Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury
Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pa...
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| Veröffentlicht in: | Journal of cerebral blood flow and metabolism 2021-11, Vol.41 (11), p.3000-3015 |
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| creator | Akeret, Kevin Buzzi, Raphael M Schaer, Christian A Thomson, Bart R Vallelian, Florence Wang, Sophie Willms, Jan Sebök, Martina Held, Ulrike Deuel, Jeremy W Humar, Rok Regli, Luca Keller, Emanuela Hugelshofer, Michael Schaer, Dominik J |
| description | Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target. |
| doi_str_mv | 10.1177/0271678X211020629 |
| format | Article |
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The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.</description><identifier>ISSN: 0271-678X</identifier><identifier>EISSN: 1559-7016</identifier><identifier>DOI: 10.1177/0271678X211020629</identifier><identifier>PMID: 34102922</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Adult ; Aged ; Biomarkers - cerebrospinal fluid ; Brain Ischemia - etiology ; Cerebrospinal Fluid - chemistry ; Female ; Hemoglobins - cerebrospinal fluid ; Humans ; Male ; Middle Aged ; Original ; Subarachnoid Hemorrhage - complications ; Vasospasm, Intracranial - etiology</subject><ispartof>Journal of cerebral blood flow and metabolism, 2021-11, Vol.41 (11), p.3000-3015</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021 2021 International Society for Cerebral Blood Flow and Metabolism</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-a59dc6d64901c891f144cc6356e5c386c86dc1e21f1ef1bc4bfe1495a44bc8e73</citedby><cites>FETCH-LOGICAL-c438t-a59dc6d64901c891f144cc6356e5c386c86dc1e21f1ef1bc4bfe1495a44bc8e73</cites><orcidid>0000-0003-4639-4474 ; 0000-0002-3057-0472 ; 0000-0003-3105-5840 ; 0000-0002-7246-3421 ; 0000-0002-6468-4013 ; 0000-0001-6114-0750</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545037/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545037/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,21798,27901,27902,43597,43598,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34102922$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akeret, Kevin</creatorcontrib><creatorcontrib>Buzzi, Raphael M</creatorcontrib><creatorcontrib>Schaer, Christian A</creatorcontrib><creatorcontrib>Thomson, Bart R</creatorcontrib><creatorcontrib>Vallelian, Florence</creatorcontrib><creatorcontrib>Wang, Sophie</creatorcontrib><creatorcontrib>Willms, Jan</creatorcontrib><creatorcontrib>Sebök, Martina</creatorcontrib><creatorcontrib>Held, Ulrike</creatorcontrib><creatorcontrib>Deuel, Jeremy W</creatorcontrib><creatorcontrib>Humar, Rok</creatorcontrib><creatorcontrib>Regli, Luca</creatorcontrib><creatorcontrib>Keller, Emanuela</creatorcontrib><creatorcontrib>Hugelshofer, Michael</creatorcontrib><creatorcontrib>Schaer, Dominik J</creatorcontrib><title>Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury</title><title>Journal of cerebral blood flow and metabolism</title><addtitle>J Cereb Blood Flow Metab</addtitle><description>Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.</description><subject>Adult</subject><subject>Aged</subject><subject>Biomarkers - cerebrospinal fluid</subject><subject>Brain Ischemia - etiology</subject><subject>Cerebrospinal Fluid - chemistry</subject><subject>Female</subject><subject>Hemoglobins - cerebrospinal fluid</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Original</subject><subject>Subarachnoid Hemorrhage - complications</subject><subject>Vasospasm, Intracranial - etiology</subject><issn>0271-678X</issn><issn>1559-7016</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>AFRWT</sourceid><sourceid>EIF</sourceid><recordid>eNp9kU9LAzEQxYMotlY_gBfZo5etSTbJbi6CFP9BwYuCByFks7NtynZTk26h394srUURPM3h_d6bYR5ClwSPCcnzG0xzIvLinRKCKRZUHqEh4VymOSbiGA17Pe2BAToLYYExLjLOT9EgY9EgKR2ijwl4KL0LK9vqJqmbzlbJHJZu1rjStknl7QZCErpSe23mrdvL3s_1DFIPjV5DlQQwrq203yal19Fm20Xnt-fopNZNgIv9HKG3h_vXyVM6fXl8ntxNU8OyYp1qLisjKsEkJqaQpCaMGSMyLoCbrBCmEJUhQKMANSkNK2sgTHLNWGkKyLMRut3lrrpyCZWBdu11o1beLuNJymmrfiutnauZ26iCM46zPuB6H-DdZwdhrZY2GGga3YLrgqI8k5wyKUVEyQ418WnBQ31YQ7DqW1F_Womeq5_3HRzfNURgvANCfKpauM7HMsI_iV99zJiA</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Akeret, Kevin</creator><creator>Buzzi, Raphael M</creator><creator>Schaer, Christian A</creator><creator>Thomson, Bart R</creator><creator>Vallelian, Florence</creator><creator>Wang, Sophie</creator><creator>Willms, Jan</creator><creator>Sebök, Martina</creator><creator>Held, Ulrike</creator><creator>Deuel, Jeremy W</creator><creator>Humar, Rok</creator><creator>Regli, Luca</creator><creator>Keller, Emanuela</creator><creator>Hugelshofer, Michael</creator><creator>Schaer, Dominik J</creator><general>SAGE Publications</general><scope>AFRWT</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4639-4474</orcidid><orcidid>https://orcid.org/0000-0002-3057-0472</orcidid><orcidid>https://orcid.org/0000-0003-3105-5840</orcidid><orcidid>https://orcid.org/0000-0002-7246-3421</orcidid><orcidid>https://orcid.org/0000-0002-6468-4013</orcidid><orcidid>https://orcid.org/0000-0001-6114-0750</orcidid></search><sort><creationdate>20211101</creationdate><title>Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury</title><author>Akeret, Kevin ; 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The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>34102922</pmid><doi>10.1177/0271678X211020629</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-4639-4474</orcidid><orcidid>https://orcid.org/0000-0002-3057-0472</orcidid><orcidid>https://orcid.org/0000-0003-3105-5840</orcidid><orcidid>https://orcid.org/0000-0002-7246-3421</orcidid><orcidid>https://orcid.org/0000-0002-6468-4013</orcidid><orcidid>https://orcid.org/0000-0001-6114-0750</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Biomarkers - cerebrospinal fluid Brain Ischemia - etiology Cerebrospinal Fluid - chemistry Female Hemoglobins - cerebrospinal fluid Humans Male Middle Aged Original Subarachnoid Hemorrhage - complications Vasospasm, Intracranial - etiology |
| title | Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury |
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