Metabolic signature in stage A/B heart failure: A study in asymptomatic Type 2 Diabetes

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

Metabolic signature in stage A/B heart failure: A study in asymptomatic Type 2 Diabetes

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

Development of an Interactive Lifestyle Programme for Adolescents at Risk of Developing Type 2 Diabetes: PRE-STARt

Background: Type 2 diabetes (T2D) is increasing in young people. Reporting on the processes used when developing prevention interventions is needed. We present the development of a family-based interactive lifestyle intervention for adolescents with risk factors for T2D in the future. Method: A multidisciplinary team in the UK site led the intervention development process with sites in Portugal, Greece, Germany and Spain. Potential programme topics and underpinning theory were gathered from literature and stakeholders. A theoretical framework based on self-efficacy theory and the COM-B (capability, opportunity, motivation, behaviour) model was developed. Sessions and supporting resources were developed and refined via two iterative cycles of session and resource piloting, feedback, reflection and refinement. Decision on delivery and content were made by stakeholders (young people, teachers, parents, paediatricians) and all sites. Materials were translated to local languages. Site-specific adaptations to the language, content and supporting resources were made. Results: The “PRE-STARt” programme is eight 90-min interactive sessions with supporting curriculum and resources. Iterative development work provided valuable feedback on programme content and delivery. Conclusion: Reporting on the intervention development process, which includes stakeholder input, could yield a flexible approach for use in this emerging ‘at risk’ groups and their families

Development of an interactive lifestyle programme for adolescents at risk of developing type 2 diabetes : PRE-STARt

Background: Type 2 diabetes (T2D) is increasing in young people. Reporting on the processes used when developing prevention interventions is needed. We present the development of a family-based interactive lifestyle intervention for adolescents with risk factors for T2D in the future. Method: A multidisciplinary team in the UK site led the intervention development process with sites in Portugal, Greece, Germany and Spain. Potential programme topics and underpinning theory were gathered from literature and stakeholders. A theoretical framework based on self-efficacy theory and the COM-B (capability, opportunity, motivation, behaviour) model was developed. Sessions and supporting resources were developed and refined via two iterative cycles of session and resource piloting, feedback, reflection and refinement. Decision on delivery and content were made by stakeholders (young people, teachers, parents, paediatricians) and all sites. Materials were translated to local languages. Site-specific adaptations to the language, content and supporting resources were made. Results: The "PRE-STARt" programme is eight 90-min interactive sessions with supporting curriculum and resources. Iterative development work provided valuable feedback on programme content and delivery. Conclusion: Reporting on the intervention development process, which includes stakeholder input, could yield a flexible approach for use in this emerging 'at risk' groups and their families

Fibro-inflammatory recovery and type 2 diabetes remission following a low calorie diet but not exercise training: A secondary analysis of the DIASTOLIC randomised controlled trial

AimsTo investigate the relationship between fibro-inflammatory biomarkers and cardiovascular structure/function in people with Type 2 Diabetes (T2D) compared to healthy controls and the effect of two lifestyle interventions in T2D.MethodsData were derived from the DIASTOLIC randomised controlled trial (RCT) and includes a comparison between those with T2D and the matched healthy volunteers recruited at baseline. Adults with T2D without cardiovascular disease (CVD) were randomized to a 12-week intervention either: (1) exercise training, (2) a low-energy (∼810 kcal/day) meal-replacement plan (MRP) or (3) standard care. Principal Component and Fisher's linear discriminant analysis were used to investigate the relationships between MRI acquired cardiovascular outcomes and fibro-inflammatory biomarkers in cases versus controls and pre- and post-intervention in T2D.ResultsAt baseline, 83 people with T2D (mean age 50.5 ± 6.4; 58% male) and 36 healthy controls (mean age 48.6 ± 6.2; 53% male) were compared and 76 people with T2D completed the RCT for pre- post-analysis. Compared to healthy controls, subjects with T2D had adverse cardiovascular remodelling and a fibro-inflammatory profile (20 differentially expressed biomarkers). The 3D data visualisations showed almost complete separation between healthy controls and those with T2D, and a marked shift towards healthy controls following the MRP (15 biomarkers significantly changed) but not exercise training.ConclusionsFibro-inflammatory pathways and cardiovascular structure/function are adversely altered before the onset of symptomatic CVD in middle-aged adults with T2D. The MRP improved the fibro-inflammatory profile of people with T2D towards a more healthy status. Long-term studies are required to assess whether these changes lead to continued reverse cardiac remodelling and prevent CVD

The ExPeCT (Examining Exercise, Prostate Cancer and Circulating Tumour Cells) trial: study protocol for a randomised controlled trial

