The roles of neutrophils linking periodontitis and atherosclerotic cardiovascular diseases.

Inflammation plays a crucial role in the onset and development of atherosclerosis. Periodontitis is a common chronic disease linked to other chronic inflammatory diseases such as atherosclerotic cardiovascular disease (ASCVD). The mechanistic pathways underlying this association are yet to be fully understood. This critical review aims at discuss the role of neutrophils in mediating the relationship between periodontitis and ASCVD. Systemic inflammation triggered by periodontitis could lead to adaptations in hematopoietic stem and progenitor cells (HSPCs) resulting in trained granulopoiesis in the bone marrow, thereby increasing the production of neutrophils and driving the hyper-responsiveness of these abundant innate-immune cells. These alterations may contribute to the onset, progression, and complications of atherosclerosis. Despite the emerging evidence suggesting that the treatment of periodontitis improves surrogate markers of cardiovascular disease, the resolution of periodontitis may not necessarily reverse neutrophil hyper-responsiveness since the hyper-inflammatory re-programming of granulopoiesis can persist long after the inflammatory inducers are removed. Novel and targeted approaches to manipulate neutrophil numbers and functions are warranted within the context of the treatment of periodontitis and also to mitigate its potential impact on ASCVD

Number of individuals among test (periodontitis) and control (healthy) groups according to HSP60 levels being undetectable, less or greater than 1000 ng/ml.

<p>Asterisk refers to statistically significant differences (P<0.05) between groups within each category as computed with Chi-square test.</p

Case control study

*<p>Differences were computed with parametric (Independent t-test) or non parametric (Mann-Whitney U-Test) dependent upon the data frequency distribution. Categorical variables were analyzed by Chi-square testing.</p>**<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001198#pone-0001198-g002" target="_blank">Figure 2</a>.</p

Differences in plasma concentrations between patients suffering from periodontitis (N = 80) and age-matched unaffected controls (N = 48).

<p>Boxes refer to the 25^th (bottom) and 75^th (up) percentiles and the median is the large horizontal line, fences refer to the 10^th (lower) and 90^th (upper) percentiles respectively. Open circles represent outliers whereas asterisks stand for extreme observations with the subject number. Statistical differences are computed with Mann-Whitney U-test.</p

Mean values (standard errors) and mean changes (standard errors) (compared to baseline) of HSP10 (A–B), BiP (C–D) and HSP60 (E–F) before, 24 hrs after and 6 months after periodontal therapy.

<p>Positive differences indicate a relative increase in plasma concentrations of various markers compared to the pre-treatment baseline. Subjects who received intensive periodontal therapy (open circles, N = 40) showed greater plasma concentrations of HSP10 at each time visit when compared to control therapy group subjects (filled circles, N = 40). No other changes were observed. Asterisks refer to statistically significant difference (P<0.05) between groups as computed with analysis of covariance.</p

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

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-γand 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