[Show abstract][Hide abstract] ABSTRACT: Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms.
[Show abstract][Hide abstract] ABSTRACT: Atrial anti-arrhythmic effects of β-adrenoceptor antagonists (β-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic β-blocker use; so-called 'pharmacological remodelling'. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K(+) currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, the consequences of these changes on mechanisms of genesis and maintenance of atrial fibrillation (AF) are unknown. Using mathematical modelling, we tested the hypothesis that the long-term adaptational decrease in human atrial Ito and IK1 caused by chronic β-blocker therapy, i.e. independent of acute electrophysiological effects of β-blockers, in an otherwise un-remodelled atrium, could suppress AF.
[Show abstract][Hide abstract] ABSTRACT: Aims
Atrial fibrillation (AF) is increased in patients with heart failure resulting from myocardial infarction (MI). We aimed to determine the effects of chronic ventricular MI in rabbits on the susceptibility to AF, and underlying atrial electrophysiological and Ca2+-handling mechanisms.
Methods and results
In Langendorff-perfused rabbit hearts, under β-adrenergic stimulation with isoproterenol (ISO; 1 µM), 8 weeks MI decreased AF threshold, indicating increased AF susceptibility. This was associated with increased atrial action potential duration (APD)-alternans at 90% repolarization, by 147%, and no significant change in the mean APD or atrial global conduction velocity (CV; n = 6–13 non-MI hearts, 5–12 MI). In atrial isolated myocytes, also under β-stimulation, L-type Ca2+ current (ICaL) density and intracellular Ca2+-transient amplitude were decreased by MI, by 35 and 41%, respectively, and the frequency of spontaneous depolarizations (SDs) was substantially increased. MI increased atrial myocyte size and capacity, and markedly decreased transverse-tubule density. In non-MI hearts perfused with ISO, the ICaL-blocker nifedipine, at a concentration (0.02 µM) causing an equivalent ICaL reduction (35%) to that from the MI, did not affect AF susceptibility, and decreased APD.
Chronic MI in rabbits remodels atrial structure, electrophysiology, and intracellular Ca2+ handling. Increased susceptibility to AF by MI, under β-adrenergic stimulation, may result from associated production of atrial APD alternans and SDs, since steady-state APD and global CV were unchanged under these conditions, and may be unrelated to the associated reduction in whole-cell ICaL. Future studies may clarify potential contributions of local conduction changes, and cellular and subcellular mechanisms of alternans, to the increased AF susceptibility.
Cardiovascular Research 04/2013; 99(1). DOI:10.1093/cvr/cvt087 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Key points The shape of the cardiac atrial action potential is influenced by the flow of a transient outward K(+) current (I(TO)) across atrial muscle cell membranes. Whether changes in I(TO) could alter atrial cell action potentials in ways that could affect mechanisms of abnormal heart rhythms (arrhythmias) is unclear, because currently available I(TO) blocking drugs are non-selective. We used the 'dynamic-clamp' technique, for the first time in atrial cells isolated from patients, and from rabbits, to electrically simulate selective changes in I(TO) during action potential recording. We found that I(TO) decrease prolonged atrial cell action potential duration and, under β-adrenergic-stimulation, provoked abnormal membrane potential oscillations (afterdepolarisations) that were preventable by I(TO) increase or a β-blocker. These results help us better understand the contribution of I(TO) to atrial cell action potential shape and mechanisms of arrhythmia, with potential implications for both the development and treatment of atrial fibrillation.
The Journal of Physiology 06/2012; 590(Pt 17):4289-305. DOI:10.1113/jphysiol.2012.235986 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review focuses on the (mal)adaptive processes in atrial excitation-contraction coupling occurring in patients with chronic atrial fibrillation. Cellular remodeling includes shortening of the atrial action potential duration and effective refractory period, depressed intracellular Ca 2+ transient, and reduced myocyte contractility. Here we summarize the current knowledge of the ionic bases underlying these changes. Understanding the molecular mechanisms of excitation-contraction-coupling remodeling in the fibrillating human atria is important to identify new potential targets for AF therapy.
