Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts

Viktor Horst; Vasilis Kola; Coline L Lemale; Sebastian Major; Maren K L Winkler; Nils Hecht; Edgar Santos; Johannes Platz; Oliver W Sakowitz; Hartmut Vatter; Christian Dohmen; Michael Scheel; Peter Vajkoczy; Jed A Hartings; Johannes Woitzik; Peter Martus; Jens P Dreier

doi:10.1093/braincomms/fcad080

Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts

Brain Commun. 2023 Mar 22;5(2):fcad080. doi: 10.1093/braincomms/fcad080. eCollection 2023.

Authors

Viktor Horst¹, Vasilis Kola¹, Coline L Lemale^{1

2}, Sebastian Major^{1

2

3}, Maren K L Winkler^{1

4}, Nils Hecht^{1

5}, Edgar Santos⁶, Johannes Platz⁷, Oliver W Sakowitz⁶, Hartmut Vatter⁸, Christian Dohmen⁹, Michael Scheel¹⁰, Peter Vajkoczy^{1

5}, Jed A Hartings¹¹, Johannes Woitzik^{1

12}, Peter Martus¹³, Jens P Dreier^{1

2

3

14

15}

Affiliations

¹ Centre for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
² Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
³ Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁴ Robert Koch Institute, Berlin, Germany.
⁵ Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁶ Department of Neurosurgery, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
⁷ Department of Neurosurgery, Herz-Neuro-Zentrum Bodensee, Kreuzlingen, Switzerland.
⁸ Department of Neurosurgery, University Hospital and Friedrich-Wilhelms-University Bonn, Bonn, Germany.
⁹ Department for Neurology and Neurological Intensive Care Medicine, LVR-Klinik Bonn, Bonn, Germany.
¹⁰ Department of Neuroradiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
¹¹ Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹² Department of Neurosurgery, Evangelisches Krankenhaus Oldenburg, University of Oldenburg, Oldenburg, Germany.
¹³ Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
¹⁴ Bernstein Centre for Computational Neuroscience Berlin, Berlin, Germany.
¹⁵ Einstein Centre for Neurosciences Berlin, Berlin, Germany.

Abstract

In DISCHARGE-1, a recent Phase III diagnostic trial in aneurysmal subarachnoid haemorrhage patients, spreading depolarization variables were found to be an independent real-time biomarker of delayed cerebral ischaemia. We here investigated based on prospectively collected data from DISCHARGE-1 whether delayed infarcts in the anterior, middle, or posterior cerebral artery territories correlate with (i) extravascular blood volumes; (ii) predefined spreading depolarization variables, or proximal vasospasm assessed by either (iii) digital subtraction angiography or (iv) transcranial Doppler-sonography; and whether spreading depolarizations and/or vasospasm are mediators between extravascular blood and delayed infarcts. Relationships between variable groups were analysed using Spearman correlations in 136 patients. Thereafter, principal component analyses were performed for each variable group. Obtained components were included in path models with a priori defined structure. In the first path model, we only included spreading depolarization variables, as our primary interest was to investigate spreading depolarizations. Standardised path coefficients were 0.22 for the path from extravascular blood_component to depolarization_component (P = 0.010); and 0.44 for the path from depolarization_component to the first principal component of delayed infarct volume (P < 0.001); but only 0.07 for the direct path from blood_component to delayed infarct_component (P = 0.36). Thus, the role of spreading depolarizations as a mediator between blood and delayed infarcts was confirmed. In the principal component analysis of extravascular blood volume, intraventricular haemorrhage was not represented in the first component. Therefore, based on the correlation analyses, we also constructed another path model with blood_component without intraventricular haemorrhage as first and intraventricular haemorrhage as second extrinsic variable. We found two paths, one from (subarachnoid) blood_component to delayed infarct_component with depolarization_component as mediator (path coefficients from blood_component to depolarization_component = 0.23, P = 0.03; path coefficients from depolarization_component to delayed infarct_component = 0.29, P = 0.002), and one from intraventricular haemorrhage to delayed infarct_component with angiographic vasospasm_component as mediator variable (path coefficients from intraventricular haemorrhage to vasospasm_component = 0.24, P = 0.03; path coefficients from vasospasm_component to delayed infarct_component = 0.35, P < 0.001). Human autopsy studies shaped the hypothesis that blood clots on the cortex surface suffice to cause delayed infarcts beneath the clots. Experimentally, clot-released factors induce cortical spreading depolarizations that trigger (i) neuronal cytotoxic oedema and (ii) spreading ischaemia. The statistical mediator role of spreading depolarization variables between subarachnoid blood volume and delayed infarct volume supports this pathogenetic concept. We did not find that angiographic vasospasm triggers spreading depolarizations, but angiographic vasospasm contributed to delayed infarct volume. This could possibly result from enhancement of spreading depolarization-induced spreading ischaemia by reduced upstream blood supply.

Keywords: cytotoxic oedema; spreading depolarization; spreading ischaemia; subarachnoid haemorrhage; vasospasm.