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Brady, Emer M. (2024) Metabolic signature in stage A/B heart failure: A study in asymptomatic Type 2 Diabetes. MRes thesis, University of Nottingham.

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Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous multi-system syndrome with limited efficacious treatment options. When coupled with the rising prevalence of Type 2 diabetes (T2D), which predisposes HFpEF, it remains one of the biggest challenges in cardiovascular medicine today. Novel therapeutic targets are required to meet this important clinical need. Deep phenotyping studies including -OMIC analyses can provide important pathogenic information to aid the identification of such targets.

Aims: The overarching aim of this project is to identify and describe the metabolic signature in people with stage A/B heart failure (HF) and response to low-calorie diet.

Methods: Post-hoc analysis of a randomised controlled trial (NCT02590822) including adults with T2D and no cardiovascular disease who completed a 12-week low-energy (∼810 kcal/day) meal-replacement plan (MRP) and matched healthy controls (HC). Echocardiography, cardiac MRI and fasting bloods for metabolomics were undertaken pre/post-intervention. Candidate biomarkers were identified from case-control comparison (fold change >1.5 and statistical significance p<0.05) and their response to the MRP reported. Association between change in biomarkers and change indices of a) cardiac remodelling and b) glycaemic control and were explored.

Results: Twenty-four people with T2D (15 males, age 51.1±5.7 years), and 25 HC (15 male, 48.3 ± 6.6 years) were included. Subjects with T2D had increased left ventricular (LV) mass:volume ratio (0.84 ± 0.13 vs. 0.70 ± 0.08, p<0.001), increased systolic function but impaired diastolic function compared to HC. The distinct metabolic signature was characterised by differential regulation of three key metabolic pathways; 1) glycerophospholipid metabolism, 2) sphingolipid/ceramide metabolism and 3) amino-acid metabolism namely glycine, serine and threonine metabolism. Their associated circulating plasma metabolites appear to shift towards the “healthy status” following significant weight-loss and normalisation of glycaemic control. However, there was no association between the change in circulating levels of these metabolites and the change in key measures of cardiovascular structure and function nor exercise capacity following the MRP.

Conclusions: A metabolomic signature distinct from healthy controls can be described in stage A/B HF. However, this signature, despite moving towards a ‘healthy status’ following the intervention is not associated with cardiac reverse remodelling. This could be attributed to the limited sample size and short exposure to the MRP and requires confirmation in larger external cohorts.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Archer, N. Gradner, D.
Keywords:	Heart failure; Type 2 diabetes complications; Metabolic signature; Low-calorie diet
Subjects:	R Medicine > RC Internal medicine
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	77674
Depositing User:	Brady, Emer
Date Deposited:	26 Jul 2024 14:15
Last Modified:	26 Jul 2024 14:15
URI:	https://eprints.nottingham.ac.uk/id/eprint/77674

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