as fixed effects. Iron indices, ferritin, and complete blood counts were measured at baseline and at 6 months with standard spectrophotometric, 2-site immunoenzymatic, and flow cytometric techniques, with data analyzed using ANCOVA adjusted for baseline values. Values of P<0.05 were considered significant. Data for this report may be shared in accordance with a data-sharing agreement.Complete erythropoietin data were available for 82 of the 90 patients who completed the study. Erythropoietin levels increased significantly after 1 month of empagliflozin treatment (adjusted difference between groups at 1 month, 3.86 mIU/mL [95% CI, 0.99 to 6.74], P<0.05; at 6 months, 1.91 mIU/mL [95% CI, −0.96 to 4.78]). Six months of empagliflozin treatment was also associated with changes in hematocrit and RBC indices (Figure). Hematocrit increased after 6 months by 2.34% (95% CI, 1.1 to 3.57; P<0.001). This occurred in the setting of reduced ferritin levels (mean difference, −21.83 μg/L [95% CI −37.96 to −5.70]; P<0.01) and mean cell hemoglobin concentration (−5.83 g/L [95% CI, −9.79 to −1.88]; P<0.01). Overall, empagliflozin treatment was associated with an early increase in plasma erythropoietin levels accompanied by an increase in hematocrit and reduced ferritin and RBC hemoglobin concentration at 6 months in people with type 2 diabetes mellitus and coronary artery disease.Download figureDownload PowerPointFigure. Effect of empagliflozin on erythropoietin (EPO), red blood cell (RBC) indices, and iron status.A, EPO levels in patients receiving empagliflozin 10 mg daily (red circles) or placebo (blue squares) plotted as mean±95% CIs. Adjusted differences are between-group differences in means of EPO levels from a linear mixed model adjusted for EPO levels at baseline. B, RBC indices, hemoglobin and hematocrit values, and iron status at baseline and after 6 months of empagliflozin or placebo. C, Proposed renal mechanisms for increased EPO with sodium-glucose cotransporter 2 (SGLT2) inhibition.A few prior studies have demonstrated a trend to an early increase in erythropoietin but did not demonstrate a relationship with iron utilization or red cell morphology. Our findings suggest that the increase in hematocrit, consistently observed across all SGLT2 inhibitor studies, is at least partly the result of increased erythropoietin levels and stimulated erythropoiesis. The increase in erythropoietin levels induced by SGLT2 inhibition may be caused by an increase in sodium detected at the distal renal tubules by the juxtaglomerular apparatus, thereby elevating afferent arteriolar tone and reducing afferent renal blood flow, glomerular filtration rate, and renal tissue oxygen delivery. Another possible mechanism is that the transfer of enhanced but less efficient oxygen-consuming active sodium reabsorption to the distal tubule leads to expression of hypoxia-inducible factors, which stimulate erythropoiesis. It is also possible that proximal tubular cells are relieved from the burden of excess glucose absorption, thereby reducing cortical oxidative stress and enhancing recovery from tubulointerstitial damage with restoration of erythropoietin production. In addition, β-hydroxybutyrate could contribute to the stimulation of erythropoietin. Evidence of enhanced erythropoiesis is supported by the observed change in RBC morphology, reduction in ferritin or iron stores, differential time course of response, and reduced RBC hemoglobin concentration, which would not occur with hemoconcentration. The increased red cell mass may contribute to improved myocardial tissue oxygen delivery and reduced left ventricular mass in these patients.5In summary, we provide convincing evidence to suggest that SGLT2 inhibition with empagliflozin may stimulate erythropoiesis via an early increase in erythropoietin production in people with type 2 diabetes mellitus. These findings enhance our understanding of the cellular mechanism by which SGLT2 inhibitors improve heart failure outcomes in clinical trials.Sources of FundingThis trial was supported by an unrestricted investigator-initiated study grant from Boehringer Ingelheim to Drs Verma and Zinman.DisclosuresDr Mazer holds a Merit Award from the Department of Anesthesia at the University of Toronto and reports receiving honoraria from Amgen, Boehringer Ingelheim, and OctaPharma. Dr Hare holds a Merit Award from the Department of Anesthesia at the University of Toronto and reports receiving an honorarium from Johnson & Johnson Inc. and research funding from Forest Laboratories Inc. Dr Gilbert holds a Canada Research Chair in Diabetes Complications and reports receiving research grants to the institution from AstraZeneca and Boehringer Ingelheim; serving on advisory panels for AstraZeneca, Boehringer Ingelheim, and Janssen; and receiving continuing medical education speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen. Dr Shehata reports honoraria and education grants from Sanofi. Dr Teoh reports receiving honorarium from Boehringer Ingelheim and writing fees for unrelated diabetes mellitus–related articles from Merck and Servier. Dr Leiter reports receiving research funding from, providing continuing medical education on behalf of, and/or acting an adviser to AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novo Nordisk, Sanofi, and Servier. Dr Zinman reports sitting on scientific advisory boards of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Dr Jüni holds a Canada Research Chair in clinical epidemiology of chronic diseases; serves as unpaid member of the steering group of trials funded by AstraZeneca, Biotronik, Biosensors, St Jude Medical, and The Medicines Company; and reports receiving research grants to the institution from AstraZeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company, as well as honoraria to the institution for participation in advisory boards from Amgen, but has not received personal payments by any pharmaceutical company or device manufacturer. Dr Goldenberg reports receiving research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, and Sanofi; serving on advisory panels for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, and Sanofi; serving on speaker bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, and Sanofi; and serving as a consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, and Sanofi. Dr Yan reports receiving research support from AstraZeneca. Dr K. Connelly holds a New Investigator Salary Award from the Canadian Institutes of Health Research and an Early Researcher Award from the Ontario Ministry of Research and Innovation; is listed as an inventor on a patent application by Boehringer Ingelheim on the use of dipeptidyl peptidase-4 inhibitors in heart failure; and reports receiving research grants to his institution from AstraZeneca and Boehringer Ingelheim, support for travel to scientific meetings from Boehringer Ingelheim, and honoraria for speaking engagements and ad hoc participation in advisory boards from AstraZeneca, Boehringer Ingelheim, and Janssen. Dr Verma holds a Canada Research Chair in Cardiovascular Surgery and reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group. He is also the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. The other authors report no conflicts.The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the article or decision to submit the article for publication. The database for the study was located and the data analyses were conducted at the not-for-profit academic research organization Applied Health Research Centre, which is integrated with the Li Ka Shing Knowledge Institute of St Michael's Hospital, and not shared with the funder. The article was modified after consultation with the coauthors. The authors had unrestricted rights to publish the results and the final decision on content was exclusively retained by the authors.Footnotes*Drs Mazer and Hare contributed equally.https://www.ahajournals.org/journal/circThe data that support the findings of this study may be available from the corresponding author on reasonable request and in accordance with a data-sharing agreement.This article was presented in part as a moderated poster at the American Heart Association Scientific Sessions in Philadelphia, Pennsylvania, on November 16 to 18, 2019.C. David Mazer, MD, Department of Anesthesia, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. Email david.[email protected]toReferences1. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381:1995–2008. doi: 10.1056/NEJMoa1911303CrossrefMedlineGoogle Scholar2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373:2117–2128. doi: 10.1056/NEJMoa1504720CrossrefMedlineGoogle Scholar3. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.Diabetologia. 2018; 61:2108–2117. doi: 10.1007/s00125-018-4670-7CrossrefMedlineGoogle Scholar4. Sano M, Goto S. 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