Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy

Marta Czesnikiewicz-Guzik, Grzegorz Osmenda, Mateusz Siedlinski, Richard Nosalski, Piotr Pelka, Daniel Nowakowski, Grzegorz Wilk, Tomasz P Mikolajczyk, Agata Schramm-Luc, Aneta Furtak, Pawel Matusik, Joanna Koziol, Miroslaw Drozdz, Eva Munoz-Aguilera, Maciej Tomaszewski, Evangelos Evangelou, Mark Caulfield, Tomasz Grodzicki, Francesco D'Aiuto, Tomasz J Guzik, Marta Czesnikiewicz-Guzik, Grzegorz Osmenda, Mateusz Siedlinski, Richard Nosalski, Piotr Pelka, Daniel Nowakowski, Grzegorz Wilk, Tomasz P Mikolajczyk, Agata Schramm-Luc, Aneta Furtak, Pawel Matusik, Joanna Koziol, Miroslaw Drozdz, Eva Munoz-Aguilera, Maciej Tomaszewski, Evangelos Evangelou, Mark Caulfield, Tomasz Grodzicki, Francesco D'Aiuto, Tomasz J Guzik

Abstract

Aims: Inflammation is an important driver of hypertension. Periodontitis is a chronic inflammatory disease, which could provide a mechanism for pro-hypertensive immune activation, but evidence of a causal relationship in humans is scarce. We aimed to investigate the nature of the association between periodontitis and hypertension.

Methods and results: We performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies participants using single nucleotide polymorphisms (SNPs) in SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci GWAS-linked to periodontitis, to ascertain their effect on blood pressure (BP) estimates. This demonstrated a significant relationship between periodontitis-linked SNPs and BP phenotypes. We then performed a randomized intervention trial on the effects of treatment of periodontitis on BP. One hundred and one hypertensive patients with moderate/severe periodontitis were randomized to intensive periodontal treatment (IPT; sub- and supragingival scaling/chlorhexidine; n = 50) or control periodontal treatment (CPT; supragingival scaling; n = 51) with mean ambulatory 24-h (ABPM) systolic BP (SBP) as primary outcome. Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of -11.1 mmHg; 95% CI 6.5-15.8; P < 0.001). Systolic BP reduction was correlated to periodontal status improvement. Diastolic BP and endothelial function (flow-mediated dilatation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, previously implicated in hypertension.

Conclusion: A causal relationship between periodontitis and BP was observed providing proof of concept for development of clinical trial in a large cohort of hypertensive patients. ClinicalTrials.gov: NCT02131922.

Keywords: Genetics; Hypertension; Inflammation; Periodontitis; Treatment; Vascular function.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
A flowchart of clinical study profile.
Figure 2
Figure 2
Effects of conventional periodontal treatment and intensive periodontal treatment on blood pressure. Changes of 24-h average systolic (A) and diastolic (B) blood pressure between baseline and 2 months following control periodontal treatment or intensive periodontal treatment are reported as mean ± 95% confidence interval. Subsequently, difference in change was calculated between randomization groups. (C) Relationship between baseline systolic blood pressure and the effect of intensive periodontal treatment on blood pressure reduction. Patients were divided in tertiles of baseline ambulatory 24-h blood pressure monitoring measured systolic blood pressure and change of systolic blood pressure between baseline and follow-up (delta systolic blood pressure) was analysed and presented as mean with 95% confidence interval. Ambulatory 24-h blood pressure monitoring Tertile 1: <130 mmHg; Tertile 2: 131–138 mmHg; and Tertile 3 >138 mmHg.
Figure 3
Figure 3
Effects of control periodontal treatment and intensive periodontal treatment on periodontal status and its relationship to blood pressure improvement. Changes of periodontal pocket depth (A) and clinical attachment loss (B) were monitored between baseline and 2 months following control periodontal treatment or intensive periodontal treatment and are reported as mean ± 95% confidence interval along with difference in change calculated between randomization groups (with 95% confidence interval). (C) Spearman correlation between improvement of systolic blood pressure and change of periodontal pocket depth in individual patients.
Figure 4
Figure 4
Effects of control periodontal treatment and intensive periodontal treatment on selected T lymphocyte and monocyte populations. (A) Heatmap presenting 23 cell subpopulations with ratio of baseline- and post-treatment levels between control periodontal treatment and intensive periodontal treatment patients. Cell types were selected on the basis of previous reports of significance for hypertension and vascular regulation. Colour of each square corresponds to a baseline and follow-up (2 months) means for intensive periodontal treatment and control periodontal treatment groups of each analysed cell type. Differences in absolute values that were significant (P < 0.05) after FDR correction in intensive periodontal treatment but not control periodontal treatment in our discovery analysis are marked with asterisk. Heatmap was generated using ClustVis software. Examples of flow cytometry (B) and average values (C) detecting cell types of activated (CD38) and immunosenescent (CD28null, CD57+) CD8+T cells between baseline and 2 months post-treatment in control periodontal treatment and intensive periodontal treatment groups. *P < 0.05 vs. baseline; two-way analysis of variance.

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