Title: Mapping complete energetic pathways in the human heart using magnetic resonance spectroscopy
Funder: The Academy of Medical Sciences

Abstract: Heart failure (HF) is one of the most common and disabling diseases in the UK, and its prognosis has stalled in recent years. The energetic theory of heart failure suggests that, irrespective of aetiology, the final path to systolic dysfunction is related to deficient ATP production, and/or its conversion to contractile activity. We have established that there are various stages in intracellular metabolism that are faulty in different disease processes, and yet are currently unable to measure actual cardiac ATP synthesis and utilisation in vivo. We propose to complete the map of energetic pathways in the human heart, using a novel MR spectroscopy sequence to measure high-energy phosphate flux within the myocyte, in order to calculate cardiac ATP synthesis and hydrolysis rates for the first time. In addition to establishing the feasibility of translating this sequence from successful preclinical studies, we will investigate the impact of imposing substrate selection, one of the key abnormalities in HF, on ATP production. 12 healthy volunteers will undergo either lipid or glucose/insulin infusion to remove metabolic flexibility, followed by MR imaging of cardiac structure and function, and 31P-MRS assessing ATP hydrolysis and transfer through creatine kinase. At a second visit, the volunteers will be allocated the alternative infusion, to enable paired comparison. This study will both establish the importance of substrate flexibility in myocardial energy metabolism, and pave the way for accurate phenotyping of energetic defects in HF, leading to better appreciation of discrete disease processes and identification of novel therapeutic targets.

Lay abstract: Heart failure (HF) is a condition which affects one million people in the UK and is caused by the heart not being able to pump enough blood round the body. People living with HF experience symptoms such as breathlessness and fatigue, and their life expectancy can be worse than in several common cancers. Although HF can be caused by different diseases, overall the heart muscle struggles to convert energy from fuel into pumping activity. Our previous work shows that this can either be a shortage of energy, inefficient use of that energy, or having the wrong type of fuel available. Currently we can use MRI scans to measure how much energy is stored and delivered, but not how much fuel the ‘engine’ of the heart is actually making or using. Scientists in our department have come up with a new MR scan to look at this. While this has been successful in model experiments, it has not yet been used in people. I propose that we use this new technique in healthy people to see if altering the fuel supplied to the heart changes the way in which energy is made or used. 12 carefully selected volunteers will be given either fat or sugar through a drip, before an MRI scan in 3 parts, taking under 2 hours in total. This is a completely safe procedure, and the results may well lead to the development of new and better treatments for this common and difficult disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR