Rate Dependence Of Action Potential Duration Research Articles

Multichannel modulation of depolarizing and repolarizing ion currents increases the positive rate‐dependent action potential prolongation

Prolongation of the action potential duration (APD) could prevent reentrant arrhythmias if prolongation occurs at the fast excitation rates of tachycardia with minimal prolongation at slow excitation rates (i.e., if prolongation is positive rate-dependent). APD prolongation by current anti-arrhythmic agents is either reverse (larger APD prolongation at slow rates than at fast rates) or neutral (similar APD prolongation at slow and fast rates), which may not result in an effective anti-arrhythmic action. In this report we show that, in computer models of the human ventricular action potential, the combined modulation of both depolarizing and repolarizing ion currents results in a stronger positive rate-dependent APD prolongation than modulation of repolarizing potassium currents. A robust positive rate-dependent APD prolongation correlates with an acceleration of phase 2 repolarization and a deceleration of phase 3 repolarization, which leads to a triangulation of the action potential. A positive rate-dependent APD prolongation decreases the repolarization reserve with respect to control, which can be managed by interventions that prolong APD at fast excitation rates and shorten APD at slow excitation rates. For both computer models of the action potential, ICaL and IK1 are the most important ion currents to achieve a positive rate-dependent APD prolongation. In conclusion, multichannel modulation of depolarizing and repolarizing ion currents, with ion channel activators and blockers, results in a robust APD prolongation at fast excitation rates, which should be anti-arrhythmic, while minimizing APD prolongation at slow heart rates, which should reduce pro-arrhythmic risks.

Populations of in silico myocytes and tissues reveal synergy of multiatrial-predominant K+ -current block in atrial fibrillation.

Pharmacotherapy of atrial fibrillation (AF), the most common cardiac arrhythmia, remains unsatisfactory due to low efficacy and safety concerns. New therapeutic strategies target atrial-predominant ion-channels and involve multichannel block (poly)therapy. As AF is characterized by rapid and irregular atrial activations, compounds displaying potent antiarrhythmic effects at fast and minimal effects at slow rates are desirable. We present a novel systems pharmacology framework to quantitatively evaluate synergistic anti-AF effects of combined block of multiple atrial-predominant K+ currents (ultra-rapid delayed rectifier K+ current, IKur , small conductance Ca2+ -activated K+ current, IKCa , K2P 3.1 2-pore-domain K+ current, IK2P ) in AF. We constructed experimentally calibrated populations of virtual atrial myocyte models in normal sinus rhythm and AF-remodelled conditions using two distinct, well-established atrial models. Sensitivity analyses on our atrial populations was used to investigate the rate dependence of action potential duration (APD) changes due to blocking IKur , IK2P or IKCa and interactions caused by blocking of these currents in modulating APD. Block was simulated in both single myocytes and one-dimensional tissue strands to confirm insights from the sensitivity analyses and examine anti-arrhythmic effects of multi-atrial-predominant K+ current block in single cells and coupled tissue. In both virtual atrial myocytes and tissues, multiple atrial-predominant K+ -current block promoted favourable positive rate-dependent APD prolongation and displayed positive rate-dependent synergy, that is, increasing synergistic antiarrhythmic effects at fast pacing versus slow rates. Simultaneous block of multiple atrial-predominant K+ currents may be a valuable antiarrhythmic pharmacotherapeutic strategy for AF.

Simulation of the Effects of Extracellular Calcium Changes Leads to a Novel Computational Model of Human Ventricular Action Potential With a Revised Calcium Handling.

