Arrhythmia: 100 years on from George Ralph Mines

This special issue on arrhythmia research builds upon the seminal observations published in The Journal of Physiology by George Ralph Mines (1886–1914) 100 years ago (Mines, 1913a,b; Dale & Mines, 1913). Mines was a talented young Cambridge physiologist whose life was tragically cut short at the age of 29 years. He has largely been forgotten in the annals of cardiology (Acierno, 1994), even though he is widely credited for being the first person to propose the basic mechanisms for re-entry arrhythmia and its vulnerable period. Little has been written on Mines’ outstanding visionary contributions to arrhythmia research (e.g. DeSilva, 1997), but in this issue Boukens & Janse (2013) review Mines’ contribution, in particular the electrophysiological experiments that subsequently provided insight into the treatment of Wolff–Parkinson–White syndrome. With a young second year undergraduate at Cambridge (Dorothy Dale), Mines went on to publish three classic papers in this Journal concerning the influence of nerve stimulation on the electrocardiogram (Dale & Mines, 1913), the functional analysis by action of electrolytes on cardiac excitability (Mines, 1913a), and his foundation paper, the dynamic equilibrium in the heart (Mines, 1913b), which established the essential criteria used today for classifying re-entry arrhythmia. This work underpinned and inspired a new dawn in quantitative electrophysiology (DeSilva, 1997).

In the current issue several publications have built on the legacy of Mines and Dale. Cardiac electrical events are underpinned by modulation of ion channels. Mutations in these channels are thought to be the leading cause of arrhythmia, and understanding the detailed biophysical properties of channelopathies is a precursor for therapeutic target discovery. This is particularly evident for mutations in sodium channels (Remme, 2013) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, especially if biological pacemakers appear in the ventricle, or mutations are seen in HCN4 channels resulting in sinus bradycardia (DiFrancesco, 2013). However, Amin et al. (2013) also argue that an important interaction between the environment and genotype should be considered in cases like long QT syndrome that need to look beyond causal mutation when viewing the large variability in disease severity.

To highlight the importance of selective targeting of ion channels, Foeger et al. (2013) elegantly demonstrated that site-specific deletion of the cytosolic accessory subunit of the K⁺ channel interacting protein 2 (KChIP2) causes loss of the Kv4.2 protein that is critical for generation of the early phase of myocardial repolarization. Importantly, reductions in action potential wavelength and wavebreak are implicated in arrhythmogenesis. This concept is reinforced by Matthews et al. (2013) who demonstrate that action potential wavelength restitution predicts alternans and arrhythmia in a murine model with a single allele defect in Scn5a. One often-asked question is how transferable are data from animal studies to humans when developing a quantitative understanding of cardiac electrophysiology?Jost et al. (2013) addressed this question directly by studying the ionic mechanisms limiting cardiac depolarization-reserve in humans compared to dogs. Interestingly they observed that humans show greater repolarization-delaying effects of I_Kr block than dogs. This was attributed to lower repolarization-reserve contributions from I_K1 and I_Ks. The study by Jost et al. (2013) certainly emphasizes species-specific determinants of repolarization, and the limitations of some animal models for human disease. Another approach to studying multiple conductance perturbations in the cardiac electrical system is to improve the sensitivity analysis of the ECG. Sadreih et al. (2013) have extended the sensitivity analysis by using unconventional high performance computing architectures to analyse the emergent electrical properties of a multi-cellular system.

The heart is not an island to itself and is hard wired to the nervous system. Activation of the sympathetic nervous system by stress is a negative cardiovascular prognostic factor, whereas an enhanced cardiac vagal activation is seen as beneficial. The cardiac vagus is nature's calcium channel antagonist (Heaton et al. 2007), and the review by Coote (2013) addresses the myths and realities of the ‘wandering nerve’ to make a compelling case for its involvement in the regulation of cardiac function. He highlights structural evidence for its presence in the ventricle to support its well-known anti-fibrillatory action on the ventricle. A neuroendocrine link has also been established by Brailoiu et al. (2013) where they showed that aldosterone increases cardiac vagal tone by activating G protein-coupled oestrogen receptors in the nucleus ambiguus to cause bradycardia. Li et al. (2013) report that the orexin receptor in the rostral ventral lateral medulla is upregulated in the hypertensive rat, and their systemic blockade lowered arterial blood pressure indicating the powerful influence of the autonomic nervous system on cardiovascular physiology. These three reports illustrate the need to also look therapeutically at the autonomic nervous system for the treatment of cardiac-related diseases.

New anti-arrhythmics for treatment of atrial fibrillation (AF) need to be atrial specific and avoid potential pro-arrhythmic actions on the ventricle. Ravens et al. (2013) review the challenges in developing such a therapeutic strategy. One way to investigate the complexity of AF is to develop a computational approach in order to study the predictability of the roles that biophysical events play in determining AF. Colman et al. (2013) constructed a realistic 3-D atrial tissue model and showed that AF-induced electrical re-modelling produces regional heterogeneous and shortened action potential duration. Together these events facilitate the initiation and maintenance of re-entrant excitation waves. Neurotransmitters are important modulators of cardiac excitability and amplify the vulnerability of the diseased heart to arrhythmia. Navarro-Polanco et al. (2013) observed that the ion channel current I_KACh is both voltage and ligand specific in feline atrial myocytes by showing that choline activates this ion channel that has been implicated in atrial fibrillation. But it is in the ventricular myocytes themselves that dysregulation of calcium signalling is seen as a major target to correct. Arnáiz-Cot et al. (2013) show that type 2 ryanodine receptor ion channel (RyR2ADA) mutations produce larger SR calcium loads associated with spontaneous Ca²⁺ release that in turn activates the potentially pro-arrhythmic current caused by sodium–calcium exchange. Although abnormal oscillations of calcium in Purkinje cells are thought to be life threatening, the mechanism by which these cells control intracellular calcium is still poorly understood. Using a combination of mathematical modelling and experimental techniques, Haq et al. (2013) were able to support the hypothesis that a thin intermediate layer of specific ER-Ca²⁺ channels controls the entire intracellular Ca²⁺ concentration in the Purkinje cell network. The implication being that an abnormality in this region (e.g. ischaemia) may facilitate arrhythmia that often commence in these cell types. It is also becoming evident that loss of the t-tubular system contributes to the generation of arrhythmias, indicating that its structure is critical for maintaining normal intracellular signalling linked to ventricular excitability (Orchard et al. 2013).

Currently the most effective strategy in dealing with potentially life-threatening arrhythmia in patients at risk is to implant convertible defibrillators (ICDs), although there is currently no reliable way of predicting the optimal ICD placement in paediatric and congenital patients. Ranter et al. (2013) have developed a new image-processing approach to constructing a novel heart–torso model from clinical MRIs to facilitate surgical placement. However, the future also looks bright with the use of cell therapy to regenerate dysfunctional myocardium following infarction. Here Yamada et al. (2013) used a regenerative medicine approach with pluripotent stem cells to achieve cardiac resynchronization in hearts suffering from ventricular wall motion disparity. The long efficacy of this regenerative approach remains to be established, but studies are now moving beyond the point of proof-of-concept. So 100 years on from George Ralph Mines the field has come a long way. Many of the papers in this issue have their origin in the work of Mines, which I am sure would have given him much pleasure if he was here today to read them.