Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension.

BACKGROUND: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels. METHODS: In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP. RESULTS: Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47-mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97-mm Hg systolic BP increase in the lowest 10% (P=1.95×10-3). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP. CONCLUSIONS: The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted.

Asthma medication use in obese and healthy weight asthma: systematic review/meta-analysis.

BACKGROUND: Obesity is a common comorbidity in asthma and associated with poorer asthma control, more frequent/severe exacerbations, and reduced response to asthma pharmacotherapy. OBJECTIVE: This review aims to compare use of all classes of asthma medications in obese (body mass index (BMI) ≤30 kg·m-2) versus healthy-weight (BMI <25 kg·m-2) subjects with asthma. DESIGN: Databases including CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane, Embase and MEDLINE were searched up to July 2019 for English-language studies that recorded medication use or dose in obese and healthy-weight adults with asthma. A critical appraisal checklist was utilised for scrutinising methodological quality of eligible studies. Meta-analysis was performed and heterogeneity was examined with the use of the Chi-squared test. This review was conducted based on a published protocol (www.crd.york.ac.uk/PROSPERO CRD42020148671). RESULTS: Meta-analysis showed that obese subjects are more likely to use asthma medications, including short-acting ß2-agonists (OR 1.75, 95% CI 1.17-2.60; p=0.006, I2=41%) and maintenance oral corticosteroids (OR 1.86, 95% CI 1.49-2.31; p<0.001, I2=0%) compared to healthy-weight subjects. Inhaled corticosteroid (ICS) dose (µg·day-1) was significantly higher in obese subjects (mean difference 208.14, 95% CI 107.01-309.27; p<0.001, I2=74%). Forced expiratory volume in 1 s (FEV1) % predicted was significantly lower in obese subjects (mean difference -5.32%, 95% CI -6.75--3.89; p<0.001, I2=42%); however, no significant differences were observed in FEV1/forced vital capacity (FVC) ratio between groups. CONCLUSIONS: We found that obese subjects with asthma have higher use of all included asthma medication classes and higher ICS doses than healthy-weight asthma subjects, despite lower FEV1 and a similar FEV1/FVC %. A better understanding of the factors driving increased medication use is required to improve outcomes in this subgroup of asthmatics.

Cardiovascular Disease Risk in Individuals Following Plant-Based Dietary Patterns Compared to Regular Meat-Eaters.

Plant-based diets (PBDs) have been associated with a lower risk of cardiovascular disease (CVD). The aim was to investigate the predicted 5-year and 10-year risk of developing CVD in individuals following PBDs compared to regular meat-eating diets. This cross-sectional study included n = 240 middle-aged adults habitually consuming dietary patterns for ≥6 months: vegan, lacto-ovo vegetarian (LOV), pesco-vegetarian (PV), semi-vegetarian (SV) or regular meat-eater (RME) (n = 48 per group). Predicted 5-year and 10-year CVD risks were quantified using the Framingham Risk Equation and the Australian Absolute CVD risk calculator, respectively. Multivariable regression analysis was used to adjust for age, sex, smoking status, physical activity, alcohol use and BMI. Over three-quarters of the participants were women, mean age of 53.8 yrs. After adjustments for potential confounders, there was no difference in the predicted risk of CVD between regular-meat diets and PBDs, although crude analyses revealed that vegans had a lower 5-year and 10-year predicted risk of CVD compared to RMEs. SVs, PVs and LOVs had lower CVD risk scores, however, not significantly. Vegans had a favourable cardiometabolic risk profile including significantly lower serum lipid levels, fasting blood glucose and dietary fats and higher dietary fibre intake compared to RMEs. This was the first study to purposefully sample Australians habitually following PBDs. We found that PBDs do not independently influence the predicted risk of CVD, although PBDs tended to have lower risk and vegans had significantly lower cardiometabolic risk factors for CVD.

Bone mineral density and body composition in Australians following plant-based diets vs. regular meat diets.

Background and aims: Bone mineral density (BMD) and body composition play an important role in maintaining metabolic health and physical functioning. Plant-based diets (PBDs) are known to be lower in protein and calcium, which can impact BMD and body composition. This study aimed to investigate the relationship between various PBDs compared to regular meat diet and whole-body BMD, body composition, and weight status. Methods: A cross-sectional study was conducted with adults (n = 240) aged 30-75 years, who habitually followed dietary patterns: vegan, lacto-vegetarian, pesco-vegetarian, semi-vegetarian, or regular meat eater (48 per group). Parameters were measured using dual-energy x-ray absorptiometry (DXA), and multivariable regression analyses were used to adjust for lifestyle confounders, socioeconomic factors, and BMI. Results: After adjustments, whole-body BMD and body composition were not significantly different between those following PBDs and regular meat diets, except for lacto-ovo vegetarians, who had significantly lower lean mass by -1.46 kg (CI: -2.78, -0.13). Moreover, lacto-ovo vegetarians had a significantly lower T-score by -0.41 SD (CI: -0.81, -0.01) compared to regular meat eaters. Waist circumference was significantly lower in individuals adhering to a PBD compared to a regular meat diet: vegans by -4.67 cm (CI: -8.10, -1.24), lacto-ovo vegetarians by -3.92 cm (CI: -6.60, -1.23), pesco-vegetarians by -3.24 cm (CI: -6.09, -0.39), and semi-vegetarians by -5.18 cm (CI: -7.79, -2.57). There were no significant differences in lean mass (%), fat mass (% and total), android/gynoid measures, body weight, or BMI across dietary patterns. All dietary patterns met the recommended dietary intake for calcium and protein, and 25-hydroxy-vitamin D status was comparable across groups. Conclusions: This cross-sectional study found that adhering to a PBD characterized by varying degrees of dairy and meat restriction is not associated with meaningful changes in BMD or body composition, provided that the dietary patterns are planned appropriately with adequate levels of calcium and protein.