The importance of electrolyte concentrations for cardiac function is well established. Electrolyte variations can lead to arrhythmias onset, due to their important role in the action potential (AP) genesis and in maintaining cell homeostasis. However, most of the human AP computer models available in literature were developed with constant electrolyte concentrations, and fail to simulate physiological changes induced by electrolyte variations. This is especially true for Ca2+, even in the O’Hara-Rudy model (ORd), one of the most widely used models in cardiac electrophysiology. Therefore, the present work develops a new human ventricular model (BPS2020), based on ORd, able to simulate the inverse dependence of AP duration (APD) on extracellular Ca2+ concentration ([Ca2+]o), and APD rate dependence at 4 mM extracellular K+. The main changes needed with respect to ORd are: (i) an increased sensitivity of L-type Ca2+ current inactivation to [Ca2+]o; (ii) a single compartment description of the sarcoplasmic reticulum; iii) the replacement of Ca2+ release. BPS2020 is able to simulate the physiological APD-[Ca2+]o relationship, while also retaining the well-reproduced properties of ORd (APD rate dependence, restitution, accommodation and current block effects). We also used BPS2020 to generate an experimentally-calibrated population of models to investigate: (i) the occurrence of repolarization abnormalities in response to hERG current block; (ii) the rate adaptation variability; (iii) the occurrence of alternans and delayed after-depolarizations at fast pacing. Our results indicate that we successfully developed an improved version of ORd, which can be used to investigate electrophysiological changes and pro-arrhythmic abnormalities induced by electrolyte variations and current block at multiple rates and at the population level.

A model for human action potential dynamics in vivo

Computational modeling based on experimental data remains an important component in cardiac electrophysiological research, especially because clinical data such as human action potential (AP) dynamics are scarce or limited by practical or ethical concerns. Such modeling has been used to develop and test a variety of mechanistic hypotheses, with the majority of these studies involving the rate dependence of AP duration (APD) including APD restitution and conduction velocity (CV). However, there is very little information regarding the complex dynamics at the boundary of repolarization (or refractoriness) and reexcitability. Here, we developed a "minimal" ionic model of the human AP, based on in vivo human monophasic AP (MAP) recordings obtained during clinical programmed electrical stimulation (PES) to address the progressive decrease in AP take-off potential (TOP) and associated CV slowing seen during three tightly spaced extrastimuli. Recent voltage-clamp data demonstrating the effect of intracellular calcium on sodium current availability were incorporated and were required to reproduce large (>15 mV) elevations in take-off potential and progressive encroachment. Introducing clinically observed APD gradients into the model enabled us to replicate the dynamic response to PES in patients leading to conduction block and reentry formation for the positive, but not the negative, APD gradient. Finally, we modeled the dynamics of reentry and show that spiral waves follow a meandering trajectory with a period of ~180 ms. We conclude that our model reproduces a variety of electrophysiological behavior including the response to sequential premature stimuli and provides a basis for studies of the initiation of reentry in human ventricular tissue.NEW & NOTEWORTHY This work presents a new model of the action potential of the human which reproduces the complex dynamics during premature stimulation in patients.

Restitution and Stability of Human Ventricular Action Potential at High and Variable Pacing Rate

Despite the key role of beat-to-beat action potential (AP) variability in the onset of ventricular arrhythmias at high pacing rate, the knowledge of the involved dynamics and of effective prognostic parameters is largely incomplete. Electrical restitution (ER), the way AP duration (APD) senses changes in preceding cycle length (CL), has been used to monitor transition to arrhythmias. The use of standard ER (sER), though, is controversial, not always suitable for in vivo and only rarely for clinical applications. By means of simulations on a human ventricular AP model, I investigate the dynamics of APD at high pacing rate under sinusoidally, saw-tooth, and randomly variable pacing CLs. AP sequences were compared in terms of beat-to-beat restitution (btb-ER) and of the collections of sER curves generated from each beat. A definition of APD stability is also proposed, based on successive APD changes introduced in an AP sequence by a premature beat. The explored CL range includes values leading to APD alternans under constant pacing. Three different types of response to CL variability were found, corresponding to progressively higher rate of beat-to-beat CL changes. Low rates (∼1 ms/beat) generate a btb-ER dominated by steady-state rate dependence of APD (type 1), intermediate rates (∼5 ms/beat) lead to a btb-ER similar to a single sER (type 2), and high rates (∼20 ms/beat) to hysteretic btb-ER under periodic pacing and to a vertically spread btb-ER in the case of random pacing (type 3). Stability of AP repolarization always increases with the rate of CL changes. Thus, rather than looking at sER slope, which requires additional interventions during the recording of cardiac electrical activity, this study provides rationale for the use of btb-ER representations as predictors of repolarization stability under extreme pacing conditions, known to be critical for the arrhythmia development.

