Sodium and calcium regulation in cardiac myocytes: from molecules to heart failure and arrhythmia

This special issue, Sodium and calcium in heart, brings together three reviews (Clancy et al. 2015; Chen-Izu et al. 2015; Shattock et al. 2015) and several original studies focused on these themes. Heart disease is the most prevalent cause of death in the developed world. In order to improve therapeutic approaches to treat heart disease, a deeper understanding of the fundamental mechanisms underlying altered heart function in specific diseases like arrhythmias, ischaemia and heart failure (HF) is essential. Cardiac function is controlled by three dynamically interacting systems – electrical, Ca²⁺ signalling, and contractile. To integrate these systems and reveal the detailed physiological and pathological mechanisms of cardiac function requires state-of-the-art experimental and computational approaches that span multiple system scales, that is, spatial scales ranging from molecules to the organism and time scales ranging from picoseconds to days or even years.

It is well recognized that Ca²⁺ handling not only governs contractile events (including systolic and diastolic function), but can undergo derangements that promote arrhythmogenesis through Ca²⁺-dependent and coupled electrophysiological effects. Na⁺ is increasingly appreciated as a major yet under-studied aspect of cardiac dysfunction (Despa & Bers, 2013; Clancy et al. 2015). This is because, in additional to the well-studied Na⁺-dependent currents and intracellular [Na⁺] ([Na⁺]_i) that are fundamental to cardiac excitability and contractility, [Na⁺]_i is tightly coupled to [Ca²⁺]_i regulation via electrogenic Na⁺/Ca²⁺ exchange (NCX). This coupling between Na⁺ and Ca²⁺ ion homeostatic subsystems means that disruption in either can have effects on contractility and arrhythmogenesis. Mitochondria also have a Na⁺/Ca²⁺ exchanger (molecularly distinct from that on the sarcolemma), but this also means that [Na⁺]_i perturbations can also perturb Ca²⁺-dependent energy metabolism and reactive oxygen production in mitochondria (Bay et al. 2013; Clancy et al. 2015). Thus Na⁺ regulation in cardiac myocytes can have broad-reaching functional effects.

Recognizing the emerging role of Na⁺ dysregulation in cardiac pathophysiology, and the need to extend our understanding from the molecular level to the integrated level of the organ, we hosted a 2 day symposium at the University of California, Davis in February 2014. The symposium Na⁺ channel and Na⁺ transport was the 3rd biennial UC Davis symposium in a series entitled Systems approach to understanding cardiac excitation–contraction coupling and arrhythmias (https://basicscience.ucdmc.ucdavis.edu/ucd-cvs-2014/). The symposia are conducted with a series of lectures, and an emphasis on open discussion time, aimed at bridging scales from molecules to whole heart. The symposia specifically bring together experimentalists and mathematical modellers from around the world to foster interdisciplinary discussion, interaction and collaboration. In this most recent symposium the emphasis was on the current state of research on Na⁺ in the heart, with goals to identify points of consensus and also controversy (where more study is needed). A summary of the symposium is contained in the series of three white papers published in this special issue (Clancy et al. 2015; Chen-Izu et al. 2015; Shattock et al. 2015) in which the lectures, discussion and outstanding questions or controversies are highlighted.

The 2 day workshop had eight sessions: (1) ‘Na⁺-induced arrhythmias: from cellular level to the whole heart’, (2) ‘Disruption of Na⁺ homeostasis’, (3) ‘Na⁺ channel structure and function’, (4) ‘Na⁺ channel regulation’, (5) ‘Trafficking, sequestration and complexing’, (6) ‘Na/Ca exchanger – structure, function and regulation’, (7) ‘Na/K pump – structure, function and regulation’, and (8) ‘Therapeutics’. In each session, speakers presented experimental results and modelling advancements, and discussion leaders, panelists and speakers held lengthy and lively debates over important questions that also highlighted critical knowledge gaps for future investigations. The white papers were jointly authored by speakers, discussion leaders and panelists and were intended to highlight the current status of these fields and emphasize questions and controversies. Clancy et al. (2015) entitled ‘Deranged sodium to sudden death’ addresses topics from Sessions 1, 2 and 8 above. Chen-Izu et al. (2015) entitled ‘Na⁺ channel function, regulation, structure, trafficking and sequestration’ covers topics from Sessions 3, 4 and 5. Shattock et al. (2015) entitled ‘Na⁺/Ca²⁺ exchange and Na⁺/K⁺-ATPase in the heart’ covers topics from Sessions 6 and 7.

This special issue also contains original research articles garnered in response to a call for papers on the topic of Na⁺ and Ca²⁺ in the heart. The original research articles address some focal questions related to the Na⁺ transport theme of the UC Davis symposium, and several contributions came from symposium participants.