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aß) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aß, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the ß-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aß, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Short-chain fatty acids as anti-inflammatory agents in overweight and obesity: a systematic review and meta-analysis.

CONTEXT: Short-chain fatty acids (SCFAs) derived from microbial fermentation of prebiotic soluble fibers are noted for their anti-inflammatory benefits against obese systemic inflammation. OBJECTIVE: A systematic review and meta-analysis were undertaken to investigate the effect of SCFAs and prebiotic interventions on systemic inflammation in obesity. DATA SOURCES: Relevant studies from 1947 to August 2019 were collected from the Cumulative Index to Nursing and Allied Health Literature, Embase, Medline, and Cochrane databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. STUDY SELECTION: Of 61 included studies, 29 were of humans and 32 of animals. DATA EXTRACTION: Methodological quality of studies was assessed using the critical appraisal checklist of the Academy of Nutrition and Dietetics. Data pertaining to population, intervention type and duration, and markers of systemic inflammation were extracted from included studies. RESULTS: Of 29 included human studies, 3 of 4 SCFA interventions and 11 of 25 prebiotic interventions resulted in a significant decrease in ≥1 biomarker of systemic inflammation. Of 32 included animal studies, 10 of 11 SCFA interventions and 18 of 21 prebiotic interventions resulted in a significant reduction of ≥1 biomarker of systemic inflammation. Meta-analysis revealed that prebiotics in humans reduced levels of plasma high-sensitivity C-reactive protein (standard mean difference [SMD], -0.83; 95%CI: -1.56 to -0.11; I2: 86%; P = 0.02) and plasma lipopolysaccharide (SMD, -1.20; 95%CI: -1.89 to -0.51; I2: 87%; P = 0.0006), and reduced TNF-α levels in animals (SMD, -0.63; 95%CI: -1.19 to -0.07; P = 0.03). Heterogeneity among supplement types, duration, and dose across studies was significant. CONCLUSION: Evidence from this review and meta-analysis supports the use of SCFAs and prebiotics as novel aids in treatment of obese systemic inflammation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020148529.

Effect of a polyphenol-rich dietary supplement containing Pinus massoniana bark extract on blood pressure in healthy adults: A parallel, randomized placebo-controlled trial.

OBJECTIVES: High blood pressure (BP) is a major risk factor for cardiovascular disease and prevalence rates continue to rise with ageing populations. Polypharmacy remains a burden among the ageing, thus alternative effective strategies are warranted. This study investigated the effects of a polyphenols rich dietary supplement containing Pinus massoniana bark extract (PMBE) for modulating BP in healthy Australian adults. DESIGN: This study is a secondary analysis of data from a double-blinded, placebo-controlled clinical trial. METHODS: Sixty-two healthy adults aged 55-75 years were randomized to receive 50 mL dietary supplement containing placebo (0 mg PMBE) or PMBE (1322 mg PMBE) daily for 12 weeks. Seated systolic BP (SBP) and diastolic (DBP) were measured at baseline, 6 weeks and 12 weeks. Effects of PMBE on modulating BP was also explored in this study stratified for SBP status (optimal v high) as well as by SBP medication status. Mixed effect regression modelling was employed involving fixed categorical effects for elapsed time, treatment assignment and their interaction as well as random subject-level intercept to account for within-subject correlations resulting from repeated measurements. Significant models were further examined by addition of covariates and power calculations were performed since this study was a secondary analysis. RESULTS: SBP significantly reduced (-3.29 mmHg, p = 0.028) after PMBE at 12 weeks compared to baseline. SBP in individuals with normal-high SBP (>120 mmHg) in the PMBE group reduced by - 6.46 mmHg (p = 0.001) at 12 weeks compared to baseline. No significant changes were reported for individuals with optimal (≤120 mmHg) SBP nor did DBP significantly change in either study groups. In individuals with non-medicated normal-high SBP, SBP significantly reduced by - 7.49 mmHg (p = 0.001) and DBP by - 3.06 mmHg (p = 0.011) at 12 weeks compared to baseline after PMBE. Cross-group comparisons were not statistically different. CONCLUSIONS: A polyphenol-rich dietary supplement derived from PMBE led to a clinically and statistically significant reduction in SBP in adults. Future studies to investigate the effects of PMBE-polyphenol supplementation on BP are warranted to confirm and explore optimal dose and impact on hypertension.