Calcium-Dependent Regulation of Potassium Channels in Cardiac Electrophysiology: A Computational Study

Calcium-dependent regulation of several potassium channels has recently been identified, but its relative importance for atrial and ventricular electrophysiology, and potentially arrhythmogenesis, is incompletely understood. Here, we employed computational modeling to study calcium-dependent regulation of potassium channels in cardiac electrophysiology. Calcium-dependent regulation of the basal inward-rectifier (IK1), slow delayed-rectifier (IKs), and small-conductance calcium-activated (ISK) potassium currents was incorporated into established atrial (Grandi-Bers) and ventricular (O’Hara-Rudy) cardiomyocyte models and compared to simulations without calcium-dependent regulation. Calcium-dependent activation of IK1 and ISK shortened atrial and ventricular action potential (AP) duration (APD), but their regulation by rate-dependent intracellular calcium loading only modestly affected APD rate dependence. The impact of calcium-dependent potassium current regulation was limited because 1) IKs has a minor impact on repolarization under basal conditions and 2) calcium-dependent activation of IK1, IKs and ISK is already almost saturated at slow rates. Accordingly, after incorporating a gain-of-function mutation that increased IKs, calcium-dependent IKs activation reduced APD without modulating APD rate dependence. Furthermore, simulated L-type calcium channel inhibition lowered intracellular calcium, decreasing calcium-dependent regulation of potassium currents and significantly prolonging APD. Finally, simulated diastolic sarcoplasmic reticulum calcium releases produced delayed afterdepolarizations in the ventricular model and triggered APs in the atrial model. Calcium-dependent augmentation of potassium currents did not affect the threshold for triggered atrial APs, but significantly reduced afterdepolarization amplitude in the ventricle due to a calcium-dependent increase in IK1. This effect was not visible in the atrial model due to the smaller IK1 and the higher sensitivity for triggered APs. Taken together, physiologic calcium-dependent potassium-channel regulation has a modest impact on basal atrial and ventricular electrophysiology, but may be further enhanced during conditions of abnormal repolarization or impaired calcium handling, and as such may play a role in cardiac arrhythmogenesis.

Andrographolide inhibits arrhythmias and is cardioprotective in rabbits.

Andrographolide has a protective effect on the cardiovascular system. To study its cardic-electrophysiological effects, action potentials and voltage-gated Na+ (INa), Ca2+ (ICaL), and K+ (IK1, IKr, Ito and IKur) currents were recorded using whole-cell patch clamp and current clamp techniques. Additionally, the effects of andrographolide on aconitine-induced arrhythmias were assessed on electrocardiograms in vivo. We found that andrographolide shortened action potential duration and reduced maximum upstroke velocity in rabbit left ventricular and left atrial myocytes. Andrographolide attenuated rate-dependence of action potential duration, and reduced or abolished delayed afterdepolarizations and triggered activities induced by isoproterenol (1 μM) and high calcium ([Ca2+]o=3.6 mM) in left ventricular myocytes. Andrographolide also concentration-dependently inhibited INa and ICaL, but had no effect on Ito, IKur, IK1, or IKr in rabbit left ventricular and left atrial myocytes. Andrographolide treatment increased the time and dosage thresholds of aconitine-induced arrhythmias, and reduced arrhythmia incidence and mortality in rabbits. Our results indicate that andrographolide inhibits cellular arrhythmias (delayed afterdepolarizations and triggered activities) and aconitine-induced arrhythmias in vivo, and these effects result from INa and ICaL inhibition. Andrographolide may be useful as a class I and IV antiarrhythmic therapeutic.

