Cardiovascular Research

Cardiovascular Research 1999 44(1):121-131; doi:10.1016/S0008-6363(99)00178-9
© 1999 by European Society of Cardiology

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Bosch, R. F. Articles by Kühlkamp, V. Search for Related Content PubMed PubMed Citation Articles by Bosch, R. F. Articles by Kühlkamp, V. Social Bookmarking          What's this?

Copyright © 1999, European Society of Cardiology

Ionic mechanisms of electrical remodeling in human atrial fibrillation

Ralph F. Bosch^*, Xiaorong Zeng, Joachim B. Grammer, Katarina Popovic, Christian Mewis and Volker Kühlkamp

Department of Cardiology, University of Tübingen, Tübingen, Germany

^* Corresponding author. Tel.: +49-7071-298-3196; fax: +49-7071-295-285 ralph.bosch{at}uni-tuebingen.de

Received 15 February 1999; accepted 23 April 1999

	Abstract

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Objectives: Atrial fibrillation (AF) is associated with a decrease in atrial ERP and ERP adaptation to rate as well as changes in atrial conduction velocity. The cellular changes in repolarization and the underlying ionic mechanisms in human AF are only poorly understood. Methods: Action potentials (AP) and ionic currents were studied with the patch clamp technique in single atrial myocytes from patients in chronic AF and compared to those from patients in stable sinus rhythm (SR). Results: The presence of AF was associated with a marked shortening of the AP duration and a decreased rate response of atrial repolarization. L-type calcium current (I_Ca,L) and the transient outward current (I_to) were both reduced about 70% in AF, whereas an increased steady-state outward current was detectable at test potentials between –30 and 0 mV. The inward rectifier potassium current (I_K1) and the acetylcholine-activated potassium current (I_KACh) were increased in AF at hyperpolarizing potentials. Voltage-dependent inactivation of the fast sodium current (I_Na) was shifted to more positive voltages in AF. Conclusions: AF in humans leads to important changes in atrial potassium and calcium currents that likely contribute to the decrease in APD and APD rate adaptation. These changes contribute to electrical remodeling in AF and are therefore important factors for the perpetuation of the arrhythmia.

KEYWORDS Experimental; Heart; Cellular; Electrophysiology; Arrhythmia (mechanisms); Ca-channel; K-channel; Na-channel; Ion channels

---

This article is referred to in the Editorial by M.A. Alessie (pages 10–12) in this issue.

	1 Introduction

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
Atrial fibrillation (AF) is the most common arrhythmia in man and its prevalence will increase with the aging of the population [1–3]. The presence of AF is associated with a considerable increase in morbidity [4,5] and in mortality [1,6]. In recent years, the functional mechanisms underlying AF have been investigated in animal models [7–10] and in humans [11–14]. From these studies, it became evident that AF is characterized by a marked decrease in the atrial ERP and in ERP adaptation to rate [7–14] as well as a decrease in atrial conduction velocity [9,12], thereby favoring the occurrence of multiple-wavelet reentry [15]. Little information is available about the ionic mechanisms underlying AF in humans. In the canine rapid pacing model of AF, Yue et al. [16] have demonstrated a decrease in I_Ca,L and in I_to as factors underlying AP shortening. In that model, a decreased I_Na was observed in AF that correlated with the slowing of atrial conduction [17]. The only study in humans reported a decrease in I_to and I_sus as well as an increase in I_K1 in left but not in right atrial myocytes in chronic AF [18]. At the moment, no data are available upon the effects of human AF on repolarization on a cellular level, on inward currents like I_Ca,L and I_Na, and only limited information is available on potassium currents. The purpose of the present study therefore was to study the effects of AF on AP in isolated myocytes, and to characterize the changes in potassium currents (I_to [19]; I_sus (I_Kur) [20,21]; I_K1 [22]; I_KACh [23]), calcium – (I_Ca,L) and sodium currents (I_Na) that underlie altered repolarization.

	2 Methods

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
2.1 Patients’ characteristics and isolation of single atrial cells
Right atrial appendages were obtained at the time of cardiac surgery by following procedures approved by the institutional review committee. The investigation conforms with the principles outlined in the Declaration of Helsinki. 17 patients were assigned to the SR group and 8 to the chronic AF group according to the underlying cardiac rhythm. Chronic AF was defined as permanent AF of at least 1 month duration, patients with paroxysmal AF were not included in the study. Patients’ characteristics are listed in Table 1. Single myocytes were isolated by enzymatic dissociation with the chunk method as previously described [24]. The specimens were transported to the laboratory in a nominally Ca²⁺-free cardioplegic solution (100% O₂, room temperature) containing (mM) KH₂PO₄ 50, MgSO₄ 8, Adenosine 5, HEPES 10, Glucose 140, Mannitol 100, Taurine 10, pH was adjusted to 7.4 with KOH. Chunks were washed in 25 ml EGTA solution containing (mM) NaCl 137, KH₂PO₄ 5, MgSO₄ 1, Glucose 10, HEPES 5, Taurine 10, EGTA 0.1, pH was adjusted to 7.4 with NaOH. After washout of blood and calcium, the chunks were incubated for 35 min in 5 ml Ca²⁺-free Enzyme Incubation Medium (EIM) with the addition of 150 U/ml collagenase (Type V, Sigma), 12.6 U/ml protease (Type XXIV, Sigma) and 1 mg/ml albumin (Sigma). The EIM solution contained (mM) NaCl 137, KH₂PO₄ 5, MgSO₄ 1, Glucose 10, HEPES 5, Taurine 10, pH 7.4 (adjusted with NaOH). The EIM was maintained at 35°C and continuously gassed with 100% O₂. This period of digestion was followed by a 1 min wash in EIM solution without any enzymes. Subsequently, the supernatant was removed and replaced by a fresh enzyme medium with the same composition but without protease until rod-shaped cells were present. Cells were kept in a "Kraftbruehe" storage solution containing (mM) KCl 20, KH₂PO₄ 10, Glucose 25, Mannitol 5, Albumin 1, L-Glutamic acid 70, β-hydroxybutyrate 10, Taurine 10, EGTA 10, pH 7.4 (adjusted with KOH).

View this table: [in this window] [in a new window]   Table 1 Patients’ characteristics

 
2.2 Patch clamp technique
Only quiescent, rod-shaped cells with clear cross striations were studied. Ionic currents were recorded using the whole cell configuration of the voltage clamp technique. Borosilicate glass electrodes (outer diameter 1.0 mm) with resistances of around 1 M to record I_Na and 3 to 5 M for recording of action potentials and other ionic currents were connected to a patch clamp amplifier (Axopatch 200B, Axon Instruments). Data were sampled with an A/D converter (Digidata 1200, Axon Instruments) and stored for subsequent analysis. The sampling frequency depended on the recording interval, with a frequency of 10 kHz used for rapidly changing currents and frequencies as low as 0.4 kHz used for long recordings of slowly changing currents. Recordings were low-pass filtered at 2 kHz. Tip potentials were zeroed before formation of the pipette-membrane seal. After rupture of the cell membrane, pipette series resistance (R_s) was electrically compensated to minimize the capacitive surge on the current recording and the voltage drop across the clamped membrane. R_s was calculated by dividing the capacitive time constant, obtained by fitting the decay of the capacitive transient before and after compensation, by the calculated membrane capacitance (the time integral of the capacitive response to a 5 mV hyperpolarizing pulse from a holding potential of –60 mV, divided by the voltage drop). Membrane capacitance was identical in the 2 groups: 72.1±3.0 pA/pF (n=167) in SR and 76.6±4.8 pA/pF (n=78) in AF; p=ns vs. SR. To control for differences in cell size, all mean current data are expressed as current densities (i.e., normalized to capacitance). Before compensation, R_s averaged 7.8±0.2 and 9.6±0.4 M in the SR and AF group, and the capacitive time constants were 537±23 and 671±35 µs, respectively. Corresponding values for R_s after compensation were 3.2±0.3 and 3.1±0.2 M, and 246±11 and 264±11 µs for the capacitive time constants. For recording I_Na, great care was taken to minimize the voltage drop across the R_s. This included the selection of small cells and of low resistance electrodes. R_s in these cells averaged 3.9±0.3 M and 1.94±0.14 M before and after compensation. Cells with a voltage drop of >7 mV were rejected, the mean voltage drop of the cells included was 4.88±0.26 mV. The compositions of the bath and pipette solutions are listed in Table 2. For the recording of potassium currents, I_Ca,L was blocked with 1 µmol/l nisoldipine [14,25]. I_Na was recorded at room temperature, all other experiment were conducted at 36°C.

