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Journal of Physiology
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The transverse (t-) tubules of mammalian ventricular myocytes are invaginations of the surface membrane. The function of many of the key proteins involved in excitation–contraction coupling is located predominantly at the t-tubules, which thus form a Ca2+-handling micro-environment that is central to the normal rapid activation and relaxation of the ventricular myocyte. Although cellular arrhythmogenesis shares many ion flux pathways with normal excitation–contraction coupling, the role of the t-tubules in such arrhythmogenesis has not previously been considered. In this brief review we consider how the location and co-location of proteins at the t-tubules may contribute to the generation of arrhythmogenic delayed and early afterdepolarisations, and how the loss of t-tubules that occurs during heart failure may alter the generation of such arrhythmias, as well as contributing to other types of arrhythmia as a result of changes of electrical heterogeneity within the whole heart.
Stabilization of Kv4 protein by the accessory K+ channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K+ currents
The fast transient outward K+ current (Ito,f) underlies the early phase of myocardial action potential repolarization, contributing importantly to the coordinated propagation of activity in the heart and to the generation of normal cardiac rhythms. Native Ito,f channels reflect the tetrameric assembly of Kv4 pore-forming () subunits, and previous studies suggest roles for accessory and regulatory proteins in controlling the cell surface expression and the biophysical properties of Kv4-encoded Ito,f channels. Here, we demonstrate that the targeted deletion of the cytosolic accessory subunit, K+ channel interacting protein 2 (KChIP2), results in the complete loss of the Kv4.2 protein, the subunit critical for the generation of mouse ventricular Ito,f. Expression of the Kcnd2 (Kv4.2) transcript in KChIP2–/– ventricles, however, is unaffected. The loss of the Kv4.2 protein results in the elimination of Ito,f in KChIP2–/– ventricular myocytes. In parallel with the elimination of Ito,f, the slow transient outward K+ current (Ito,s) is upregulated and voltage-gated Ca2+ currents (ICa,L) are decreased. In addition, surface electrocardiograms and ventricular action potential waveforms in KChIP2–/– and wild-type mice are not significantly different, suggesting that the upregulation of Ito,s and the reduction in ICa,L compensate for the loss of Ito,f. Additional experiments revealed that Ito,f is not ‘rescued' by adenovirus-mediated expression of KChIP2 in KChIP2–/– myocytes, although ICa,L densities are increased. Taken together, these results demonstrate that association with KChIP2 early in the biosynthetic pathway and KChIP2-mediated stabilization of Kv4 protein are critical determinants of native cardiac Ito,f channel expression.
Reductions in cardiac action potential wavelength, and the consequent wavebreak, have been implicated in arrhythmogenesis. Tachyarrhythmias are more common in the Brugada syndrome, particularly following pharmacological challenge, previously modelled using Scn5a+/– murine hearts. Propagation latencies and action potential durations (APDs) from monophasic action potential recordings were used to assess wavelength changes with heart rate in Langendorff-perfused wild-type (WT) and Scn5a+/– hearts. Recordings were obtained from right (RV) and left (LV) ventricular, epicardial and endocardial surfaces during incremental pacing, before and following flecainide or quinidine challenge. Conduction velocities (), action potential wavelengths ( = APD x ), and their corresponding alternans depended non-linearly upon diastolic interval (DI). Maximum was lower in Scn5a+/– RV epicardium than endocardium. Flecainide further reduced , accentuating this RV conduction block. Quinidine reduced maximum in WT and caused earlier conduction failure in the RV of both Scn5a+/– and WT. Use of recovery wavelengths (0 = DI x ) rather than DI, provided novel restitution plots of against 0, which sum to a basic cycle distance permitting feedback analysis. restitution gradient better correlated with alternans magnitude than either APD or restitution gradient. The large differences in and APD restitution contrasted with minor differences in maximum between epi- and endocardia of untreated hearts, and quinidine-treated WT hearts. Strikingly, all regions and conditions converged to a common instability point, implying a conserved relationship. Flecainide or quinidine decreased the pacing rates at which this occurred, through reducing basic cycle distance, in the Scn5a+/– RV epicardium, directly predictive of its arrhythmic phenotype.
The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective IKr block (50–100 nmol l–1 dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 mol l–1 BaCl2) and IKs block (1 mol l–1 HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na+–Ca2+ exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKs -subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human–canine ion current differences confirmed the role of IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.
