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The sinoatrial node (SAN) is the dominant pacemaker structure in the mammalian heart. It is endowed with robust intrinsic automaticity, providing periodic electrical excitation with a cycle widely modulated by autonomic influences. A number of membrane channels and transporters contribute to the net membrane current supporting SAN electrical activity, whose periodicity is determined by the interplay of two oscillators termed ‘membrane’ and ‘calcium’ clock respectively. This chapter describes the structure of the SAN, the peculiarities of its electrical cycle, the nature and modulation of the underlying clocks, and SAN interaction with atrial muscle. Moreover, the features and determinants of the temporal variability of the pacemaker cycle, clinically used to assess autonomic balance, are briefly discussed.

et al., [Aims]: Polyunsaturated fatty n-3 acids (PUFAs) have been reported to exhibit antiarrhythmic properties. However, the mechanisms of action remain unclear. We studied the electrophysiological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on IKs, and on the expression and location of Kv7.1 and KCNE1. [Methods and results]: Experiments were performed using patch-clamp, western blot, and sucrose gradient techniques in COS7 cells transfected with Kv7.1/KCNE1 channels. Acute perfusion with both PUFAs increased Kv7.1/KCNE1 current, this effect being greater for DHA than for EPA. Similar results were found in guinea pig cardiomyocytes. Acute perfusion of either PUFA slowed the activation kinetics and EPA shifted the activation curve to the left. Conversely, chronic EPA did not modify Kv7.1/KCNE1 current magnitude and shifted the activation curve to the right. Chronic PUFAs decreased the expression of Kv7.1, but not of KCNE1, and induced spatial redistribution of Kv7.1 over the cell membrane. Cholesterol depletion with methyl-β-cyclodextrin increased Kv7.1/KCNE1 current magnitude. Under these conditions, acute EPA produced similar effects than those induced in non-cholesterol-depleted cells. A ventricular action potential computational model suggested antiarrhythmic efficacy of acute PUFA application under IKr block. [Conclusions]: We provide evidence that acute application of PUFAs increases Kv7.1/KCNE1 through a probably direct effect, and shows antiarrhythmic efficacy under IKr block. Conversely, chronic EPA application modifies the channel activity through a change in the Kv7.1/KCNE1 voltage-dependence, correlated with a redistribution of Kv7.1 over the cell membrane. This loss of function may be pro-arrhythmic. This shed light on the controversial effects of PUFAs regarding arrhythmias., This work was supported by grants from CICYT (SAF2010-14916 and SAF2013-45800-R to C.V.; BFU2011-23268 and CSD2008-00005 to A.F.) and FIS (PI11/02459, RD06/0014/0006, and RD12/0042/0019 to C.V.). C.M. and M.G. hold FPI grants. N.C. and A.d.l.C. hold Juan de la Cierva and RIC contracts, respectively.

Cardiac electrophysiology has evolved into an important subspecialty in cardiovascular medicine. This is in part due to the significant advances made in our understanding and treatment of heart rhythm disorders following more than a century of scientific discoveries and research. More recently, the rapid development of technology in cellular electrophysiology, molecular biology, genetics, computer modelling, and imaging have led to the exponential growth of knowledge in basic cardiac electrophysiology. The paradigm of evidence-based medicine has led to a more comprehensive decision-making process and most likely to improved outcomes in many patients. However, implementing relevant basic research knowledge in a system of evidence-based medicine appears to be challenging. Furthermore, the current economic climate and the restricted nature of research funding call for improved efficiency of translation from basic discoveries to healthcare delivery. Here, we aim to (i) appraise the broad challenges of translational research in cardiac electrophysiology, (ii) highlight the need for improved strategies in the training of translational electrophysiologists, and (iii) discuss steps towards building a favourable translational research environment and culture.

Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current ( I NaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive I NaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available I NaL blocker, may prevent constitutive I NaL enhancement and PAH-induced myocardial remodelling. Methods and results PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. I NaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, I NaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented I NaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. Conclusion PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive I NaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.

featured contributions on the computational analysis of ‘arrhythmias mechanisms’, the present Issue mainly focuses on the descriptions of novel computational approaches for diagnosis and interventions in clinical arrhythmology. In this sense, although there are clearly many challenges that must still be overcome along the way, the articles in this issue show that Computational Cardiac Electrophysiology is moving towards Translational Medicine. With regard to the application of the computational approach to the antiarrhythmic therapies, Trayanova and Rantner 2 review the insights provided by the three-dimensional (3D) computational models of defibrillation and of shock-induced arrhythmogenesis, including the description of a relevant attempt of clinical translation regarding the model-based prediction of the optimal ICD placement in paediatric and congenital heart defect patients. An original contribution also related to the understanding of arrhythmia induction and defibrillation is the study by Colli Franzoneetal. 3 on the spatial distribution of intracellular calcium (Cai) dynamics following premature stimulations. In agreement with recent experimental investigations, they found significant regions of Cai elevation located at the virtual cathode regions. Such spatial heterogeneity in Cai dynamics may feedback on membrane potential and play an important role in arrhythmia induction by programmed stimulation. Ravelli and Mase ` 4 review the state of the art of computational mapping in atrial fibrillation (AF). The experimental studies, the signal processing methods and the clinical studies focused on the analysis of rate and organization of AF are reviewed. They point out how the integration of signal-derived maps may guide the localization of critical sources and the planning of new target ablation strategies.