[Show abstract][Hide abstract] ABSTRACT: Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K(+) currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K(+) currents (I(TO), I(KSUS) and I(K1)) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in I(TO) density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. I(K1) was reduced by 34% at -120 mV (p < 0.05). Neither I(KSUS), nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of I(TO)- and I(K1)-decrease could result in a 28% increase in APD(90). Chronic β-blockade did not alter mRNA or protein expression of the I(TO) pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in I(K1). A reduction in atrial I(TO) and I(K1) associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits.
Pflügers Archiv - European Journal of Physiology 12/2011; 463(4):537-48. DOI:10.1007/s00424-011-1061-z · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca2+ transport in remodeled human atrium, but appropriate models are limited.
To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model.
Atria versus ventricles have lower I(K1), resulting in more depolarized resting membrane potential (≈7 mV). We used higher I(to,fast) density in atrium, removed I(to,slow), and included an atrial-specific I(Kur). I(NCX) and I(NaK) densities were reduced in atrial versus ventricular myocytes according to experimental results. SERCA function was altered to reproduce human atrial myocyte Ca2+ transients. To simulate chronic AF, we reduced I(CaL), I(to), I(Kur) and SERCA, and increased I(K1),I(Ks) and I(NCX). We also investigated the link between Kv1.5 channelopathy, [Ca2+]i, and AF. The sinus rhythm model showed a typical human atrial AP morphology. Consistent with experiments, the model showed shorter APs and reduced AP duration shortening at increasing pacing frequencies in AF or when I(CaL) was partially blocked, suggesting a crucial role of Ca2+ and Na+ in this effect. This also explained blunted Ca2+ transient and rate-adaptation of [Ca2+]i and [Na+]i in chronic AF. Moreover, increasing [Na+]i and altered I(NaK) and I(NCX) causes rate-dependent atrial AP shortening. Blocking I(Kur) to mimic Kv1.5 loss-of-function increased [Ca2+]i and caused early afterdepolarizations under adrenergic stress, as observed experimentally.
Our study provides a novel tool and insights into ionic bases of atrioventricular AP differences, and shows how Na+ and Ca2+ homeostases critically mediate abnormal repolarization in AF.
Circulation Research 09/2011; 109(9):1055-66. DOI:10.1161/CIRCRESAHA.111.253955 · 11.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na(+) channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca(2+) channel blockers; the "upstream therapies", e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as "atrial-selective" multiple ion channel blockers, gap junction-enhancers, and intracellular Ca(2+)-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms.
[Show abstract][Hide abstract] ABSTRACT: The goal was to terminate atrial fibrillation (AF) by targeting atrioventricular differences in ionic properties.
Optical mapping was used to record electrical activity during carbachol (0.25-0.5 μM)-induced AF in pig hearts. The atrial-specific current, I(Kur), was blocked with 100 μM 4-aminopyridine (4-AP) or with 0.5 μM DPO-1. Hearts in AF and ventricular fibrillation (VF) were also subjected to increasing levels of extracellular K(+) ([K(+)](o): 6-12 mM), compared with controls (4 mM). We hypothesized that due to the more negative steady-state half inactivation voltage for the atrial Na(+) current, I(Na), compared with the ventricle, AF would terminate before VF in hyperkalaemia. Mathematical models were used to interpret experimental findings. The I(Kur) block did not terminate AF in a majority of experiments (6/9 with 4-AP and 3/4 with DPO-1). AF terminated in mild hyperkalaemia ([K(+)](o) ≤ 10.0 mM; N = 8). In contrast, only two of five VF episodes terminated at the maximum ([K(+)](o): 12 mM [K(+)](o)). The I(Kur) block did not terminate a simulated rotor in cholinergic AF because its contribution to repolarization was dwarfed by the large magnitude of the acetylcholine-activated K(+) current (I(K,ACh)). Simulations showed that the lower availability of the atrial Na(+) current at depolarized potentials, and a smaller atrial tissue size compared with the ventricle, could partly explain the earlier termination of AF compared with VF during hyperkalaemia.
I(Kur) is an ineffective anti-arrhythmic drug target in cholinergic AF. Manipulating Na(+) current 'availability' might represent a viable anti-arrhythmic strategy in AF.