Quantifying the origins of population variability in cardiac electrical activity through sensitivity analysis of the electrocardiogram
Altered function of ion channels in the heart can increase the risk of sudden arrhythmic death. Hundreds of genetic variants exist in these cardiac ion channel genes. The challenge is how to interpret the effects of multiple conductance perturbations on the complex multi-variable cardiac electrical system? In theory, sensitivity analysis can address this question. However, to date this approach has been restricted by computational overheads to analysis of isolated cells, which has limited extrapolation to physiologically relevant scales. The goal of this study was to extend existing sensitivity analyses to electrocardiogram (ECG) signals derived from multicellular systems and quantify the contribution of ionic conductances to emergent properties of the ECG. To achieve this, we have developed a highly parallelised simulation environment using unconventional high performance computing architectures to analyse the emergent electrical properties of a multicellular system. This has permitted the first systematic analysis of the molecular basis of the T wave amplitude, revealing important but distinct roles for delayed rectifier and inward rectifier K+ currents. In addition to quantifying how interactions between multiple ion channels influence ECG parameters we show that these sensitivities are dynamic functions of heart rate. This study provides a significant advance in our understanding both of how individual ion conductances define ECG signals and of epistatic modification of cardiac electrical phenotypes. The parallelised simulation environment we have developed removes the computational roadblock that has limited this approach and so provides the framework for future analysis of more complex tissue and whole organ systems.
In addition to acting on mineralocorticoid receptors, aldosterone has been recently shown to activate the G protein-coupled oestrogen receptor (GPER) in vascular cells. In light of the newly identified role for GPER in vagal cardiac control, we examined whether or not aldosterone activates GPER in rat nucleus ambiguus. Aldosterone produced a dose-dependent increase in cytosolic Ca2+ concentration in retrogradely labelled cardiac vagal neurons of nucleus ambiguus; the response was abolished by pretreatment with the GPER antagonist G-36, but was not affected by the mineralocorticoid receptor antagonists, spironolactone and eplerenone. In Ca2+-free saline, the response to aldosterone was insensitive to blockade of the Ca2+ release from lysosomes, while it was reduced by blocking the Ca2+ release via ryanodine receptors and abolished by blocking the IP3 receptors. Aldosterone induced Ca2+ influx via P/Q-type Ca2+ channels, but not via L-type and N-type Ca2+ channels. Aldosterone induced depolarization of cardiac vagal neurons of nucleus ambiguus that was sensitive to antagonism of GPER but not of mineralocorticoid receptor. in vivo studies, using telemetric measurement of heart rate, indicate that microinjection of aldosterone into the nucleus ambiguus produced a dose-dependent bradycardia in conscious, freely moving rats. Aldosterone-induced bradycardia was blocked by the GPER antagonist, but not by the mineralocorticoid receptor antagonists. In summary, we report for the first time that aldosterone decreases heart rate by activating GPER in cardiac vagal neurons of nucleus ambiguus.
Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats
In normal rats, central administration of orexin or exposure to certain forms of stress can induce significant increases in blood pressure and sympathetic nerve activity, which can be blocked by orexin receptor antagonists. The resting blood pressure is, however, unaffected by such antagonists, but is significantly lower in rodents with total loss of orexin, such as prepro-orexin knockout mice and orexin neuron-ablated orexin/ataxin-3 transgenic rats. We hypothesize that orexin is involved in the pathophysiology and maintenance of high blood pressure in the spontaneously hypertensive rat (SHR), a model of primary hypertension. To test this hypothesis, we measured orexin-A mRNA expression in the rostral ventrolateral medulla and antagonized both orexin receptors using an orally administered potent dual orexin receptor antagonist, almorexant, in SHRs and normotensive Wistar–Kyoto rats. In SHRs, there was a strong trend towards an increased orexin-A mRNA expression in the rostral ventrolateral medulla, and blocking orexin receptors markedly lowered blood pressure (from 182/152 ± 5/6 to 149/119 ± 9/8 mmHg; P < 0.001), heart rate (P < 0.001), sympathetic vasomotor tone (P < 0.001) and the noradrenaline levels in cerebrospinal fluid and plasma (P < 0.002). The significant antihypertensive effects of almorexant were observed in wakefulness and non-rapid eye movement sleep during both dark and light phases of the diurnal cycle only in SHRs. Blocking orexin receptors had no effect on blood pressure and sympathetic tone in normotensive Wistar–Kyoto rats. Our study links the orexin system to the pathogenesis of high blood pressure in SHRs and suggests that modulation of the orexin system could be a potential target in treating some forms of hypertension.
Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria
Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche–Ramirez–Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca2+ handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate initiation and maintenance of re-entrant excitation waves.
