European Heart Journal Advance Access originally published online on April 7, 2008
European Heart Journal 2008 29(9):1190-1197; doi:10.1093/eurheartj/ehn140
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Downregulation of the calcium current in human right atrial myocytes from patients in sinus rhythm but with a high risk of atrial fibrillation
1 Cardiology Department, Hôpital Antoine-Béclère, Assistance Publique-Hôpitaux de Paris, Clamart, France
2 Inserm, UMRS621, Faculté Pierre-Marie Curie, 91 boulevard de l’Hôpital, 75013 Paris, France
3 Université Pierre et Marie Curie-Paris 6, UMRS621, Paris, France
4 CNRS-UMR-8162, Université Paris-XI, Hopital Marie-Lannelongue, Le-Plessis-Robinson, France
5 Institut de Cardiologie, Hôpital Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France
6 Centre de Recherche Pierre-Fabre, Castres, France
7 Inserm, UMRS698, Paris, France
8 Université Paris-Diderot, Paris, France
9 Department of Physiology, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France
10 Department of Cardiology, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France
Received 11 August 2007; revised 25 February 2008; accepted 13 March 2008; online publish-ahead-of-print 7 April 2008.
* Corresponding author. Tel: +33 1 40 77 95 84, Fax: +33 1 40 77 98 72. Email: stephane.hatem{at}chups.jussieu.fr
See page 1084 for the editorial comment on this article (doi:10.1093/eurheartj/ehn051)
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Abstract |
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Aims: A decrease in L-type calcium current (ICaL) is an important mechanism favouring atrial fibrillation (AF). Here, we aimed to identify pathogenic factors associated with ICaL downregulation.
Methods and results: Atrial myocytes were isolated from right atrial appendages obtained from 86 adult patients in sinus rhythm with coronary artery disease, aortic valve disease, or mitral valve disease (MVD). Current was recorded in isolated myocytes using the whole-cell patch-clamp technique. The ICaL recorded in the 172 myocytes studied showed a marked variability of peak density ranging from 0.1 to 9.0 pA/pF. The ICaL peak density did not correlate with membrane capacitance or changes in current biophysical properties. The ICaL peak density was homogeneous for a given sample. Small ICaL values were recorded in patients with MVD or with a low left ventricular ejection fraction (<45%). Small ICaL values were more sensitive to the β-adrenergic agonist, isoproterenol (1 µM), and to the phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (10 µM).
Conclusion: In human atrial myocytes, the variability of ICaL is related to the clinical history of the donors. The downregulation of ICaL is already observed in patients in sinus rhythm with a high risk of AF and is associated with the greatest response to β-adrenergic agonist.
Key Words: Atrial dilatation • Atrial fibrillation • Calcium current • Atrial myocytes • Catecholamine
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Introduction |
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Atrial fibrillation (AF) is the most frequent cardiac arrhythmia and is favoured by several factors, including valve diseases, heart failure, hypertension, and ageing.1 The pathophysiology of AF is complex and this condition is usually associated with profound functional and structural alterations of the atrial myocardium.2–5 At the cellular level, the arrhythmogenic substrate is characterized by a shortened action potential (AP) without plateau phase and that adapts poorly to changes in heart rate.4 This cellular electrical remodelling is believed to contribute to the reduction of effective refractory periods (ERPs) and to favour the constitution of microwavelet re-entry.6,7
A major mechanism of AP shortening during AF is the reduction of the L-type calcium current (ICaL). A decrease of 
70% in ICaL has been consistently observed during AF in both human atrial myocytes and experimental models.5,8,9 This current is the main depolarizing current that activates during the plateau phase of the AP. Moreover, Ca2+ channels are the target for several neuromediators which regulate cardiac function by modulating channel phosphorylation via several protein kinases and phosphatases and, in turn, the current amplitude. In addition to its role in shaping the AP, ICaL triggers the release of calcium from the sarcoplasmic reticulum and is thus a key actor for the activation of the contraction. Indeed, its downregulation during AF is an important determinant of the depressed atrial contractility.10
A number of studies have attempted to identify pathogenic factors underlying ICaL downregulation during AF. Both alterations in the expression level and activity of Ca2+ channels have been described during arrhythmia.5,11–13 Experimentally it was demonstrated that a high beating rate, chronic atrial volume overload, or heart failure can cause the downregulation of ICaL.8,14,15 Here, we examined clinical parameters associated with changes in the atrial ICaL in human patients. The possibility of obtaining samples of right atrial appendage during routine cardiac surgery permits the recording of calcium currents associated with various clinical conditions. We found that the peak ICaL varies between atrial myocytes and that this variability is related to the clinical history of the patient.