Cardiovascular Research 11/2010; 89(4):843-51. DOI:10.1093/cvr/cvq359 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it causes substantial mortality. The autonomic nervous system, and particularly the adrenergic/cholinergic balance, has a profound influence on the occurrence of AF. Adrenergic stimulation from catecholamines can cause AF in patients. In human atrium, catecholamines can affect each of the electrophysiological mechanisms of AF initiation and/or maintenance. Catecholamines may produce membrane potential oscillations characteristic of afterdepolarisations, by increasing Ca(2+) current, [Ca(2+)](i) and consequent Na(+)-Ca(2+) exchange, and may also enhance automaticity. Catecholamines might affect reentry, by altering excitability or conduction, rather than action potential terminal repolarisation or refractory period. However, which arrhythmia mechanisms predominate is unclear, and likely depends on cardiac pathology and adrenergic tone. Heart failure (HF), a major cause of AF, causes adrenergic activation and adaptational changes, remodelling, of atrial electrophysiology, Ca(2+) homeostasis, and adrenergic responses. Chronic AF also remodels these, but differently to HF. Myocardial infarction and AF cause neural remodelling that also may promote AF. beta-Adrenoceptor antagonists (beta-blockers) are used in the treatment of AF, mainly to control the ventricular rate, by slowing atrioventricular conduction. beta-Blockers also reduce the incidence of AF, particularly in HF or after cardiac surgery, when adrenergic tone is high. Furthermore, the chronic treatment of patients with beta-blockers remodels the atria, with a potentially antiarrhythmic increase in the refractory period. Therefore, the suppression of AF by beta-blocker treatment may involve an attenuation of arrhythmic activity that is caused by increased [Ca(2+)](i), coupled with effects of adaptation to the treatment. An improved understanding of the involvement of the adrenergic system and its control in basic mechanisms of AF under differing cardiac pathologies might lead to better treatments.
Archiv für Experimentelle Pathologie und Pharmakologie 12/2009; 381(3):235-49. DOI:10.1007/s00210-009-0474-0 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic heart failure increases the risk of atrial fibrillation (AF), with the prevalence of AF paralleling the severity of heart failure.1 Factors that underlie this increased susceptibility to AF may include electrical, structural, and neurohumoral changes.2 In AF, it is recognized that atrial electrophysiological remodelling occurs and contributes to the perpetuation of the arrhythmia, most notably the decrease of effective refractory period (ERP) which predisposes to re-entry by shortening the wavelength. Does heart failure cause similar changes in atrial electrophysiology that predispose to the arrhythmia?
Cardiovascular Research 09/2009; 84(2):180-1. DOI:10.1093/cvr/cvp299 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear.
This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF.
Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique.
The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 +/- 8 ms; 52 cells, 18 patients vs 233 +/- 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% +/- 4%, n = 15) than in those without LVSD (62% +/- 2%, n = 31; P <0.05). In cells from patients with LVEF <or= 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics.
LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF.
Heart rhythm: the official journal of the Heart Rhythm Society 05/2009; 6(4):445-51. DOI:10.1016/j.hrthm.2008.12.028 · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation (AF) causes substantial morbidity and mortality. It may be triggered and sustained by either reentrant or nonreentrant electrical activity. Human atrial cellular refractory period is shortened in chronic AF, likely aiding reentry. The ionic and molecular mechanisms are not fully understood and may include increased inward rectifier K(+) current and altered Ca(2+) handling. Heart failure, a major cause of AF, may involve arrhythmogenic atrial electrical remodeling, but the pattern is unclear in humans. Beta-blocker therapy prolongs atrial cell refractory period; a potentially antiarrhythmic influence, but the ionic and molecular mechanisms are unclear. The search for drugs to suppress AF without causing ventricular arrhythmias has been aided by basic studies of cellular mechanisms of AF. It remains to be seen whether such drugs will improve patient treatment.
