Integrative Physiology

Human Atrial Action Potential and Ca2+ ModelNovelty and Significance

Sinus Rhythm and Chronic Atrial Fibrillation

Eleonora Grandi, Sandeep V. Pandit, Niels Voigt, Antony J. Workman, Dobromir Dobrev, José Jalife, Donald M. Bers
https://doi.org/10.1161/CIRCRESAHA.111.253955
Circulation Research. 2011;109:1055-1066
Originally published October 13, 2011

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Abstract

Rationale: Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca2+ transport in remodeled human atrium, but appropriate models are limited.

Objective: To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model.

Methods and Results: Atria versus ventricles have lower IK1, resulting in more depolarized resting membrane potential (≈7 mV). We used higher Ito,fast density in atrium, removed Ito,slow, and included an atrial-specific IKur. INCX and INaK 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 ICaL, Ito, IKur and SERCA, and increased IK1,IKs and INCX. 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 ICaL 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 INaK and INCX causes rate-dependent atrial AP shortening. Blocking IKur to mimic Kv1.5 loss-of-function increased [Ca2+]i and caused early afterdepolarizations under adrenergic stress, as observed experimentally.

Conclusions: 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.

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia observed clinically, and is the main cause of embolic stroke.1 The mechanisms underlying AF remain unclear, and AF is thought to be maintained either via ectopic foci, multiple wavelets, or fibrillatory conduction emanating from a small number of stable rotors.2 Electrical and structural remodeling have emerged as key elements in the development of the AF substrate (eg, the tendency for persistence of AF).3 Electrical remodeling includes changes in Ca2+ and K+ currents leading to shortening of the action potential (AP) duration (APD) and loss of APD rate-dependent adaptation, whereas structural remodeling leads to changes in atrial myocyte and tissue morphology (eg, cell hypertrophy, fibrosis).3–5

At present, mechanisms leading to perpetuation of AF are still undetermined. Growing experimental evidence points to abnormal intracellular Ca2+ handling as a key mediator in AF pathophysiology,6,7 but the mechanism through which Ca2+-related abnormalities can lead to the occurrence and maintenance of AF are poorly understood. Models of human atrial myocytes have been developed and used to gain mechanistic insights into human atrial cell physiology and pathophysiology8–10; however, none of these included detailed descriptions of Ca2+ (or Na+) regulatory processes. A recent simulation study incorporated and studied the subcellular nature of Ca2+ homeostasis and its relation to human atrial action potentials11; however, the role of Ca2+ in mediating AF was not investigated.

We recently developed a model of the human ventricular myocyte AP and Ca2+ transient (CaT),12 a major advance over prior human ventricular models in robustly describing excitation-contraction coupling, and the model was extensively validated against a broad range of experimental data.

The aims of the present study were 2-fold: (1) to derive a new human atrial cell model with detailed Ca2+ handling, by implementing experimentally documented structural and ionic differences in atrial versus ventricular cells13 and starting from our recently published model of human ventricular myocytes12; (2) to study how Ca2+ homeostasis is involved in abnormal APs seen in chronic AF (cAF) and AF related to adrenergic stress in patients with Kv1.5 mutations.14 Ionic currents in the ventricular model were modified based on experimental data comparing protein expression and function in atrial versus ventricular myocytes. Importantly, we utilized new experimental data addressing the poorly understood molecular basis of impaired atrial Ca2+ signaling in cAF to constrain our model parameters.

We validated our model by testing its ability to recapitulate a wide range of physiological behaviors observed in experiments. We next investigated the mechanisms of APD and CaT rate-adaptation in sinus rhythm and cAF, and assessed the effects of blocking the atrial-specific ultrarapid K+ current (IKur) in the absence and presence of β-adrenergic activation, to understand arrhythmogenesis in AF related to Kv1.5 channelopathy and adrenergic stress. Finally, right-to-left gradients in repolarizing currents were also included in the model, since in a number of instances the driving source of the AF (reentry or foci) is located in the left atrium.2

Methods

Cellular [Ca2+]i and electrophysiological methods are described in the Online Supplement available at http://circres.ahajournals.org and were used to tune our model and for validation. The Table shows key changes made in our new human atrial model versus our ventricular myocyte model,12 to account for ionic remodeling in cAF, and to simulate the effects of β-adrenergic and cholinergic stimulation. Further details are in Online Supplement, including formulation of IKur block by AVE0118.