Sulforaphane reduces pro-inflammatory response to palmitic acid in monocytes and adipose tissue macrophages.

Chronic low-grade systemic inflammation (SI), including activation of the NLRP3 inflammasome, is a feature of obesity, associated with increased circulating saturated fatty acids, such as palmitic acid (PA), and bacterial endotoxin lipopolysaccharide (LPS). PA and LPS may contribute to SI observed in obesity, while the dietary antioxidant sulforaphane has been shown to reduce activation of the NLRP3 inflammasome. This study investigated immune cell responses from obese subjects to PA, and the effects of sulforaphane on NLRP3 activation/inflammation. Peripheral blood monocytes isolated from obese (n = 8) and non-obese (n = 8) subjects and adipose tissue macrophages (ATMs) isolated from visceral fat obtained from obese subjects (n = 10) during bariatric surgery were pre-treated with/without sulforaphane (40 µM) for 3 hours then stimulated with PA (500 µM) ± LPS (1 ng/mL monocytes; 100 ng/mL ATMs) for 15 hours. Culture supernatants were assessed for tumor necrosis factor-α and interleukin-ß (IL-1ß) by enzyme-linked immunosorbent assay, NLRP3 inflammasome gene expression was assessed by quantitative polymerase chain reaction, IL-1ß and NLRP3 expression were higher in both unstimulated and PA treated monocytes from obese compared to nonobese subjects. In ATMs neither PA alone or combined with LPS increased cytokine production or inflammasome gene expression. Sulforaphane reduced tumor necrosis factor-α and IL-1ß from monocytes in both groups, however inflammasome associated genes were only reduced in monocytes from obese subjects. Sulforaphane reduced cytokine production and inflammasome gene expression in ATMs. NLRP3 inflammasome activation by PA is higher in obesity, which maybe driven by baseline activation of the NLRP3 inflammasome. Sulforaphane modulates inflammatory responses in immune cells and may play a role in reducing SI in obesity.

Weight Loss and Short-Chain Fatty Acids Reduce Systemic Inflammation in Monocytes and Adipose Tissue Macrophages from Obese Subjects.

BACKGROUND: Chronic low-grade systemic inflammation is a characteristic of obesity that leads to various non-communicable diseases. Weight loss and SCFAs are potential strategies for attenuating obese systemic inflammation. METHODS: Blood samples were collected from 43 obese subjects (BMI ≥ 30 kg/m2) scheduled for laparoscopic bariatric sleeve surgery, 26 obese subjects at follow-up 12-18 months post-surgery and 8 healthy weight subjects (BMI 18.5-24.9 kg/m2). Monocytes were isolated from blood and adipose tissue macrophages from visceral adipose tissue of obese subjects only. Isolated cells stimulated with 1 ng/mL LPS and treated simultaneously with 300 mM of sodium acetate or 30 mM of sodium propionate or butyrate and supernatant were harvested after 15 h incubation. TNF-α and IL-6 cytokines were measured via ELISA and mRNA gene expression of FFAR2 and FFAR3, HDAC1, HDAC2 and HDAC9, RELA and NFKB1 and MAPK1 via RT-qPCR. RESULTS: TNF-α and IL-6 production and NFKB1 and RELA mRNA expression were significantly decreased in follow-up subjects compared to baseline. SCFAs significantly reduced TNF-α and IL-6 and altered FFAR and HDAC mRNA expression in monocytes and macrophages from obese subjects. CONCLUSION: Weight loss and ex vivo SCFA treatments were successful in combatting systemic inflammation in obesity. Results highlighted molecular changes that occur with weight loss and as a result of SCFA treatment.

Characterising a Weight Loss Intervention in Obese Asthmatic Children.

The prevalence of obesity in asthmatic children is high and is associated with worse clinical outcomes. We have previously reported that weight loss leads to improvements in lung function and asthma control in obese asthmatic children. The objectives of this secondary analysis were to examine: (1) changes in diet quality and (2) associations between the baseline subject characteristics and the degree of weight loss following the intervention. Twenty-eight obese asthmatic children, aged 8-17 years, completed a 10-week diet-induced weight loss intervention. Dietary intake, nutritional biomarkers, anthropometry, lung function, asthma control, and clinical outcomes were analysed before and after the intervention. Following the intervention, the body mass index (BMI) z-score decreased (Δ = 0.18 ± 0.04; p < 0.001), %energy from protein increased (Δ = 4.3 ± 0.9%; p = 0.002), and sugar intake decreased (Δ = 23.2 ± 9.3 g; p= 0.025). Baseline lung function and physical activity level were inversely associated with Δ% fat mass. The ΔBMI z-score was negatively associated with physical activity duration at baseline. Dietary intervention is effective in achieving acute weight loss in obese asthmatic children, with significant improvements in diet quality and body composition. Lower lung function and physical engagement at baseline were associated with lesser weight loss, highlighting that subjects with these attributes may require greater support to achieve weight loss goals.