Heart rhythm: the official journal of the Heart Rhythm Society 06/2008; 5(6 Suppl):S1-6. DOI:10.1016/j.hrthm.2008.01.016 · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 5-Hydroxytryptamine (5-HT) is proarrhythmic in atrial cells from patients in sinus rhythm (SR) via activation of 5-HT(4) receptors, but its effects in atrial cells from patients with atrial fibrillation (AF) are unknown. The whole-cell perforated patch-clamp technique was used to record L-type Ca(2+) current (I(CaL)), action potential duration (APD) and arrhythmic activity at 37 degrees C in enzymatically isolated atrial cells obtained from patients undergoing cardiac surgery, in SR or with chronic AF. In the AF group, 5-HT (10microM) produced an increase in I(CaL) of 115+/-21% above control (n=10 cells, 6 patients) that was significantly smaller than that in the SR group (232+/-33%; p<0.05; n=27 cells, 12 patients). Subsequent co-application of isoproterenol (1microM) caused a further increase in I(CaL) in the AF group (by 256+/-94%) that was greater than that in the SR group (22+/-6%; p<0.05). The APD at 50% repolarisation (APD(50)) was prolonged by 14+/-3ms by 5-HT in the AF group (n=37 cells, 14 patients). This was less than that in the SR group (27+/-4ms; p<0.05; n=58 cells, 24 patients). Arrhythmic activity in response to 5-HT was observed in 22% of cells in the SR group, but none was observed in the AF group (p<0.05). Atrial fibrillation was associated with reduced effects of 5-HT, but not of isoproterenol, on I(CaL) in human atrial cells. This reduced effect on I(CaL) was associated with a reduced APD(50) and arrhythmic activity with 5-HT. Thus, the potentially arrhythmogenic influence of 5-HT may be suppressed in AF-remodelled human atrium.
Journal of Molecular and Cellular Cardiology 01/2007; 42(1):54-62. DOI:10.1016/j.yjmcc.2006.08.007 · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated whether post-cardiac surgery (CS) new-onset atrial fibrillation (AF) is predicted by pre-CS atrial cellular electrophysiology, and whether the antiarrhythmic effect of beta-blocker therapy may involve pre-CS pharmacological remodeling.
Atrial myocytes were obtained from consenting patients in sinus rhythm, just prior to CS. Action potentials and ion currents were recorded using whole-cell patch-clamp technique. Post-CS AF occurred in 53 of 212 patients (25%). Those with post-CS AF were older than those without (67 +/- 2 vs 62 +/- 1 years, P = 0.005). In cells from patients with post-CS AF, the action potential duration at 50% and 90% repolarization, maximum upstroke velocity, and effective refractory period (ERP) were 13 +/- 4 ms, 217 +/- 16 ms, 185 +/- 10 V/s, and 216 +/- 14 ms, respectively (n = 30 cells, 11 patients). Peak L-type Ca(2+) current, transient outward and inward rectifier K(+) currents, and the sustained outward current were -5.0 +/- 0.5, 12.9 +/- 2.4, -4.1 +/- 0.4, and 9.7 +/- 1.0 pA/pF, respectively (13-62 cells, 7-19 patients). None of these values were significantly different in cells from patients without post-CS AF (P > 0.05 for each, 60-279 cells, 29-86 patients), confirmed by multiple and logistic regression. In patients treated >7 days with a beta-blocker pre-CS, the incidence of post-CS AF was lower than in non-beta-blocked patients (13% vs 27%, P = 0.038). Pre-CS beta-blockade was associated with a prolonged pre-CS atrial cellular ERP (P = 0.001), by a similar degree (approximately 20%) in those with and without post-CS AF.
Pre-CS human atrial cellular electrophysiology does not predict post-CS AF. Chronic beta-blocker therapy is associated with a reduced incidence of post-CS AF, unrelated to a pre-CS ERP-prolonging effect of this treatment.
[Show abstract][Hide abstract] ABSTRACT: Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca(2+) current (I(CaL)) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 muM prolonged the action potential duration at 50% repolarisation (APD(50): 54 +/- 10 vs. 28 +/- 5 ms; P < 0.05, N = 15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD(50), and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 microM) produced arrhythmic depolarisations (P < 0.05). Each was abolished by ET-1 at 10 nM (P < 0.05). ISO (0.05 microM) increased peak I(CaL) from -5.5 +/- 0.4 to -14.6 +/- 0.9 pA/pF (P < 0.05; N = 79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98 +/- 10% (P < 0.05), with no effect on basal I(CaL). Chronic treatment of patients with a beta-blocker did not significantly alter basal APD(50) or I(CaL), the increase in APD(50) or I(CaL) by 0.05 microM ISO, nor the subsequent reversal of this effect on APD(50) by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I(CaL), without affecting ERP and independently of beta-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure.
Journal of Molecular and Cellular Cardiology 05/2006; 40(5):717-24. DOI:10.1016/j.yjmcc.2006.01.012 · 4.66 Impact Factor