View this table: [in this window] [in a new window]   Table 2 Composition of bath and pipette solutions

 
2.3 Data analysis
Group data are expressed as mean±SE. Comparisons between SR and AF groups were made using a Student’s non-paired t-test. Differences with a two-tailed p value<0.05 were considered statistically significant. A nonlinear least-square curve-fitting program (CLAMPFIT in pCLAMP 6.0 or Sigma Plot) was used to perform curve fitting procedures.

	3 Results

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
3.1 Effects of chronic AF on action potentials
AP were recorded in single atrial myocytes 5 min after cell membrane rupture at stimulation frequencies between 0.2 and 4 Hz. 40–50 stimuli were applied to achieve steady state conditions. The resting membrane potential (RMP) was corrected for the junction potential, mean values were –76.3±2.2 mV (n=10) in SR and –78.9±2,9 mV in AF (n=8, p=ns vs. SR). AP amplitudes at 1 Hz averaged 116±3 mV (n=10) in SR and 120±2 mV (n=8; p=ns vs. SR) in AF. Fig. 1 shows typical AP recorded from an SR (Fig. 1A) and from an AF cell (Fig. 1B). In SR, the AP duration (APD) is much longer at all frequencies and the cell displays a clear frequency dependent adaptation of the APD with a shortening at higher stimulation rates. In contrast, in AF, the APD is already very short at slow rates and there is almost no further shortening as the stimulation frequency is increased, rather, the AP at 1, 2 and 4 Hz are overlapping (Fig. 1B). The APD₉₀ was greatly reduced in AF as illustrated in Fig. 1C. At 0.2 Hz, the APD₉₀ was 319±48 ms in SR vs. 134±12 ms in AF, at 1 Hz, 255±45 ms vs. 104±9 ms and at 4 Hz, 213±26 ms vs. 98±8 ms (p<0.001 vs. SR for all frequencies)

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 AP recorded at 36°C from a human atrial cell of an SR patient (Panel A) and an AF patient (Panel B) at different stimulation frequencies. The units on the x-axis are ms, and mV on the y-axis. In Panel C, the AP duration to 90% repolarization (APD90) from 10 cells of the SR and 8 cells of the AF group is shown as a function of the stimulation frequency.

 
3.2 Effects of AF on potassium currents
In Fig. 2, representative recordings of steady-state currents from a cell of an SR patient and a cell of an AF patient are displayed. Currents were recorded under conditions designed to eliminate I_Na and I_Ca as described in the figure legend. Steady-state current densities are presented in Fig. 2C. The presence of AF was associated with a significant increase in inward currents at hyperpolarizing test potentials, representing the inward component of the inward rectifier potassium current (I_K1). For example, at –90 mV current densities averaged –9.83±0.96 pA/pF in SR and –19.91±1.72 pA/pF in AF (p<0.001). AF cells displayed increased outward currents at test potentials between –30 and 0 mV. For a test potential of –20 mV, current densities were 0.85±0.24 pA/pF in SR and 2.85±0.63 pA/pF in AF (p<0.01). At potentials positive to 0 mV, there were identical current densities in both groups. The reversal potential was not altered by AF: mean values were –36.7±3.6 mV in SR and –39.1±3.2 mV in AF (p=ns).

View larger version (12K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Representative examples of steady-state current recordings in a human atrial cell from an SR patient (A) and from an AF patient (B). Currents were recorded at 36°C with 200 ms steps from a holding potential of –40 mV to test potentials between –100 mV and +20 mV. Stimulation frequency was 0.1 Hz and sustained currents were measured as current amplitudes at the end of the 200 ms test pulse. 1 µmol/l nisoldipine were added to the superfusion solution to block ICa,L. 0 indicates 0 current level. C: Steady-state current densities in SR and AF. n=43 for SR and 35 for AF, *p<0.05, **p<0.01, ***p<0.001 vs. SR.

 
I_KACh was studied after addition of 1 µmol/l acetylcholine (ACh) to the bath solution (Fig. 3). In both groups, ACh led to an increase in current amplitudes. Current densities after ACh simulation were significantly larger in the AF group (Fig. 3C): mean I_KACh densities at –90 mV were –20.7±1.6 pA/pF in SR and –30.0±2.7 mV in AF (p<0.01 vs. SR).

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 IKACh in human AF. IKACh was recorded at 36°C with 200 ms test pulses to potentials between –60 and –120 mV, in 10 mV increments, from a holding potential of –40 mV. Panels A and B show the increase in potassium inward currents in response to 1 µmol/l acetylcholine in a cell from a patient in SR and from a patient in AF at a test potential of –90 mV. NT indicates the current in normal Tyrode’s solution and ACh is the current measured after 10 min of superfusion with acetylcholine. 1 µmol/l nisoldipine were added to block ICa,L. C: Mean current densities at a TP of –90 mV for the SR (n=37) and for the AF (n=34) group. **p<0.01 vs. SR.

 
AF led to a marked reduction in I_to currents in human atrial cells. Typical cells from an SR and an AF patient are shown in Fig. 4. In SR, a large, transient, rapidly inactivating I_to is visible which is almost absent in AF. In contrast, I_sus at the end of the 200 ms test pulse had similar current amplitudes at positive potentials in both cells. I_to and I_sus were measured in 30 SR and in 15 AF cells. The current voltage (I–V) relations for I_to and I_sus are illustrated in Fig. 4C, D. I_to current densities were significantly reduced at all test potentials positive to 0 mV, i.e. at +50 mV from 7.84±0.76 pA/pF in SR to 1.24±0.28 pA/pF in AF (p<0.001 vs. SR), whereas I_sus current densities were identical in the 2 groups. The voltage dependence of I_to was assessed by expressing current amplitudes at a given voltage normalized to maximum current in each cell. The normalized I–V curves were shifted to more positive voltages in AF. To further evaluate the mechanism of a decreased I_to, we studied the voltage-dependent and kinetic properties (Table 3). Voltage-dependent activation was determined from the IV-relation with changes in driving force corrected by dividing the current during the test pulse (TP) by the driving force, TP–E_rev. E_rev is the reversal potential that was obtained as the reversal potential of I_to tail currents (–71.3 mV). The obtained curve was fit by a Boltzman relation. Voltage-dependent inactivation was determined with a 1s prepulse from a holding potential of –80 mV to potentials between –100 and +70 mV, followed by a 500 ms test pulse to +60 mV to record I_to. The obtained curve was fit by a Boltzman relation. AF was associated with a significant shift of I_to voltage-dependent activation to more positive potentials. Recovery from inactivation was assessed with a dual pulse protocol, in which two identical 300 ms pulses, P1 and P2, were applied from a holding potential of –80 mV to +50 mV at an increasing P1–P2-interval. The amplitude of P2 was normalized to the amplitude of P1. The recovery curve was best fit by a monoexponential function and was not altered by AF. I_to inactivation kinetics were determined by obtaining the inactivation time constant _inact from a monoexponential curve fit of the current decay during a depolarization to +50 mV. _inact was identical in the SR and in the AF group.

View larger version (27K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Transient outward currents Ito at 36°C in human atrial cells were obtained with the pulse protocol shown in the inset. A 30 ms prepulse was used to inactivate INa and 1 µmol/l nisoldipine were added to the bath solution to inhibit ICa,L. In panel A, a cell from a patient in SR is shown, the recordings in panel B are from a patient in chronic AF. Ito was measured as the difference between peak outward current and the outward current at the end of the 200 ms test pulse. Isus was the current amplitude at the end of the depolarizing step. 0 indicates 0 current level. C: Ito current densities. D: Isus current densities. TP: Test potential. **p<0.01, ***p<0.001 vs. SR.

