Refocussing therapeutic strategies for cardiac arrhythmias: defining viable molecular targets to restore cardiac ion flux

Abstract

Background: Despite the global prevalence, mortality and morbidity associated with cardiac arrhythmias, there is a paucity of effective anti-arrhythmic strategies. Existing pharmacological approaches are, at best, suboptimal and, at worst, actually provoke arrhythmias. Objectives: From the perspectives of clinical efficacy, mechanisms of action and socioeconomic factors, the authors shed light on possible reasons why innovative approaches for developing anti-arrhythmics have so far not been translated into better, safer anti-arrhythmics. Methods: The scope of this review was defined by recent advances in the pharmacological regulation of molecules located on the surface of cardiac cells (K⁺ and Ca²⁺ channels, pumps and exchangers and gap junctions). In addition, the authors considered rapidly evolving concepts that involve modulation of components in intracellular compartments such as mitochondria or sarcoplasmic reticulum. Information was taken from primary scientific papers and patent literature relating to anti-arrhythmic development from 1990 to the present day. Results: The authors are optimistic that recent developments in anti-arrhythmic design offer potentially vastly improved therapies. In particular, the prospective therapeutic benefits of manipulation of novel targets, including atrially-restricted K_v1.5 channels, mitochondrial K_ATP channels, ryanodine receptors and CaMKII are emerging. This necessary diversification of therapeutic targets likely marks the beginning of a paradigm shift toward anti-arrhythmic design based on a broad range of cellular targets. The future expansion of the cardioactive pharmacopeia will harness rational chemical design and explore the use of naturally occurring compounds. These new approaches for developing anti-arrhythmics are dependent on cardiac cell-based screening strategies for identifying and characterising novel compounds.

Keywords::

• anti-arrhythmics
• cardiac arrhythmias
• devices
• drugs
• fibrillation
• innovation

Acknowledgements

CH George is a British Heart Foundation Lecturer in the Wales Heart Research Institute, School of Medicine, Cardiff University. SR Barberini-Jammaers is a recipient of a British Heart Foundation PhD Studentship in the Wales Heart Research Institute, School of Medicine, Cardiff University. CT Muller is a Faculty member of the School of Biosciences, Cardiff University. The authors thank the British Heart Foundation for financial support.

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