Larger rate dependence of late sodium current in cardiac Purkinje cells: A potential link to arrhythmogenesis

Purkinje cells (PCs) have a steeper rate dependence of repolarization and are more susceptible to arrhythmic activity than do ventricular myocytes (VMs). Late sodium current (INaL) is rate dependent and contributes to rate dependence of repolarization. This study sought to test our hypothesis that PCs have a larger rate dependence of INaL, contributing to their steeper rate dependence of repolarization and highersusceptibility to arrhythmic activity, than do VMs. INaL was recorded in isolated rabbit PCs and VMs with the whole-cell patch clamp technique. Action potential was examined using the microelectrode technique. Compared with VMs, PCs exhibited a significantly larger rate dependence of INaL with a larger INaL to basic cycle length (BCL) slope. Moreover, PCs had a larger rate dependence of INaL decay and slower recovery kinetics. Interestingly, the larger rate dependence of INaL matched to a steeper rate dependence of action potential duration (APD) in PCs. The INaL blocker tetrodotoxin significantly blunted, while the INaL enhancer anemone toxin (ATX-II) significantly increased, the rate dependence of INaL and APD in PCs and VMs. In the presence of ATX-II, the rate dependence of INaL in PCs was markedly larger than that in VMs, causing a much steeper rate dependence of APD in PCs. Accordingly, PCs exhibited greater rate-dependent electrical instability and were more prone to ATX-II-induced early afterdepolarizations, which were completely inhibited by the INaL inhibitor ranolazine. PCs have a significantly larger rate dependence of INaL than do VMs because of distinctive INaL decay and recovery kinetics, which contributes to their larger rate adaptation, and simultaneously predisposes them to a higher risk of arrhythmogenesis.

Comparison between Hodgkin–Huxley and Markov formulations of cardiac ion channels

When simulating the macroscopic current flowing through cardiac ion channels, two mathematical formalisms can be adopted: the Hodgkin–Huxley model (HHM) formulation, which describes openings and closings of channel ‘gates’, or the Markov model (MM) formulation, based on channel ‘state’ transitions. The latter was first used in 1995 to simulate the effects of mutations in ionic currents and, since then, its use has been extended to wild-type channels also. While the MMs better describe the actual behavior of ion channels, they are mathematically more complex than HHMs in terms of parameter estimation and identifiability and are computationally much more demanding, which can dramatically increase computational time in large-scale (e.g. whole heart) simulations. We hypothesize that a HHM formulation obtained from classical patch-clamp protocols in wild-type and mutant ion channels can be used to correctly simulate cardiac action potentials and their static and dynamic properties. To validate our hypothesis, we selected two pivotal cardiac ionic currents (the rapid delayed rectifier K+ current, IKr, and the inward Na+ current, INa) and formulated HHMs for both wild-type and mutant channels (LQT2-linked T474I mutation for IKr and LQT3-linked ΔKPQ mutation for INa). Action potentials were then simulated using the MM and HHM versions of the currents, and the action potential waveforms, biomarkers and action potential duration rate dependence properties were compared in control conditions and in the presence of physiological variability. While small differences between ionic currents were found between the two models (correlation coefficient ρ>0.92), the simulations yielded almost identical action potentials (ρ>0.99), suggesting that HHMs may also be valid to simulate the effects of mutations affecting IKr and INa on the action potential.

The Contribution of Ionic Currents to Rate-Dependent Action Potential Duration and Pattern of Reentry in a Mathematical Model of Human Atrial Fibrillation.

Persistent atrial fibrillation (PeAF) in humans is characterized by shortening of action potential duration (APD) and attenuation of APD rate-adaptation. However, the quantitative influences of particular ionic current alterations on rate-dependent APD changes, and effects on patterns of reentry in atrial tissue, have not been systematically investigated. Using mathematical models of human atrial cells and tissue and performing parameter sensitivity analysis, we evaluated the quantitative contributions to action potential (AP) shortening and APD rate-adaptation of ionic current remodeling seen with PeAF. Ionic remodeling in PeAF was simulated by reducing L-type Ca2+ channel current (ICaL), increasing inward rectifier K+ current (IK1) and modulating five other ionic currents. Parameter sensitivity analysis, which quantified how each ionic current influenced APD in control and PeAF conditions, identified interesting results, including a negative effect of Na+/Ca2+ exchange on APD only in the PeAF condition. At high pacing rate (2 Hz), electrical remodeling in IK1 alone accounts for the APD reduction of PeAF, but at slow pacing rate (0.5 Hz) both electrical remodeling in ICaL alone (-70%) and IK1 alone (+100%) contribute equally to the APD reduction. Furthermore, AP rate-adaptation was affected by IKur in control and by INaCa in the PeAF condition. In a 2D tissue model, a large reduction (-70%) of ICaL becomes a dominant factor leading to a stable spiral wave in PeAF. Our study provides a quantitative and unifying understanding of the roles of ionic current remodeling in determining rate-dependent APD changes at the cellular level and spatial reentry patterns in tissue.

