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Published in final edited form as: Am J Physiol Heart Circ Physiol. 2020 May 8;318(6):H1436–H1440. doi: 10.1152/ajpheart.00224.2020

Reduced Na+ current in Purkinje fibers explains cardiac conduction defects and arrhythmias in Duchenne muscular dystrophy

Janine Ebner 1, Pavel Uhrin 2, Petra L Szabo 3, Attila Kiss 3, Bruno K Podesser 3, Hannes Todt 1, Karlheinz Hilber 1,✉, Xaver Koenig 1
PMCID: PMC7618121  EMSID: EMS108534  PMID: 32383994

Abstract

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a degenerative muscle disease triggered by mutations in the gene encoding for the intracellular protein dystrophin. A major source for the arrhythmias in patients with DMD is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, decreased cardiac output, and the development of reentrant mechanisms. The reason for ventricular conduction impairments and the associated arrhythmias in the dystrophic heart has remained unidentified. In the present study, we explored the hypothesis that dystrophin-deficient cardiac Purkinje fibers have reduced Na+ currents (INa), which would represent a potential mechanism underlying slowed ventricular conduction in the dystrophic heart. Therefore, by using a Langendorff perfusion system, we isolated Purkinje fibers from the hearts of adult wild-type control and dystrophin-deficient mdx mice. Enhanced green fluorescent protein (eGFP) expression under control of the connexin 40 gene allowed us to discriminate Purkinje fibers from eGFP-negative ventricular working cardiomyocytes after cell isolation. Finally, we recorded INa from wild-type and dystrophic mdx Purkinje fibers for comparison by means of the whole cell patch clamp technique. We found substantially reduced INa densities in mdx compared with wild-type Purkinje fibers, suggesting that dystrophin deficiency diminishes INa. Because Na+ channels in the Purkinje fiber membrane represent key determinants of ventricular conduction velocity, we propose that reduced INa in Purkinje fibers at least partly explains impaired ventricular conduction and the associated arrhythmias in the dystrophic heart.

New & Noteworthy

Dystrophic cardiac Purkinje fibers have abnormally reduced Na+ current densities. This explains impaired ventricular conduction in the dystrophic heart.

Keywords: arrhythmias, Duchenne muscular dystrophy, Na+ current, Purkinje fibers, ventricular conduction

Introduction

Duchenne muscular dystrophy (DMD), a degenerative muscle disease triggered by mutations in the gene encoding for the intracellular protein dystrophin, is associated with severe cardiovascular complications. Among those, cardiac arrhythmias significantly contribute to mortality in patients with DMD (5, 18, 21). Since the specific mechanisms that cause these arrhythmias are poorly understood, current strategies to treat patients are not evidence based, and life-threatening ventricular tachycardias cannot be prevented.

A major source for arrhythmias in patients with DMD is impaired ventricular impulse conduction, which manifests as prolonged His-ventricular intervals and bundle branch block (8, 23, 33). Abnormally slowed ventricular conduction, predisposing for ventricular asynchrony, decreased cardiac output, and the development of reentrant arrhythmias has also been observed in the most commonly used mouse model for DMD, the dystrophin-deficient mdx mouse (6, 24). Despite decades of research, the reason for ventricular conduction impairments and the associated arrhythmias in the dystrophic heart has remained unidentified as yet.

We and others have previously reported that ventricular “working” cardiomyocytes from mdx mouse hearts exhibit an abnormally reduced Na+ current (INa), entailing a slowed action potential upstroke in these cells (1, 10, 20, 21). According with this finding, Nav1.5 Na+ channel protein expression in mdx compared with wild-type mouse hearts is diminished (1, 10). Although reduced INa in working cardiomyocytes may contribute to slowed ventricular conduction in the dystrophic heart, a functional impairment of this particular cell type cannot provide an explanation for prolonged His-ventricular intervals and bundle branch block in patients with DMD. The molecular basis of such abnormalities in the DMD heart must rather reside in the specialized ventricular conduction system, consisting of the His bundle with associated left and right branches and the cardiac Purkinje fiber network.

Because voltage-gated Na+ channels in the Purkinje fiber membrane represent key determinants of ventricular conduction velocity (4, 29, 32) and since dystrophin is abundantly expressed in this cell type (2, 25, 34), we thus hypothesized that dystrophin-deficient Purkinje fibers may have reduced INa, which could be the sought-after pathomechanism. In the present study, we tested this hypothesis by comparing INa in Purkinje fibers derived from wild-type and dystrophic mdx mouse hearts. Indeed, we found INa in dystrophin-deficient fibers to be substantially reduced.