 

View this table: [in this window] [in a new window]   Table 3 Properties of Ito, ICa and INa in SR and in AFa

 
3.3 L-type calcium current
I_Ca,L was studied 5 min after cell membrane rupture in all cells to avoid contaminating effects of I_Ca,L rundown. Fig. 5 shows a typical example of calcium currents recorded from a cell of an SR and an AF patient. AF was associated with a marked decrease in I_Ca,L amplitude. Fig. 5C shows the I–V relation for 42 cells in the SR and 18 cells in the AF group. The AF group had a highly significant decrease in I_Ca,L current densities, for example at a test potential of +10 mV current densities were –6.97±0.50 pA/pF in SR and –1.88±0.19 pA/pF in AF (p<0.001 vs. SR). The voltage dependence of the current was not affected by AF, the normalized I–V relations were superimposed (Fig. 5D).

View larger version (17K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 5 Effects of AF on L-type calcium current in humans. Representative recordings from a cell of an SR patient (Panel A) and a cell from an AF patient (Panel B) are illustrated. Currents were recorded at 36°C with 200 ms depolarizing pulses to TP between –70 and +40 mV from a holding potential of –80 mV and a stimulation frequency of 0.1 Hz. In Panel C, current densities are plotted as a function of the test potential (TP). **p<0.01, ***p<0.001 vs. SR. The voltage dependence of ICa was not altered by AF, shown in Panel D as an overlap of the curves when current amplitudes were normalized to the maximum current in each cell. E: ICa inactivation kinetics. Two representative traces of ICa recorded upon a depolarization to +10 mV are shown. Inactivation kinetics were analyzed by fitting a biexponential relation to the time course of current decay. The fit is shown as the solid line overlapping the current trace. The time constants fast and slow were obtained for each cell in that fashion. In the inset, the values for the fast and slow time constants are displayed. AF was associated with a slowing in ICa inactivation with a reduction of the fast time constant fast.

 
To evaluate the mechanisms involved in the reduction of I_Ca,L, we studied the voltage-dependent and kinetic properties of the current (Table 3). The voltage dependence of activation was assessed by dividing peak current at a given test potential by the driving force. The driving force was calculated as the difference between the test potential and the I_Ca,L reversal potential which was determined from the I–V relation as the intercept with the x-axis of the ascending limb of the curve. The results were fit by a Boltzman relation. Voltage-dependent inactivation was obtained with a double pulse protocol with a 1 s inactivating prepulse to voltages between –100 and +40 mV from a HP of –80 mV, followed by a 200 ms test pulse to +10 mV. The currents were normalized to the maximum current and fit to a Boltzman relation. Both voltage-dependent activation and inactivation were not affected by AF. Recovery from inactivation was determined by the ratio of the current during a 300 ms depolarizing pulse to +10 mV (P2) from a HP of –80 mV to that during an identical conditioning pulse (P1) with a varying P1–P2 interval. Recovery was best fit by a monoexponential function and was identical in SR and in AF. In AF cells, the inactivation kinetics of calcium currents were slower than in SR. A typical example is shown in Fig. 5 Panels E, F. Cells from the AF group had a significantly longer fast time constant _fast, whereas _slow was not changed.

3.4 Sodium current
To avoid contaminating effects of time-dependent changes in the I_Na I–V relationship, all experiments were carried out 15 min after cell membrane rupture. Representative examples of I_Na recorded from an SR and an AF cell are shown in Fig. 6. Both cells had identical current amplitudes. Overall results for I_Na current densities are displayed in Fig. 6C. Neither current densities nor the voltage dependence of the current was altered by chronic AF in humans. Mean values at –40 mV were –50.2±3.1 pA/pF in SR (n=44) and –46.1±4.5 pA/pF in AF (n=25; p=ns vs. SR).

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 6 Sodium current density in human atrium is not altered by AF. Representative recordings of sodium currents at room temperature are shown for an SR cell in Panel A and for an AF cell in Panel B. Currents were elicited from a HP of –140 mV with 40 ms depolarizing steps to TP between –80 and 0 mV. The intracellular and extracellular sodium concentration was 5 mmol/L. C: I–V relation of INa current densities.

 
Voltage-dependent activation of I_Na was assessed by dividing current amplitudes by the driving force (the difference of the test potential and the reversal potential, which was obtained by the intercept of the ascending limb of the I–V relation with the x-axis). A double-pulse protocol at a HP of –140 mV was used to determine the voltage-dependent inactivation with a 1s conditioning pulse to voltages between –140 and –55 mV, followed by a 30 ms test pulse to –40 mV at 0.1 Hz. The test pulse current was then normalized to current without a prepulse and fit by a Boltzman relation. Voltage-dependent activation was not affected by AF (Table 3). Voltage-dependent inactivation of I_Na was shifted to more positive voltages in AF cells (Fig. 7), from –97.2±0.3 mV in SR to –87.6±0.2 mV in AF (p<0.01 vs. SR). The time-dependent recovery of I_Na was studied with the use of a double pulse protocol with two identical 30 ms pulses (P1 and P2) to –40 mV from a HP of –140 mV at an increasing P1–P2 interval. P2 amplitude was normalized to the amplitude of P1 and plotted as a function of the P1–P2 interval. Recovery kinetics were best fit by a monoexponential function and were not altered by AF. Activation and inactivation kinetics were obtained by fitting a monoexponential function to the activating and the inactivating portion of the current at a test potential of –35 mV. Neither activation nor inactivation kinetics were altered by AF.

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 7 INa voltage-dependent inactivation in SR and AF. Panels A and B illustrate typical examples of currents recorded with a double-pulse protocol. A 1 s conditioning pulse to voltages between –140 and –55 mV, from a HP of –140mV, was followed by a 30 ms test pulse to –40 mV. For reasons of clarity, only currents recorded with the test pulse are shown. In the inset, the inactivation curve is plotted as a function of the conditioning pulse potential for the respective cell. In Panel C, overall results for inactivation curves for the SR (n=29) and AF group (n=13) are shown. TP indicates the conditioning pulse potential. Vh is the half inactivation potential for INa.

 

	4 Discussion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
We have shown that chronic AF in humans leads to a marked shortening in atrial AP duration and to a decreased frequency-dependent adaptation of APD. Additionally, we have characterized the ionic mechanisms that underlie electrical remodeling in human AF. This study is the first to demonstrate that presence of the arrhythmia was associated with a marked decrease in I_Ca,L in humans. Furthermore AF led to a decrease in I_to current densities as well as an increase in the steady-state outward current at potentials between –30 and 0 mV. These currents, therefore, seem to play a major role in the shortening of repolarization in AF. At hyperpolarizing potentials, we observed an increase in I_K1 and in I_KACh current densities in AF. I_Na voltage-dependent inactivation was shifted to more positive potentials by AF in humans.

4.1 Comparisons with previous findings on the effect of AF on repolarization
We observed a decrease in APD and APD adaptation to rate in chronic human AF. These findings are consistent with previous reports about a shortening of atrial repolarization in vivo. In a goat model, Wijffels et al. [7] demonstrated that AF was associated with a shortening of the atrial ERP and a decreased ERP adaptation to rate. These findings were confirmed in three studies in the canine rapid atrial pacing model of AF [8–10]. In this model, Yue et al. [16] have also recorded AP where they found a progressive shortening of the APD and a decreased APD adaptation to rate with an increased duration of rapid pacing. Boutjidir et al. [14] studied the effect of chronic AF on ERP and AP in multicellular preparations of human atria. AF was associated with a marked shortening of the ERP and AP as well as an increased dispersion of repolarization. In a study that addressed the effects of short-term, pacing-induced AF in humans [12], a reversible shortening of atrial ERP was noted. A marked shortening of the ERP was also present in patients in chronic lone AF briefly after conversion to SR [11]. Our findings provide likely ionic mechanisms of shortened repolarization in AF with a decrease in I_Ca,L and I_to current densities as well as an increase in steady-state outward current densities at potentials relevant to phase 3 of the atrial AP. I_Ca,L is important in rate-dependent changes in human atrial APD [26]. Like in animal models [16], the observed reduction in I_Ca,L in our study is the likely mechanism for a decrease in APD rate adaptation in AF.

