{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:41:13Z","timestamp":1790185273672,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dutch Heart Foundation","award":["CVON2014-40 DOSIS"],"award-info":[{"award-number":["CVON2014-40 DOSIS"]}]},{"name":"ZonMW and Dutch Heart Foundation","award":["Translational Research Program, project 95105003"],"award-info":[{"award-number":["Translational Research Program, project 95105003"]}]},{"name":"NWO-ZonMW","award":["91818602 VICI grant"],"award-info":[{"award-number":["91818602 VICI grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients. Methods: Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation. Results: The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR. Conclusion: Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery.<\/jats:p>","DOI":"10.3390\/ijms22073569","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T09:57:04Z","timestamp":1617098224000},"page":"3569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8287-3707","authenticated-orcid":false,"given":"Beau Olivier van","family":"van Driel","sequence":"first","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-6190","authenticated-orcid":false,"given":"Maike","family":"Schuldt","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sila","family":"Alg\u00fcl","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeni","family":"Levin","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Universiteit van Amsterdam, Internal and Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"G\u00fccl\u00fc","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjeerd","family":"Germans","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Cardiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1714-4652","authenticated-orcid":false,"given":"Albert C. van","family":"Rossum","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Cardiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Pei","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Universiteit Utrecht, Cardiology, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Harakalova","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Universiteit Utrecht, Cardiology, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Baas","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Universiteit Utrecht, Genetics, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith J. M.","family":"Jans","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Universiteit Utrecht, Genetics, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-5788","authenticated-orcid":false,"given":"Jolanda","family":"van der Velden","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Physiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1161\/CIRCULATIONAHA.119.043391","article-title":"Global, Regional, and National Burden of Calcific Aortic Valve and Degenerative Mitral Valve Diseases, 1990\u20132017","volume":"141","author":"Yadgir","year":"2020","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1016\/j.jacc.2012.02.093","article-title":"Calcific Aortic Stenosis: A Disease of the Valve and the Myocardium","volume":"60","author":"Dweck","year":"2012","journal-title":"J. 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