Model differential equations were implemented in Matlab (Mathworks Inc, Natick, MA) and solved numerically using a variable order solver (ode15s). APDs were obtained after pacing digital cells at indicated frequencies at steady-state. APD was measured as the interval between AP upstroke and 90% repolarization level (APD90).

Results

The baseline alterations to our ventricular cell model resulted in a typical Type-3 human atrial AP morphology15 (Figure 1A, right panel). The higher density of K+ currents that are active in AP phase 1 (early repolarization, Ito+IKur) confers the AP a triangular shape lacking a plateau phase. We have investigated the impact on AP shape of varying Ito and IKur densities, and quantified the changes in the plateau potential, which gets more depolarized as the degree of K+ channel blockade increases (Online Figure I, Online Supplement). AP waveform also feeds back onto ion channel gating determining notable differences in atrial currents. For example, although atrial Ito is almost twice as large in voltage clamp experiments (see Online Figure II), in current clamp conditions it is comparable to ventricular Ito,fast (Figure 1G, right versus left panel). Maximal velocity of AP upstroke was comparable to that measured in experiments of ≈140 V/s (versus 250 V/s in cAF)16 and was smaller than in the ventricular cell model (372 V/s in the epicardial cell model paced at 1 Hz12). In fact, INa is remarkably reduced in atrial versus ventricular cells (Figure 1C, right versus left panel) during the AP, due to more inactivated channels (because of slower recovery from inactivation at more depolarized atrial resting membrane potential). Although IKr or IKs were not modified versus ventricular myocytes, the spiky AP reduced net IKr and IKs (Figure 1E and 1F). It is noteworthy that the reduction of INCX from the ventricular model resulted in larger INCX in the atrial model (Figure 1K). This is presumably because of the short early repolarization in atrium and the slightly larger CaT, both favoring inward INCX. ICaL is similar in atria and ventricle in voltage-clamp conditions, but the AP shape causes ICaL to be much larger in atrial versus ventricular myocyte model (Figure 1D). IK1 is smaller in atria, consistent with its lower maximal conductance. INaK is decreased (not as much as its pump rate because the higher [Na+]i, 9.1 in atrium versus 8.2 mmol/L in ventricle at 1 Hz pacing rate, activates the pump more).

Figure 1.
Figure 1.

Steady-state human cardiac AP and major underlying currents and CaT at 1-Hz pacing (A through K) for ventricle (left) and atrium (right). Thicker traces represent currents for which density was increased (in atria versus ventricle or vice versa) because of altered maximal conductance or pump rate to generate the atrial cell model from the ventricular cell model.

View this table:
Table.

Main Changes to our Human Ventricular Model to Generate the Human Atrial Model, Simulate cAF, and β-Adrenergic Stimulation

A typical Ca2+ transient is shown in Figure 1B (right panel): at 1-Hz pacing rate, diastolic [Ca2+]i is 207 nmol/L and peaks at 462 nmol/L. Simultaneous ICaL and [Ca2+]i measurements in human atrial myocytes at physiological temperature are shown in Figure 2D through 2G and compared with simulated traces (Figure 2A and 2B; 0.5 Hz). Simulated CaT amplitude and rate of CaT decay matched the experimental data (Figure 2B gray line versus E, and Figure 2H and 2I), as did peak ICaL (−6.47 A/F versus −6.78±0.36 in experiments, Figure 2A gray line versus D). When cAF was simulated, by accounting for ion channel remodeling as illustrated in the methods, ICaL was greatly diminished (Figure 2A, black versus gray lines), as shown in experiments (Figure 2D versus F).4,17,18 The reduced ICaL could explain the reduced sarcoplasmic reticulum (SR) Ca2+ release and CaT amplitude (Figure 2B, 2E, 2G, and 2H), even if SR Ca2+ content were unaltered. However, the reduced ICaL and SERCA function (rate of twitch [Ca2+]i decline; Figure 2I) and the elevated SR Ca2+ leak and NCX function (greater INCX for a given [Ca2+]i; Figure 3A through 3G) all tend to lower SR Ca2+ content in cAF, which is apparent in the model (but not significantly so in the experiments; Figure 3H).

Figure 2.
Figure 2.

