Abstract
BackgroundVascular malformations in the central nervous system are difficult to monitor and treat due to their inaccessible location. Angiogenic and inflammatory proteins are secreted into the bloodstream and may serve as useful biomarkers for identifying patients at risk for complications or with certain disease phenotypes.MethodsA validated multiplex protein array consisting of 26 angiogenic and inflammatory biomarkers (Angiome) was assessed in plasma isolated from healthy controls and patients with either sporadic brain arteriovenous malformation (BAVM), familial cerebral cavernous malformation (CCM), or hereditary hemorrhagic telangiectasia (HHT). These samples were obtained from archives of ongoing research studies at the University of California San Francisco and through prospective collection at the Toronto HHT Centre at St. Michael’s Hospital.ResultsWe compared circulating biomarker levels from each patient group to healthy controls and analyzed each pairwise combination of patient groups for differences in biomarker levels. Additionally, we analyzed the HHT samples to determine the association between biomarker levels and the following HHT-specific phenotypes, BAVM, pulmonary arteriovenous malformation (PAVM), liver vascular malformation (LVM), and gastrointestinal (GI) bleeding. Compared to controls, levels of SDF1 were significantly elevated in HHT patients (Proportional Increase [PI] = 1.87, p < 0.001, q = 0.011). Levels of sENG were significantly reduced in HHT patients compared to controls (PI = 0.56, p < 0.001, q < 0.001), reflecting the prevalence of HHT1 patients in this cohort. Levels of IL6 (PI = 3.22, p < 0.001, q < 0.001) and sTGFβR3 (PI = 0.70, p = 0.001, q < 0.029) differed significantly in CCM patients compared to controls. Compared to controls, ten of the biomarkers were significantly different in sporadic BAVM patients (q-values < 0.05). Among the pairwise combinations of patient groups, a significant elevation was observed in TGFβ1 in CCM patients compared to sporadic BAVM patients (PI = 2.30, p < 0.001, q = 0.034). When examining the association of circulating biomarker levels with HHT-specific phenotypes, four markers were significantly lower in HHT patients with BAVM (q-values < 0.05), and four markers were significantly higher in patients with LVM (q-values < 0.05).ConclusionsThis pilot study suggests that the profile of circulating angiogenic and inflammatory biomarkers may be unique to each type of vascular malformation. Furthermore, this study indicates that circulating biomarkers may be useful for assessing phenotypic traits of vascular malformations.
Highlights
Vascular malformations in the central nervous system are difficult to monitor and treat due to their inaccessible location
Biomarker levels associated with disease phenotypes in hemorrhagic telangiectasia (HHT) patients we performed analyses using only HHT samples to assess the association of biomarker levels with disease phenotypes in HHT patients
We found that HHT patients with brain arteriovenous mal‐ formation (BAVM) had lower levels of glycoprotein 130 (GP130) (PI = 0.78, 95% confidence intervals (CI) 0.68 to 0.89, p < 0.001, q = 0.017), soluble vascular endothelial growth factor receptor 3 (PI = 0.75, 95% CI 0.63 to 0.88, p = 0.001, q = 0.017), soluble intracellular adhesion molecule 1 (PI = 0.74, 95% CI 0.62 to 0.88, p = 0.001, q = 0.017), and thrombospondin 2 (TSP2) (PI = 0.59, 95% CI 0.44 to 0.80, p = 0.001, q = 0.017) compared to HHT patients without BAVM
Summary
Vascular malformations in the central nervous system are difficult to monitor and treat due to their inaccessible location. Angiogenic and inflammatory proteins are secreted into the bloodstream and may serve as use‐ ful biomarkers for identifying patients at risk for complications or with certain disease phenotypes. Due to the presence of vascular malformations in the central nervous system, these patients may experience a range of debilitating and/or life-threatening symptoms including seizures, headache, and increased risk of cerebral hemorrhage. There is a lack of effective and targeted therapies for these patients and quality of life suffers as a result. These vascular malformations are difficult to monitor due to a reliance on imaging and the inability to biopsy the vascular malformations, while the localization of these lesions in the central nervous system complicates treatment. It would be valuable to identify biomarkers from a non-invasive tissue source, such as blood, that are associated with disease phenotypes or outcomes
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