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Antiangiogenesis and medical therapy failure in intracranial atherosclerosis

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Abstract

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months. Thirteen pro- and eight antiangiogenic factors were measured in the participants’ serum using a sandwich multiplex ELISA. Angiogenic profiles were calculated using principal component analysis. We tested the association between angiogenic profiles and recurring cerebrovascular events despite intensive medical therapy, disability at 6 months after enrollment, and angiographic neovascularization in patients who failed medical treatment and underwent indirect revascularization surgery. There is a strong association between a functionally antiangiogenic profile and recurrent stroke or TIA in patients with ICAD (OR = 7.2, CI 2.4–34.4). Multivariable regression analysis showed that this antiangiogenic profile was also associated with poor functional status after 6 months (p = 0.002), independent from other clinical features such as history of previous stroke, diabetes, and age. In patients who failed medical management and underwent indirect revascularization surgery, high endostatin and angiostatin levels were also associated with low angiographic neovascularization (p = 0.02). The results of this study point to the striking importance of antiangiogenesis as a determinant of ICAD patient prognosis and suggest a possible new target for therapy.

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Acknowledgements

This work was supported by grants from the American Heart Association (12PILT12760011 and 14ISA20870000), the NIH (K23 NS079477-01A1), as well as the Stotter Chair Endowment to NRG. We are grateful to Robert Elashoff, PhD, for statistical revision, as well as the UCLA Stroke Center members (Neal Rao, Lucas Restrepo, Jason Hitman, and Neil Martin) and the Cedars Sinai Stroke Center members (Patrick Lyden, Konrad Schlick, and Shlee Song) for their support and continuous collaboration. Also, we warmly thank the research coordination team led by Antoinette Anderson.

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Authors and Affiliations

  1. Department of Neurosurgery, Cedars Sinai Medical Center, 127 S San Vicente Blvd., Suite A6600, Los Angeles, CA, 90048, USA

    Nestor R. Gonzalez & Florian Kurth

  2. School of Medicine, Stanford University, Stanford, CA, USA

    Raymond Liou

  3. School of Medicine, Zhejiang University, Hangzhou, China

    Hao Jiang

  4. Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA

    Jeffrey Saver

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  1. Nestor R. Gonzalez
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  2. Raymond Liou
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  3. Florian Kurth
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  4. Hao Jiang
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  5. Jeffrey Saver
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Correspondence to Nestor R. Gonzalez.

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Gonzalez, N.R., Liou, R., Kurth, F. et al. Antiangiogenesis and medical therapy failure in intracranial atherosclerosis. Angiogenesis 21, 23–35 (2018). https://doi.org/10.1007/s10456-017-9578-1

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