Ca2+ current (A) and transient (B) were simulated for a voltage-clamp protocol (A, inset) where membrane potential was stepped to +10 mV for 100 ms after a 100-ms duration ramp to −40 mV to inactivate fast INa from a holding potential of −80 mV (pacing at 0.5 Hz). For cAF Ca2+ current amplitude is small compared with sinus rhythm (A, gray versus black traces), as in experiments at physiological temperature in human atrial cells (D versus F, protocol in D, inset). This leads to a strong reduction in CaT amplitude (B and H), also observed experimentally (E versus G, H), which also limits the increase in junctional [Ca2+] (C). Twitch [Ca2+]i decline rate (indicative of SERCA function) is slowed in cAF, in agreement with experiments (I).

Figure 3.
Figure 3.

Caffeine-induced CaT and INCX in sinus rhythm (A and C) and cAF (B and D) reveal a smaller SR Ca2+ content in cAF compared with sinus rhythm (H). The slope of NCX current versus [Ca2+]i during the decaying phase of the caffeine-evoked CaT (E and F) was higher in cAF versus sinus rhythm (G).

We next tested the response of our model to changes in pacing frequency. Simulated human atrial cell APs under baseline conditions (Figure 4D) shorten with faster pacing rates (Figure 4J, black circles) as shown in atrial myocytes from patients in normal sinus rhythm (Figure 4A and 4M, black circles).19 To illustrate the effect of a reduction in ICaL Van Wagoner et al19 recorded APs from the same myocytes at various cycle lengths in the presence of the ICaL blocker nifedipine (10 μmol/L), showing little rate-dependent change in APD (Figure 4C and 4 M, gray open circles). Li and Nattel20 obtained analogous results. Similarly, simulated APs after 50% ICaL block (Figure 4F) exhibited impaired APD rate-adaptation (Figure 4J, gray open circles). Myocytes from chronic AF patients (Figure 4B) are characterized by shorter APD90 values,16,19,21–23 with less variation as a function of cycle length than control (sinus rhythm) myocytes (Figure 4M, squares).4,16,19,22,23 Analogously, our cAF model predicts shorter APs than sinus rhythm (solid versus dashed line in Figure 4D, inset), and reduced adaptation to changes in pacing frequency (Figure 4J, squares). At 4-Hz pacing, AP duration alternates (Figure 4E, and so does [Ca2+]i in Figure 4H). The sinus rhythm model exhibits this behavior at higher frequency (Figure 4O at 6-Hz pacing rate).

Figure 4.
Figure 4.

APs recorded at different cycle lengths in a control human atrial myocyte (A), in a cell from cAF patient (B), and in the same control myocyte exposed to Ca2+ channel block (10 μmol/L nifedipine, C).19 Simulated steady-state AP and CaT traces are shown for pacing frequencies 0.5, 1, 2, 3, and 4 Hz, for sinus rhythm (sr, D and G), cAF (E and H), and sr with 50% ICaL block (F and I). Simulated APD90 (J) decreases at increasing pacing frequency in sr, but rate-adaptation is impaired in cAF or with ICaL partially inhibited. Experimental results19 are also reported (M). Predicted CaT amplitude (K) and [Na+]i (L) increase with frequency in sr cells, in agreement with changes in aequorin signals in human atrial muscle strips (N, gray circles). Frequency dependence of [Ca2+]i, [Na+]i and force is limited in cAF or when ICaL is partially inhibited (K, L, N). Alternating long and short APs and CaTs (O) are predicted in sr and cAF cells paced at 6 Hz.

The model predicts a positive dependency of CaT amplitude on the pacing rate in sinus rhythm (Figure 4G and 4K, black circles), which is in agreement with intracellular [Ca2+] measurements by aequorin light signals (Figure 4N, gray circles and dashed line)24 and twitch force measurements (Figure 4N, open circles and solid line).25 Positive dependency is impaired when ICaL is partially inhibited (Figure 4F and 4K, gray open circles) and in cAF (Figure 4E and 4K, squares). Similarly, atrial myocytes from patients with cAF show impaired contractility (Figure 4N, squares).25 Our model also predicts the increase of intracellular [Na+] with increasing pacing frequency, as shown in Figure 4L (and Online Figure III, A), which is more limited in cAF and with inhibition of ICaL compared with sinus rhythm (squares and gray open circles versus black circles).