Methods

Ethical approval

The investigation conforms to the guiding principles of the Declaration of Helsinki and coincides with the rules of our University Animal Welfare Committee. The protocols were approved by the Austrian Science Ministry (respective ethics vote for keeping and breeding dystrophic mice for organ withdrawal from euthanized animals has the following number: BMWFW-66.009/0175-WF/V/3b/2015.

Mouse models

Four male dystrophin-deficient mdx mice on the BL10 background (C57BL/10ScSn-Dmdmdx/J) and four male wild-type control mice (C57BL/10ScSnJ) in an age range between 15 and 22 wk were used for the experiments. These mouse lines (originally purchased from Charles River Laboratories) were crossbred with a transgenic mouse line (Cx40eGFP/+; BL10 background) expressing enhanced green fluorescent protein (eGFP) under the control of the connexin 40 (Cx40) gene (22) to reveal wild-type-Cx40eGFP/+ single and mdx-Cx40eGFP/+ double transgenic mice. Genotyping of the mice was performed using standard PCR assays.

Purkinje fiber isolation and discrimination from ventricular cardiomyocytes

Single Purkinje fibers for the patch-clamp experiments were isolated by Langendorff perfusion and enzymatic digestion. The procedure was identical to the isolation procedure for ventricular working cardiomyocytes previously described in Koenig et al. (20), except an additional enzyme incubation step following retrograde perfusion of the heart through the aorta. Therefore, the ventricles were cut open along the aorta and placed in a petri dish containing perfusion buffer and LiberaseTH (0.17 mg/ml; Roche) for 8 min at room temperature to further liberate Purkinje fibers. The described isolation procedure revealed both ventricular myocytes (vast majority) and Purkinje fibers. Because only Purkinje fibers, but not working cardiomyocytes, do express Cx40 and thus exhibit an eGFP signal (22) (Fig. 1), we were able to unambiguously identify the former cell type for the INa recordings.

Fig. 1.

Fig. 1

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A: exemplary microscopic images of a Purkinje fiber (PF) and ventricular working cardiomyocytes (vCMs) isolated from a 22-wk-old Cx40eGFP/+ wild-type mouse heart. B: Cx40-positive Purkinje fiber shows an enhanced green fluorescent protein-fluorescence signal. C: overlay of A and B.

Na+ current recordings

A detailed description of the INa recordings is given in our earlier work (20). In brief, currents were recorded from Purkinje fibers up to 6 h after preparation at room temperature (25 ± 1.5°C), using an Axoclamp 200B patch-clamp amplifier (Axon Instruments, Union City, CA). Pipettes were formed from alumino-silicate glass (AF150-100-10; Science Products, Hofheim, Germany) with a P-97 horizontal puller (Sutter Instruments, Novato, CA) and had resistances between 1.2 and 1.8 MΩ when filled with pipette solution. Data acquisition was performed with pClamp 10 software (Axon Instruments) through a 16-bit A-D/D-A interface (Digidata 1440; Axon Instruments). Data were low-pass filtered with 10 kHz (3 dB) and digitized at 35 kHz. Leak currents and capacity transients were subtracted using a P/4 protocol. Data analysis was executed using Clampfit 10.2 (Axon Instruments) and GraphPad Prism 5.01 (San Diego, CA) software. Current-voltage (I-V) relationships were fit with the function: I = Gmax·(V − Vrev)/{1 + exp[(V0.5 − V)/K]} where I is the current, Gmax is the maximum conductance, V is the membrane potential, Vrev is the reversal potential, V0.5 is the voltage at which half-maximum activation occurred, and K is the slope factor. Membrane voltages were corrected for liquid junction potentials. To obtain current density-voltage relations, the current amplitudes at various voltages were measured. These were then divided by the cell capacitance to obtain current densities. A holding potential of −80 mV, from which the channels were activated by depolarizing voltage steps, was chosen to reduce the current amplitudes and allow for a proper voltage control. Decay half-time, a measure of the kinetics of inactivation, was obtained by analyzing the time period between the current peak and the time point at which the current had decayed to 50%. Recordings were made in a bath solution that consisted of (in mM) 15 NaCl, 125 N-methyl-D-glucamine (NMDG), 2.5 KCl, 1 CaCl2, 1 MgCl2, and 10 HEPES, with adjusted pH 7.4 with HCl; the pipette solution contained 105 CsF, 10 NaCl, 10 EGTA, and 10 HEPES, with adjusted pH 7.3 with CsOH. Chemicals originated from Sigma.

Statistical analyses

Data are expressed as means ± SE. Statistical comparisons between wild-type and mdx Purkinje fibers were made using an unpaired two-tailed Student’s t test. A P value < 0.01 was considered significantly different.