Background: Prostate cancer (PrCa) is the second most common cancer in Ireland. Many men present with locally advanced or metastatic cancer for whom curative surgery is inappropriate. Advanced cancer patients are encouraged to remain physically active and therefore there is a need to investigate how patients with metastatic disease tolerate physical activity programmes. Physical activity reduces levels of systemic inflammatory mediators and so an aerobic exercise intervention may represent an accessible and cost-effective means of ameliorating the pro-inflammatory effects of obesity and subsequently decrease poor cancer-specific outcomes in this patient population. This study will assess the feasibility and safety of introducing a structured aerobic exercise intervention to an advanced cancer population. This study will also examine if the evasion of immune editing by circulating tumour cells (CTCs) is an exercise-modifiable mechanism in obese men with prostate cancer. Methods: This international multicentre prospective study will recruit men with metastatic prostate cancer. Participants will be recruited from centres in Dublin (Ireland) and London (UK). Participants will be divided into exposed and non-exposed groups based on body mass index (BMI) ≥ 25 kg/m2 and randomised to intervention and control groups. The exercise group will undertake a regular supervised aerobic exercise programme, whereas the control group will not. Exercise intensity will be prescribed based on a target heart rate monitored by a polar heart rate monitor. Blood samples will be taken at recruitment and at 3 and 6 months to examine the primary endpoint of platelet cloaking of CTCs. Participants will complete a detailed questionnaire to assess quality of life (QoL) and other parameters at each visit. Discussion The overall aim of the ExPeCT trial is to examine the relationship between PrCa, exercise, obesity, and systemic inflammation, and to improve the overall QoL in men with advanced disease. Results will inform future work in this area examining biological markers of prognosis in advanced prostate cancer. Trial registration Clinicaltrials.gov NLM identifier: NCT02453139. Registered on 12 May 2015. This document contains excerpts from the ExPeCT trial protocol Version 1.5, 28 July 2016

An evaluation of heart failure clinicians' knowledge, attitudes and clinical practice in the diagnosis and treatment of obstructive sleep apnoea

Background/aimsObstructive sleep apnoea is a public health problem that remains under recognised. Despite obstructive sleep apnoea being associated with the incidence and progression of heart failure, clinician awareness is lacking within and across clinical specialities. This study aimed to evaluate heart failure clinicians' knowledge, attitudes and clinical practice in the diagnosis and treatment of obstructive sleep apnoea.MethodsThis study used a web-based, cross-sectional survey, using the modified Obstructive Sleep Apnoea Knowledge and Attitudes questionnaire among heart failure clinicians in the UK.ResultsThe survey was completed by 102 heart failure clinicians. Out of a possible score of 37, the median knowledge scores were 29 (78%; interquartile range 26–31), 26 (70%; interquartile range 22–28) and 18 (49%; interquartile range 16.5–23.5) for doctors, nurses and pharmacists, respectively. The majority of doctors and nurses felt that obstructive sleep apnoea was important; however, confidence in the identification and management of obstructive sleep apnoea was low across all three groups of clinicians.ConclusionsThere is a knowledge deficit regarding the diagnosis and treatment of obstructive sleep apnoea among heart failure clinicians.</div

Role of inflammation in diabetic cardiomyopathy

The prevalence of type 2 diabetes (T2D) has reached a pandemic scale. Systemic chronic inflammation dominates the diabetes pathophysiology and has been implicated as a causal factor for the development of vascular complications. Heart failure (HF) is regarded as the most common cardiovascular complication of T2D and the diabetic diagnosis is an independent risk factor for HF development. Key molecular mechanisms pivotal to the development of diabetic cardiomyopathy include the NF-κB pathway and renin–angiotensin–aldosterone system, in addition to advanced glycation end product accumulation and inflammatory interleukin overexpression. Chronic myocardial inflammation in T2D mediates structural and metabolic changes, including cardiomyocyte apoptosis, impaired calcium handling, myocardial hypertrophy and fibrosis, all of which contribute to the diabetic HF phenotype. Advanced cardiovascular magnetic resonance imaging (CMR) has emerged as a gold standard non-invasive tool to delineate myocardial structural and functional changes. This review explores the role of chronic inflammation in diabetic cardiomyopathy and the ability of CMR to identify inflammation-mediated myocardial sequelae, such as oedema and diffuse fibrosis

The safety and effectiveness of non-insulin glucose lowering agents in the treatment of people with Type 2 Diabetes who observe Ramadan: A systematic review and meta-analysis

Aims: To determine which non-insulin glucose lowering treatment regimens are most appropriate in people with type 2 diabetes who choose to fast during Ramadan. Materials and methods: Electronic databases were searched for randomised controlled trials (RCT) and observational studies comparing non-insulin glucose lowering agents in people with type 2 diabetes fasting during Ramadan reporting hypoglycaemia, weight and HbA1c change were included. Data were pooled using random effects models. Results: Sixteen studies included; nine RCTs and seven observational studies. There was evidence that DPP-4 inhibitors led to less hypoglycaemic events compared to sulphonylureas. Sitagliptin significantly reduced the number of patients ≥1 hypoglycaemic episodes during Ramadan (RR 0.48, 95%CI 0.36, 0.64, p>0.0001), this was not replicated in the RCTs of vildagliptin but a significant reduction was found in the observational studies (RR 0.28, 95%CI 0.10, 0.75, p=0.01) with high heterogeneity (I2=86.7%). Significant reductions in HbA1c and weight were seen in the observational studies of vildagliptin vs. sulfonylureas. The use of liraglutide led to significant weight loss (-1.81kg, 95%CI -2.91, -0.71, p=0.001) compared to sulfonylureas. Pioglitazone significantly increased weight compared to placebo (3.48kg, 95%CI 2.82, 4.14, p<0.0001). Conclusions: The analysis supports the use of DPP-4 inhibitors during Ramadan over sulfonylureas for reduction in hypoglycaemic episodes without a cost to diabetes control and weight. The GLP-1 agonist liraglutide provides clinical benefits, but more studies are required. RCTs of DPP-4 inhibitors against GLP-1 agonists and novel therapies including the SGLT-2 and alpha-glucosidase inhibitors are needed to inform evidence based guidelines