Figure 5 and Online Figure III show that [Na+]i is critical for APD rate-adaptation. Time courses of APD90 and [Na+]i changes subsequent to an increase in pacing frequency from 0.5 to 1 Hz (Online Figure III, C) suggest that non steady-state measurements (before [Na+]i slowly reaches steady-state) may give rise to highly variable experimental APD adaptation curves. Moreover, if [Na+]i is clamped in the model, the APD rate adaptation is nearly abolished (Figure 5A). Simulation of partial block of NKA causes a biphasic APD response (Figure 5D): first, APD prolongation by acute NKA current block, then as [Na+]i rises it increases outward NKA causing APD shortening. Importantly, we validated these model predictions in isolated human atrial myocytes challenged with strophanthidin (10 μmol/L). Acute NKA inhibition was confirmed by abrupt and relatively sustained depolarization of resting membrane potential (Figure 5C). Figure 5C shows a typical time course of APD90 from a representative cell and pooled data (n=10). Strophanthidin application produces an initial marked increase and subsequent decrease in APD90 (Figure 5C, right). Similar behavior has been described in guinea pig ventricular myocytes,26 human atrial fibers,27 and rabbit atrial myocytes (not shown).

Figure 5.
Figure 5.

A, APD90 decreases with increasing pacing frequency from 0.5 to 2 Hz and [Na+]i changes freely (black circles). If the atrial myocyte is paced at low frequency, but with [Na+]i clamped at 10.5 mmol/L (level predicted at fast rate), APD90 shortens (white circles) to APD90 value at 2 Hz. Similarly, when the atrial myocyte is paced at fast rate and [Na+]i is clamped to the low level predicted with slow pacing, APD90 lengthens (gray circles) to APD90 value at 0.5 Hz. B, NKA and NCX currents at 0.5- and 2-Hz pacing rate. Experimental and simulated time courses of APD90 (C and D), resting membrane potential (C), and [Na+]i (D) after application of strophanthidin (C) and partial (50%) INaK block (D, at time 0) at 0.5-Hz pacing rate. Effect of strophanthidin on mean APD90 (C, right). P<0.05 and **P<0.001 with paired t test and Bonferroni correction (n=10 myocytes from 5 patients).

Blockade of the atrial specific current IKur has been proposed to improve atrial contractility without increasing the risk of ventricular arrhythmias. In fact, in human atrial myocardium, block of IKur results in a prolongation and elevation of the AP plateau, which elicit a positive inotropic effect.28,29 Thus, we assessed the impact of IKur block (modeled as shown in Online Methods and Online Figure IV) on APD and CaT (Figure 6 and Online Figure V). Moderate blockade of IKur (by 25% to 50%) increases CaT amplitude (Figure 6B) with little effects on APD (Figure 6A) both in sinus rhythm and cAF models, in agreement with experimental results (Figure 6A and 6B, insets).28,29 Enhancement of CaT amplitude is greatly increased when IKur is more fully (75% to 100%) blocked (Figure 6B), paralleled by AP prolongation (Figure 6A) in agreement with14 (see also Figure 6D, inset). A more moderate increase in CaT amplitude is also predicted in cAF. In Figure 6C the predicted impact of various degrees of IKur block on sinus rhythm and cAF CaT amplitude (gray symbols and axis) shows good agreement with the reported effect of the IKur inhibitor AVE0118 on contractile force of atrial trabeculae from patients in sinus rhythm and in AF (black symbols and axis).29

Figure 6.
Figure 6.

Effect of different degrees of IKur block on simulated human atrial APD (A) and CaT (B and C) in sinus rhythm (sr) and cAF is compared with experimental AP recordings28 (A, inset) and twitch force measurements29 (B, inset, and C). D, ISO application causes EADs (green dashed line) in the presence of IKur blockade, as shown experimentally by Olson et al (D, inset).14 Blocking IKs does not have the same deleterious effect (red solid line).

