Periodontitis and hypertension: causally linked by immune mechanisms

This editorial refers to ‘Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy’†, by M. Czesnikiewicz-Guzik et al., on page 3459. The role of the immune system in hypertension has been demonstrated over the last few years. Innate immunity was first shown to play a role in rodent hypertension,1 , 2 then adaptive immune lymphocytes were implicated.3 Later, a role was demonstrated for anti-inflammatory T-regulatory lymphocytes.4 , 5 More recently, the infrequent γ/δ T lymphocytes were implicated in both rodent and human hypertension. Thus, increasingly, the participation of immunity in the mechanisms of hypertension has been increasingly appreciated, to the point that hypertension has been considered a bone marrow disease.7 Hypertension-inducing mechanisms include genetics and environmental factors such as salt and activation of the renin–angiotensin–aldosterone system and endothelin. These may initiate hypertension by stimulating the brain, resulting in increased activity of the sympathetic nervous system, vasoconstriction, and elevation of blood pressure. This in turn affects the vasculature and the kidney and, either by generation of danger signals, damage-activated molecular patterns (DAMPs) and neoantigens, or by direct sympathetic stimulation of the bone marrow and spleen, activates innate and then adaptive immunity, contributing to low-grade inflammation. The latter induces further vascular and kidney damage, leading to further elevation of blood pressure. Thus, a vicious circle is generated that perpetuates the blood pressure elevation (Take home figure). Other mechanisms may also be involved, including the effect of salt on the gut microbiome leading to activation of T-helper 17 (Th17) lymphocytes.8 Hypertension is probably initiated by activation of brain mechanisms that via the sympathetic nervous system lead to an initial blood pressure elevation and vascular injury, which generates danger signals (damage-activated molecular patterns or DAMPs), or neoantigens, that activate the innate and then the adaptive immune system. Stimulation of the bone marrow or the spleen by the sympathetic nervous system will also activate immune cells of the innate immune system and adaptive immunity. Inflamed periodontal tissue infected with Porphyromonas gingivalis originates pathogen-associated molecular patterns (PAMPs) that also activate the immune system. Senescent effector cells that are CD28 null and CD57+ are immune cells that have been implicated in human hypertension. Production of proinflammatory cytokines such as interleukin (IL)-6 and interferon (IFN)-γ as in the present study, or IL-17 lead to vascular and kidney injury. A vicious circle of chronic immune activation, inflammation, and oxidative stress promotes progression of disease, causing endothelial dysfunction and end-organ damage. CD28, cluster of differentiation 28; CD57, cluster of differentiation 57; CNS, central nervous system; DC, dendritic cells; M, macrophages; MHC II, major histocompatibility complex II; ROS, reactive oxygen species; TCR, T cell receptor; TLRs, Toll-like receptors. Infection and subsequent recognition of pathogen-associated molecular patterns (PAMPs) could also activate immunity and lead to blood pressure elevation, and is thus an additional pathway that can contribute to hypertension. Periodontal disease is a chronic inflammatory disorder of the tissues surrounding the teeth, which could, through infection or generation of systemic inflammatory mediators, have cardiovascular consequences. Tonetti et al.9 demonstrated that individuals with periodontitis, 6 months after intensive treatment, experienced improved oral health and endothelial function, which could affect blood pressure regulation. Some studies have indeed shown the impact of oral health on blood pressure control.10 Pietropaoli et al. examined results from the National Health and Nutrition Examination Survey from 2009 to 2014. They found that among treated hypertensive adults, systolic blood pressure was 2.3–3 mmHg higher if they had periodontitis, which was also associated with unsuccessful antihypertensive treatment, particularly if the disease was severe. In this issue of the European Heart Journal, Czesnikiewicz-Guzik et al.11 demonstrate that similarly to the study by Tonetti et al.,9 intensive treatment of periodontitis in hypertensive individuals improved endothelial function and lowered blood pressure together with reduction of proinflammatory cytokines. In the randomized trial of 101 hypertensive patients with moderate/severe periodontitis, intensive periodontal treatment improved periodontal status after 2 months, and reduced systolic blood pressure by a mean difference of 11.1 mmHg compared with the subjects randomized to control periodontal treatment. Diastolic blood pressure, and endothelial function measured by flow-mediated dilatation, were also improved in the intensive treatment group. In addition to the blood pressure reduction, circulating interferon-γ and interleukin-6, as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, which have been implicated in hypertension,12 were reduced. The systolic blood pressure reduction of 7.5 mmHg [measured by ambulatory blood pressure monitoring (ABPM)] in the subgroup treated intensively led to a difference of 11.1 mmHg compared with usual care, which is quite surprising in magnitude, especially with a baseline 24-h ambulatory systolic blood pressure of 135 mmHg. Although the authors state that they only enrolled hypertensive patients, 33% of patients had systolic blood pressure <130 mmHg by ABPM. During the 2-month follow-up, the authors excluded from the analysis those who needed to increase antihypertensive treatment. Thus, patients may not have had stable blood pressure before entering the study, and the observed blood pressure lowering may be partly the result of changes in antihypertensive drugs before entering the 2-month period of intensive vs. usual periodontitis treatment. As a result of carry-over of newly introduced or increased antihypertensive therapy, this could have led to blood pressure lowering beyond the effect of intensive periodontitis treatment, because patients who needed increases in antihypertensive agents during the 2 months of the trial were excluded. Accordingly, the trial data require confirmation. Importantly, the authors used a second approach, Mendelian randomization, to confirm potential causality between periodontitis and blood pressure control, and confirm their findings. Mendelian randomization can be used to test causal relationships between risk factors and phenotypes such as blood pressure.13 Many single nucleotide polymorphisms (SNPs) have been associated with risk factors by genome-wide association studies (GWAS), including periodontitis. Thus, these SNPs can be used as measures of lifetime exposure to a risk factor without the threat of reverse causality, and can be tested for association with the phenotype of interest. The authors performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/ICBP-GWAS participants using SNPs linked to periodontitis by GWAS located in the SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci, to evaluate their effect on blood pressure. They demonstrated a significant relationship between periodontitis-linked SNPs and blood pressure phenotypes. Mendelian randomization is an established epidemiological method that provides evidence about possible causal relationships between risk factors and disease using genetic variants as ‘instruments’.13 Importantly, it is not affected by confounding or reverse causality due to the random independent assortment of genetic variants. This is in contrast to other observational methods that must correct for differences in confounders between study participants. Like all analytical approaches, however, Mendelian randomization requires that the plausibility of the assumptions on which it is based be evaluated. In addition, the relevance of results requires supporting evidence. Thus, the study of Czesnikiewicz-Guzik et al.,11 by using two independent approaches, Mendelian randomization and a randomized clinical trial of intensive vs. usual treatment of periodontitis, the latter with some controversial aspects, establishes that periodontitis may indeed cause immune-mediated blood pressure elevation associated with endothelial dysfunction, with severity of hypertension proportional to the severity of the periodontal inflammation and the lack of oral health. Their study has contributed to mechanistic insight, but additional work is warranted to confirm the details of the suggested pathways (Take home figure) that link periodontal disease with hypertension, as well as confirmation of the precise blood pressure-lowering effects of intensive treatment of periodontitis. Oral diseases are among the most prevalent diseases globally14 and have a high frequency particularly in low- and middle-income countries where non-communicable diseases are increasingly common. In addition to their many other consequences such as pain, sepsis, reduced quality of life, and decreased work productivity, we are now realizing that oral diseases may also contribute to blood pressure elevation, a major cause of cardiovascular morbidity and mortality, and this is one more reason for addressing oral health as a global health priority. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.