Oral inflammatory load predicts vascular function in a young adult population: a pilot study.

Background: The periodontium is a highly vascularized area of the mouth, and periodontitis initiates negative functional and structural changes in the vasculature. However, mild oral inflammation, including levels experienced by many apparently healthy individuals, has an unclear impact on cardiovascular function. The purpose of this pilot study is to investigate the effects of objectively measured whole mouth oral inflammatory load (OIL) on vascular function in apparently healthy individuals. Methods: In this cross-sectional and correlational analysis, we recruited 28 young (18-30 years) and systemically healthy participants (16 male, 12 female). Using oral neutrophil counts, a validated measure for OIL, we collected participant's mouth rinse samples and quantified OIL. Blood pressure, arterial stiffness (pulse-wave velocity) and endothelial function (brachial artery flow-mediated dilation) were also measured. Results: Only oral neutrophil count significantly predicted flow-mediated dilation % (p = 0.04; R2 = 0.16, ß = - 1.05) and those with OIL levels associated with >2.5 × 105 neutrophil counts (n = 8) had a lower flow-mediated dilation % (6.0 ± 2.3%) than those with counts associated with gingival health with less than 2.5 × 105 neutrophil counts (10.0 ± 5.2%, p = 0.05). There were no significant predictors for arterial stiffness. Conclusion: We found that OIL was a predictor of reduced flow-mediated dilation. An impairment in flow-mediated dilation is an indicator of future possible risk of cardiovascular disease-one of the leading causes of death in North America. Therefore, this study provides evidence for the importance of oral health and that OIL may impact endothelial function.

Roles of Hormone Replacement Therapy and Menopause on Osteoarthritis and Cardiovascular Disease Outcomes: A Narrative Review.

Osteoarthritis (OA) is a highly prevalent condition characterized by degradation of the joints. OA and cardiovascular disease (CVD) are leading contributors to disease burden worldwide, with a high level of overlap between the risk factors and occurrence of both conditions. Chief among the risk factors that contribute to OA and CVD are sex and age, which are both independent and interacting traits. Specifically, the prevalence of both conditions is higher in older women, which may be mediated by the occurrence of menopause. Menopause represents a significant transition in a women's life, and the rapid decline in circulating sex hormones, estrogen and progesterone, leads to complex physiological changes. Declines in hormone levels may partially explain the increase in prevalence of OA and CVD in post-menopausal women. In theory, the use of hormone therapy (HT) may buffer adverse effects of menopause; however, it is unclear whether HT offers protective effects for the onset or progression of these diseases. Studies have shown mixed results when describing the influence of HT on disease risk among post-menopausal women, which warrants further exploration. The roles that increasing age, female sex, HT, and CVD play in OA risk demonstrate that OA is a multifaceted condition. This review provides a timely consolidation of current literature and suggests aims for future research directions to bridge gaps in the understanding of how OA, CVD, and HT interact in post-menopausal women.

Cerebral haemodynamics during arrhythmia in health, ischaemic heart disease and heart failure with reduced ejection fraction, and in a preclinical swine model.

Ventricular arrhythmias are associated with neurological impairment and could represent a source of cerebral hypoperfusion. In the present study, data from healthy individuals (n = 11), patients with ischaemic heart disease (IHD; ejection fraction >40%; n = 9) and patients with heart failure with reduced ejection fraction (HFrEF; EF = 31 (5)%, n = 11), as well as data from swine surgeries, where spontaneous ventricular arrhythmias were observed during cerebrovascular examination (transcranial Doppler ultrasound in humans and laser Doppler in swine) were analysed retrospectively to investigate the effect of arrhythmia on cerebral microvascular haemodynamics. A subset of participants also completed the Montreal Cognitive Assessment (MoCA). Middle cerebral artery mean blood velocity (MCAVmean ) decreased during premature ventricular contraction (PVC) in all groups, and data from swine indicate PVCs reduced cerebral microvascular perfusion. Overall MCAVmean was decreased in the HFrEF vs. control group. Further, %∆MCAVmean /%∆mean arterial pressure during the PVC was greater in the HFrEF vs. control group and was correlated with decreased MoCA scores. Subanalysis of HFrEF data revealed that during bigeminy MCAVmean decreased owing to reductions during irregular beats only. During non-sustained ventricular tachycardia, MCAVmean decreased but recovered above baseline upon return to sinus rhythm. Also, haemodynamic perturbations during and following the PVC were greater in the brachial artery vs. the MCA. Therefore, ventricular arrhythmias decreased indices of cerebral perfusion irrespective of IHD or HFrEF. The relative magnitude of arrhythmia-induced haemodynamic perturbations appears to be population specific and arrhythmia type and organ dependent. The cumulative burden of arrhythmia-induced deficits may exacerbate existing cerebral hypoperfusion in HFrEF and contribute to neurological abnormalities in this population. KEY POINTS: Irregular heartbeats are often considered benign in isolation, but individuals who experience them frequently have a higher prevalence of cerebrovascular and/or cognitive associated disorders. How irregular heartbeats affect blood pressure and cerebral haemodynamics in healthy and cardiovascular disease patients, those with and without reduced ejection fraction, remains unknown. Here it was found that in the absence of symptoms associated with irregular heartbeats, such as dizziness or hypotension, single, multiple non-sustained and sustained irregular heartbeats influence cerebral haemodynamics in a population-specific, arrhythmia-type and organ-dependent manner. Relative deficits in the index of cerebral blood flow normalized to relative deficits in blood pressure were greatest in patients with heart failure with reduced ejection and inversely related with cognitive performance. Chronic arrhythmias may exacerbate existing cerebral hypoperfusion in heart failure with reduced ejection fraction, thereby providing a mechanistic link between otherwise benign irregular heartbeats and cognitive dysfunction, independent of embolism.