4.2 Comparison with previous studies of ionic changes in atrial disease
Little is known about ionic changes in AF. The only report in humans by Van Wagoner et al. [18] showed a clear reduction in I_to current densities that was in the same order of magnitude as in the present study. A reduction in I_to current densities was involved in atrial electrical remodeling in the canine rapid pacing model [16].

In our study, I_sus current density was not different from patients in normal SR. This is in contrast to the study by Van Wagoner et al., who showed a decrease in I_sus current densities and a decreased Kv1.5 protein expression in human AF [18]. The reasons for these contrasting results may reflect differences in patients’ underlying cardiac disease or in left ventricular function. Reduced left ventricular function and heart failure are known to alter electrophysiology and potassium currents in the atria [22,27,28]. Most of our patients had a preserved or only mildly impaired left ventricular function. In the study of Van Wagoner et al. these data are not given, so differences in left ventricular function could account for the differences observed. Further reasons might include the duration of AF or the patients’ medications. In the canine rapid pacing model, I_Kur,d, which underlies the sustained outward current in that species, was not altered by AF [16]. This current however, appears to have a different molecular basis than I_Kur in human atrium [29].

I_K1 at hyperpolarizing potentials was increased in appendages from AF patients in the present study. This was also found in the report by Van Wagoner et al. [18], however, they observed an increase in left atrial myocytes only. In cells from the right atrium, I_K1 was not affected by AF. In contrast, I_K1 current densities were not altered in dogs subjected to rapid atrial pacing [16]. I_KACh was also substantially enlarged in our AF patients at hyperpolarizing potentials. We are not aware of any studies about the effects of AF on I_KACh. The current is important in contributing to the resting membrane potential and is involved in atrial APD shortening by acetylcholine [30]. Cholinergic modulation of atrial repolarization is largely based on the activation of I_KACh [30,31], and is associated with an increase in the heterogeneity of atrial repolarization [32,33]. Vagal stimulation facilitates the induction of AF in experimental models and an increased vagal tone seems to facilitate certain types of clinical AF [34,35]. It is therefore likely that changes in I_KACh current density or heterogeneous expression are important factors both in the induction and in the maintenance of AF.

In AF, I_Ca,L current densities were reduced by 73% compared to SR. Similar reductions in I_Ca,L were observed after chronic rapid atrial pacing in dogs [16,36] and in a preliminary report in humans [37]. In the dog model [36], like in our study, I_Ca,L inactivation was slowed in AF cells, possibly contributing to a decreased Ca²⁺ influx especially at rapid rates.

Sodium current densities were identical in patients in SR and in AF in our study. These results contrast with observations that showed a progressive reduction in I_Na density as a function of atrial tachycardia in the dog [17]. Another preliminary report in the rapid pacing model also described a reduction in I_Na current densities, however, this was attributed to an increase in cell size, since current amplitudes remained unchanged [36]. The reasons for these contrasting results might include differences in the type of AF (experimental vs. clinical AF), influences of the underlying cardiac disease or interspecies differences. In our AF group, voltage-dependent inactivation of I_Na was shifted by 9.6 mV to more positive potentials, which would increase availability at the resting potential, and thus increase conduction velocity. Therefore, other mechanisms must be involved in the slowing of intraatrial conduction in AF. Several studies have investigated the effects of AF on atrial gap junctions, which are a major determinant in myocardial conduction [38,39]. Elvan et al. [40] found an increase in connexin 43 (Cx43) protein expression as well as a redistribution of the protein towards the lateral sides of the myocytes in experimental AF in dogs. In contrast, van der Velden et al. [41] did not observe a change in Cx43 mRNA or protein expression, but a redistribution of Cx40 expression in the AF goat model. In human AF, Cx43 protein expression was reduced compared to SR [42]. Although the results about the exact changes in gap junctions are still contrasting, altered intercellular coupling seems to be an important component in the remodeling process in AF. These changes might overcompensate the AF-associated shift in voltage-dependent inactivation of I_Na, thereby causing an overall slowing of intraatrial conduction in AF.

4.3 Potential mechanisms by which AF changes ionic currents
Few data are available upon the mechanisms by which AF alters cardiac ionic currents. In the present report, half-maximal activation of I_to was shifted to more positive voltages. However, this shift is not sufficient to account for the total reduction of I_to, because maximal I_to conductance was decreased, (i.e. at +50 mV: 1.46±0.15 µS in SR and 0.46±0.11 µS in AF). Therefore, other mechanisms seem to be involved in the downregulation of I_to. Yue et al. have reported, with the canine rapid pacing model, a decrease in Kv4.3 mRNA after 42 days of rapid atrial pacing [43] which is in the same range as the current reduction observed in our AF patients. In the same study, the authors also observed a downregulation of the L-type calcium channel 1c-subunit in chronically paced dogs [43]. In one preliminary report in humans, the I_Ca,L 1-subunit was decreased in AF lasting more than 6 months, but not in short-term AF [44].

4.4 Potential limitations
In human atrial appendages, the chunk method is the only possibility of cell isolation. The use of this method has important implications on the results obtained in single human atrial cells. 1) Yue et al. [45] provided evidence that I_K is present in a much smaller percentage of cells with smaller current amplitudes if the chunk method is used for cell isolation compared to arterial cannulation. In our preparations, I_K was present only in a small number of cells (<5%) with very small current amplitudes. Most of the time, the current displayed rapid rundown, so a comparison between different groups or a systematic pharmacological approach was not possible. 2) We observed an increase in I_K1 and in I_KACh in the AF group. As both currents are important contributors to the maintenance of the resting membrane potential (RMP), a more negative value would be expected in AF. However, in isolated human atrial cells the RMP is highly variable, which again seems to be a consequence of the isolation procedure. For the recording of AP, only cells with a very good RMP were eligible. Consequently, RMP and AP were measured in a highly-selected cell population which may not be representative. Although the RMP had a more negative value in the AF group, the difference was not statistically significant. 3) We have demonstrated a marked shortening of the APD in AF. AP in SR cells had a duration similar to those previously described for AP in multicellular preparations [14] and for the ERP in vivo [11]. In contrast, our APD in isolated AF cells were shorter than AP or ERP in these studies. This might reflect a different suspectibility of currents to the isolation procedure in AF and may have contributed to the marked shortening of repolarization in our study.

I_Na was recorded at room temperature and with an external Na concentration of 5 mmol/l. These unphysiological conditions might have affected the I_Na recordings and may have contributed to the differences observed in the two groups.

4.5 Potential significance
Although rapid progress in defining the electrophysiological substrates of AF has been made over the last few years [7–12], the clinical management of AF is still limited by low efficacy or severe adverse events of current therapeutic approaches [46]. The present study is the first to demonstrate the effects of chronic AF on repolarization in isolated human atrial cells. We have also defined the ionic changes underlying altered repolarization in this arrhythmia. The understanding of these mechanisms may have an important impact on the development of new pharmacological or non-pharmacological therapies. These could include the modulation of specific molecular targets to prevent or to reverse electrophysiological changes that allow the induction or the maintenance of AF. Our results warrant further investigation on the mechanisms involved in ionic current remodeling, namely studies on the regulatory functions of ion channels, differences in regional distribution as well as channel expression on the transcriptional and post-transcriptional level.

