Abstract
Introduction
Extremely low birth weight (ELBW) survivors have microvascular structural differences already described in kidney and retina, suggesting changes in endothelial integrity. A biomarker of endothelial integrity is perfused boundary region (PBR), which measures glycocalycal thickness. The endothelial glycocalyx is a complex, highly versatile structure with essential roles in vascular integrity and function. We explored PBR patterns together with other microvascular markers in healthy controls and former ELBW children.
Methods
In the PREMATCH cohort (87 healthy controls, 93 ELBW survivors), we assessed endothelial integrity by calculating PBR (sidestream dark-field imaging), several microvascular markers (blood pressure, estimated glomerular filtration rate (eGFRcysC)), and retinal imaging in early adolescence. We explored differences between both groups, and searched for perinatal determinants of PBR and correlations between different microvascular markers.
Results
We provided reference values for PBR (average 1.90 µm, SD 0.30) in children. PBR was not different from ELBW survivors during early adolescence, despite their higher blood pressure, lower eGFRcysC, and different retinal vessel width and tortuosity.
Conclusions
We generated reference values for PBR in early adolescence. Despite some correlations between microvascular parameters, there seem to be numerous confounders to propose PBR as a marker for endothelial integrity in ELBW survivors.
Impact
-
The endothelial glycocalyx is a complex and versatile structure. Changes in blood pressure and retinal and renal vascularization suggest a disturbance of its integrity in extremely low birth weight (ELBW) survivors. Its thickness can be measured by calculating perfused boundary region (PBR) using sidestream dark-field imaging, with a higher PBR indicating a thinner glycocalyx.
-
We generated reference values for PBR in healthy adolescents. These values were not different in former ELBW children.
-
Despite some correlations of PBR with other microvascular biomarkers, these are not strong enough to describe endothelial integrity and its covariates in former ELBW children.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 14 print issues and online access
$259.00 per year
only $18.50 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The corresponding author can be contacted to share the raw data, if based on a reasonable request and study protocol.
References
Risnes, K. et al. Mortality among young adults born preterm and early term in 4 Nordic nations. JAMA Netw. Open 4, e2032779, https://jamanetwork-com.kuleuven.e-bronnen.be/journals/jamanetworkopen/fullarticle/2774718 (2021).
Stock, K. et al. The impact of being born preterm or small for gestational age on early vascular aging in adolescents. J. Pediatr. 201, 49–54.e1, https://pubmed.ncbi.nlm.nih.gov/29960764/ (2018).
de Jong, F., Monuteaux, M. C., van Elburg, R. M., Gillman, M. W. & Belfort, M. B. Systematic review and meta-analysis of preterm birth and later systolic blood pressure. Hypertension 59, 226–234, https://pubmed.ncbi.nlm.nih.gov/22158643/ (2012).
Haikerwal, A. et al. High blood pressure in young adult survivors born extremely preterm or extremely low birthweight in the post surfactant era. Hypertension 75, 211–217, https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.119.13780 (2020).
Juonala, M. Effect of birth weight on life-course blood pressure levels among children born premature: The Cardiovascular Risk in Young Finns Study. J. Hypertension 33, 1542–1548 (2015).
Crump, C., Sundquist, J. & Sundquist K. Association of preterm birth with lipid disorders in early adulthood: a Swedish cohort study. PLoS Med. 16, e1002947. https://pubmed.ncbi.nlm.nih.gov/31626652/ (2019).
Crump, C., Sundquist, J. & Sundquist, K. Risk of hypertension into adulthood in persons born prematurely: a national cohort study. Eur. Heart J. 41, 1542–1550. https://pubmed.ncbi.nlm.nih.gov/31872206/ (2020).
Crump, C., Sundquist, J. & Sundquist, K. Stroke risks in adult survivors of preterm birth: National Cohort and Cosibling Study. Stroke 52, 2609–2617, https://www-ahajournals-org.kuleuven.e-bronnen.be/doi/abs/10.1161/STROKEAHA.120.033797 (2021).
Crump, C. et al. Association of preterm birth with risk of ischemic heart disease in adulthood. JAMA Pediatr. 173, 736–743, https://pubmed.ncbi.nlm.nih.gov/31157896/ (2019).
Carr, H., Cnattingius, S., Granath, F., Ludvigsson, J. F. & Bonamy, A. K. E. Preterm birth and risk of heart failure up to early adulthood. J. Am. Coll. Cardiol. 69, 2634–2642 (2017).
Raaijmakers, A. et al. Does extremely low birth weight predispose to low-renin hypertension? Hypertension 69, 443–449, https://pubmed-ncbi-nlm-nih-gov.kuleuven.ezproxy.kuleuven.be/28115515/ (2017).
Wei, F. F. et al. Association between cognition and the retinal microvasculature in 11-year old children born preterm or at term. Early Hum. Dev. 118, 1–7 (2018).
Suzuki, K. The developing world of DOHaD. J. Dev. Orig. Health Dis. 9, 266–269. https://doi.org/10.1017/S2040174417000691 (2018).
Bavineni, M. et al. Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood. Eur. Heart J. 40, 1107–1112, https://pubmed.ncbi.nlm.nih.gov/30753448/ (2019).
Bassareo, P. P. et al. Reduced brachial flow-mediated vasodilation in young adult ex extremely low birth weight preterm: a condition predictive of increased cardiovascular risk? J. Matern. Fetal Neonatal Med. 23, 121–124. https://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 (2010).
