{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T11:55:59Z","timestamp":1775822159103,"version":"3.50.1"},"reference-count":57,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathophysiology"],"abstract":"<jats:p>Atherosclerosis remains the leading cause of death worldwide and imposes a major healthcare burden. Physiologically, elimination of cholesterol from the arterial wall depends on reverse cholesterol transport (RCT). RCT requires access to HDL and apolipoprotein A-I (ApoA-I) to lesional macrophages\/foam cells. The endothelial glycocalyx is a dynamic and injury-sensitive layer of proteoglycans and glycosaminoglycans (including hyaluronan). It contributes to vascular barrier properties, leukocyte adhesion, mechanotransduction, and macromolecular transport. In atherosclerosis, glycocalyx structure and function are altered; this may facilitate entry\/retention of atherogenic lipoproteins and may also alter transport conditions relevant to cholesterol efflux pathways. This article presents a mechanistic hypothesis: short, transient, systemic hyaluronidase exposure could temporarily remodel glycocalyx\/extracellular matrix components and thereby facilitate conditions permissive for regulated transport processes relevant to RCT. However, the proposed link between glycocalyx remodeling and improved lesional cholesterol efflux remains theoretical. Direct in vivo evidence that the endothelial glycocalyx is a dominant barrier limiting HDL- or ApoA-I-mediated cholesterol efflux from plaque macrophages is currently limited. Moreover, glycocalyx degradation is widely associated with endothelial dysfunction, increased permeability, inflammation, and thrombosis, all of which could aggravate rather than ameliorate atherosclerosis. Human pharmacokinetic data indicate a very short plasma half-life of circulating hyaluronidase activity, suggesting that any systemic enzymatic effect is brief. Nevertheless, the biological consequences of repeated degradation\u2013regeneration cycles, especially in high-risk states such as diabetes, inflammation, oxidative stress, or chronic kidney disease, remain incompletely understood. Evidence supporting clinical benefit in atherosclerosis is currently limited to heterogeneous animal experiments, historical uncontrolled reports, and a small number of anecdotal case observations, whereas randomized trials have only been performed in other settings such as acute myocardial infarction and do not establish efficacy for plaque regression. We therefore provide a balanced evaluation of knowns, uncertainties, alternative interpretations, potential risks, dosing unknowns, and a translational research agenda including mechanistic preclinical studies, biomarker development, imaging, and carefully designed early-phase clinical investigation.<\/jats:p>","DOI":"10.3390\/pathophysiology33020026","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T10:20:16Z","timestamp":1775816416000},"page":"26","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transient Glycocalyx Remodeling by Intravenous Hyaluronidase in Atherosclerosis: A Hypothesis-Generating Review"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2385-0887","authenticated-orcid":false,"given":"Andreas","family":"Pf\u00fctzner","sequence":"first","affiliation":[{"name":"Pf\u00fctzner Science & Health Institute, PSHI Praxis GmbH, Haifa-Alle 18, D-55128 Mainz, Germany"},{"name":"Department of Biotechnology & Bioinformatics, Technische Hochschule Bingen, D-55411 Bingen am Rhein, Germany"},{"name":"Institute for Digital Technology in Medicine and Dentistry, Institut Sup\u00e9rieur de Formation Continue, Schuttrange, L-5359 Luxembourg, Luxembourg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Gantner","sequence":"additional","affiliation":[{"name":"Healthcare Futurists GmbH, D-50935 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"Burgard","sequence":"additional","affiliation":[{"name":"Practice for Integrative Environmental Medicine, D-66787 Wadgassen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tilman","family":"Steinmeier","sequence":"additional","affiliation":[{"name":"Biologicum\u2014Zentrum f\u00fcr Umweltmedizin, D-20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduard","family":"Stappler","sequence":"additional","affiliation":[{"name":"MedDentcon GmbH, D-50667 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7103-6973","authenticated-orcid":false,"given":"Julia","family":"Jantz","sequence":"additional","affiliation":[{"name":"Pf\u00fctzner Science & Health Institute, PSHI Praxis GmbH, Haifa-Alle 18, D-55128 Mainz, Germany"},{"name":"Institute for Digital Technology in Medicine and Dentistry, Institut Sup\u00e9rieur de Formation Continue, Schuttrange, L-5359 Luxembourg, Luxembourg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Wiechel","sequence":"additional","affiliation":[{"name":"Swiss Mountain Clinic, CH-6540 Castaneda, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1097\/CM9.0000000000002839","article-title":"Global and national burden of atherosclerosis from 1990 to 2019: Trend analysis based on the Global Burden of Disease Study 2019","volume":"136","author":"Chen","year":"2023","journal-title":"Chin. 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