	5 Conclusions

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 
We have demonstrated that chronic AF in man is associated with a marked shortening and an impaired rate adaptation of repolarization in single atrial myocytes. The arrhythmia leads to important changes in ionic currents that determine atrial repolarization. These include a significant decrease in I_Ca,L and I_to, as well as an increase in the steady-state outward current at potentials relevant during phase 3 of the AP. Furthermore, I_K1 and I_KACh are increased at hyperpolarizing potentials. The understanding of the mechanisms underlying electrical remodeling in AF are crucial for the development of more efficient and less harmful therapeutic approaches to the arrhythmia.

Time for primary review 16 days.

	Acknowledgements

 
This study was supported by the Bundesministerium für Bildung und Forschung (BMBF-DLR 01EC 9405), by the Franz-Loogen-Stiftung and by the Dr. Karl-Kuhn-Stiftung. The authors thank Dr. Stanley Nattel for editorial comments.

	References

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Conclusions References

 

1. Kannel W.B., Abbott R.D., Savage D.D., McNamara P.M. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med (1982) 306:1018–1022.[Abstract]
2. The National Heart La. Atrial fibrillation. Current understandings and research imperatives. J Am Coll Cardiol (1993) 22:1830–1834.[Abstract]
3. Halperin J.L., Hart R.G. Atrial fibrillation and stroke: new ideas, persisting dilemmas. Stroke (1988) 19:937–941.[Free Full Text]
4. Wolf P.A., Dawber T.R., Thomas H.E., Kannel W.B. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology (1978) 28:973–977.[Abstract/Free Full Text]
5. Cairns J.A., Connelly S.J. Nonrheumatic atrial fibrillation: risk of stroke and antithrombotic therapy. Circulation (1991) 84:469–481.[Free Full Text]
6. Krahn A.D., Manfreda J., Tate R.B., Mathewson F.A.L., Cuddy T.E.D. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba follow-up study. Am J Med (1995) 98:476–484.[CrossRef][Web of Science][Medline]
7. Wijffels M.C.E.F., Kirchhof C.J.H.J., Dorland R., Allessie M.A. Atrial fibrillation begets atrial fibrillation: a study in awake, chronically instrumented goats. Circulation (1995) 92:1954–1968.[Abstract/Free Full Text]
8. Morillo C.A., Klein G.J., Jones D.L., Guiraudon C.M. Chronic rapid atrial pacing: structural, functional and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation (1995) 91:1588–1595.[Abstract/Free Full Text]
9. Gaspo R., Bosch R.F., Talajic M., Nattel S. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation (1997) 96:4027–4035.[Abstract/Free Full Text]
10. Elvan A., Wylie K., Zipes D.P. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs – Electrophysiological remodeling. Circulation (1996) 94:2953–2960.[Abstract/Free Full Text]
11. Kumagai K., Akimitsu S., Kawahira K., et al. Electrophysiological properties in chronic lone atrial fibrillation. Circulation (1991) 84:1662–1668.[Abstract/Free Full Text]
12. Daoud E.G., Bogun F., Goyal R., et al. Effects of atrial fibrillation on atrial refractoriness in humans. Circulation (1996) 94:1600–1606.[Abstract/Free Full Text]
13. Misier A.R., Opthof T., van-Hemel N.M., et al. Increased dispersion of "refractoriness" in patients with idiopathic paroxysmal atrial fibrillation. J Am Coll Cardiol (1992) 19:1531–1535.[Abstract]
14. Zhang S., Sawanobori T., Hirano Y., Hiraoka M. Multiple modulations of action potential duration by different calcium channel blocking agents in guinea pig ventricular myocytes. J Cardiovasc Pharmacol (1997) 30:489–496.[CrossRef][Web of Science][Medline]
15. Allessie M.A. Cardiac electrophysiology – From cell to bedside. Zipes D.P., Jalife J., eds. (1995) Philadelphia: Saunders. 562–566.
16. Yue L., Feng J., Gaspo R., et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res (1997) 81:512–525.[Abstract/Free Full Text]
17. Gaspo R., Bosch R.F., BouAbboud E., Nattel S. Tachycardia-induced changes in Na⁺ current in a chronic dog model of atrial fibrillation. Circ Res (1997) 81:1045–1052.[Abstract/Free Full Text]
18. Van Wagoner D.R., Pond A.L., McCarthy P.M., Trimmer J.S., Nerbonne J.M. Outward K⁺ current densities and Kv1.5 Expression are reduced in chronic human atrial fibrillation. Circ Res (1997) 80:772–781.[Abstract/Free Full Text]
19. Escande D., Coulombe A., Faivre J.F., Deroubaix E., Corabouef E. Two types of transient outward currents in adult human atrial cells. Am J Physiol (1987) 252:H142–H148.[Web of Science][Medline]
20. Wang Z., Fermini B., Nattel S. Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K⁺ current similar to Kv1.5 cloned channel currents. Circ Res (1993) 73:1061–1076.[Abstract/Free Full Text]
21. Fedida D., Wible B., Wang Z., et al. Identity of a novel delayed rectifier current from human heart with a cloned K⁺ channel current. Circ Res (1993) 73:210–216.[Abstract]
22. Koumi S.I., Backer C.L., Arentzen C.E. Characterization of inwardly rectifying K⁺ channel in human cardiac myocytes. Circulation (1995) 92:164–174.[Abstract/Free Full Text]
23. Heidbüchel H., Vereecke J., Carmeliet E. The electrophysiological effects of acetycholine in single human atrial cells. J Mol Cell Cardiol (1987) 19:1207–1219.[CrossRef][Web of Science][Medline]
24. Bosch R.F., Milek I.V., Popovic K., et al. Ambasilide prolongs the action potential and blocks multiple potassium currents in human atrium. J Cardiovasc Pharmacol (1999) 289:156–165.
25. Gotoh Y., Imaizumi Y., Watanabe M., et al. Inhibition of transient outward K⁺ current by DHP Ca²⁺ antagonists and agonists in rabbit cardiac myocytes. Am J Physiol (1991) 260:H1737–H1742.[Web of Science][Medline]
26. Li G.R., Nattel S. Properties of human atrial ICa at physiological temperatures and relevance to action potential. Am J Physiol (1997) 272:H227–H235.[Web of Science][Medline]
27. Wang Y.G., Schreieck J., Weyerbrock S., Overbeck M., Meisner H. Unterschiedlicher transienter Auswärtsstrom (Ito) in atrialen Kardiomyozyten von Patienten mit und ohne Herzinsuffizienz. Z Kardiol (1998) 87:125. (Abstract).[CrossRef][Medline]
28. Wegener J.W., Nawrath H. Action of tertiary phenylalkylamines on cardiac transient outward current from outside the cell membrane. Naunyn Schmiedebergs Arch Pharmacol (1996) 354:746–754.[CrossRef][Web of Science][Medline]
29. Yue L., Feng J., Li G.R., Nattel S. Characterization of an ultrarapid delayed rectifier potassium channel involved in canine atrial repolarization. J Physiol Lond (1996) 496:647–662.[Abstract/Free Full Text]
30. Zaza A., Malfatto G., Schwartz P.J. Effects on atrial repolarization of the interaction between K⁺ channel blockers and muscarinic receptor stimulation. J Pharmacol Exp Ther (1995) 273:1095–1104.[Abstract/Free Full Text]
31. Visentin S., Wu S.N., Belardinelli L. Adenosine-induced changes in atrial action potential: contribution of Ca- and K-currents. Am J Physiol (1990) 258:H1070–H1078.[Web of Science][Medline]
32. Allessie R., Nusynowitz M., Abildskov J.A., Moe G.K. Non-uniform distribution of vagal effects on atrial refractory period. Am J Physiol (1958) 194:406–410.[Abstract/Free Full Text]
33. Allessie M.A., Lammers W.J., Bonke I.M., Hollen J. Intra-atrial reentry as a mechanism for atrial flutter induced by acetylcholine and rapid pacing in the dog. Circulation (1984) 70:123–135.[Abstract/Free Full Text]
34. Coumel P. Role of the autonomic nervous system in paroxysmal atrial fibrillation. Clin Cardiol (1990) 13:209–212.[Web of Science][Medline]
35. Waxman M.B., Cameron D.A., Wald R.W. Cardiac electrophysiology: from cell to bedside. Zipes D.P., Jalife J., eds. (1995) Philadelphia: W.B. Saunders Company. 699–722.
36. Pu J., Shvilkin A., Hara M., Danilo P., Boyden P.A. Altered inward currents in myocytes from chronically fibrillating canine atria. Circulation (1997) 96:1–180. (abstract).
37. Van Wagoner D.R., Lamorgese M., Kirian P. Calcium current density is reduced in atrial myocytes isolated from patients in chronic atrial fibrillation. Circulation (1997) 96:1–180. (abstract).
38. Pressler M., Munster P., Huang C.D. Cardiac electrophysiology: from cell to bedside. Zipes D., Jalife J., eds. (1995) Philadelphia, PA: W.B. Saunders. 144–151.
39. Spach M.S., Starmer C.F. Altering the topology of gap junctions, a major therapeutic target for atrial fibrillation. Cardiovasc Res (1995) 30:337–344.[CrossRef][Web of Science][Medline]
40. Elvan A., Huang X.D., Pressler M.L., Zipes D.P. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation (1997) 96:1675–1685.[Abstract/Free Full Text]
41. van derVelden H.M.W., van Kempen M.J.A., Wijffels M.C.E.F., et al. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol (1998) 9:596–607.[Web of Science][Medline]
42. Patel P., Jones D.G., Dupont E. Remodelling of atrial connexin43 expression in human atrial fibrillation. Eur Heart J (1998) 19:465. (Abstract).
43. Yue L., Wang Z., Gaspo R., Nattel S. The molecular mechanism of ionic remodeling of repolarization in a dog model of atrial fibrillation. Circulation (1997) 96:1–180. (abstract).
44. Brundel B.J., Van Gelder I.C., Hennings R.H. Downregulation of the mRNA expression of L-type calcium channel and acetylcholine-activated potassium channel in chronic atrial fibrillation. Eur Heart J (1997) 18:193. (abstract).
45. Yue L., Feng J., Li G.R., Nattel S. Transient outward and delayed rectifier currents in canine atrium. properties and role of isolation methods. Am J Physiol (1996) 270:H2157–H2168.[Medline]
46. Nattel S., Hadjis T., Talajic M. The treatment of atrial fibrillation. An evaluation of drug therapy, electrical modalities and therapeutic considerations. Drugs (1994) 48:345–371.[Web of Science][Medline]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				A. Sridhar, Y. Nishijima, D. Terentyev, M. Khan, R. Terentyeva, R. L. Hamlin, T. Nakayama, S. Gyorke, A. J. Cardounel, and C. A. Carnes Chronic heart failure and the substrate for atrial fibrillation Cardiovasc Res, November 1, 2009; 84(2): 227 - 236. [Abstract] [Full Text] [PDF]