Lee, H. N., Dichtl, S., Mormanova, Z., Dalla Pozza, R. & Genzel-Boroviczeny, O. In adolescence, extreme prematurity is associated with significant changes in the microvasculature, elevated blood pressure and increased carotid intima – media thickness. Arch. Dis. Child. Educ. Pract. Ed. 99, 907–911, https://pubmed.ncbi.nlm.nih.gov/24879769/ (2014).
Markopoulou, P. et al. Increased circulating endothelial progenitor cells (EPCs) in prepubertal children born prematurely: a possible link between prematurity and cardiovascular risk. Pediatr. Res. 90, 156–165 https://pubmed.ncbi.nlm.nih.gov/33038874/ (2021).
Markopoulou, P. et al. Elevated circulating endothelial microparticles (EMPs) in prepubertal children born preterm. Pediatr. Res. 91, 1754–1761 https://pubmed.ncbi.nlm.nih.gov/34285352/ (2022).
Ushiyama, A., Kataoka, H. & Iijima T. Glycocalyx and its involvement in clinical pathophysiologies. J. Intensive Care 4, 59. https://pubmed.ncbi.nlm.nih.gov/27617097/ (2016).
Rovas, A. et al. Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions in resuscitated sepsis. Crit. Care 23, 1–11, https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2542-2 (2019).
Hubble, S. M. A., Kyte, H. L., Gooding, K. & Shore, A. C. Variability in sublingual microvessel density and flow measurements in healthy volunteers. Microcirculation 16, 183–191, https://pubmed.ncbi.nlm.nih.gov/19206003/ (2009).
Lee, D. H. et al. Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion. PLoS ONE 9, e96477 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096477 (2014).
Gorshkov, A. Y., Klimushina, M., Boytsov, S. A., Kots, A. Y. & Gumanova, N. G. Increase in perfused boundary region of endothelial glycocalyx is associated with higher prevalence of ischemic heart disease and lesions of microcirculation and vascular wall. Microcirculation 25, e12454. https://pubmed-ncbi-nlm-nih-gov.kuleuven.ezproxy.kuleuven.be/29608790/ (2018).
Raaijmakers, A. et al. Design and feasibility of “PREMATurity as predictor of children’s Cardiovascular-renal Health” (PREMATCH): a pilot study. Blood Press 24, 275–283. https://www.tandfonline.com/action/journalInformation?journalCode=iblo20 (2015).
George, I., Mekahli, D., Rayyan, M., Levtchenko, E. & Allegaert, K. Postnatal trends in creatinemia and its covariates in extremely low birth weight (ELBW) neonates. Pediatr. Nephrol. 26, 1843–1849, https://pubmed.ncbi.nlm.nih.gov/21499946/ (2011).
Raaijmakers, A. et al. Catch–up growth in the first two years of life in extremely low birth weight (ELBW) infants is associated with lower body fat in young adolescence. PLoS ONE 12, e0173349. https://dx.plos.org/10.1371/journal.pone.0173349 (2017).
Gu, Y. M. et al. Characteristics and determinants of the sublingual microcirculation in populations of different ethnicity. Hypertension 65, 993–1001, https://www-ahajournals-org.kuleuven.e-bronnen.be/doi/abs/10.1161/HYPERTENSIONAHA.114.05119 (2015).
Muntner, P. et al. Measurement of blood pressure in humans: a scientific statement from the American Heart Association. Hypertension 73, E35–66, https://www.heart.org/permissions (2019).
Wei, F. F. Retinal microvascular diameter, a hypertension-related trait, in ECG-gated vs. non-gated images analyzed by IVAN and SIVA. Hypertension Res. 39, 12, https://www.nature.com.kuleuven.e-bronnen.be/articles/hr201681 (2016).
Huang, Q. F. et al. Reproducibility of retinal microvascular traits decoded by the Singapore I Vessel Assessment Software across the human age range. Am. J. Hypertension 31, 438–449, https://academic-oup-com.kuleuven.e-bronnen.be/ajh/article/31/4/438/4657093 (2018).
Puchwein-Schwepcke, A., Artmann, S., Rajwich, L., Genzel-Boroviczény, O. & Nussbaum, C. Effect of gestational age and postnatal age on the endothelial glycocalyx in neonates. Sci. Rep. 11, 3133. https://pubmed.ncbi.nlm.nih.gov/33542284/ (2021).
Acknowledgements
We gratefully acknowledge the contribution of the nurses working at the examination center (Linda Custers, Marie-Jeanne Jehoul, Daisy Thijs, and Hanne Truyens) and the clerical staff at the Studies Coordinating Centre at the time of data acquisition (Vera De Leebeeck and Renilde Wolfs).
Funding
The PREMATCH study was supported by the Agency for Innovation by Science and Technology in Flanders (IWT) through the SAFE-PEDRUG project [IWT/SBO 130033]. KU Leuven Internal Funds (STG-18–00379) supported the Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, Leuven.
Author information
Authors and Affiliations
Contributions
K.A., E.L., J.A.S., and A.R. conceived and designed the PREMATCH study and obtained the funding. The data on perfused boundary region were analyzed by L.v.L, assisted by K.A., J.A.S., and A.R. All authors were involved in the interpretation and drafting of the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Informed consent
Parents or custodians and children provided written informed consent and assent respectively.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Van Loo, L., Allegaert, K., Levtchenko, E. et al. Perfused boundary region as biomarker for endothelial integrity in former preterms in adolescence. Pediatr Res 93, 1936–1942 (2023). https://doi.org/10.1038/s41390-022-02321-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41390-022-02321-3