Background Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently ...contributes to each one of these risk factors, potentially mediated via gut microbial‐derived metabolites such as short‐chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors. Methods and Results We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α‐diversity (eg, number of microbes) and β‐diversity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF ( P =0.001). We did not find an association between β‐diversity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so ( P =0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short‐chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day; P =0.016). Conclusions We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.
Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives ...cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18-55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise.
Animal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II ...hypertensive model. However, the gut microbiome is influenced by internal and external experimental factors which are not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations.
We conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomised into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced α-diversity (P = 0.0137) and β-diversity (i.e., composition of the microbiome, P < 0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid-producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both α- and β-diversity (all P < 0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%).
Our large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable.
Increasing evidence supports a role for the gut microbiota in the development of cardiovascular diseases such as hypertension and its progression to heart failure (HF). Dietary fibre has emerged as a ...modulator of the gut microbiota, resulting in the release of gut metabolites called short-chain fatty acids (SCFAs), such as acetate. We have shown previously that fibre or acetate can protect against hypertension and heart disease in certain models. HF is also commonly caused by genetic disorders. In this study we investigated whether the intake of fibre or direct supplementation with acetate could attenuate the development of HF in a genetic model of dilated cardiomyopathy (DCM) due to overexpression of the cardiac specific mammalian sterile 20-like kinase (Mst1). Seven-week-old male mice DCM mice and littermate controls (wild-type, C57BL/6) were fed a control diet (with or without supplementation with 200 mM magnesium acetate in drinking water), or a high fibre diet for 7 weeks. We obtained hemodynamic, morphological, flow cytometric and gene expression data. The gut microbiome was characterised by 16S rRNA amplicon sequencing. Fibre intake was associated with a significant shift in the gut microbiome irrespective of mouse genotype. However, neither fibre or supplementation with acetate were able to attenuate cardiac remodelling or cardiomyocyte apoptosis in Mst1 mice. Furthermore, fibre and acetate did not improve echocardiographic or hemodynamic parameters in DCM mice. These data suggest that although fibre modulates the gut microbiome, neither fibre nor acetate can override a strong genetic contribution to the development of heart failure in the Mst1 model.
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•The phenolics from the OliveNet™ Library were utilised in molecular modelling studies of Alzheimer’s disease.•Molecular docking studies were performed against the major pathogenic ...proteins, β-amyloid (Aβ) and tau.•Key binding sites were identified using molecular docking, highlighting the hairpin-turn of the Aβ1−40 and Aβ1−42 peptides.•The flavonoid, glucoside and secoiridoid subclasses were found to bind with highest affinity to the pathogenic proteins.•Dynamic simulations depicted can be used to investigate anti-aggregatory effects of compounds from the OliveNet™ Library.
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that affects over 47 million people worldwide, and is the most common form of dementia. There is a vast body of literature demonstrating that the disease is caused by an accumulation of toxic extracellular amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles that consist of hyperphosphorylated tau. Adherence to the Mediterranean diet has been shown to reduce the incidence of AD and the phenolic compounds in extra virgin olive oil, including oleocanthal, have gained a significant amount of attention. A large number of these ligands have been described in the pre-existing literature and 222 of these compounds have been characterised in the OliveNet™ database. In this study, molecular docking was used to screen the 222 phenolic compounds from the OliveNet™ database and assess their ability to bind to various forms of the Aβ and tau proteins. The phenolic ligands were found to be binding strongly to the hairpin-turn of the Aβ1−40 and Aβ1−42 monomers, and binding sites were also identified in the tau fibril protein structures. Luteolin-4′-O-rutinoside, oleuricine A, isorhoifolin, luteolin-7-O-rutinoside, cyanidin-3-O-rutinoside and luteolin-7,4-O-diglucoside were predicted to be novel lead compounds. Molecular dynamics (MD) simulations performed using well-known olive ligands bound to Aβ1−42 oligomers highlighted that future work may examine potential anti-aggregating properties of novel compounds in the OliveNet™ database. This may lead to the development and evaluation of new compounds that may have efficacy against Alzheimer’s disease.
This paper reports the results of an international interlaboratory study led by the National Institute of Standards and Technology (NIST) on the measurement of high-pressure surface excess carbon ...dioxide adsorption isotherms on NIST Reference Material RM 8852 (ammonium ZSM-5 zeolite), at 293.15 K (20 °C) from 1 kPa up to 4.5 MPa. Eleven laboratories participated in this exercise and, for the first time, high-pressure adsorption reference data are reported using a reference material. An empirical reference equation
n
e
x
=
d
(
1
+
exp
-
ln
(
P
)
+
a
/
b
)
c
,
n
ex
-surface excess uptake (mmol/g),
P
-equilibrium pressure (MPa),
a
= −6.22,
b
= 1.97,
c
= 4.73, and
d
= 3.87 along with the 95% uncertainty interval (
U
k
= 2
= 0.075 mmol/g) were determined for the reference isotherm using a Bayesian, Markov Chain Monte Carlo method. Together, this zeolitic reference material and the associated adsorption data provide a means for laboratories to test and validate high-pressure adsorption equipment and measurements. Recommendations are provided for measuring reliable high-pressure adsorption isotherms using this material, including activation procedures, data processing methods to determine surface excess uptake, and the appropriate equation of state to be used.
We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic ...levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 × 1012 vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of ∼8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression*.
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