Voltage sensitivity of M2 muscarinic receptors underlies the delayed rectifier-like activation of ACh-gated K+ current by choline in feline atrial myocytes
Choline (Ch) is a precursor and metabolite of the neurotransmitter acetylcholine (ACh). In canine and guinea pig atrial myocytes, Ch was shown to activate an outward K+ current in a delayed rectifier fashion. This current has been suggested to modulate cardiac electrical activity and to play a role in atrial fibrillation pathophysiology. However, the exact nature and identity of this current has not been convincingly established. We recently described the unique ligand- and voltage-dependent properties of muscarinic activation of ACh-activated K+ current (IKACh) and showed that, in contrast to ACh, pilocarpine induces a current with delayed rectifier-like properties with membrane depolarization. Here, we tested the hypothesis that Ch activates IKACh in feline atrial myocytes in a voltage-dependent manner similar to pilocarpine. Single-channel recordings, biophysical profiles, specific pharmacological inhibition and computational data indicate that the current activated by Ch is IKACh. Moreover, we show that membrane depolarization increases the potency and efficacy of IKACh activation by Ch and thus gives the appearance of a delayed rectifier activating K+ current at depolarized potentials. Our findings support the emerging concept that IKACh modulation is both voltage- and ligand-specific and reinforce the importance of these properties in understanding cardiac physiology.
Cardiac calcium signalling pathologies associated with defective calmodulin regulation of type 2 ryanodine receptor
Cardiac ryanodine receptor (RyR2) is a homotetramer of 560 kDa polypeptides regulated by calmodulin (CaM), which decreases its open probability at diastolic and systolic Ca2+ concentrations. Point mutations in the CaM-binding domain of RyR2 (W3587A/L3591D/F3603A, RyR2ADA) in mice result in severe cardiac hypertrophy, poor left ventricle contraction and death by postnatal day 16, suggesting that CaM inhibition of RyR2 is required for normal cardiac function. Here, we report on Ca2+ signalling properties of enzymatically isolated, Fluo-4 dialysed whole cell clamped cardiac myocytes from 10–15-day-old wild-type (WT) and homozygous Ryr2ADA/ADA mice. Spontaneously occurring Ca2+ spark frequency, measured at –80 mV, was 14-fold lower in mutant compared to WT myocytes. ICa, though significantly smaller in mutant myocytes, triggered Ca2+ transients that were of comparable size to those of WT myocytes, but with slower activation and decay kinetics. Caffeine-triggered Ca2+ transients were about three times larger in mutant myocytes, generating three- to four-fold bigger Na+-Ca2+ exchanger NCX currents (INCX). Mutant myocytes often exhibited Ca2+ transients of variable size and duration that were accompanied by similarly alternating and slowly activating INCX. The data suggest that RyR2ADA mutation produces significant reduction in ICa density and ICa-triggered Ca2+ release gain, longer but infrequently occurring Ca2+ sparks, larger sarcoplasmic reticulum Ca2+ loads, and spontaneous Ca2+ releases accompanied by activation of large and potentially arrhythmogenic inward INCX.
Evoked centripetal Ca2+ mobilization in cardiac Purkinje cells: insight from a model of three Ca2+ release regions
Despite strong suspicion that abnormal Ca2+ handling in Purkinje cells (P-cells) is implicated in life-threatening forms of ventricular tachycardias, the mechanism underlying the Ca2+ cycling of these cells under normal conditions is still unclear. There is mounting evidence that P-cells have a unique Ca2+ handling system. Notably complex spontaneous Ca2+ activity was previously recorded in canine P-cells and was explained by a mechanistic hypothesis involving a triple layered system of Ca2+ release channels. Here we examined the validity of this hypothesis for the electrically evoked Ca2+ transient which was shown, in the dog and rabbit, to occur progressively from the periphery to the interior of the cell. To do so, the hypothesis was incorporated in a model of intracellular Ca2+ dynamics which was then used to reproduce numerically the Ca2+ activity of P-cells under stimulated conditions. The modelling was thus performed through a 2D computational array that encompassed three distinct Ca2+ release nodes arranged, respectively, into three consecutive adjacent regions. A system of partial differential equations (PDEs) expressed numerically the principal cellular functions that modulate the local cytosolic Ca2+ concentration (Cai). The apparent node-to-node progression of elevated Cai was obtained by combining Ca2+ diffusion and ‘Ca2+-induced Ca2+ release'. To provide the modelling with a reliable experimental reference, we first re-examined the Ca2+ mobilization in swine stimulated P-cells by 2D confocal microscopy. As reported earlier for the dog and rabbit, a centripetal Ca2+ transient was readily visible in 22 stimulated P-cells from six adult Yucatan swine hearts (pacing rate: 0.1 Hz; pulse duration: 25 ms, pulse amplitude: 10% above threshold; 1 mm Ca2+; 35°C; pH 7.3). An accurate replication of the observed centripetal Ca2+ propagation was generated by the model for four representative cell examples and confirmed by statistical comparisons of simulations against cell data. Selective inactivation of Ca2+ release regions of the computational array showed that an intermediate layer of Ca2+ release nodes with an ~30–40% lower Ca2+ activation threshold was required to reproduce the phenomenon. Our computational analysis was therefore fully consistent with the activation of a triple layered system of Ca2+ release channels as a mechanism of centripetal Ca2+ signalling in P-cells. Moreover, the model clearly indicated that the intermediate Ca2+ release layer with increased sensitivity for Ca2+ plays an important role in the specific intracellular Ca2+ mobilization of Purkinje fibres and could therefore be a relevant determinant of cardiac conduction.
