Endothelial function assessment in atherosclerosis: Comparison of brachial artery flow‑mediated vasodilation and peripheral arterial tonometry

INTRODUCTION Endothelial dysfunction, characterized by the loss of nitric oxide bioavailability, is a key element in the pathogenesis of atherosclerosis and an important prognostic factor in cardiovascular diseases. Therefore, the development of reliable, safe, and noninvasive methods of endothelial function assessment is important for their use in cardiovascular risk stratification. Brachial artery flow‑mediated dilation (FMD) is widely used in research but technical difficulties and problems with calibration between laboratories limit its clinical use. Reactive hyperemia–peripheral artery tonometry (RH‑PAT, EndoPAT) has been developed as a simpler, cheaper, and potentially more reproducible method. OBJECTIVES We aimed to investigate associations between RH‑PAT and FMD in relation to atherosclerotic risk factor profile. PATIENTS AND METHODS The study involved 80 subjects (52 men, 28 women) aged 43.6 ±14.8 years, with moderate‑to‑low cardiovascular risk (mean SCORE, 2.2% ±2%), in whom FMD, RH‑PAT, and intima–media thickness (IMT) were determined. RESULTS The reactive hyperemia index (RHI) measured by RH‑PAT correlated with FMD (r = 0.35, P <0.01). However, no significant correlation was observed between RHI and IMT, SCORE, or the number of classical atherosclerotic risk factors (hypertension, smoking, diabetes, hypercholesterolemia), while FMD was significantly correlated with IMT (r = –0.53, P <0.001), risk factors (r = –0.55, P <0.05), and SCORE (r = –0.4, P <0.05). CONCLUSIONS Despite its technical requirements, FMD is a more sensitive method than RH‑PAT in evaluating the effect of classical atherosclerotic risk factors on vascular endothelial function. Microvasculature response during RH‑PAT needs to be further studied, including the assessment of nonendothelial factors that may affect the measurements, before RH‑PAT becomes the universal tool for the evaluation of the endothelial cells

Treatment of denture-related stomatitis improves endothelial function assessed by flow-mediated vascular dilation

Introduction: The presence of oral inflammation has recently been linked with the pathogenesis of cardiovascular diseases. While numerous studies have described links between periodontitis and endothelial dysfunction, little is known about the influence of denture-related stomatitis (DRS) on cardiovascular risk. Therefore, the aim of this study was to determine whether the treatment of DRS can lead to improvement of the clinical measures of vascular dysfunction. Material and methods: The DRS patients were treated with a local oral antifungal agent for 3 weeks. Blood pressure, flow-mediated dilatation (FMD) and nitroglycerine-mediated vascular dilatation (NMD) were measured during three study visits: before treatment, one day and two months after conclusion of antifungal therapy. Results: Flow-mediated dilatation measurements showed significant improvement of endothelial function 2 months after treatment (FMD median 5%, 95 CI: 3–8.3 vs. 11%, 95% CI: 8.8–14.4; p < 0.01), while there was no difference in control, endothelium-independent vasorelaxations (NMD; median = 15.3%, 95% CI: 10.8–19.3 vs. 12.7%, 95% CI: 10.6–15; p = 0.3). Other cardiovascular parameters such as systolic (median = 125 mm Hg; 95% CI: 116–129 vs. 120 mm Hg, 95% CI: 116–126; p = 0.1) as well as diastolic blood pressure and heart rate (median = 65.5 bpm, 95% CI: 56.7–77.7 vs. 71 bpm, 95% CI: 66.7–75; p = 0.5) did not change during or after the treatment. Conclusions: Treatment of DRS is associated with improvement of endothelial function. Since endothelial dysfunction is known to precede the development of severe cardiovascular disorders such as atherosclerosis and hypertension, patients should be more carefully screened for DRS in general dental practice, and immediate DRS treatment should be advised

The effect of the treatment of denture related stomatitis on peripheral T cells and monocytes

Purpose: Systemic immune activation has been recently linked to chronic inflammatory disorders of the oral cavity, particularly to periodontitis. The purpose of this study was to determine whether treatment of a fungus-induced oral inflammation, namely denture-related stomatitis (DRS), can affect the activation of the systemic immune response. Materials and Methods: Peripheral blood from patients with denture-related stomatitis caused by Candida albicans infection (n = 15) was collected at three time points: before treatment with nystatin, at the end of therapy and 2 months after finishing therapy. Activation of T cells and monocytes was assessed by flow cytometry. Results: The percentages of peripheral lymphocytes, T cells and their subpopulations, as well as monocytes were similar before, immediately following and two months after nystatin treatment. Cells expressing early activation marker CD69 and RANTES C-C chemokine receptor type 5 significantly increased immediately after treatment and returned to baseline levels after two months. Th17 cells, which have been implicated in the pathogenesis of DRS, remained unchanged. Central memory CD4+ subset and intermediate subset of monocytes were lower after therapy and this effect was sustained for two months. Conclusion: Treatment of denture-related stomatitis does not seem to affect the general state of the cellular components of the immune system. The results suggest a potential proinflammatory effect of the antifungal agent, nystatin. Although transient and not intense, this effect might be of particular clinical importance, because of relationships between inflammation and certain diseases. Further studies are required to clarify this aspect

Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis

Background and Purpose: Inflammation plays a key role in atherosclerosis. A protective role of angiotensin-(1-7) in vascular pathologies opened a possibility for therapeutic use of small molecule non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms of these vaso-protective effects of a Mas receptor agonist, AVE0991, remain unclear. Experimental approach: We investigated the effects of AVE0991 on the spontaneous atherosclerosis in ApoE-/- mice, in the context of vascular inflammation and plaque stability. Key Results: AVE0991 has significant anti-atherosclerotic properties in ApoE-/- mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using descending aorta of chow fed ApoE-/- mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (pVAT) and adventitial infiltration with macrophages and T cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability as a measure of endothelial function. AVE0991 inhibited perivascular inflammation, through the reduction of chemokine expression in pVAT, as well as through direct actions on monocytes/macrophages inhibiting their activation, characterized by IL-1β, TNF-α, MCP-1 and CXCL10 and differentiation to M1 phenotype. Pre-treatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in pVAT and in THP-1 cells in vitro and anti-inflammatory effects of AVE0991 were partially Mas dependent. Conclusions & implications: Selective Mas receptor agonist AVE0991 possesses anti-atherosclerotic and anti-inflammatory properties, affecting monocyte/macrophage differentiation and recruitment to perivascular space at early stages of atherosclerosis in ApoE-/- mice

Periodontitis and Hypertension: Is the Association Causal?

High blood pressure (BP) and periodontitis are two highly prevalent conditions worldwide with a significant impact on cardiovascular disease (CVD) complications. Poor periodontal health is associated with increased prevalence of hypertension and may have an influence on BP control. Risk factors such as older age, male gender, non-Caucasian ethnicity, smoking, overweight/obesity, diabetes, low socioeconomic status, and poor education have been considered the common denominators underpinning this relationship. However, recent evidence indicates that the association between periodontitis and hypertension is independent of common risk factors and may in fact be causal in nature. Low-grade systemic inflammation and redox imbalance, in particular, represent the major underlying mechanisms in this relationship. Neutrophil dysfunction, imbalance in T cell subtypes, oral-gut dysbiosis, hyperexpression of proinflammatory genes, and increased sympathetic outflow are some of the pathogenetic events involved. In addition, novel findings indicate that common genetic bases might shape the immune profile towards this clinical phenotype, offering a rationale for potential therapeutic and prevention strategies of public health interest. This review summarizes recent advances, knowledge gaps and possible future directions in the field

Th17 responses are not altered by natural exposure to seasonal allergens in pollen-sensitive patients

Background: Allergic rhinitis affects 10–30 % of the global population and this number is likely to increase in the forthcoming years. Moreover, it commonly co-exists with allergic asthma as a chronic allergic respiratory syndrome. While the involvement of Th2 cells in allergy is well understood, alterations of pro-inflammatory Th17 responses remain poorly characterized. The aim of our study was to determine whether natural seasonal allergen exposure causes changes in T cell subset characteristics in patients with allergic rhinitis and asthma. Methods: Sixteen patients with allergic rhinitis/atopic asthma (9M, 7F; age 31.8 ± 12.1) and 16 healthy controls were recruited into the study (9M, 7F; age 31.2 ± 5.3). Blood samples were collected from the patients 1–3 months before pollen season (visit 1), within 7 days of the appearance of pollen/initiation of allergic symptoms (visit 2) and 2 weeks after visit 2 following the introduction of symptomatic treatment with antihistamines (visit 3). Flow cytometry was used to assess major T cell subsets (naïve, central memory, effector memory and CD45RA+ effector) and key T cell cytokine production (IFNγ, IL-17A, TNF and IL-4) using intracellular staining. Data were analyzed using repeated measures ANOVA and paired t test. Results: As expected, an increase in the percentage of IL‐4+ CD4+ cells was observed during natural pollen exposure in patients with allergic respiratory syndrome. No significant changes were observed in the production of other cytokines, including Th17 cells, which tended to be lower than in the control population but unchanged during pollen exposure. Introduction of antihistamine treatment led to only moderate changes in cytokine production from CD4 and CD8 T cells. Selective changes in CD8+ T cells were observed during natural pollen exposure including a decrease in transient cells (with features of CD45RA+ and CD45RO+ cells) and a decrease in the percentage of central memory cells in the peripheral circulation. Within the CD4 cell group the total percentage of CD45RA positive CD4 cells was increased during pollen exposure. Conclusions: Th1 and Th17 responses are not altered during pollen season but allergen exposure affects T cell activation and memory cell status in patients with allergic respiratory syndrome

Microvascular dysfunction in ankylosing spondylitis is associated with disease activity and is improved by anti-TNF treatment.

