Rationale and design of the United Kingdom Heart Failure with Preserved Ejection Fraction Registry

\ua9 Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.Objective: Heart failure with preserved ejection fraction (HFpEF) is a common heterogeneous syndrome that remains imprecisely defined and consequently has limited treatment options and poor outcomes. Methods: The UK Heart Failure with Preserved Ejection Fraction Registry (UK HFpEF) is a prospective data-enabled cohort and platform study. The study will develop a large, highly characterised cohort of patients with HFpEF. A biobank will be established. Deep clinical phenotyping, imaging, multiomics and centrally held national electronic health record data will be integrated at scale, in order to reclassify HFpEF into distinct subgroups, improve understanding of disease mechanisms and identify new biological pathways and molecular targets. Together, these will form the basis for developing diagnostics and targeted therapeutics specific to subgroups. It will be a platform for more effective and efficient trials, focusing on subgroups in whom targeted interventions are expected to be effective, with consent in place to facilitate rapid recruitment, and linkage for follow-up. Patients with a diagnosis of HFpEF made by a heart failure specialist, who have had natriuretic peptide levels measured and a left ventricular ejection fraction >40% are eligible. Patients with an ejection fraction between 40% and 49% will be limited to no more than 25% of the cohort. Conclusions: UK HFpEF will develop a rich, multimodal data resource to enable the identification of disease endotypes and develop more effective diagnostic strategies, precise risk stratification and targeted therapeutics. Trial registration number: NCT05441839

Antiaggregation Potential of Padina gymnospora against the Toxic Alzheimer's Beta-Amyloid Peptide 25-35 and Cholinesterase Inhibitory Property of Its Bioactive Compounds.

Inhibition of β-amyloid (Aβ) aggregation in the cerebral cortex of the brain is a promising therapeutic and defensive strategy in identification of disease modifying agents for Alzheimer's disease (AD). Since natural products are considered as the current alternative trend for the discovery of AD drugs, the present study aims at the evaluation of anti-amyloidogenic potential of the marine seaweed Padina gymnospora. Prevention of aggregation and disaggregation of the mature fibril formation of Aβ 25-35 by acetone extracts of P. gymnospora (ACTPG) was evaluated in two phases by Thioflavin T assay. The results were further confirmed by confocal laser scanning microscopy (CLSM) analysis and Fourier transform infrared (FTIR) spectroscopic analysis. The results of antiaggregation and disaggregation assay showed that the increase in fluorescence intensity of aggregated Aβ and the co-treatment of ACTPG (250 μg/ml) with Aβ 25-35, an extensive decrease in the fluorescence intensity was observed in both phases, which suggests that ACTPG prevents the oligomers formation and disaggregation of mature fibrils. In addition, ACTPG was subjected to column chromatography and the bioactivity was screened based on the cholinesterase inhibitory activity. Finally, the active fraction was subjected to LC-MS/MS analysis for the identification of bioactive compounds. Overall, the results suggest that the bioactive compound alpha bisabolol present in the alga might be responsible for the observed cholinesterase inhibition with the IC50 value < 10 μg/ml for both AChE and BuChE when compared to standard drug donepezil (IC50 value < 6 μg/ml) and support its use for the treatment of neurological disorders

LC-MS/MS profile of ACTPG showing the presence of bioactive compounds.

<p>LC-MS/MS profile of ACTPG showing the presence of bioactive compounds.</p

Bioactivity guided fractionation of ACTPG.

<p>Bioactive fractions were eluted with linear gradient of solvent with increasing polarity from n-hexane to water and the 18 fractions (F1-F18) were collected and subjected to cholinesterase inhibition assay.</p

Effects of ACTPG on Aβ _25–35 fibrillogenesis.

<p>Analysis of the deposited amyloid aggregates as assessed by thioflavin T (ThT) assays in Phase I (20, 48 h) & II (96 h & 9days). Quantitative effects of ACTPG on Aβ _25–35 fibrillogenesis by ThT assay showing the bar diagram of thioflavin-T fluorescence of Aβ _25–35 in the presence and absence of ACTPG. The emission spectrum of ACTPG and galantamine alone was subtracted, and emission data of peptide dispersions were normalized. Values are expressed as Mean ± SD (n = 3).</p

Effects of ACTPG on antiaggregation and disaggregation property of Aβ _25–35.

<p>Analysis of the deposited amyloid aggregates as assessed by Confocal Laser Microscope System (CLSM FV300, Olympus, Tokyo, Japan) in (A) Phase I (20, 48 h) & (B) Phase II (96 h & 9days) and processed by Adobe Photoshop (Adobe Systems, Mountain View, CA, USA). The fluorescence intensity was visualized in each of three random fields of the sample. Confocal microscopic image represents a view of deposited Aβ _25–35 amyloid aggregates, with representative fibrils from Aβ _25–35 samples (control) and Aβ _25–35 samples incubated with the presence and absence of ACTPG and galantamine.</p

Butyrylcholinesterase inhibitory activity of the active compounds (10–50 μg/ml).

<p>The result of BuChE inhibitory activity clearly shows that among the different treatment groups, alpha-bisabolol alone treatment possessed a maximum BuChE inhibitory activity(66%), with the IC50 value <10 μg/ml and showed significant inhibition (*p<0.1) at 50 μg/ml. Further, standard drug donepezil (IC50 value <6 μg/ml) and the compound of our interest, alpha-bisabolol displayed a significant inhibition on BuChE. Values are expressed as Mean ± SD (n = 3).</p

AChE inhibitory activity of the column fractions (F1-F18).

<p>The eluted fractions (F1-F18) were subjected to AChE inhibitory assay. Among the fractions, F10 (EA: MET-9:1) showed highest inhibitory activity (93%) against AChE, but similar when compared to positive control donepezil (97%). Values are expressed as Mean ± SD (n = 3).</p

LC-MS/MS spectrum of active fraction (F10) of ACTPG.

<p>LC-MS/MS spectrum of active F10 fraction of ACTPG showed the presence of essential oil alpha-bisabolol.</p