Dairy and Dairy Alternative Supplementation Increase Integrated Myofibrillar Protein Synthesis Rates, and Are Further Increased when Combined with Walking in Healthy Older Women.

BACKGROUND: The stimulation of muscle protein synthesis (MPS) by dietary protein is reduced with age. We hypothesized that twice-daily milk consumption would increase daily rates of MPS in older women relative to a nondairy milk alternative and that MPS would be enhanced by increased physical activity (PA). METHODS: Twenty-two older women were randomly assigned to 1 of 3 experimental groups: whole milk (WM; n = 7, 69 ± 3 y), skim milk (SM; n = 7, 68 ± 3 y), or an almond beverage (AB; n = 8, 63 ± 3 y). From days 1 to 3, participants consumed a standardized diet (0.8 g protein⋅kg-1 ⋅d-1) and performed their habitual PA (Phase 1, Baseline). From days 4 to 6, participants continued to perform habitual PA, but consumed an intervention diet consisting of the standardized diet plus twice-daily beverages (250 mL each) of either WM, SM, or AB (Phase 2, Diet Intervention). Finally, from days 7 to 9, the intervention diet was consumed, and PA via daily steps was increased to ∼150% of habitual daily steps (Phase 3, Intervention Diet + PA). Deuterated water was ingested throughout the study, and muscle biopsies were taken on days 1, 4, 7, and 10 to measure MPS. RESULTS: Daily MPS rates were not differentially affected by the addition of WM, SM, or AB to a standardized diet. There was, however, a significant effect of study phase such that, when collapsed across conditions, MPS was significantly increased from Phase 1 to Phase 2 (+0.133%⋅d-1; 95% CI: 0.035-0.231; P < 0.01) and further increased from Phase 2 to Phase 3 (+0.156%⋅d-1; 95% CI: 0.063-0.250; P < 0.01). CONCLUSIONS: Increasing PA through walking was sufficient to increase daily MPS rates in older women, irrespective of whether dietary protein intake is increased beyond the recommended intake of 0.8 g⋅kg-1 ⋅d-1. The trial was registered at clinicaltrials.gov as NCT04981652.

AP-002: A novel inhibitor of osteoclast differentiation and function without disruption of osteogenesis.

AP-002 is a novel, gallium-based, anti-cancer oral compound in clinical development for cancer patients with bone metastases. We examined the effects of AP-002 on osteoclastogenesis, fusion, and osteogenesis. AP-002 exhibited a dramatic effect on osteoclast function without causing osteoclast cell death. The expression of tartrate-resistant acid phosphatase and cathepsin K mRNA levels was down-regulated in RAW264.7 cells treated with AP-002 in the presence of soluble receptor activator of NF-κB ligand. AP-002 was also found to block the fusion of osteoclasts from RAW264.7 cells. AP-002 had a similar inhibitory effect on RANKL-induced mouse primary bone marrow monocytes fusion. Human blood monocytes treated with AP-002 failed to form TRAcP/ACP5-positive cells. AP-002 caused these inhibitory effects without causing osteoclast cell death, which was in contrast to zoledronic acid controls. Furthermore, unlike zoledronic acid, AP-002 did not inhibit Rac1 activation. Gene expression analysis by microarrays showed that AP-002 significantly reverses the effects of RANKL-induced gene expression. These include several key osteoclast-differentiation/function-associated genes such as: Scinderin, OCSTAMP, Atp6v0d2, OSCAR, RhoU, Usp18, MMP9, and Trim30. The difference between AP-002 and zoledronic acid is also seen in its effects on osteogenesis. Osteoblast mineralization was promoted by AP-002 (0.1-3.0 µM), whereas zoledronic acid showed toxicity to osteoblasts at the concentration >0.5 µM, in the same dose range where it causes osteoclast cell death. Zoledronic acid therefore has no therapeutic window in its toxic effect on osteoclasts and osteoblasts. AP-002 promotes osteogenesis in this therapeutic window, while blocking osteoclast development. We therefore conclude that AP-002 has potential as a new anti-bone resorption agent, with a mechanism of action different compared with other currently marketed anti-bone resorption agents.

IL1ß and TNFα promote RANKL-dependent adseverin expression and osteoclastogenesis.

Adseverin is an actin-binding protein involved in osteoclastogenesis, but its role in inflammation-induced bone loss is not well-defined. Here, we examined whether IL1ß and TNFα regulate adseverin expression to control osteoclastogenesis in mouse primary monocytes and RAW264.7 cells. Adseverin was colocalized with subcortical actin filaments and was enriched in the fusopods of fusing cells. In precursor cells, adseverin overexpression boosted the formation of RANKL-induced multinucleated cells. Both IL1ß and TNFα enhanced RANKL-dependent TRAcP activity by 1.6-fold and multinucleated cell formation (cells with ≥3 nuclei) by 2.6- and 3.3-fold, respectively. However, IL1ß and TNFα did not enhance osteoclast formation in adseverin-knockdown cells. RANKL-dependent adseverin expression in bone marrow cells was increased by both IL1ß (5.4-fold) and TNFα (3.3-fold). Luciferase assays demonstrated that this expression involved transcriptional regulation of the adseverin promoter. Activation of the promoter was restricted to a 1118 bp sequence containing an NF-κB binding site, upstream of the transcription start site. TNFα also promoted RANKL-induced osteoclast precursor cell migration. We conclude that IL1ß and TNFα enhance RANKL-dependent expression of adseverin, which contributes to fusion processes in osteoclastogenesis.