Placement of implantable cardioverter-defibrillators in paediatric and congenital heart defect patients: a pipeline for model generation and simulation prediction of optimal configurations
There is currently no reliable way of predicting the optimal implantable cardioverter-defibrillator (ICD) placement in paediatric and congenital heart defect (CHD) patients. This study aimed to: (1) develop a new image processing pipeline for constructing patient-specific heart–torso models from clinical magnetic resonance images (MRIs); (2) use the pipeline to determine the optimal ICD configuration in a paediatric tricuspid valve atresia patient; (3) establish whether the widely used criterion of shock-induced extracellular potential (e) gradients 5 V cm–1 in 95% of ventricular volume predicts defibrillation success. A biophysically detailed heart–torso model was generated from patient MRIs. Because transvenous access was impossible, three subcutaneous and three epicardial lead placement sites were identified along with five ICD scan locations. Ventricular fibrillation was induced, and defibrillation shocks were applied from 11 ICD configurations to determine defibrillation thresholds (DFTs). Two configurations with epicardial leads resulted in the lowest DFTs overall and were thus considered optimal. Three configurations shared the lowest DFT among subcutaneous lead ICDs. The e gradient criterion was an inadequate predictor of defibrillation success, as defibrillation failed in numerous instances even when 100% of the myocardium experienced such gradients. In conclusion, we have developed a new image processing pipeline and applied it to a CHD patient to construct the first active heart–torso model from clinical MRIs.
Induced pluripotent stem cell intervention rescues ventricular wall motion disparity, achieving biological cardiac resynchronization post-infarction
Dyssynchronous myocardial motion aggravates cardiac pump function. Cardiac resynchronization using pacing devices is a standard-of-care in the management of heart failure. Post-infarction, however, scar tissue formation impedes the efficacy of device-based therapy. The present study tests a regenerative approach aimed at targeting the origin of abnormal motion to prevent dyssynchronous organ failure. Induced pluripotent stem (iPS) cells harbour a reparative potential, and were here bioengineered from somatic fibroblasts reprogrammed with the stemness factors OCT3/4, SOX2, KLF4, and c-MYC. In a murine infarction model, within 30 min of coronary ligation, iPS cells were delivered to mapped infarcted areas. Focal deformation and dysfunction underlying progressive heart failure was resolved prospectively using speckle-tracking imaging. Tracked at high temporal and spatial resolution, regional iPS cell transplantation restored, within 10 days post-infarction, the contractility of targeted infarcted foci and nullified conduction delay in adjacent non-infarcted regions. Local iPS cell therapy, but not delivery of parental fibroblasts or vehicle, prevented or normalized abnormal strain patterns correcting the decrease in peak strain, disparity of time-to-peak strain, and pathological systolic stretch. Focal benefit of iPS cell intervention translated into improved left ventricular conduction and contractility, reduced scar, and reversal of structural remodelling, protecting from organ decompensation. Thus, in ischaemic cardiomyopathy, targeted iPS cell transplantation synchronized failing ventricles, offering a regenerative strategy to achieve biological resynchronization.
George Ralph Mines studied the basic principles of reentry and published his data in The Journal of Physiology in 1913. Exactly 100 years later we discuss his first electrophysiological experiments and how his results lead to the insight that was the basis for the treatment of the clinical arrhythmias seen in Wolff–Parkinson–White syndrome.
