This will be an observational study to explore differences in pathophysiology between groups of people with and without heart failure (HF) (reduced and preserved ejection fraction) and with and without diabetes mellitus (DM) with a particular focus on cross-talk (fat, muscle, vascular tissue and the heart). The investigators will invite 600 people to partcipate (100 with HFrEF+DM, 100 with HFpEF+DM, 100 with HFpEF-DM, 100 with HFrEF-DM, 100 with DM, 100 without either HR or DM). Special heart scans, exercise testing, blood testing, testing of the automatic nervous system will be performed and in some, samples of fat and muscle and endothelial cells will be collected.

These data will be used to create a cohort of well phenotyped patients with a variety of comprehensively collected clinical information, a cell atlas, and a comprehensive assessment of metabolomics, proeomics and cross-talk in between tissues, allowing comparisons between each group.

Heart failure is a leading cause of mortality and morbidity worldwide, and is characterized by symptoms such as shortness of breath, peripheral oedema and impaired exercise capacity due to structural or functional heart disease. The condition is associated with impaired longevity, high levels of morbidity (poor quality of life) and enormous costs for the healthcare system. In the western world, approximately 1-2% of the population suffer from heart failure, increasing to over 10% of people over the age of 70. The prognosis of patients with severe heart failure is similar to that of patients with cancer.

Diabetes mellitus is reaching pandemic proportions across the globe. A condition previously characterised simply as a relative or absolute deficiency of insulin and diagnosed by elevated sugar levels in the bloodstream, it is now much better understood as a syndrome of impaired glucose tolerance accompanied by a range of metabolic abnormalities that can be observed in all tissues of the body. This metabolic remodelling is accompanied by higher risks of chronic disease particularly cardiovascular disease including atherosclerosis but also, even in the absence of coronary artery disease, a considerable increase in the risk of heart failure.

These two morbid and life-limiting illnesses commonly occur together, each worsening the other in a synergistic relationship that leads to greater symptoms, resistance to therapies and shorter longevity.

Further detail on how these diseases interact is urgently required. However, in addition to understanding the clinical impacts on patients, in order to focus existing therapies and develop new options, it is necessary to understand how these diabetes mellitus an heart failure interact at a metabolic level, which cellular-based pathways are affected and how these lead to abnormal cellular function, and thereby to tissue and organ dysfunction. Further understanding of how communication between tissues contributes to the overall pathophysiology is required.

The present investigation will therefore be a single-centre non-randomised, observational study involving an unselected but highly phenotyped cohort of patients with and without heart failure and with and without type 2 diabetes mellitus and controls without disease. Patients will be recruited from heart failure and diabetes clinics and controls will be identified from these patients' carers and their relatives through direct contact and advertisements in outpatient departments.

Participants will undergo cardiac ultrasound, exercise testing, assessments of lung function, non-invasive haemodynamics, autonomic function, hand and leg muscle strength, and lung function assessment along with blood testing, longer term glucose monitoring and blood sampling. A small sample of fat and muscle will be collected. A subgroup will undergo an MRI scan of the heart and their thigh muscles. Participants' involvement will end at that point although they will continue to be monitored using their digital records on an annual basis for up to 10 years to gain information on the prognostic value of the metabolic and haemodynamic testing.

Tissue and blood samples will be coded and stored in a Human Tissue Authority-approved freezer until analysis following which they will be related to clinical variables with the aim of identifying mechanisms by which metabolic disease (in this case diabetes mellitus) influences the progression of heart failure with the long term objective of informing the development of more effective treatment strategies.

The present investigation will allow the investigators to advance the understanding of how metabolic disease and heart failure interact with the goal of developing targeted interventions that could open new treatment avenues.

Inclusion Criteria:

• Age >18 years
• Ability to provide written informed consent
• Persons who are legally competent and mentally able to follow the instructions of the study staff

Exclusion Criteria:

• Anaemia Hb <8 mg/dl
• Patients with acute infectious diseases (e.g. pneumonia)
• Patients with heart failure due to sepsis
• People with acute myocardial ischemia, which is manifested, for example, by angina pectoris or ECG changes under stress
• Patients with acute liver or kidney failure or severe COPD (FEV1<1.0)
• Pregnant and breastfeeding women
• People who are institutionalized on official or court orders
• People who are dependent or employed by the sponsor or investigator
• Taking study medication (of an investigational drug) 30 days before the start of the study

People attending heart failure clinics, diabetes clinics (either secondary or primary care) or control subjects attending hospital with relatives or accumulated from the community by word of mouth or advertisement.

An anonymised version of the database and the samples will be available to other researchers including outside of the University of Leeds in response to a reasonable request and confirmation of appropriate data protection policies and a mutual data sharing agreement.

6 months after the end of the study

Requests to be made to the Trial Management Group