				I. Lenaerts, V. Bito, F. R. Heinzel, R. B. Driesen, P. Holemans, J. D'hooge, H. Heidbuchel, K. R. Sipido, and R. Willems Ultrastructural and Functional Remodeling of the Coupling Between Ca2+ Influx and Sarcoplasmic Reticulum Ca2+ Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation Circ. Res., October 23, 2009; 105(9): 876 - 885. [Abstract] [Full Text] [PDF]

				Y.-H. Yeh, B. Burstein, X. Y. Qi, M. Sakabe, D. Chartier, P. Comtois, Z. Wang, C.-T. Kuo, and S. Nattel Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia: A Molecular Basis for Tachycardia-Bradycardia Syndrome Circulation, March 31, 2009; 119(12): 1576 - 1585. [Abstract] [Full Text] [PDF]

				G. Michael, L. Xiao, X.-Y. Qi, D. Dobrev, and S. Nattel Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis Cardiovasc Res, February 15, 2009; 81(3): 491 - 499. [Abstract] [Full Text] [PDF]

				R. B. Sekar, E. Kizana, H. C. Cho, J. M. Molitoris, G. G. Hesketh, B. P. Eaton, E. Marban, and L. Tung IK1 Heterogeneity Affects Genesis and Stability of Spiral Waves in Cardiac Myocyte Monolayers Circ. Res., February 13, 2009; 104(3): 355 - 364. [Abstract] [Full Text] [PDF]

				G.-R. Li, H.-Y. Sun, X.-H. Zhang, L.-C. Cheng, S.-W. Chiu, H.-F. Tse, and C.-P. Lau Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes Cardiovasc Res, February 1, 2009; 81(2): 286 - 293. [Abstract] [Full Text] [PDF]

				X. Y. Qi, Y.-H. Yeh, L. Xiao, B. Burstein, A. Maguy, D. Chartier, L. R. Villeneuve, B. J.J.M. Brundel, D. Dobrev, and S. Nattel Cellular Signaling Underlying Atrial Tachycardia Remodeling of L-type Calcium Current Circ. Res., October 10, 2008; 103(8): 845 - 854. [Abstract] [Full Text] [PDF]

				R. Laszlo, C. Eick, N. Rueb, S. Weretka, H.-J. Weig, J. Schreieck, and R. F Bosch Inhibition of the renin-angiotensin system: effects on tachycardia-induced early electrical remodelling in rabbit atrium Journal of Renin-Angiotensin-Aldosterone System, September 1, 2008; 9(3): 125 - 132. [Abstract] [PDF]

				J. L. Serra and M. Bendersky Review: Atrial fibrillation and renin-angiotensin system Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 215 - 223. [Abstract] [PDF]

				Z. Yang, C. F. Browning, H. Hallaq, L. Yermalitskaya, J. Esker, M. R. Hall, A. J. Link, A.-J. L. Ham, M. J. McGrath, C. A. Mitchell, et al. Four and a half LIM protein 1: a partner for KCNA5 in human atrium Cardiovasc Res, June 1, 2008; 78(3): 449 - 457. [Abstract] [Full Text] [PDF]

				G.-R. Li, H.-B. Wang, G.-W. Qin, M.-W. Jin, Q. Tang, H.-Y. Sun, X.-L. Du, X.-L. Deng, X.-H. Zhang, J.-B. Chen, et al. Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs Circulation, May 13, 2008; 117(19): 2449 - 2457. [Abstract] [Full Text] [PDF]

				D. R. Van Wagoner Evaluating the impact of atrial dilatation on atrial calcium cycling Eur. Heart J., May 1, 2008; 29(9): 1084 - 1085. [Full Text] [PDF]

				J. R. Ehrlich, P. Biliczki, S. H. Hohnloser, and S. Nattel Atrial-Selective Approaches for the Treatment of Atrial Fibrillation J. Am. Coll. Cardiol., February 26, 2008; 51(8): 787 - 792. [Abstract] [Full Text] [PDF]

				K. Tsujimae, S. Murakami, and Y. Kurachi In silico study on the effects of IKur block kinetics on prolongation of human action potential after atrial fibrillation-induced electrical remodeling Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H793 - H800. [Abstract] [Full Text] [PDF]

				N. Voigt, A. Maguy, Y.-H. Yeh, X. Qi, U. Ravens, D. Dobrev, and S. Nattel Changes in IK,ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes Cardiovasc Res, January 1, 2008; 77(1): 35 - 43. [Abstract] [Full Text] [PDF]

				C. A. Carnes, P. M. L. Janssen, M. L. Ruehr, H. Nakayama, T. Nakayama, H. Haase, J. A. Bauer, M. K. Chung, I. M. Fearon, A. M. Gillinov, et al. Atrial Glutathione Content, Calcium Current, and Contractility J. Biol. Chem., September 21, 2007; 282(38): 28063 - 28073. [Abstract] [Full Text] [PDF]

				E. Saygili, O. R. Rana, E. Saygili, H. Reuter, K. Frank, R. H. G. Schwinger, J. Muller-Ehmsen, and C. Zobel Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal myocytes Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2898 - H2905. [Abstract] [Full Text] [PDF]