Lin et al. (2015) studied mice with a Na⁺ channel β subunit (Scn1b) knockout that has been linked with inherited arrhythmias in patients. The Scn1b knockout caused altered spatial distribution of Na⁺ channels and current (I_Na) in mouse myocytes and increased the expression of the neuronal Scn3a gene (vs. the cardiac Scn5a gene that encodes Na_V1.5). They also found prolonged action potential (AP) duration (APD), delayed afterdepolarizations (DADs) and triggered beats. This study reveals a new mechanism by which altered Na⁺ channel gene expression can disrupt myocyte Ca²⁺ homeostasis and trigger NCX-dependent arrhythmias.

Mishra et al. (2015), using a gene-silencing approach, reported that another neuronal Na⁺ channel (Na_V1.1) may be relatively important in the late Na⁺ current (I_NaL) that is known to both directly prolong APD (as seen in long QT3 mutations derived from mutations in Na_V1.5) and contribute to myocyte Ca²⁺ overloading. That can lead to triggered arrhythmias initiated by either DADs or early afterdepolarization (EAD). Thus, as discussed in Chen-Izu et al. (2015), the specific molecular basis and functional impact of I_NaL is still under active investigation.

Yang et al. (2015) used guinea-pig experiments and an updated AP model to show how a novel I_NaL-selective blocker could be beneficial in reducing the vulnerability of cells to small current perturbations during the vulnerable AP plateau phase. This raises a novel therapeutic strategy, along the lines addressed in both Clancy et al. (2015) and Chen-Izu et al. (2015) white papers.

While increased Na⁺ influx via I_Na and I_NaL can cause sarcoplasmic reticulum (SR) Ca²⁺ release and NCX-dependent DADs (and some EADs), mutations in the cardiac ryanodine receptor (RyR2) linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) can cause diastolic SR Ca²⁺ release that activates inward NCX and DADs that are independent of Na⁺ loading. Lou et al. (2015) studied a CPVT mouse model of focal atrial arrhythmias, related to atrial fibrillation. Using simultaneous Ca²⁺/voltage optical mapping, they found that arrhythmic events in CPVT mice with sensitized RyR2 required both diastolic SR Ca²⁺ release-driven DADs (via NCX current) and spatio-temporal synchronization via tetrodotoxin-sensitive current-driven APs. This exemplifies the tight Na⁺–Ca²⁺ electrophysiological feedback discussed extensively at the UC Davis symposium. Hohendanner et al. (2015) addressed how SR Ca²⁺ release via inositol-1,4,5 trisphosphate (InsP₃) receptor channels can promote the recruitment of RyR2, both at rest and during paced beats. This resulted in both an increase in Ca²⁺ sparks and arrhythmogenic Ca²⁺ waves (as above), especially in atrial myocytes and in HF where these InsP₃ receptors are more highly expressed compared to normal ventricular myocytes. In HF rabbits this contributed to an increase of Ca²⁺ transients in atrial myocytes, vs. the depressed ventricular myocyte Ca²⁺ transients seen in this same HF model.

Myles et al. (2015) used whole heart optical mapping of arrhythmia induction in response to focal β-adrenergic challenge and SR Ca²⁺ release and NCX-driven DADs. They found that there was arrhythmogenic synergy between sensitized RyR2-mediated diastolic SR Ca²⁺ release and reduced function of the inward rectifier K⁺ current I_K1 (both of which occur in HF). Moreover, Poláková et al. (2015) reported that β-adrenergic activation of both protein kinase A (PKA) and Ca²⁺-calmodulin-dependent protein kinase (CaMKII) may be required to maximally increase the propensity for spontaneous SR Ca²⁺ release. Hence, understanding the dynamic interactions between molecules involved in Na⁺, Ca²⁺ and membrane voltage regulation is essential for decipher-ing the cardiac arrhythmia mechanisms.

Aronsen et al. (2015) studied Na⁺/K⁺-ATPase effects during hypokalaemia ([K⁺]_o = 2.7 mm), which is a known risk factor for cardiac arrhythmias. They found that hypokalaemia reduced Na⁺/K⁺-ATPase current and enhanced Ca²⁺ transient amplitude, but that selective inhibition of the Na⁺/K⁺-ATPase α2 isoform (the minor form in heart) prevented these effects of hypokalaemia. This agrees with a preferential role for the α2 subunit of Na⁺/K⁺-ATPase in modulating cardiac Ca²⁺ transients (Despa et al. 2012; Shattock et al. 2015). In related work Lewalle et al. (2014) recently developed a framework for mathematical modelling studies to help deal with the issue that models of Na⁺/K⁺-ATPase (and other transporters and channels) are often derived from experimental data in different animal species and under different conditions. They show how to retune model parameters using species-consistent data sets. This may be beneficial in a range of experiment–model continuity issues that was much discussed at the UC Davis symposium, as an inherent challenge in multispecies/multiscale modelling.

In conclusion, we hope that readers will find this special issue of interest for the collective group insights in the white papers on timely topics of Na⁺-related effects in cardiac myocytes related to HF and arrhythmias, as well as for the related original contributions which further advance our detailed and integrative understanding of the dynamic and multiscale interactions between cardiac Na⁺, Ca²⁺, electrophysiology and contractility in both health and disease.