To study AF associated with Kv1.5 mutation during β-adrenergic activation, we also investigated the effect of adrenergic stimulation on atrial AP (Figure 6D) by incorporating steady-state effects of PKA-dependent phosphorylation on ICa, IKs, IKur, PLN-SERCA2a, RyR2, troponin Ca2+ affinity, and Na/K-ATPase (see Online Supplement). In our simulations, administration of isoproterenol (ISO) causes the CaT amplitude to increase (by ≈65%, not shown) without major changes in the duration of repolarization (Figure 6D, solid black versus blue lines), in agreement with data from human atrial preparations.30 When simulating the block of IKur (a current which is enhanced during adrenergic activation) in the presence of ISO, early after-depolarizations (EADs) occurred (Figure 6D, green dashed line). These results are in agreement with data from Olson et al14 (Figure 6D, inset) showing that 4-AP (50 μmol/L) prolonged APD in human atrial myocytes and caused EADs and triggered activity upon ISO (1 μmol/L) challenge. Notably, simulation of IKs (also increased by ISO) blockade (50%) did not affect atrial AP markedly (Figure 6D, red line almost completely overlaps black line).

To reflect parasympathetic effects, we also included an IKACh model (fitted with human data) and demonstrate a dose-dependent reduction in human atrial AP and CaT in response to the parasympathetic transmitter acetylcholine (Online Figure VI). The APD shortening is consistent with experiments in human atria. We did not integrate crosstalk between β-adrenergic and acetylcholine or CaMKII pathways, or develop compartmentalized dynamic G-protein–coupled receptor models as done recently for animal myocyte models,31,32 but those would be logical extensions of our model.

There are limited data available concerning intra-atrial heterogeneities in repolarizing currents in human atrial myocytes. Caballero et al found a gradient of IKur with 20% higher density in right atrium (RA) versus left atrium (LA).33 We incorporated such heterogeneity to simulate RA and LA APs and CaT (Figure 7A). The slightly higher IKur density in RA has negligible effects on AP and mildly decreases CaT amplitude (Figure 7A, left; see also Figure 6). cAF decreases Ito and IKur differentially in right versus left atrium.33 Indeed, cAF greatly reduced Ito in the RA (≈80%) and to a lesser extent in the LA (≈45%), thus generating RA-LA Ito gradient. In contrast, IKur was more markedly reduced in the RA (−55%) than in the LA (−45%), thus abolishing the atrial right-to-left IKur gradient observed in sinus rhythm. We simulated these perturbed left-to-right gradients in cAF. IK1 in LA was 2-fold higher in both paroxysmal AF and cAF than in SR, with a left-to-right gradient in paroxysmal AF only.34 Thus, we did not simulate such gradient here. The model predicted a longer AP in the RA during cAF, similar to experimental data,35 with slightly larger CaT amplitude (Figure 7A, right, solid versus dashed lines), but reduced APD adaptation (Figure 7A, right, solid gray to black versus dashed gray to black lines). Thus, these changes modify the left-to-right gradients and may contribute to the perpetuation of arrhythmia. To account for variability in AP morphology between and within atria, we also varied K+ and Ca2+ current densities (reduced IKur by 50%, increased ICaL and IKr by 50% and 400%, respectively) to produce a Type-1 AP, that is, similar to the manipulation attempted in an earlier modeling study by Nygren et al.9 This results in a larger IK and IK/Ito ratio, more depolarized plateau potential, and steeper phase 3 repolarization (Figure 7B, left) as reported by the Nattel group36 (Figure 7B, right). Importantly, as in experiments,28,37 we show that when IKur is blocked Type-3 AP prolongs (7C, left), whereas Type-1 APD is almost unaltered (7C, right).

Figure 7.
Figure 7.

A, Simulated APs and CaTs from right and left atria (RA and LA) at 1 Hz and 3 Hz are shown in sinus rhythm (left) and cAF (right). B, Type-1 AP (dashed line and bottom panel) was obtained by modifying K+ and Ca2+ current densities in the nominal Type-3 AP (top panel, solid line). C, IKur block prolongs Type-3 APs (left) but has little effect on APD90 of Type-1 APs (right), as shown experimentally (insets).28,37 CaTs are shown in bottom panels.

Discussion

We developed a new mathematical model of human atrial myocyte with detailed electrophysiology and Ca2+ handling, including ionic and Ca2+ handling remodeling in cAF. This places our present understanding of atrial myocyte function in a useful quantitative framework to understand how changes in ion channel and Ca2+ handling influence function.