Ankylosing spondylitis (AS) is associated with high cardiovascular morbidity and mortality. Recent studies indicate that microvascular dysfunction may underlie cardiovascular risk in AS. We hypothesized, that microvascular morphology and dysfunction is linked to AS activity and is modifiable by TNF-α inhibitor (TNFi) treatment. Functional Laser Doppler Flowmetry with post-occlusive reactive hyperemia, and structural nailfold capillaroscopy were performed in 54 patients with AS and 28 matched controls. Active AS was diagnosed based on BASDAI ≥ 4 (n = 37). Effects of 3-month TNFi on microcirculation in active AS were studied. AS was associated with prolonged time to peak hyperemia compared to healthy controls. High disease activity was associated with increased time to peak hyperemia and decreased peak hyperemia when compared to patients with inactive AS. In capillaroscopy, AS was associated with morphological abnormalities indicating increased neoangiogenesis and pericapillary edema compared to controls. Microvascular function improved following 3 months of TNFi in reference to basal flow as well as post-occlusive parameters. TNFi reduced pericapillary edema, while other parameters of capillary morphology remained unchanged. Microvascular dysfunction and capillary neovascular formation are associated with disease activity of AS. Anti-TNF-α treatment may restore microcirculation function and capillary edema but does not modify microvascular structural parameters

Relative homogeneity of oral bacterial flora in Crohn’s disease compared to ulcerative colitis and its connections with antioxidant defense — preliminary report

Introduction: Interactions between oral microbiota and systemic diseases have been suggested. We aimed to examine the composition of oral microbiota with reference to antioxidative defense and its correlation with clinical state in Crohn’s disease (CD) in comparison to ulcerative colitis (UC). Materials and Methods: Smears were taken from the buccal and tongue mucosa of patients with CD, UC and controls, and cultured with classical microbiology methods. Bacterial colonies were identified using matrix-assisted laser desorption/ionization (MALDI) with a time-of-flight analyzer (TOF). Blood morphology and C-reactive protein (CRP) were analyzed in the hospital laboratory. Antioxidative defense potential (FRAP) was determined using spectrophotometry in saliva and serum. Results: Oral microbiota in CD patients were characterized by lower diversity in terms of the isolated bacteria species compared to UC and this correlated with reduced FRAP in the oral cavity and intensified systemic inflammation. Oral microbiota composition in CD did not depend on the applied treatment. In CD patients, a negative correlation was observed between the FRAP value in saliva and serum and the CRP value in serum. Individual diff erences in the composition of oral microbiota suggest that diff erent bacteria species may be involved in the induction of oxidative stress associated with a weakening of antioxidative defense in the oral cavity, manifested by ongoing systemic inflammation. Conclusion: Analysis of both the state of the microbiota and antioxidative defense of the oral cavity, as well as their referencing to systemic infl ammation may potentially prove helpful in routine diagnostic applications and in aiding a better understanding of CD and UC pathogenesis associated with oral microbiota

Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis

Aim: Quantitative comparison of the effects of intensive (IPT) or conventional (CPT) periodontal treatment on arterial blood pressure, endothelial function and inflammatory/metabolic biomarkers. / Materials and methods: A systematic search was conducted to identify randomized controlled trials (RCT) of IPT (supra and subgingival instrumentation). Eight RCTs were included in the meta-analysis. Difference in change of systolic blood pressure (SBP) and diastolic blood pressure (DBP) before and after IPT or CPT were the primary outcomes. The secondary outcomes included: endothelial function and selected inflammatory/anti-inflammatory (CRP, IL-6, IL-10, IFN-γ) and metabolic biomarkers (HDL, LDL, TGs). / Results: The overall effect estimates (pooled Weighted Mean Difference (WMD)) of the primary outcome for SBP and DBP was −4.3 mmHg [95%CI: −9.10–0.48], p = 0.08 and −3.16 mmHg [95%CI: −6.51–0.19], p = 0.06 respectively. These studies were characterized by high heterogeneity. Therefore, random effects model for meta-analysis was performed. Sub-group analyses confirmed statistically significant reduction in SBP [WMD = −11.41 mmHg (95%CI: −13.66, −9.15) P < 0.00001] and DBP [WMD = −8.43 mmHg (95%CI: −10.96,−5.91)P < 0.00001] after IPT vs CPT among prehypertensive/hypertensive patients, while this was not observed in normotensive individuals. The meta-analyses showed significant reductions in CRP and improvement of endothelial function following IPT at all analysed timepoints. / Conclusions: IPT leads to improvement of the cardiovascular health in hypertensive and prehypertensive individuals