There is continuing belief that cardiac parasympathetic postganglionic fibres are sparse or absent from the ventricles. This review of the literature shows that the supposition is a myth. Early studies considered that fine silver-stained fibres coursing amongst ventricle myocardial cells were most likely cardiac parasympathetic postganglionic fibres. The conclusions were later supported by acetyl cholinesterase staining using a method that appeared not to be associated with noradrenaline nerve fibres. The conclusion is critically examined in the light of several recent histological studies using the acetyl cholinesterase method and also a more definitive technique (CHAT), that suggest a widespread location of parasympathetic ganglia and a relatively dense parasympathetic innervation of ventricular muscle in a range of mammals including man. The many studies demonstrating acetylcholine release in the ventricle on vagal nerve stimulation and a high density of acetylcholine M2 receptors is in accord with this as are tests of ventricular performance from many physiological studies. Selective control of cardiac functions by anatomically segregated parasympathetic ganglia is discussed. It is argued that the influence of vagal stimulation on ventricular myocardial action potential refractory period, duration, force and rhythm is evidence that vagal fibres have close apposition to myocardial fibres. This is supported by clear evidence of accentuated antagonism between sympathetic activity and vagal activity in the ventricle and also by direct effects of vagal activity independent of sympathetic activity. The idea of differential control of atrial and ventricular physiology by vagal C and vagal B preganglionic fibres is examined as well as differences in chemical phenotypes and their function. The latter is reflected in medullary and supramedullary control. Reference is made to the importance of this knowledge to understanding the normal physiology of cardiac autonomic control and significance to pathology.
New antiarrhythmic drugs for treatment of atrial fibrillation should ideally be atrial selective in order to avoid pro-arrhythmic effects in the ventricles. Currently recognized atrial selective targets include atrial Nav1.5 channels, Kv1.5 channels and constitutively active Kir3.1/3.4 channels, each of which confers atrial selectivity by different mechanisms. Na+ channel blockers with potential- and frequency-dependent action preferentially suppress atrial fibrillation because of the high excitation rate and less negative atrial resting potential, which promote drug binding in atria. Kv1.5 channels are truly atrial selective because they do not conduct repolarizing current IKur in ventricles. Constitutively active IK,ACh is predominantly observed in remodelled atria from patients in permanent atrial fibrillation (AF). A lot of effort has been invested to detect compounds which will selectively block Kir3.1/Kir3.4 in their remodelled constitutively active form. Novel drugs which have been and are being developed aim at atrial-selective targets. Vernakalant and ranolazine which mainly block atrial Na+ channels are clinically effective. Newly designed selective IKur blockers and IK,ACh blockers are effective in animal models; however, clinical benefit in converting AF into sinus rhythm (SR) or reducing AF burden remains to be demonstrated. In conclusion, atrial-selective antiarrhythmic agents have a lot of potential, but a long way to go.
Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects
Over the last two decades, an increasing number of SCN5A mutations have been described in patients with long QT syndrome type 3 (LQT3), Brugada syndrome, (progressive) conduction disease, sick sinus syndrome, atrial standstill, atrial fibrillation, dilated cardiomyopathy, and sudden infant death syndrome (SIDS). Combined genetic, electrophysiological and molecular studies have provided insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes. However, risk stratification and patient management is hindered by the reduced penetrance and variable disease expressivity in sodium channelopathies. Furthermore, various SCN5A-related arrhythmia syndromes are known to display mixed phenotypes known as cardiac sodium channel overlap syndromes. Determinants of variable disease expressivity, including genetic background and environmental factors, are suspected but still largely unknown. Moreover, it has become increasingly clear that sodium channel function and regulation is more complicated than previously assumed, and the sodium channel may play additional, as of yet unrecognized, roles in cardiac structure and function. Development of cardiac structural abnormalities secondary to SCN5A mutations has been reported, but the clinical relevance and underlying mechanisms are unclear. Increased insight into these issues would enable a major next step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification and treatment strategies.
Many diverse data support a role of the funny current (If) in pacemaking and heart rate control. Among them, clinically relevant applications have special impact, since they translate the concept of funny channel-based pacemaking into practical developments of potential therapeutic value. For example, the If role in pacemaking is the basis for a pharmacological approach to heart rate control. Ivabradine, a specific f-channel blocker acting as a ‘pure heart rate reducing' agent, is used today as a therapeutic tool in chronic stable angina and heart failure. Also, the pacemaking capability of funny channels has been the main rationale behind the development of ‘biological' pacemakers, whose aim is to eventually replace the electronic pacemakers implanted today. Finally, the role of If in pacemaking implies that dysfunctional funny channels can contribute to rhythm disorders. This consideration has led to the search for inheritable forms of cardiac arrhythmias potentially linked to functional changes of HCN4 channels, the molecular correlates of funny channels. This review addresses recent reports where investigation of families with arrhythmias has allowed the identification of specific HCN4 channel mutations associated with different types of rhythm disorders, specifically with sinus bradycardia. The perspective of future research in this field is also addressed.