Increased levels of circulating endostatin are linked to orthostatic hypotension

Abstract Background Orthostatic hypotension (OH) occurs when blood pressure regulation fails. The underlying molecular mechanism of OH remain largely unexplored. Endostatin is a biologically active molecule cleaved by matrix metalloproteinases, elastases and cathepsins from collagen XVIII in the extracellular matrix and inhibits angiogenesis. Circulating levels of endostatin have been proposed to be involved in blood pressure (BP) regulation, by inducing nitric oxide release. To date, the relationship between endostatin and OH have not been examined. Purpose We aimed to investigate circulating levels of endostatin in patients with verified OH by tilt test at a tertiary syncope unit compared with healthy age- and sex-matched controls from the same geographical region. Methods We performed an age- and sex-matched case-control study in 150 patients with OH verified by positive head-up tilt-testing and other cardiovascular autonomic tests at a tertiary syncope unit, and 150 healthy controls with negative active standing tests and no history of syncope, orthostatic intolerance, and endocrine disease. High-sensitivity chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin in a blinded fashion. Receiver operating characteristic curves were constructed to analyze the discriminative ability of endostatin in OH compared with healthy controls. Multivariate logistic regression was used to assess the association between endostatin, OH and hemodynamic variables adjusting for age and sex. Results Study characteristics are displayed in the Table. Patients with OH had significantly higher absolute levels of circulating endostatin compared with healthy controls (59,024 ± 2513 vs. 44,090 ± 1978 pg/mL, p<0.001). Multivariate-adjusted logistic regression analysis controlling for age, sex, minimum systolic and minimum diastolic BP during tilt, identified endostatin as an independent determinant for OH (beta-coefficient 0.80, p=0.025). The obtained area under the curve was 0.70, P<0.001, Figure). Conclusions Our findings indicate that patients with orthostatic hypotension have increased circulating levels of endostatin, independent of age, sex, and hemodynamic variables. Our results highlight the relevance of investigating the molecular pathways related to orthostatic hypotension. Further studies are warranted to assess the prognostic and therapeutic role of endostatin assessment in individuals with orthostatic hypotension.Tablestudy characteristicsFigureROC Curve