Boosting the reserves: additive regulation of cardiac repolarisation

Since the first description of the mechanism of digitalis toxicity in The Journal of Physiology in 1978 (Kass et al. 1978), abnormal calcium handling has been established as a key player across a spectrum of ventricular arrhythmias. Subsequent decades of research have taught us how calcium signalling is tightly coupled to cardiomyocyte membrane electrophysiology, meaning any disturbance to the electrical system will unavoidably affect calcium signalling and vice versa. We now appreciate the role of calcium handling in the pathogenesis of cardiac dysfunctions ranging from complex multifactorial degenerative diseases such as heart failure to primary arrhythmias such as Timothy syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). Similarly, adrenergic signalling is central to arrhythmogenesis in primary electrical disorders, heart failure or post-infarct. Teasing out the intricacies of the relationship between these two processes in relation to electrophysiology of the heart is therefore a key focus area for cardiovascular physiology. The interplay between calcium and adrenergic signalling pathways in arrhythmogenesis is perhaps demonstrated most clearly in the repolarisation disorder long QT syndrome type 1 (LQTS1), which occurs as a result of mutations in the KCNQ1 gene that codes for the pore forming subunit of the slow delayed rectifier current (IKs). In LQTS1, reduced repolarisation reserve in the context of high adrenergic tone results in reactivation of calcium channels to cause ectopic membrane depolarisations that may initiate the ventricular tachyarrhythmia torsades de pointes. The converse of this scenario is how does IKs in the normal heart protect against the generation of ectopic beats, especially in the setting of increased adrenergic stimulation? In this issue of The Journal, Bartos et al. show how intracellular calcium and adrenergic stimulation individually and additively regulate the activity of IKs in rabbit cardiomyocytes (Bartos et al. 2017). Historically, the first suggestion that the delayed rectifying current (IK) might be regulated by calcium came 40 years ago (McGuigan & Tsien, 1974) and this was demonstrated experimentally some years later (Tohse, 1990). Bartos et al. expand on this to tease out the calcium dependence of individual components of IK (separated into slow and rapid components: IKs and IKr) in a human-relevant larger mammal model. Surprisingly, they show that rather than being dynamically regulated as [Ca2+] rises and falls over the course of the transient, IKs is maximally activated at concentrations continuously present in the sub-membrane space throughout the action potential. Furthermore, they demonstrate that adrenergic stimulation, while having similar effects on the functional properties of IKs, is additive at all concentrations of calcium. Importantly, the authors go further and incorporate these findings into their established in silico models of ventricular electrophysiology. In recent years, such computational approaches have flourished and provide new avenues for quantitative analysis of cellular mechanisms and understanding of disease. In relation to measuring and modelling calcium homeostasis, much of recent progress has been driven by the Bers group, including many of the additions and updates to contemporary in silico models that paved the way for the current study. However, a key factor that has been largely absent from many existing models is an adequate description of the complex interplay between calcium handling, sympathetic tone and membrane electrophysiology – including major components of repolarisation reserve such as IKs. The findings by Bartos et al. begin to fill this important knowledge gap and will no doubt help realise the potential of in silico electrophysiology for interrogating mechanism and ultimately risk stratification in disease. What then are the implications of the Bartos study for our understanding of disease? The authors suggest that under conditions of calcium overload – such as in the failing heart – calcium regulation of IKs might be disrupted to contribute to the occurrence of lethal arrhythmias. This is certainly an important area for research as up to half of deaths in heart failure patients occur suddenly (Ørn & Dickstein, 2002). Typically, in heart failure there is elevated diastolic calcium with reduced or attenuated peak of the transient. Even so, since peak sub-membrane calcium concentrations are almost an order of magnitude higher than that shown to be required for maximal activation of IKs, it is unlikely, even in the failing heart, that sub-membrane calcium is lowered sufficiently to reduce IKs activity during the action potential. However, the findings of Bartos et al. offer several other potential routes to pathogenesis. First, they show that the effect of adrenergic stimulation in activating IKs is completely additive, over and above the effect of calcium. In the failing heart, β-adrenergic signal transduction can be dramatically reduced as a result of receptor desensitisation as well as changes in enzyme expression (Bristow, 1993). This would significantly reduce the IKs contribution to repolarisation, regardless of the calcium concentration and particularly at high heart rates. A second, more subtle possibility raised by the authors relates to the kinetics of IKs activation. In addition to changes in the baseline and amplitude of the calcium transient, those from failing hearts also have a slower rising phase which could result in slower IKs activation and hence reduced repolarisation in phase 2 of the action potential. Whilst in the present study the authors were not able to accurately measure this, it poses an interesting question for future work to explore the kinetics of IKs activation in relation to dynamic changes in calcium. The Bartos paper therefore presents several important findings around quantification of the regulation of IKs by calcium and adrenergic stimulation and updates their in silico ventricular model to reflect them – thus filling an important knowledge gap in computational electrophysiology. The study also sets the scene for future work, perhaps in tissue from human failing hearts, that would help further tease out the subtleties of regulation of the repolarisation reserve by both calcium and adrenergic signalling. None declared.