Abstract

One significant challenge for translational biology is understanding how genomic variation affects temporo-spatial and quantitative expression of genes, the activity and localisation of proteins and how these relate to physiological function. In this presentation I will argue that ‘human heart excitation’ provides an appealing model system for examination.

Cardiac excitation is highly evolved, stable, robust, essentially genetic and safely measurable clinically, with patterns of activity highly quantifiable. Furthermore in the population electrocardiograms provide for readily applicable phenotyping as a comparator at scale and we also have hugely abundant albeit yet to be understood GWAS data.

Disturbances of the heartbeat (arrhythmias) have major public health impacts including sudden death, heart failure and stroke and greater understanding of their underlying biology will be invaluable.

The presentation will first consider how linkage analysis identified candidate disease genes encoding ion channels and how these were characterized using model systems. I will go on to discuss deep intracardiac phenotyping of patients with genetically complex disease that has already facilitated both risk assessment and guidance of therapy. I will then close by describing technology we have also developed to sample cells from human hearts with multiple clinical applications. Application of this approach will bridge critical gaps using spatial-omics to provide functional insights into tissue architectures underpinning excitation and the heartbeat itself.

Bio

Andrew Grace is Professor of Experimental Cardiology at the University of Cambridge. He trained in cardiology in London and Cambridge and then delivered a consistently high-volume interventional practice focused on arrhythmias over >30 years. He completed post-doctoral studies as a Fulbright Scholar in the Department of Medicine, University of California, San Diego returning to Cambridge as British Heart Foundation Senior Research Fellow. He is a recognized innovator having a particular interest in ‘disruptive’ technologies that have included devices, diagnostics and drugs. Some of his work has changed practice significantly and he made some of the ‘most important contributions’ to the development and implementation of subcutaneous defibrillators. His clinical research focus is currently on both activation mapping and risk prediction of ventricular fibrillation. He has spent over 25 years addressing the impact of genetic variation on the heartbeat and most recently has established a network of colleagues based respectively in Cambridge, Seattle, Sydney and San Diego to provide a physically robust model of cardiac electrical measurement extending from charge movements through structurally resolved sodium channels to surface recordings. Working with the Theory of Condensed Matter Physics Group (Cavendish Laboratory, Cambridge) and the Wellcome Trust Sanger Institute high-resolution charge density mapping of cardiac activation is being linked to multi-omics in single cells acquired through novel in vivo freeze-sampling; there is high anticipation of therapeutic target identification and rescue.