Ventricular hypertrophy amplifies transmural dispersion of repolarization by preferentially increasing the late sodium current in endocardium

BackgroundThe late sodium current (INa-L) contributes importantly to rate-dependent change in action potential duration (APD) and transmural dispersion of repolarization (TDR). However, little is known about the mechanisms of increased APD rate-dependence and amplified TDR in left ventricular hypertrophy (LVH) and failure. The purpose of this study was to investigate the role of INa-L in rate-adaptation of transmural APD heterogeneity. MethodsAPD, its rate-dependence and INa-L current were examined in myocytes isolated from the endocardium and epicardium of the control and LVH rabbits. AP was recorded using the standard microelectrode technique, and INa-L was recorded using the whole-cell patch clamp technique. ResultsEarly afterdepolarizations (EADs) were frequently recorded in the isolated myocytes of the LVH rabbits but not in those of controls. LVH prolonged APD more significantly in the endocardial myocytes than in the epicardium (31.7±3.4 vs. 21.6±1.5% n=6, p<0.05), leading to a marked increase in TDR. LVH endocardial myocytes exhibited a greater rate-dependent change in APD compared to the epicardial myocytes. INa-L densities were significantly increased in both LVH endocardium and epicardium. However, LVH increased the INa-L density preferentially in the endocardial myocytes compared to the epicardial myocytes (54.5±4.8% vs. 39.2±3.3%, n=6, p<0.05). ConclusionsOur results demonstrate that LVH increased the INa-L preferentially in the endocardium over the epicardium, which contributes importantly to the stronger rate-dependent change in repolarization and longer APD in the endocardium. This results in an amplified TDR capable of initiating EAD and ventricular arrhythmias.

Overcoming Reverse Rate Dependence in Ventricular Cell Models

Reverse rate dependence (RRD) is a problematic property of antiarrhythmic drugs that prolong the action potential duration (APD). The prolongation caused by RRD agents will increase at slow rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmogenesis at slow. The opposite property, forward rate dependence (FRD), would theoretically overcome these parallel problems, yet FRD antiarrhythmics remain elusive. Moreover, there is evidence that RRD is an intrinsic property of perturbations to the action potential (AP). We have addressed the possibility of FRD by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we were able to simultaneously predict the rate-dependent effects on the APD of changes in any of an average of 40 parameters per model. The analysis produced several important results. First, while models often display RRD, a variety of ion current perturbations do in fact produce FRD. Second, additional simulations of FRD perturbations provide mechanistic insight into how FRD behavior can be produced. For instance, increasing L-type calcium conductance (GCaL) is FRD when accompanied by concomitant, indirect, rate-dependent changes in slow delayed rectifier current (IKs). Third, comparisons of results between models revealed that changes in IKs are almost always RRD whereas changes in GCaL or the Na-K pump can potentially be FRD. Fourth, the general capacity for FRD correlates strongly with the degree of rate-dependent change in AP shape. Models that display minimal changes in AP shape with rate have little capacity for FRD whereas models with large shape changes have considerable FRD potential. Overall, this study provides new insight into the determinants of APD rate dependence and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.

Impaired Na+-dependent regulation of acetylcholine-activated inward-rectifier K+ current modulates action potential rate dependence in patients with chronic atrial fibrillation

Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K+ currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na+ ([Na+]i) enhances IK,ACh in experimental models but the effect of [Na+]i-dependent regulation of inward-rectifier K+ currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na+]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na+]i in SR. This [Na+]i-dependent IK,ACh regulation was absent in cAF. Including [Na+]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na+]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na+]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na+-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”.

Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure

Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na+ current (INaL) is relevant and is currently under investigation. In this study we examined the role of INaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of INaL. A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human INaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for INaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca2+ transient. A mechanistic investigation of intracellular Na+ accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na+/K+ pump, the Na+/Ca2+ exchanger and INaL. The results of the simulations also showed that in failing myocytes, the enhancement of INaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the INaL prolong APD and alter Ca2+ transient facilitating the development of early afterdepolarizations. An enhanced INaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca2+]i homeostasis of failing myocytes.

Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation

Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca2+ versus voltage dependent inactivation of L-type Ca2+ current (ICaL); kinetics for the transient outward, rapid delayed rectifier (IKr), Na+/Ca2+ exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by IKr block during slow pacing, and AP and Ca2+ alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling. INaCa linked Ca2+ alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na+]i, via its modulation of the electrogenic Na+/K+ ATPase current. At fast pacing rates, late Na+ current and ICaL were also contributors. APD shortening during restitution was primarily dependent on reduced late Na+ and ICaL currents due to inactivation at short diastolic intervals, with additional contribution from elevated IKr due to incomplete deactivation.

Contribution of late sodium current (INa-L) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents

Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization. The purpose of this study was to examine the role of the late sodium current (I(Na-L)) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents. The effects of I(Na-L) blockade, I(Na-L) enhancement, I(Kr) blockade, and changes in extracellular potassium concentration ([K(+)](o)) on rate adaptation of the QT interval and action potential duration (APD) were examined in isolated rabbit ventricular wedges and single myocytes. Rate dependence of I(Na-L), delayed rectifier potassium current (I(K)), and L-type calcium current (I(Ca)) was determined using a whole-cell, voltage clamp technique. At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when [K(+)](o) remained constant. The rate dependence of APD was significantly enhanced by reduction of [K(+)](o) from 4 to 1 mM or by I(Na-L) enhancement but was markedly blunted by the selective sodium channel blocker tetrodotoxin. The I(Kr) blocker dofetilide (3 nM) amplified the QT to basic cycle length slope (71.2 ± 13.1 ms/s vs 35.1 ± 8.8 ms/s in control, n = 4, P <.05). This reverse use-dependence was abolished by tetrodotoxin at 5 μM (11.4 ± 4.3 ms/s, n = 4, P <.01). There were no significant differences in I(Ca) or I(K) over the range of basic cycle lengths from 2,000 to 500 ms. However, I(Na-L) exhibited a significant rate-dependent reduction. I(Na-L) is sensitive to rate change due to its slow inactivation and recovery kinetics and plays a central role in the rate dependence of APD/QT and in the reverse use-dependence of select APD/QT-prolonging agents.

Self‐augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential: implications for reverse rate dependency

The aims of the present work were to study the mechanism of the reverse rate dependency of different interventions prolonging cardiac action potential duration (APD). The reverse rate-dependent lengthening effect of APD-prolonging interventions and the possible involvement of I(Kr) (rapid component of the delayed rectifier potassium current) and I(K1) (inward rectifier potassium current) were studied by using the standard microelectrode and the whole-cell patch-clamp techniques in dog multicellular ventricular preparations and in myocytes isolated from undiseased human and dog hearts. All applied drugs--dofetilide (1 micromol.L(-1)), BaCl(2) (10 micromol.L(-1)), BAY-K-8644 (1 micromol.L(-1)), veratrine (1 microg.mL(-1))--lengthened APD in a reverse rate-dependent manner regardless of their mode of action, suggesting that reverse rate dependency may not represent a specific mechanism of APD prolongation. The E-4031-sensitive current (I(Kr)) and the Ba(2+)-sensitive current (I(K1)) were recorded during repolarizing voltage ramps having various steepness and also during action potential waveforms with progressively prolonged APD. Gradually delaying repolarization results in smaller magnitude of I(Kr) and I(K1) currents at an isochronal phase of the pulses. This represents a positive feedback mechanism, which appears to contribute to the reverse rate-dependent prolongation of action potentials. Action potential configuration may influence the reverse rate-dependent APD prolongation due to the intrinsic properties of I(Kr) and I(K1) currents. Drugs lengthening repolarization by decreasing repolarizing outward, or increasing depolarizing inward, currents are expected to cause reverse rate-dependent APD lengthening with high probability, regardless of which current they modify.

Rate-dependent propagation of cardiac action potentials in a one-dimensional fiber

Action potential duration (APD) restitution, which relates APD to the preceding diastolic interval (DI), is a useful tool for predicting the onset of abnormal cardiac rhythms. However, it is known that different pacing protocols lead to different APD restitution curves (RCs). This phenomenon, known as APD rate dependence, is a consequence of memory in the tissue. In addition to APD restitution, conduction velocity restitution also plays an important role in the spatiotemporal dynamics of cardiac tissue. We present results concerning rate-dependent restitution in the velocity of propagating action potentials in a one-dimensional fiber. Our numerical simulations show that, independent of the amount of memory in the tissue, the wave-back velocity exhibits pronounced rate dependence and the wave-front velocity does not. Moreover, the discrepancy between wave-back velocity RCs is most significant for a small DI. We provide an analytical explanation of these results, using a system of coupled maps to relate the wave-front and wave-back velocities. Our calculations show that rate-dependent wave-back velocity can be present even if neither APD nor wave-front velocity exhibits rate dependence.

Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade.

1. The kinetics of shortening of action potential duration (APD) following an increase in pacing rate, from 2 to 3.3 Hz, was characterized in guinea-pig ventricular preparations. Terikalant (RP62719), an inhibitor of the inwardly rectifying K+ current (IK1), and dofetilide, a specific inhibitor of the rapidly activating delayed-rectifier current (IKr), were applied to determine the effect of inhibition of these ion currents on slow APD shortening. 2. Action potentials were recorded from isolated guinea-pig ventricular myocytes using the perforated-patch patch-clamp technique, and monophasic action potentials were recorded from Langendorff-perfused guinea-pig ventricles using a contact epicardial probe. 3. Under control conditions, after an increase in pacing rate, APD immediately decreased, and then shortened slowly with an exponential time course. In ventricular myocytes, the time constant of this exponential shortening was 28+/-4 s and the amount of slow shortening was 21.9+/-0.9 ms (n=8) for an increase in rate from 2 to 3.3 Hz. Similar values were observed in Langendorff-perfused ventricles. 4. Terikalant dose-dependently increased APD and the increase was enhanced by rapid pacing ('positive' rate-dependence). The drug dose-dependently decreased the time constant of shortening and amount of slow APD shortening. In contrast, dofetilide, an inhibitor of IKr, which shows 'reverse' rate-dependent APD widening, had no significant effect on the time constant or amount of slow shortening. 5. These observations suggest that IK1 plays a role in rate-dependent shortening of APD. The results appear to support the hypothesis that 'reverse' rate-dependent effects of IKr blockers are due to these drugs not affecting the ion current(s) mediating intrinsic rate-dependent slow shortening of APD.

Electrophysiological aspects of changes in heart rate.

Cardiac action potentials undergo characteristic changes in response to increasing pacing frequency, i.e., the resting potential becomes less negative (depolarization), the amplitude decreases, and the action potential duration (APD) shortens. The electrophysiological properties of the major cardiac inward and outward currents are discussed with respect to their possible contribution to rate-dependent changes in AP shape. Short diastolic intervals may not allow sufficient time for channel recovery. Incomplete recovery from inactivation will reduce both inward (INa, ICa) and outward (Ito) currents and hence lead to APD shortening or prolongation, respectively. Incomplete deactivation during diastole will increase current and, in the case of the delayed rectifier IKs, produces rate-dependent APD shortening. Heterogeneity in current density of myocytes from various regions within the ventricular wall complicates the direct translation of rate-dependent changes in APD into changes of the QT interval of the ECG. With increasing rates of stimulation, K+ accumulates within the tubular system. Membrane depolarization may be attributed to this frequency-dependent increase in [K+]o, whereas APD shortening is not mimicked by high [K+]o. Nevertheless, the various cardiac K+ channels differ in their sensitivity to extracellular [K+]o. Some of the frequency-dependent effects of drugs with class III action may be related to an influence of [K+]o on drug potency to block K+ channels.