Alicia D’Souza
University of Manchester, UK

https://doi.org/10.36866/pn.108.8a

It was a tremendous compliment to receive the inaugural award. Much more so, once I learned about the life and work of Jean Banister from one of her former pupils, Hilary Brown. What really struck a chord is that Jean Banister’s former mentees (including Hilary Brown, Susan Noble, Wayne Giles and Dario DiFrancesco) went on to discover concepts fundamental to our modern understanding of pacemaker electrophysiology, the current focus of my research. And thus, for engineering a connection to the historical greats in the field, I am forever indebted to The Society.

I received my PhD in 2011 studying structural remodelling in diabetic cardiomyopathy with Jaipaul Singh at the University of Central Lancashire. It was at this time that my interest in electrophysiology was piqued, and I subsequently moved to The University of Manchester to investigate exercise-induced arrhythmogenic cardiac remodelling with Mark Boyett.

Veteran athletes are prone to cardiac arrhythmias including sinus bradycardia, heart block and atrial tachyarrhythmias but the underlying mechanisms are poorly understood. Our work in mice has shown that training-induced sinus bradycardia and first-degree heart block, the most common rhythm disturbances in athletes, are due to diffuse downregulation of pacemaking ion channels in the sinus and atrioventricular nodes. Delineating the transcriptional ‘switch’ that produces this phenotype could lead to new targets for managing arrhythmogenesis in athletes and hence our focus is on upstream control mechanisms with specific emphasis on microRNAs and transcription factors.

In the R Jean Banister Prize lecture I present evidence demonstrating that the transcription factor NKX2.5 upregulates microRNA-423, causing downregulation of the pacemaker channel HCN4 and sinus bradycardia in the athletic heart. I also present novel evidence that the core circadian clock transcription factor BMAL1 drives a rhythmic circadian variation in HCN4 and ultimately intrinsic heart rate, explaining an increased incidence of nocturnal bradyarrhythmias, also known to be more frequent in the athlete. We are delighted that our work has received prominence through publicity in the popular media and awards including a shortlisting for the GW Mendel Medal at ‘SET for Britain’ (now called STEM for Britain) in 2013, the 2014 International Society for Heart Research/Servier Fellowship Prize and the 2016 Cairn Electronics ‘New and Notable’ award.

I am filled with enthusiasm for the future, as we continue to identify key players in training-induced electrical remodelling and work with clinical colleagues towards translating these findings into small molecule therapies for arrhythmias in the athlete. Within the broader remit, I envisage that our future studies may reveal novel therapeutic strategies for other pathological conditions where ion channels are dysregulated, e.g. atrial fibrillation and heart failure.