An analysis of the immune and vascular systems in untreated hypertension

Murray, Eleanor C. (2024) An analysis of the immune and vascular systems in untreated hypertension. MD thesis, University of Glasgow.

Abstract

Background: Blood pressure regulation leads to hypertension through complex environmental and genetic interactions, mediated by cardiac, vascular, endocrine, and renal systems. The immune system interacts with all of these, and may have a role in hypertension and associated organ damage.

Methods and Results: The Inflammatension study comprehensively assessed vascular function (endothelial function, arterial stiffness, intima-media thickness, and cardiovascular variability), the immune cell ‘signature’ (including B and T cell subsets, monocyte and dendritic cells, and intracellular stimulation studies), and circulating protein biomarkers, in an untreated hypertensive group compared to normotensive controls, and in consideration of phenotypic groups, as follows.

Does cardiovascular function differ between incident hypertension versus healthy controls? Hypertensive disease progression involves early arterial stiffness. Carotid atherosclerosis and impairment in endothelial function were not detected. Measures of arterial stiffness strongly correlate with each other, with ambulatory and central BP, and with cardiovascular variability.

Are phenotypic subgroups apparent in hypertension? White coat hypertension patients demonstrated arterial stiffening in excess of sustained hypertension; masked hypertension patients vascular characteristics were akin to normotension. Machine learning techniques generated three phenotypic groups of hypertension, ‘arterially stiffened’, ‘vaso-protected’, and ‘non-dipper’.

Identifying immune cell ‘signature’ in patients: Flow cytometry demonstrated lower CD4+ naïve cells (CD45RA+CCR7+CD45RO+CD62L+) in hypertension. CD4+ T central memory cells were expanded in hypertension, along with CD62- T effector memory cells in an adjusted model. Hypertensive group had proportionally fewer CD28+ lymphocytes and CD8+ TEMRA cells, and T cells polarised towards Th1/Tc1 and Th17.1/Tc17.1. Intermediate monocytes demonstrated a differing pattern of CCR2 and CCR5 chemokine receptor expression, and alterations in STAT1 and STAT6 phosphorylation cascades. Increased NK cell CD56+Dim expression and reduced NKT and T lymphocytes CD122 expression was linked to hypertension. Nocturnal non-dipping was associated with similar immune cell signature changes as hypertension, and dendritic cell mannose receptor downregulation in addition.

The circulating protein biomarker ‘signature’ of untreated hypertension and hypertensive phenotypes: Cytokines and chemokines dominated the 34 biomarkers differing between normotension and hypertension, though failed to meet Bonferroni-adjusted thresholds. Inflammatory biomarkers correlated with BP and arterial stiffness, but not endothelial function. Associations were concordant across systolic and diastolic BP; TPP1, CCL7, CCL11, and CCL21 positively correlating; IL18R1, and KYNU negatively. These relationships were more pronounced in the hypertensive subgroup, especially CD molecules and cytokines. HGF, AGE, and CCL21 showed greatest between-group differences and correlations across arterial parameters. Systolic nocturnal dipping demonstrated negative correlation with immune cell interaction and cellular adhesion biomarkers (CTRC, EPHA1, LGALS4, SIT1, SMOC, IL-18 and TNFSF11). Sixteen of the 85 correlating biomarkers also differed between the ‘arterially stiffened’, ‘vaso-protected’, and ‘non-dipper’ phenotypic groups.

Conclusions: In untreated hypertension arterial stiffness is already detectable, and along with nocturnal dipping and estimates of central BP, categorise hypertensive phenotypes. The exploratory data support alterations of circulating immune biomarkers, and innate (monocytes) and adaptive (T cells) immune compartments. Nocturnal dipping and hypertension phenotypes especially demonstrate immune system variances.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from the European Research Council.
• Subjects: R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Funder's Name: European Research Council (ECR)
• Supervisor's Name: Delles, Professor Christian and Guzik, Professor Tomasz
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84492
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 21 Aug 2024 14:16
• Last Modified: 23 Aug 2024 13:27
• Thesis DOI: 10.5525/gla.thesis.84492
• URI: https://theses.gla.ac.uk/id/eprint/84492

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