				N. Voigt, A. Friedrich, M. Bock, E. Wettwer, T. Christ, M. Knaut, R. H. Strasser, U. Ravens, and D. Dobrev Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation Cardiovasc Res, June 1, 2007; 74(3): 426 - 437. [Abstract] [Full Text] [PDF]

				S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]

				H. E. D. J. ter Keurs and P. A. Boyden Calcium and Arrhythmogenesis Physiol Rev, April 1, 2007; 87(2): 457 - 506. [Abstract] [Full Text] [PDF]

				S. A. Jones, M. R. Boyett, and M. K. Lancaster Declining Into Failure: The Age-Dependent Loss of the L-Type Calcium Channel Within the Sinoatrial Node Circulation, March 13, 2007; 115(10): 1183 - 1190. [Abstract] [Full Text] [PDF]

				S. C.M. Choisy, L. A. Arberry, J. C. Hancox, and A. F. James Increased Susceptibility to Atrial Tachyarrhythmia in Spontaneously Hypertensive Rat Hearts Hypertension, March 1, 2007; 49(3): 498 - 505. [Abstract] [Full Text] [PDF]

				U. Schotten, S. de Haan, S. Verheule, E. G.A. Harks, D. Frechen, E. Bodewig, M. Greiser, R. Ram, J. Maessen, M. Kelm, et al. Blockade of atrial-specific K+-currents increases atrial but not ventricular contractility by enhancing reverse mode Na+/Ca2+-exchange Cardiovasc Res, January 1, 2007; 73(1): 37 - 47. [Abstract] [Full Text] [PDF]

				F. Holmqvist, M. Stridh, J. E.P. Waktare, L. Sornmo, S. B. Olsson, and C. J. Meurling Atrial fibrillatory rate and sinus rhythm maintenance in patients undergoing cardioversion of persistent atrial fibrillation Eur. Heart J., September 2, 2006; 27(18): 2201 - 2207. [Abstract] [Full Text] [PDF]

				T.-J. Cha, J. R. Ehrlich, D. Chartier, X.-Y. Qi, L. Xiao, and S. Nattel Kir3-Based Inward Rectifier Potassium Current: Potential Role in Atrial Tachycardia Remodeling Effects on Atrial Repolarization and Arrhythmias Circulation, April 11, 2006; 113(14): 1730 - 1737. [Abstract] [Full Text] [PDF]

				R. Ochi, Y. Momose, K. Oyama, and W. R. Giles Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents Cardiovasc Res, April 1, 2006; 70(1): 88 - 96. [Abstract] [Full Text] [PDF]

				D. P. Zankov, M. Omatsu-Kanbe, T. Isono, F. Toyoda, W.-G. Ding, H. Matsuura, and M. Horie Angiotensin II Potentiates the Slow Component of Delayed Rectifier K+ Current via the AT1 Receptor in Guinea Pig Atrial Myocytes Circulation, March 14, 2006; 113(10): 1278 - 1286. [Abstract] [Full Text] [PDF]

				D. Dobrev, A. Friedrich, N. Voigt, N. Jost, E. Wettwer, T. Christ, M. Knaut, and U. Ravens The G Protein-Gated Potassium Current IK,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation Circulation, December 13, 2005; 112(24): 3697 - 3706. [Abstract] [Full Text] [PDF]

				M. Shah, F. G. Akar, and G. F. Tomaselli Molecular Basis of Arrhythmias Circulation, October 18, 2005; 112(16): 2517 - 2529. [Abstract] [Full Text] [PDF]

				N. Gaborit, M. Steenman, G. Lamirault, N. Le Meur, S. Le Bouter, G. Lande, J. Leger, F. Charpentier, T. Christ, D. Dobrev, et al. Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation Circulation, July 26, 2005; 112(4): 471 - 481. [Abstract] [Full Text] [PDF]

				M. Duytschaever, Y. Blaauw, and M. Allessie Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs Cardiovasc Res, July 1, 2005; 67(1): 69 - 76. [Abstract] [Full Text] [PDF]

				H. Zhang, C. J. Garratt, J. Zhu, and A. V. Holden Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans Cardiovasc Res, June 1, 2005; 66(3): 493 - 502. [Abstract] [Full Text] [PDF]

				E. P. Anyukhovsky, E. A. Sosunov, P. Chandra, T. S. Rosen, P. A. Boyden, P. Danilo Jr., and M. R. Rosen Age-associated changes in electrophysiologic remodeling: a potential contributor to initiation of atrial fibrillation Cardiovasc Res, May 1, 2005; 66(2): 353 - 363. [Abstract] [Full Text] [PDF]

				D. I. Leftheriotis, G. N. Theodorakis, D. Poulis, P. G. Flevari, E. G. Livanis, E. K. Iliodromitis, A. Papalois, and D. Th. Kremastinos The effects of 5-HT4 receptor blockade and stimulation, during six hours of atrial fibrillation Europace, January 1, 2005; 7(6): 560 - 568. [Abstract] [Full Text] [PDF]

				J. Li, M. McLerie, and A. N. Lopatin Transgenic upregulation of IK1 in the mouse heart leads to multiple abnormalities of cardiac excitability Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2790 - H2802. [Abstract] [Full Text] [PDF]

				T. Christ, P. Boknik, S. Wohrl, E. Wettwer, E.M. Graf, R.F. Bosch, M. Knaut, W. Schmitz, U. Ravens, and D. Dobrev L-Type Ca2+ Current Downregulation in Chronic Human Atrial Fibrillation Is Associated With Increased Activity of Protein Phosphatases Circulation, October 26, 2004; 110(17): 2651 - 2657. [Abstract] [Full Text] [PDF]

				E. Wettwer, O. Hala, T. Christ, J. F. Heubach, D. Dobrev, M. Knaut, A. Varro, and U. Ravens Role of IKur in Controlling Action Potential Shape and Contractility in the Human Atrium: Influence of Chronic Atrial Fibrillation Circulation, October 19, 2004; 110(16): 2299 - 2306. [Abstract] [Full Text] [PDF]

				T.-J. Cha, J. R. Ehrlich, L. Zhang, and S. Nattel Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure Circulation, September 21, 2004; 110(12): 1520 - 1526. [Abstract] [Full Text] [PDF]

				G. Lonardo, E. Cerbai, S. Casini, G. Giunti, M. Bonacchi, F. Battaglia, B. Fiorani, P. L. Stefano, G. Sani, and A. Mugelli Atrial natriuretic peptide modulates the hyperpolarization-activated current (If) in human atrial myocytes Cardiovasc Res, August 15, 2004; 63(3): 528 - 536. [Abstract] [Full Text] [PDF]

				J. R. Ehrlich, T.-J. Cha, L. Zhang, D. Chartier, L. Villeneuve, T. E. Hebert, and S. Nattel Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium J. Physiol., June 1, 2004; 557(2): 583 - 597. [Abstract] [Full Text] [PDF]

				S. Wasson, H. K. Reddy, and M. L. Dohrmann Current Perspectives of Electrical Remodeling and Its Therapeutic Implications Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2004; 9(2): 129 - 144. [Abstract] [PDF]

				D. M. Todd, S. P. Fynn, A. P. Walden, W. J. Hobbs, S. Arya, and C. J. Garratt Repetitive 4-Week Periods of Atrial Electrical Remodeling Promote Stability of Atrial Fibrillation: Time Course of a Second Factor Involved in the Self-Perpetuation of Atrial Fibrillation Circulation, March 23, 2004; 109(11): 1434 - 1439. [Abstract] [Full Text] [PDF]

				K. J Wirth, T. Paehler, B. Rosenstein, K. Knobloch, T. Maier, J. Frenzel, J. Brendel, A. E Busch, and M. Bleich Atrial effects of the novel K+-channel-blocker AVE0118 in anesthetized pigs Cardiovasc Res, November 1, 2003; 60(2): 298 - 306. [Abstract] [Full Text] [PDF]

				W. Dun, P. Chandra, P. Danilo Jr., M. R. Rosen, and P. A. Boyden Chronic atrial fibrillation does not further decrease outward currents. It increases them. Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1378 - H1384. [Abstract] [Full Text] [PDF]

