{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T03:03:21Z","timestamp":1787627001767,"version":"build-2736575974"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,9,17]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifiers: NCT05603520 and NCT01805739.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.123.064747","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T05:13:18Z","timestamp":1717564398000},"page":"952-965","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction"],"prefix":"10.1161","volume":"150","clinical-trial-number":[{"clinical-trial-number":"nct05603520","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01805739","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0405-989X","authenticated-orcid":true,"given":"Christine","family":"Quast","sequence":"first","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5701-2596","authenticated-orcid":true,"given":"Florian","family":"B\u00f6nner","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5891-9672","authenticated-orcid":true,"given":"Amin","family":"Polzin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."},{"name":"Cardiovascular Research Institute D\u00fcsseldorf, Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany. (A.P., C.J., U.F., N.G., M.M.C.-K., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2744-2154","authenticated-orcid":true,"given":"Verena","family":"Veulemans","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3994-5285","authenticated-orcid":true,"given":"Ramesh","family":"Chennupati","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Gyamfi Poku","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8591-6186","authenticated-orcid":true,"given":"Susanne","family":"Pfeiler","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Kramser","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Nankinova","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Staub","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6739-476X","authenticated-orcid":true,"given":"Elric","family":"Zweck","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."},{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (E.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Jokiel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Keyser","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmina","family":"Hoffe","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5398-7572","authenticated-orcid":true,"given":"Sven","family":"Witkowski","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6876-6035","authenticated-orcid":true,"given":"Katrin","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Leuders","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saif","family":"Zako","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3373-652X","authenticated-orcid":true,"given":"Ralf","family":"Erkens","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8325-250X","authenticated-orcid":true,"given":"Christian","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."},{"name":"Cardiovascular Research Institute D\u00fcsseldorf, Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany. (A.P., C.J., U.F., N.G., M.M.C.-K., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7181-4392","authenticated-orcid":true,"given":"Ulrich","family":"Fl\u00f6gel","sequence":"additional","affiliation":[{"name":"Experimental Cardiovascular Imaging, Department of Molecular Cardiology, Heinrich Heine University, D\u00fcsseldorf, Germany (U.F.)."},{"name":"Cardiovascular Research Institute D\u00fcsseldorf, Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany. (A.P., C.J., U.F., N.G., M.M.C.-K., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Engineering, Institute of Applied Medical Engineering, Medical Faculty, Rheinisch-Westf\u00e4lische Technische Hochschule (RWTH) Aachen, Germany (T.W., M. Neidlin, U.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5582-6905","authenticated-orcid":true,"given":"Michael","family":"Neidlin","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Engineering, Institute of Applied Medical Engineering, Medical Faculty, Rheinisch-Westf\u00e4lische Technische Hochschule (RWTH) Aachen, Germany (T.W., M. Neidlin, U.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8065-9803","authenticated-orcid":true,"given":"Ulrich","family":"Steinseifer","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Engineering, Institute of Applied Medical Engineering, Medical Faculty, Rheinisch-Westf\u00e4lische Technische Hochschule (RWTH) Aachen, Germany (T.W., M. Neidlin, U.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8095-5824","authenticated-orcid":true,"given":"Sven Thomas","family":"Niepmann","sequence":"additional","affiliation":[{"name":"Heart Center Bonn, Clinic for Internal Medicine II, University Hospital Bonn, Germany (S.T.N., S. Zimmer)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Heart Center Bonn, Clinic for Internal Medicine II, University Hospital Bonn, Germany (S.T.N., S. Zimmer)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4546-7208","authenticated-orcid":true,"given":"Norbert","family":"Gerdes","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."},{"name":"Cardiovascular Research Institute D\u00fcsseldorf, Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany. (A.P., C.J., U.F., N.G., M.M.C.-K., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0593-1192","authenticated-orcid":true,"given":"Miriam M.","family":"Cortese-Krott","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. Zako, R.E., C.J., N.G., M.M.C.-K., T.Z., M.K.)."},{"name":"Cardiovascular Research Institute D\u00fcsseldorf, Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany. (A.P., C.J., U.F., N.G., M.M.C.-K., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2320-1158","authenticated-orcid":true,"given":"Martin","family":"Feelisch","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, University of Southampton, United Kingdom (M.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4517-0068","authenticated-orcid":true,"given":"Tobias","family":"Zeus","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, University Hospital and Medical Faculty, Heinrich Heine University, D\u00fcsseldorf, Germany (C.Q., F.B., A.P., V.V., R.C., I.G.P., S.P., N.K., M. Nankinova, N.S., E.Z., J.J., F.K., J.H., S.W., K.B., P.L., S. 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