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Clinical data and cardiac myocyte preparation
With approval of our Ethics Committee, specimens of right atrial appendage were obtained between 2001 and 2006 from 86 patients (32–90 years, mean 56 ± 4 years) undergoing heart surgery for coronary bypass (n = 56), mitral (n = 10), or aortic (n = 20) valve repair/replacement. As the right atrial sample is considered surgical tissue waste, no consent has to be obtained from donor. Left ventricle ejection fraction (LVEF) was measured by echocardiography or isotopic assay. All patients were in sinus rhythm during the inhospital period. However, it is possible that some of them had experienced episodes of paroxysmal or silent AF. Most of the patients were treated with β-adrenergic antagonists and angiotensin-converting enzyme-inhibitors (Table 1). Treatments were stopped at least 8 h before surgery. Myocytes were isolated as described previously.16 The criterion for inclusion in the study was for patients to undergo a cardiac surgery with an extracorporeal circulation allowing to obtain a right atrial sample. The yield of live isolated myocytes and the quality of the current recording were the final criteria for inclusion.
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Current measurements
Whole-cell Ca2+ currents were recorded using the patch-clamp technique as described previously.16 For calcium current inactivation measurement, test pulses were preceded by 2 s conditioning pulses. Activation plots were generated by dividing peak ICaL measured at a given potential by the difference between measured and reversal potential. Data on the conductance/voltage activation and inactivation curves were best fitted to a Boltzmann distribution equation:
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Solutions and reagents
Composition of the standard external solution in mM: NaCl 136, KCl 5.4, CaCl2 2, glucose 10, MgCl2 1.06, NaH2PO4 0.33, HEPES 10; pH was adjusted to 7.4 with NaOH; and of the internal solution in mM: CsCl 130, MgCl2 2, HEPES 10, EGTA 15, glucose 10, MgATP 3; pH was adjusted to 7.2 with CsOH. For ICaL recording, NaCl was replaced by tetraethylammonium chloride. ISO and 3-isobutyl-1- methyl-xanthine (IBMX) were purchased from Sigma-Aldrich (France) and diluted in the extracellular perfusion solution. Experiments were carried out at room temperature (22–24°C).
Statistical analysis
The reproducibility of current measurements in the various cells isolated from a given tissue sample was assessed using the Bland–Altman method.17 A plot of the difference between measures against their mean was constructed and the bias (mean difference ± SD) was calculated. ICaL density was compared according to gender, LV dysfunction, and the type of cardiopathy by Wilcoxon’s rank sum test for non-normally distributed data. The clinical variables were defined a priori as the main variable known to be associated with a risk of AF. A univariable analysis and a stepwise multivariate linear regression analysis with age, gender, LV dysfunction, and cardiopathy were performed to identify factors associated with ICaL variability using a probability value of P < 0.05. The generated model was validated internally with the use of bootstrap re-sampling method according to the ‘boot’ package [Bootstrap R (S-Plus) Functions (Canty); R package version 1.2–30] in ‘R’ (R Foundation for Statistical Computing, Vienna, Austria; ISBN 3-900051-07-0, URL http://www.R-project.org). We generated 9999 same-sized duplicates for the original database and analysed distribution for each selected variable parameter. Ninety-five per cent confidence intervals (bias corrected, accelerated) were then estimated for each parameter. No sample size calculation was performed for this observational study. The study was stopped when we considered to have enough data to perform analysis on the basis of the other studies of the literature conducted on human atrial myocytes. Tests were two-sided, and the significance level was fixed at 5%. All results are shown as means ± SD.
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Results |
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Marked variability of calcium current density between atrial myocytes
A calcium current could be recorded during 300 ms step depolarization in the 172 myocytes studied. However, there was an important scattering of its peak density ranging from 0.1 to 9.0 pA/pF. Membrane capacitance, an indicator of the myocyte size, was also dispersed, ranging from 40 to 150 pF, suggesting different populations of atrial myocytes. However, there was only a weak correlation between peak current amplitude or current density and membrane capacitance, suggesting that the number of functional channels per membrane surface was rather variable (Figure 1B and C). In order to examine whether peak ICaL heterogeneity reflected changes in current properties, we arbitrarily defined a group A of currents with a density <2.5 pA/pF and a group B of currents with a density >2.5 pA/pF. In both groups, the threshold of current activation was around –40 mV, ICaL peaked at 0 mV, and its apparent reversal potential was measured at 100 mV (Figure 2A). The voltage-dependent activation and steady-state inactivation relationships of ICaL did not differ between the two groups (Figure 2B and C). These results indicated that although ICaL density varied between atrial samples, this was not due to changes in current properties or to different populations of myocytes.
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Clinical parameters associated with variation of calcium current density
We next examined whether clinical parameters were associated with changes in ICaL. As only a few myocytes could be studied per sample (from 2 to 7), we first verified that the density of ICaL recorded in myocytes from the same sample was homogeneous. This question was addressed by testing the similarity between two ICaL values measured from two distinct myocytes of the same sample.17 Comparison of the difference between the means of ICaL measurements (Figure 3) showed that measures were in good agreement. The vast majority of ICaL values were situated within two standard errors of the mean (bias 4.69%). For the overall data, the mean difference is 0.12 (–0.17 to 0.42) and the limits of agreement (with their 95% confidence interval) are lower limit –2.10 (–2.61 to –1.59); upper limit 2.35 (1.84–2.86). However, as shown in Figure 3, a relation between difference and mean is observed, smaller limit of agreements being obtained for small ICaL values (<2 pA/pF): mean difference –0.09 (–0.33 to 0.15); lower limit –1.29 (–1.72 to –0.86); and upper limit 1.11 (0.68–1.54). In this group, the mean differences for the vast majority of ICaL values (90% of measures) were contained between –0.5 and 0.5 pA/pF. There was also a good correlation between two ICaL measurements from the same group of myocytes (r2 = 0.68, Figure 3). This statistical analysis was repeated with all cell pairs and yielded similar results. These data indicated that peak ICaL density was relatively homogeneous for a given sample, especially when the current was of small density. Thus, even if only a few current measurements could be performed per sample, they could be considered representative of the whole sample.
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Univariable analysis revealed two conditions associated with small ICaL density. First, patients suffering from mitral valve disease (MVD) had a smaller ICaL density compared with other patients [0.99 ± 0.62 pA/pF (n = 10 patients) vs. 3.27 ± 2.01 pA/pF (n = 76 patients), P < 0.0007]. Membrane capacitance in the former group was also increased (92 ± 28 vs. 69 ± 25 pF; P < 0.001). Secondly, a small ICaL value was also observed in patients with a decreased LV function (LVEF < 45%) and suffering from ischaemic heart disease or aortic valve disease: 1.78 ± 0.86 (LVEF < 45%, n = 29) vs. 3.63 ± 2.18 (LVEF > 45%, n = 57) (P < 0.0001) (Figure 4). Membrane capacitance was also increased in this group of patients (99 ± 31 vs. 69 ± 24 pF; P < 0.001). Multivariable linear regression analysis including age, gender, MVD, and LV function confirmed that MVD (regression coefficient –2.46 ± 0.59, P < 0.0001) and decreased LV (regression coefficient –1.80 ± 0.39, P < 0.001) were both independently associated with the downregulation of ICaL. The bootstrap statistics (mean, 95% CI) of the regression coefficient were MVD –2.26 (–3.26 to –1.24); LV dysfunction –1.42 (–2.18 to –0.66); gender 0.89 (–0.38 to 2.16), thus, confirming the effect of MVD and LV dysfunction on ICaL density but ruled out an effect of gender. Taken together, these results indicate that the variability of peak ICaL is related to the clinical history of the donors.
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Enhanced response of small calcium currents to a β-adrenergic agonist
To examine whether ICaL heterogeneity could be due to variations in current phosphorylation, we studied the effect of the β-adrenergic agent, ISO (1 µM), on ICaL. There was an important variation in the response of ICaL to ISO, varying from no effect to a marked stimulatory effect (Figure 5). Plotting the percentage of the ISO effect on ICaL against current density showed that small currents were more sensitive to ISO (r = 0.51; P < 0.0001) (Figure 5). The concentration-dependent effect of ISO on ICaL was compared between a group of myocytes obtained from patients with MVD or with a low LV ejection fraction (n = 5) and patients with coronary artery disease (CAD) and normal LV function (n = 5). At each concentration tested, the response of ICaL to ISO was much higher in the group of patients with a small ICaL value without difference in the EC50 (29.6 ± 7.8 vs. 29.2 ± 10.5 nM for the CAD group) (Figure 5). In both groups, the phosphodisterase inhibitor IBMX increased ICaL, but this effect was much more pronounced in myocytes from patients with MVD or low LV ejection fraction (n = 7 myocytes from three atria) than in those from CAD patients (n = 6 myocytes, from three atria) (P < 0.001) (Figure 5).
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Discussion |
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A reduction in the L-type calcium current has been consistently reported during AF and is believed to constitute an important arrhythmogenic factor through the shortening of AP duration and refractory periods.7 In the present study, we found that a marked reduction of ICaL is already observed in atrial myocytes from patients known to be the most susceptible to develop AF. Moreover, the variation of current is due, for a large part, to changes in β-adrenergic effects on ICaL.
The variability of ICaL between human atrial samples cannot be explained by alterations in current biophysical properties as indicated by the absence of variation in the voltage-gating properties of ICaL. Different populations of atrial myocytes are unlikely to explain current changes given the lack of correlation between cell size and the peak or density of ICaL. It rather suggests that the density of functional calcium channels varies between samples. Transcriptional and post-transcriptional regulation of calcium channels have been described in the atrial myocardium.5,11–13 During AF, myocytes contain less L-type Ca2+ channels.12,18 Another important mechanism underlying ICaL downregulation during AF is the decrease in channel activity.11 A high sensitivity of ICaL to β-adrenergic agonists has been reported during AF, suggesting that basal phosphorylation of calcium channels is reduced.5 Here, we also found that the smallest ICaL value have the greatest response to β-adrenergic agonist. In cardiac myocytes, basal phosphorylation of calcium channels is necessary to maintain normal channel function.19,20 It is thus plausible that in diseased atria, a number of channels become silent in basal conditions but can be recruited upon β-adrenergic stimulation. Phosphodiesterases are important determinants of cAMP metabolism, notably in atrial myocytes.21 Our finding that small ICaL values are more sensitive to phosphodiesterase inhibition than control currents provides another argument in favour of the existence of variations in phosphorylation of calcium channels. Several phosphatases are also involved in the regulation of Ca2+ channels and their activity is increased during AF, most likely contributing to the downregulation of ICaL.22
We found that ICaL variability is related to the clinical history of the patient. Patients with MVD or in chronic heart failure exhibited a marked downregulation of ICaL as observed during AF. This finding is in good agreement with a transcriptomic study showing a reduction of CACNAIC transcript during both AF and MVD.13 During chronic atrial dilatation in human, AP becomes shorter and ICaL is downregulated.9 Furthermore, it has been demonstrated that a moderate volume overload of the atrium is sufficient to cause ICaL reduction.15 Collectively, these studies indicate that changes in atrial haemodynamic conditions play an important role in the electrical remodelling of the atrial myocardium.23 MVDs or HF are most often associated with some degree of haemodynamic overload of the right atrium as the consequence of the increase in post-capillary pulmonary pressure. In these patients, the increase in myocyte size, i.e. larger membrane capacitance, supports the possibility of hypertrophic myocardial remodelling in response to right atrial haemodynamic overload. Several neuromediators or peptides could also be involved in the altered channel activity during HF or MVDs including endothelin, angiotensin-II, or atrial natriuretic peptide (ANP).24 Of note, in some patients of the present study, plasma ANP was increased (>100 pg/mL) in patients with small ICaLvalue. In human atrial myocytes, ANP reduces ICaL by stimulating cGMP-dependent phosphodiesterase.16 It has been shown that in dilated atria of rats in HF, the downregulation of ICaL is due to an abnormal intracellular accumulation of cGMP and a subsequent abnormal activation of PDE.14 The redox state could be also altered in atrial myocytes from patients with MVD or in HF.25 Interestingly, glutathione, an important modulator of cellular redox state, is decreased during AF26 and its level determines the amplitude of ICaL in human atrial myocyte directly, by changing the nirosylation of calcium channels,26 or indirectly, via the modulation of kinase/phosphatases.27
During AF, the downregulation of ICaL is believed to be a major determinant of the shortening of ERP. Unlike in AF, ERP was not found to be reduced in dilated atria or during CHF.28–30 Thus, the role of ICaL downregulation in the vulnerability to AF in these clinical settings is not clear. One explanation could be that during atrial haemodynamic overload, the right appendage undergoes an early and severe electrical remodelling compared with the rest of the atria which contributes importantly to the global refractory period. Indeed, trabeculae of dilated human right atrial appendage exhibit a short ERP.9 The lack of change of refractory periods might be explained by a paralleled decrease in repolarizing currents that can mask the reduction in ICaL. For instance, the delayed rectifier current, Ikr, is reduced in CHF but not in the rapid pacing dog models.8 Atrial stretch which can alter repolarizing currents might be particularly pronounced during chronic atrial haemodynamic overload.31,32 Finally, ICaL downregulation might be a protective mechanism against calcium overload and activation of calcium-dependent signalling cascades known to be responsible for phenotypic changes of the atrial myocardium.33
Limitations of the study
Only myocytes from right atrial appendage were studied while the electrical remodelling of the atrial myocardium may not be homogeneous between the different atrial areas. However, similar electrical remodelling was observed between left and right atria.5 Secondly, although a relationship between ICaL downregulation and alterations of the electrical properties of atrial myocytes is well established,7 we have no direct information on consequences of the alteration of ICaL on AP duration, ERP, and on atrial vulnerability to AF. We did not find a relation between post-operative AF and small ICaL in keeping with a study showing that changes in ionic currents of human atrial myocytes do not predict the occurrence of AF during the post-operative period.34 Also, it was not possible to perform a longitudinal follow-up of patients in order to study the occurrence of AF because, fortunately, the cardiopathies of these patients have been cured. Nevertheless, it seems reasonable to conclude that an important determinant of normal atrial excitability is altered before AF.
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Our observation that patients in sinus rhythm with an increased risk of AF have a small ICaL as during AF suggests that this alteration precedes the arrhythmia. This is reminiscent of observations that fibrosis, myocyte apoptosis, or alteration of gap junctions can be observed before AF.2,35,36 This is also in agreement with the observation of a similar transcriptomic ionic channel profile between the atria of patients in AF or with valve diseases in sinus rhythm.13 Thus, besides rapid beating, several pathogenic factors could favour the development of the AF substrate. Their identification is of major importance and to define new therapeutic strategies for the prevention of AF.
Conflict of interest: none declared.
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This study was supported by the Agence Nationale de la Recherche (ANR-05-PCOD-006-01) and the Société Française de Cardiologie. J.-J.M. is supported in part by an EU FP6 grant LSHM-CT- 2005-018833, EUGeneHeart. We thank Dr Mary Osborne-Pelegrin for her editorial assistance and Dr Gurkan Mutlu for his help in the statistical analysis.
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- Evaluating the impact of atrial dilatation on atrial calcium cycling
- David R. Van Wagoner
EHJ 2008 29: 1084-1085.[Extract] [FREE Full Text]
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  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]
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