				F. Sarmast, A. Kolli, A. Zaitsev, K. Parisian, A. S Dhamoon, P. K Guha, M. Warren, J. M.B Anumonwo, S. M Taffet, O. Berenfeld, et al. Cholinergic atrial fibrillation: IK,ACh gradients determine unequal left/right atrial frequencies and rotor dynamics Cardiovasc Res, October 1, 2003; 59(4): 863 - 873. [Abstract] [Full Text] [PDF]

				A. J Workman, K. A Kane, and A. C Rankin Characterisation of the Na, K pump current in atrial cells from patients with and without chronic atrial fibrillation Cardiovasc Res, September 1, 2003; 59(3): 593 - 602. [Abstract] [Full Text] [PDF]

				C. Valenzuela Pharmacological electrical remodelling in human atria induced by chronic {beta}-blockade Cardiovasc Res, June 1, 2003; 58(3): 498 - 500. [Full Text] [PDF]

				W. Dun, T. Yagi, M. R Rosen, and P. A Boyden Calcium and potassium currents in cells from adult and aged canine right atria Cardiovasc Res, June 1, 2003; 58(3): 526 - 534. [Abstract] [Full Text] [PDF]

				R. F. Bosch, C. R. Scherer, N. Rub, S. Wohrl, K. Steinmeyer, H. Haase, A. E. Busch, L. Seipel, and V. Kuhlkamp Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa,L and Ito in rapid atrial pacing in rabbits J. Am. Coll. Cardiol., March 5, 2003; 41(5): 858 - 869. [Abstract] [Full Text] [PDF]

				F. Xie, Z. Qu, A. Garfinkel, and J. N. Weiss Electrical refractory period restitution and spiral wave reentry in simulated cardiac tissue Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H448 - H460. [Abstract] [Full Text] [PDF]

				S. Nattel, M. Allessie, and M. Haissaguerre Spotlight on atrial fibrillation--the 'complete arrhythmia' Cardiovasc Res, May 1, 2002; 54(2): 197 - 203. [Full Text] [PDF]

				M. Allessie, J. Ausma, and U. Schotten Electrical, contractile and structural remodeling during atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 230 - 246. [Abstract] [Full Text] [PDF]

				R. F Bosch and S. Nattel Cellular electrophysiology of atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 259 - 269. [Full Text] [PDF]

				B. J.J.M. Brundel, R. H. Henning, H. H. Kampinga, I. C. Van Gelder, and H. J.G.M. Crijns Molecular mechanisms of remodeling in human atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 315 - 324. [Abstract] [Full Text] [PDF]

				S. Nattel Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res, May 1, 2002; 54(2): 347 - 360. [Abstract] [Full Text] [PDF]

				D. Dobrev, E. Wettwer, A. Kortner, M. Knaut, S. Schuler, and U. Ravens Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 397 - 404. [Abstract] [Full Text] [PDF]

				T. Yagi, J. Pu, P. Chandra, M. Hara, P. Danilo Jr., M. R Rosen, and P. A Boyden Density and function of inward currents in right atrial cells from chronically fibrillating canine atria Cardiovasc Res, May 1, 2002; 54(2): 405 - 415. [Abstract] [Full Text] [PDF]

				J. Kneller, H. Sun, N. Leblanc, and S. Nattel Remodeling of Ca2+-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation Cardiovasc Res, May 1, 2002; 54(2): 416 - 426. [Abstract] [Full Text] [PDF]

				T. Korte, M. Niehaus, G. Borchert, and J. Tebbenjohanns Significant prolongation of atrial monophasic action potential duration: short-term reverse electrophysiological changes after internal cardioversion of atrial fibrillation Cardiovasc Res, March 1, 2002; 53(4): 944 - 951. [Abstract] [Full Text] [PDF]

				U. Schotten, M. Greiser, D. Benke, K. Buerkel, B. Ehrenteidt, C. Stellbrink, J. F Vazquez-Jimenez, F. Schoendube, P. Hanrath, and M. Allessie Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort Cardiovasc Res, January 1, 2002; 53(1): 192 - 201. [Abstract] [Full Text] [PDF]

				Y.-J. Chen, S.-A. Chen, Y.-C. Chen, H.-I Yeh, P. Chan, M.-S. Chang, and C.-I Lin Effects of Rapid Atrial Pacing on the Arrhythmogenic Activity of Single Cardiomyocytes From Pulmonary Veins: Implication in Initiation of Atrial Fibrillation Circulation, December 4, 2001; 104(23): 2849 - 2854. [Abstract] [Full Text] [PDF]

				D. Dobrev, E. Graf, E. Wettwer, H. M. Himmel, O. Hala, C. Doerfel, T. Christ, S. Schuler, and U. Ravens Molecular Basis of Downregulation of G-Protein-Coupled Inward Rectifying K+ Current (IK,ACh) in Chronic Human Atrial Fibrillation: Decrease in GIRK4 mRNA Correlates With Reduced IK,ACh and Muscarinic Receptor-Mediated Shortening of Action Potentials Circulation, November 20, 2001; 104(21): 2551 - 2557. [Abstract] [Full Text] [PDF]

				A. J Workman, K. A Kane, and A. C Rankin The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation Cardiovasc Res, November 1, 2001; 52(2): 226 - 235. [Abstract] [Full Text] [PDF]

				B. J. J. M. Brundel, I. C. Van Gelder, R. H. Henning, A. E. Tuinenburg, M. Wietses, J. G. Grandjean, A. A. M. Wilde, W. H. Van Gilst, and H. J. G. M. Crijns Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels J. Am. Coll. Cardiol., March 1, 2001; 37(3): 926 - 932. [Abstract] [Full Text] [PDF]

				H. Sun, D. Chartier, N. Leblanc, and S. Nattel Intracellular calcium changes and tachycardia-induced contractile dysfunction in canine atrial myocytes Cardiovasc Res, March 1, 2001; 49(4): 751 - 761. [Abstract] [Full Text] [PDF]

				B. J. J. M. Brundel, I. C. Van Gelder, R. H. Henning, R. G. Tieleman, A. E. Tuinenburg, M. Wietses, J. G. Grandjean, W. H. Van Gilst, and H. J. G. M. Crijns Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation Circulation, February 6, 2001; 103(5): 684 - 690. [Abstract] [Full Text] [PDF]

				U. Schotten, J. Ausma, C. Stellbrink, I. Sabatschus, M. Vogel, D. Frechen, F. Schoendube, P. Hanrath, and M. A. Allessie Cellular Mechanisms of Depressed Atrial Contractility in Patients With Chronic Atrial Fibrillation Circulation, February 6, 2001; 103(5): 691 - 698. [Abstract] [Full Text] [PDF]

				M. A. Allessie, P. A. Boyden, A. J. Camm, A. G. Kleber, M. J. Lab, M. J. Legato, M. R. Rosen, P. J. Schwartz, P. M. Spooner, D. R. Van Wagoner, et al. Pathophysiology and Prevention of Atrial Fibrillation Circulation, February 6, 2001; 103(5): 769 - 777. [Full Text] [PDF]

				S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]

				D. Dobrev, E. Wettwer, H. M. Himmel, A. Kortner, E. Kuhlisch, S. Schuler, W. Siffert, and U. Ravens G-Protein {beta}3-Subunit 825T Allele Is Associated With Enhanced Human Atrial Inward Rectifier Potassium Currents Circulation, August 8, 2000; 102(6): 692 - 697. [Abstract] [Full Text] [PDF]

				M. A Allessie Atrial fibrillation-induced electrical remodeling in humans: What is the next step? Cardiovasc Res, October 1, 1999; 44(1): 10 - 12. [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Bosch, R. F. Articles by Kühlkamp, V. Search for Related Content PubMed PubMed Citation Articles by Bosch, R. F. Articles by Kühlkamp, V. Social Bookmarking          What's this?

Online ISSN 1755-3245 - Print ISSN 0008-6363

Copyright © 2009 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics