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Houman Ashrafian

Visiting Professor of Experimental Therapeutics

Cell and Molecular Biology

Cardiac metabolism and function are inextricably linked. Maintaining energy flux is essential to the functioning of the heart which requires more energy (ATP) per gram of tissue than any other organ. The heart consumes approximately ~8–15 ml O2/min/100 g tissue compared to the brain’s ~3 ml O2/min/100 g tissue. Matching the supply of metabolic substrates to myocardial work, requiring more than 70 ml O2/min/100 g tissue during vigorous exercise, requires profound adaptive cellular responses for generating ATP over large dynamic and temporal ranges. It is therefore unsurprising that metabolism has been linked to cardiac health and disease. As altered metabolism is thought to be central to the energy deficiency of heart failure and cardiomyopathy, it is likely that variations in metabolism contribute to the clinical heterogeneity of cardiomyopathy.

Characterising cardiac metabolism in different models of cardiomyopathy is therefore likely to: (i) contribute to our understanding of fundamental cardiac pathophysiology, (ii) illuminate the basis of its clinical variability and delineate disease subgroups by identifying stratifying diagnostic biomarkers and (iii) guide novel metabolic therapeutic strategies.

By striving to understand basic mechanisms determining the complexity of cardiac metabolism, for example by investigating pathways identified in cancer medicine to the cardiovascular system, we aim to take translate these insights from bench to bedside.

Our work demonstrating the cardioprotective properties of basic biological molecules such as fumarate and insulin underline the potential for discovery biology to have a rapid clinical impact. Our identification and exemplification of perhexiline (a metabolic modulator), in conjunction with collaborators in Aberdeen and London, as a promising treatment for defined subgroups of patients with cardiomyopathy and heart failure, supports the value of this metabolic strategy for diagnostic and therapeutic progress.