ESC William Harvey Lecture in Basic Science
Inherited arrhythmias: Novel disease mechanisms in cardiomyocytes and beyond
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The presenter of today’s ESC William Harvey Lecture in Basic Science is Associate Professor Carol Ann Remme (Amsterdam University Medical Centre - Amsterdam, Netherlands) whose research has brought us closer to identifying novel targets for the management of inherited disorders associated with cardiac arrhythmias and the prevention of sudden cardiac death.
What are the key themes of your lecture?
A major focus of our research has been the role of cardiac sodium channels in inherited arrhythmia conditions, such as Brugada syndrome and long-QT syndrome. Since causal mutations in the SCN5A gene encoding the cardiac sodium channel Nav1.5 were first reported in 1995, research has come a long way. Although the advent of better tools, such as transgenic mouse models and human induced pluripotent stem cell-derived cardiomyocytes, has really helped to propel the field forwards, we are still only scratching the surface. There is clinical complexity, with different mutations in the same gene causing various phenotypes but also a single SCN5A mutation giving rise to multiple phenotypes, even within the same family. There is also biological complexity; sodium channels form part of a large macromolecular complex, the composition of which varies depending on its location within the cardiomyocyte.1 Within these complexes, sodium channel proteins can influence the behaviour of other proteins, and vice versa. One example is the interaction between sodium channels and desmosomal proteins, whose gene mutations are associated with arrhythmogenic cardiomyopathy.2 Alterations in Nav1.5 may contribute to arrhythmias in the early phase of the disease in individuals who still have an apparently structurally normal heart. Through our work we now have a better understanding of the mechanisms underlying Nav1.5 (dys)function, enabling the development of much-needed, novel therapeutic strategies.3,4
How do you think your field will evolve in the future?
One exciting avenue of research involves looking beyond cardiomyocytes in isolation, and there is considerable interest in the role of neurons and the autonomic nervous system. Many deaths in individuals with arrhythmia syndromes are triggered either by a sympathetic surge, for example during exercise, or high parasympathetic activity, such as during sleep. We know that Nav1.5 is expressed in extracardiac tissues, including neurons,5 and we are currently exploring the contribution of these cells to inherited arrhythmias.
Valuable information also comes from our recent research in a model of catecholaminergic polymorphic ventricular tachycardia, which showed that a mutation in the calcium release channel ryanodine receptor 2 (RYR2) resulted in sympathetic hyperinnervation of the ventricular myocardium.6 Looking outside cardiomyocytes may not only enable the identification of new therapeutic targets but also of novel ways to investigate the huge variability in disease severity and expressivity. Identification of patients at risk remains difficult; why, among patients with the same mutation, do some have a normal lifespan while others suffer cardiac death at an early age? How do comorbidities, such as hypertension or diabetes, impact on the prognosis of a patient carrying a relevant mutation? And what is the role of genetic modifiers?
We have a host of powerful tools – including molecular and omics investigations, together with genome-wide association studies – to help us try to unravel the complex pathways of the cardiomyocyte- and non-cardiomyocyte-related mechanisms involved. Combining these with our core techniques and expertise of cellular electrophysiology into a multidisciplinary, translational approach will provide unique scientific opportunities in the coming years.
References
- Rivaud MR, et al. Cardiovasc Res. 2020;116:1557–1570.
- van der Voorn SM, et al. Cardiovasc Res. 2020;116:1571–1584.
- Marchal GA, et al. Circ Res. 2021;129:349–365.
- Nasilli G, et al. Cardiovasc Res. 2024;120:723–734.
- Remme CA. Phil Trans R Soc. 2023;B378:20220164.
- O’Reilly M, et al. Cardiovasc Res. 2024;120(Suppl_1):cvae088.098.