Atrial Versus Ventricular Cell Models

Understanding atrioventricular ionic differences is important, has been investigated in simulations and experiments,38,39 and may lead to safer therapy as a result of targeting atrial-specific ion channels for AF.1,40 We used the Grandi-Pasqualini-Bers model of the human ventricular AP and CaT12 as a framework for model development. As a result, the 2 models have a common format and similar aspects that may be convenient for integrating into whole heart models. Similarities include the Ca2+ handling processes, which are also based on the Shannon-Bers model of the rabbit ventricular myocyte.41 However, appropriate changes to many model parameters were introduced to recapitulate experimental findings in atrial samples from patients in sinus rhythm and cAF. Specific amalgams of ion channel expression and function confer differential AP characteristics for various cardiac regions.42,43 For example, it is well known that atrial IK1 density is smaller than ventricular IK1, explaining the slightly less negative atrial diastolic membrane potential (by ≈5–10 mV), reduced Na+ channel availability and slower phase-3 repolarization.43 Again, in humans, IKur is present in atria but not in ventricles,44 and in human atrium, Ito is encoded entirely by Kv4.3 (responsible for Ito,fast),45 whereas both fast and slow Ito components are detected in human ventricle. We also simulated different AP morphologies and included right-to-left gradients in Ito and IKur as reported recently in human myocytes from the RA and the LA from patients in sinus rhythm or with cAF. This new set of models accounting for tissue-specific ion current differences will be useful for understanding regional electrophysiology, Ca2+ handling and arrhythmia mechanisms.

Novelties of the Model Compared With Previous Models

Computational cell modeling has been widely used to understand how individual ionic/molecular components (often studied in isolation) interact in the integrated environment of the cardiac myocyte. For human atrial myocyte models, the Courtemanche10 and Nygren9 models, which focused primarily on ion channels generating the atrial AP, have been useful to investigate physiological46,47 and pathophysiological48,49 mechanisms of the human atrium. However, those models have vastly different properties, especially in their rate-dependent behavior.50 Recently, Maleckar et al8 incorporated new experimental K+ current data into the Nygren model, including formulations of IKur and Ito that we have also adopted here. They also studied the early and late phase of atrial repolarization and improved the rate-dependent properties of the AP model.

However, no previous model focused on Ca2+ handling properties of human atrial myocytes, and it is increasingly clear that Ca2+-handling and electrophysiology are intimately linked with respect to arrhythmias.7 Cherry et al50 showed CaT differences between the 2 above models, with a more gradual longer lasting transient in the Courtemanche compared with a much sharper CaT in the Nygren/Maleckar models. Our human model uses the Ca2+ handling framework developed by Shannon et al for rabbit ventricular myocytes,41 which was the first to introduce both a junctional cleft (where ryanodine receptor, RyR, and most ICaL function) and also a subsarcolemmal Ca2+ compartment, where Ca2+-dependent currents (eg, INCX and ICl(Ca)) sense different local [Ca2+]i compared with bulk [Ca2+]i.51 We have characterized Ca2+ handling properties in atrial myocytes from patients in sinus rhythm and with cAF, and modified the Ca2+ handling parameters in our model accordingly. This recapitulates experimental data including simultaneous measurements of ICaL and CaT, caffeine-induced CaT amplitude (ie, SR content) and decay time (ie, SERCA and NCX function) and SR Ca2+ leak at physiological temperature. Our human atrial model provides an accurate representation of Ca2+ homeostasis in human atrial myocytes.

Recently, the Tavi group proposed a model describing heterogeneous subcellular Ca2+ dynamics for human atrial cells presumed to lack t-tubules.11 They produced a biphasic rise of [Ca2+]i, as seen at 22°C in human atrial myocytes.52 In their model the biphasic [Ca2+]i rise resulted from delay between peripheral and central SR Ca2+ release. An extensive t-tubular network has been reported in atrial myocytes from large mammals.53 Because we did not observe biphasic [Ca2+]i rise in our human atrial myocytes at 37°C (time to peak ≈60 ms) and quantitative data on t-tubule organization in human atrial myocytes are lacking, we did not assume slowly propagating Ca2+ release toward the cell center.

