Cardiac substrate metabolism: it's all about the energy
The study of metabolism has a strong historical basis in Oxford, and in the last 20 years research in this field has undergone a renaissance. Abnormalities in cardiac metabolism have been identified in many pathologies, and have been shown to directly impair the function of the heart, accelerate disease progression and to predict mortality. Given the pivotal role of metabolism in cardiac disease, a greater understanding of the why metabolism is abnormal, how this modifies the disease and whether this information can be used to develop new treatments may lead to new therapies for cardiovascular disease.
The heart metabolises the fuels we consume, such as glucose and fatty acids, to make energy in the form of ATP. The majority of ATP is made by mitochondria within the cardiomyocytes, and requires a large amount of oxygen for this to occur. Abnormalities in the supply of these fuels, in the functioning of the mitochondria or in the availability of oxygen can affect ATP generation, which is required in high concentrations to keep the heart contracting.
Type 2 diabetes increases the incidence of cardiovascular disease, and one of the potential mechanisms involved is abnormal cardiac ATP generation and metabolic inflexibility, which prevents the heart adapting metabolism to changes in oxygen and substrate delivery. Given the increasing prevalence of diabetes and metabolic syndrome in society, a greater understanding of how diabetes specifically affects the heart, and whether this can be rectified by therapy are important questions.
Our research can be divided into five key questions:
1. How is metabolism modified in cardiac disease? - Given that the heart can use multiple fuels, how does the balance of fuel selection change in cardiac disease and how is this related to the function of the heart.
2. How does type 2 diabetes affect cardiac metabolism and the ability of the diabetic heart to adapt to stress?
3. How do type 2 diabetes and cardiovascular disease affect mitochondrial ATP production and oxygen consumption?
4. What are the mechanisms regulating changes in cardiac metabolism?
5. Can these mechanisms be targeted by pharmacological therapies to treat the heart?