Rate-Dependent APD Adaptation

Using our human ventricular myocyte model, we found that the increase in [Na+]i at fast pacing rates feeds back to shorten APD through outward (repolarizing) shifts in Na+/K+ pump (NKA) and NCX currents.12 Our human atrial model (Figure 5) and that of the Tavi group11 exhibit analogous behavior. The model showed negligible APD-rate adaptation when [Na+]i was clamped to a certain value (Figure 5A). Notably, we confirmed experimentally in human atrial myocytes the prediction of our model that acutely blocking NKA causes AP prolongation followed by APD shortening (Figure 5C and 5D), thus supporting the involvement of [Na+]i in APD (through shift in NKA current, Figure 5B) and rate-dependent APD adaptation in human atrial cells. Furthermore, we show that ICaL block has a similar effect on normal (sinus rhythm) and cAF human atrial action potentials (Figure 4), and in fact similar reductions in APD and APD rate-dependence occur in atrial myocytes isolated from patients with chronic AF. If ICaL is blocked, APD is shorter (less depolarizing current), but also the CaT is greatly diminished, causing less extrusion of Ca2+ and less Na+ entry via NCX. In addition, the positive inotropy observed in normal atrial myocytes is lost in cAF, also limiting NCX-dependent Na+ accumulation at fast rates (as in Figure 4I). Thus, our model recapitulated experimental results and points to [Na+]i and ICaL as critical components of the normal rate-dependent modulation of atrial APD. Although direct effects of [Na+]i on APD are compelling and logical, additional experimental validation of these effects would be valuable. We have discussed previously the role of delayed-rectifier K+ currents in APD rate adaptation,12 and showed in Online Figure VII that IKr block has little effect on APD. Here we ruled out an important role of the atrial-predominant IKur (see Online Figure VIII).

Role of [Ca2+]i in Mediating AF in the Presence of IKur Channelopathies

Atrial contractility is decreased in cAF, largely due to electrical remodeling that is associated with downregulation of ICaL,28,29 which reduces CaT amplitude. Our simulation demonstrated that block of IKur enhances CaT amplitude of human atrial myocytes, both in patients in sinus rhythm or AF (Figure 6), thus pointing to IKur as an atrial-specific target to counteract hypocontractility associated to cAF. Indeed, experiments have shown that IKur blockers in ventricle did not appreciably alter APD or CaT.29

We hypothesize that IKur in the atrium may serve the same function as IKs in the ventricle, that is opposing AP prolongation expected from larger inward ICaL and INCX during β-adrenergic stress.54 Indeed, our simulations showed that block of IKur (to mimic Kv1.5 mutation that leads to nonfunctional current, and AF) in the presence of adrenergic challenge causes EADs (Figure 6D). That agrees with experimental data,14 where IKur inhibition led to EADs in human atrial myocytes challenged with ISO. On the other hand, IKs block did not appreciably affect APD. Administration of ISO also led to cellular arrhythmic depolarizations when stimulating our model at low pacing frequency (not shown), in accordance with experimental work.14,55

Conclusions

We developed a new computational framework to study the contribution of individual ionic pathway differences between atrial and ventricular cells to AP phenotype differences in the human atrium versus ventricle. It also established that Ca2+ and Na+ handling processes are major contributors to atrial APD and its rate-related behavior in both normal and cAF conditions, and identified the role of IKur in helping prevent EADs in the presence of adrenergic stress. This model (available at https://somapp.ucdmc.ucdavis.edu/Pharmacology/bers/) will also be useful for integrating into multicellular models of the human heart.

Sources of Funding

This study was supported by National Heart, Lung, and Blood Institute grants P01-HL080101 and R37-HL30077 (D.M.B.), P01-HL039707, P01-HL087226; and the Leducq Foundation (J.J.); an American Heart Association Scientist Development Grant (S.V.P.); British Heart Foundation Basic Science Lectureship BS/06/003 (A.J.W.); and Fondation Leducq Transatlantic Alliances for Atrial Fibrillation (D.D.) and CaMKII (D.M.B.).

Disclosures

None.

Acknowledgments

We thank the Heidelberg Cardiosurgeon Team for the provision of human atrial tissue and Claudia Liebetrau and Katrin Kupser for excellent technical assistance. We also thank the cardiothoracic surgical team, Golden Jubilee National Hospital, Glasgow, United Kingdom, for provision of human atrial tissue.

Footnotes

  • In July 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.5 days.

  • ↵† These authors share senior authorship.

  • Non-standard Abbreviations and Acronyms

    AF
    atrial fibrillation
    AP
    action potential
    APD
    action potential duration
    APD90
    action potential duration at 90% repolarization
    cAF
    chronic atrial fibrillation
    CaT
    Ca2+ transient
    EAD
    early after depolarization
    GNaL
    late Na+ current maximal conductance
    ICaL
    L-type Ca2 current
    ICl(Ca)
    Ca2+-activated Cl− current
    IKACh
    acetylcholine-activated K+ current
    IKr
    rapidly activating delayed rectifier K+ current
    IKs
    slowly activating delayed rectifier K+ current
    IKur
    ultrarapid delayed rectifier K+ current
    IK1
    inward rectifier K+ current
    INa
    fast Na+ current
    INCX
    Na+/Ca2+ exchange current
    INaK
    Na+/K+ pump current
    ISO
    isoproterenol
    Ito
    transient outward K+ current
    LA
    left atrium
    NCX
    Na+/Ca2+ exchange
    NKA
    Na+/K+ ATPase
    PKA
    protein kinase A
    PLN
    phospholamban
    RA
    right atrium
    RyR
    ryanodine receptor
    SERCA
    sarcoplasmic reticulum Ca2+ ATPase
    SK2
    Ca2+-activated K+ channels
    SR
    sarcoplasmic reticulum
    Tnl Ca2+
    affinity of troponin I

  • Received August 1, 2011.
  • Revision received August 18, 2011.
  • Accepted August 24, 2011.

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Novelty and Significance

What is Known?

  • Atrial cells exhibit electrophysiological characteristics that differ from those of ventricular cells due to structural differences and specific combinations of ion channel/transporter expression and function.

  • During chronic atrial fibrillation (AF), electrical and structural remodeling contributes to the development of the AF substrate, and abnormalities in intracellular Ca2+ cycling have emerged as key mediators in AF pathophysiology.

  • Detailed models of myocyte Ca2+ cycling have typically focused on ventricular rather than atrial myocytes, in part because of limited appropriate experimental data (especially from human atrial myocytes).

What New Information Does This Article Contribute?

  • Based on recent data from human atrial cells, we have developed a new mathematical model of the human atrial myocyte that accounts for the electrophysiological and Ca2+ handling properties of atrial cells in both normal and chronic AF conditions.

  • Simulations indicate that heart rate-dependent action potential duration (APD) shortening in healthy atrial cells involves the accumulation of intracellular [Na+] at high frequencies that causes outward shifts in Na+/Ca2+ exchange and Na+/K+ pump currents, whereas ionic and Ca2+ handling remodeling lead to reduced Na+ accumulation in chronic AF, which causes a blunted APD rate-dependent response.

  • Our modeling suggests that IKur is a key component of the adrenergic response of human atrial cells, as its loss (such as in Kv1.5 channelopathy) results in predisposition to early afterdepolarizations in the presence of isoproterenol and may help explain the bouts of stress mediated AF observed in these patients.

It is increasingly clear that Ca2+-handling and electrophysiology are intimately linked to the development and perpetuation of AF. Thus, understanding AF requires an integrated quantitative understanding of ionic currents and Ca2+ transport in healthy and remodeled human atrium. However, no previous model focused on Ca2+ transport in human atrial myocytes in chronic AF. We developed a new human atrial myocyte model that incorporates the latest experimental data and modern concepts relating to intracellular Ca2+ homeostasis and related electrophysiology, including ionic and Ca2+ handling remodeling seen in chronic AF. Our simulation showed that IKur block enhances the amplitude of the Ca2+ transient of human atrial myocytes, representing an atrial-specific target to counteract hypocontractility associated to cAF. This current is also predicted to oppose APD prolongation expected from larger inward ICaL and INCX during β-adrenergic stress. Our model provides novel insights into the mechanism of APD rate-dependent adaptation, by showing that accumulation of [Na+]i at fast heart rates feeds back to shorten APD via outward shifts in Na+/Ca2+ exchange and Na+/K+ pump currents. This human atrial model provides a useful tool to investigate atrioventricular differences with respect to arrhythmogenesis and therapeutic approaches.

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  • Human Atrial Action Potential and Ca2+ ModelNovelty and Significance
    Eleonora Grandi, Sandeep V. Pandit, Niels Voigt, Antony J. Workman, Dobromir Dobrev, José Jalife and Donald M. Bers
    Circulation Research. 2011;109:1055-1066, originally published October 13, 2011
    https://doi.org/10.1161/CIRCRESAHA.111.253955
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