Results

Figure 1 shows exemplary microscopic images displaying two ventricular working cardiomyocytes and a Purkinje fiber. The latter Cx40-expressing cell type could easily be identified and discriminated from working myocytes based on its eGFP fluorescence signal (Fig. 1, B and C). In addition, the Purkinje fiber shows characteristic morphological features: consistent with the literature (16, 35), it is long and spindle-shaped, shows less cross-striations, and has a greater length-to-width ratio than the working myocytes (Fig. 1A).

Examples of INa typical for wild-type (wt) and mdx eGFP-positive Purkinje fibers are shown in Fig. 2A. These were elicited by the pulse protocol displayed in the inset. INa density-voltage relationships were derived from a series of such experiments (Fig. 2B). It can be observed that over a wide range of voltages tested, INa in dystrophin-deficient mdx Purkinje fibers is substantially decreased when compared with that of wild-type fibers. At −32 mV, the potential at which the current was maximum, the current density in mdx Purkinje fibers was significantly diminished by ~40% (Fig. 2C). These results suggest that the lack of dystrophin in Purkinje fibers leads to considerable loss of INa.

Fig. 2. Na+ current properties in wild-type (wt) and dystrophic (mdx) Purkinje fibers.

Fig. 2

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A: typical original current traces of a wt and mdx Purkinje fiber, elicited by the pulse protocol displayed in the inset. B: from a series of such experiments (n = 12 cells from 4 male wt hearts; n = 20 cells from 4 male mdx hearts), current density-voltage relationships were derived. Data points represent means ± SE. C: dot plot compares the maximum current densities in wt and mdx Purkinje fibers at −32 mV. **P = 0.0008, significant difference between wt and mdx (unpaired Student’s t test). Fits of the current-voltage relationships (function given in METHODS) revealed the following parameters for wt and mdx Purkinje fibers, respectively: voltage at half-maximum activation, −42 ± 2 and −40 ± 1 mV (P = 0.4); slope factor, 5.7 ± 0.5 and 5.9 ± 0.3 mV (P = 0.6); and reversal potential, 17 ± 1.5 and 11 ± 1.7 mV (P = 0.02). D: typical examples of Na+ current decay after channel activation elicited by a voltage step to −32 mV. To allow for direct comparison between wt and mdx, the current peak amplitudes were normalized. Arrows indicate the current peaks, and the time points at which the decay half-times (see METHODS) were measured. E: comparison between decay half-times at various step potentials (voltages) in wt (n = 12) and mdx (n = 20) Purkinje fibers. Except for −12 and −7 mV, a significant difference (P < 0.01) existed between wt and mdx cells. F: dot plot comparing cell capacitance values of wt and mdx Purkinje fibers. ns, not significant (P = 0.1; unpaired Student’s t test).

Figure 2D shows an enlarged image of INa decays after channel activation at −32 mV in a typical wild-type and mdx Purkinje fiber. The decay half-time (see METHODS), a measure of the kinetics of channel inactivation, was significantly increased in mdx compared with wild-type fibers over a wide range of voltages tested (Fig. 2E). This suggests that the lack of dystrophin in Purkinje fibers slows INa inactivation. Finally, cell size of wt and mdx Purkinje fibers was comparable, as suggested by similar cell capacitance values (Fig. 2F).

Discussion

We and others have previously reported that working cardiomyocytes from mdx mouse hearts exhibit abnormally reduced INa (1, 10, 20, 21). This finding has provided a potential explanation for the prolonged QRS complex observed in the electrocardiograms of dystrophic mdx when compared with wild-type mice (10, 20). The mechanism behind prolonged His-ventricular intervals and bundle branch block, indicators of impaired ventricular impulse conduction and major sources for arrhythmias in patients with DMD (8, 23, 33), however, has remained unidentified as yet. Here, for the first time, we report that INa in dystrophic (mdx) Purkinje fibers is reduced by ~40%. An INa reduction of this magnitude in Purkinje fibers is believed to generate a considerable slowing of ventricular conduction velocity (19, 32). Consequently, we propose that reduced INa in dystrophin-deficient Purkinje fibers at least partly explains impaired ventricular conduction in the dystrophic heart. This may predispose patients with DMD to ventricular asynchrony, reentrant mechanisms, and the development of lethal ventricular arrhythmias.

Here it should be mentioned that our INa recordings do not allow for accurate quantification of channel expression and channel biophysical properties in wild-type and mdx fibers. INa was elicited from a holding potential of −80 mV at which channel availability is far less than 100%. Thus, the amount of INa reduction observed in dystrophic Purkinje fibers may not accurately reflect the real difference between wt and mdx. This represents a limitation of the study. A further limitation is that the absence of dystrophin in dystrophic Purkinje fibers from mdx mice has not yet been proven experimentally. Absence of full-length dystrophin in cardiac Purkinje fibers, however, was shown in a dog model of DMD (7, 34).

Besides reduced INa in Purkinje fibers, other factors may also contribute to conduction slowing in the dystrophic heart. Here, myocardial fibrosis and abnormal connexin expression or localization in Purkinje fibers represent conceivable mechanisms. Concerning fibrosis, reduced ventricular conduction velocities have already been observed in young adult mdx mice (6, 24), which in contrast to old mdx mice, do not show considerable cardiac fibrosis (12, 27). This suggests that conduction slowing in the dystrophic heart occurs before significant development of fibrosis. To the best of our knowledge, potential alterations in connexin isoform expression and/or localization in dystrophic Purkinje fibers have not been studied so far. There is controversial evidence relating to the expression of connexins in mdx mouse whole heart samples. It was found normal (10) or altered (6, 11), and in ventricular cardiomyocytes from mdx mice (6, 11) and patients with DMD (11), Cx43 is mislocalized. A potential contribution of connexin-related abnormalities in Purkinje fibers to slowed ventricular conduction in the dystrophic heart cannot therefore be excluded. Stein et al. (32) studied how the reduction of excitability (reduced INa) and diminished intercellular coupling (reduced Cx43) affects conduction velocity in the mouse heart. These authors concluded that INa is the crucial factor. This confirms our view that reduced INa in Purkinje fibers is a major mechanism responsible for slowed ventricular conduction in the dystrophic heart.

In the following, besides providing a potential mechanism underlying ventricular conduction abnormalities in patients with DMD (see above), we point out several additional reasons for the particular relevance of having studied INa abnormalities in dystrophic Purkinje fibers in addition to the already known INa abnormalities in dystrophic working cardiomyocytes (1, 10, 20, 21):

  • 1)

    Considerable differences exist between Purkinje fibers and working cardiomyocytes with regard to ion-channel transcriptional signatures (9, 13) and, in particular, voltage-gated Na+ channels. INa in Purkinje fibers is larger, and the two cell types significantly differ in Na+ channel isoform expression, e.g., Haufe et al. (14, 15) and Sampson et al. (28). Hence, it was not a priori clear if dystrophic INa abnormalities in Purkinje fibers do exist or if potential abnormalities resemble those previously observed in working cardiomyocytes. The findings of the present study together with previous work (1, 20) suggest that INa is diminished in a comparable manner in dystrophic (mdx) Purkinje fibers and working cardiomyocytes. Thus, significant heterogeneity in this respect (i.e., spatial nonuniformity in INa), which would have predisposed the dystrophic heart for reentrant mechanisms (17, 31), is not directly implied by our data. On the contrary, with regard to the kinetics of INa inactivation, there is a different effect of dystrophin deficiency on Purkinje fibers and working cardiomyocytes. When compared with wild-type, mdx working myocytes have normal inactivation kinetics (10, 20), whereas mdx Purkinje fibers show slightly but significantly slowed kinetics (present study). It is, however, questionable if this small difference is physiologically relevant. The cause for different INa in-activation kinetics in wild-type and mdx Purkinje fibers is unknown but may be related to different Na+ channel isoform expression. Besides the main cardiac Na+ channel isoform Nav1.5, Purkinje fibers express other Na+ channels, i.e., Nav1.1 and Nav1.2 (15), Nav1.4 (26), and Nav1.8 (30), with specific biophysical properties. Dystrophin deficiency may alter the relative contribution of different Na+ channel isoforms to INa and thereby the current properties. The present work, however, has not tested this hypothesis, which represents a study limitation. This important issue should be addressed in future studies.

  • 2)

    Purkinje fibers seem especially affected in dystrophic cardiomyopathy. Thus, dystrophin deficiency at early stages of disease in dystrophic dogs resulted in selective Purkinje fiber (but not ventricular myocardium) degeneration, which could be related to the occurring ECG abnormalities and arrhythmias (34).

  • 3)

    When compared with working cardiomyocytes, Purkinje fibers are exceptionally vulnerable for the initiation of ventricular arrhythmias, e.g., Boyden et al. (3, 4) and Haissaguerre et al. (13). INa abnormalities in Purkinje fibers may therefore represent a particularly relevant source for arrhythmia generation in the dystrophic heart.

To conclude, if a causative relation between reduced INa in dystrophin-deficient Purkinje fibers and ventricular conduction impairments can be confirmed in the human dystrophic heart, restoration of functional Na+ channels in the dystrophic Purkinje fiber membrane emerges as promising new therapeutic approach for arrhythmia prevention in patients with DMD.

Acknowledgments

We thank L. Miquerol (Aix-Marseille Univ.) for providing the Cx40eGFP/+ mice, and J. Uhrinova (Med. Univ. Vienna) for excellent technical assistance.

Footnotes

Grants

This work was supported by the Austrian Science Fund (FWF) P30234-B27 (to K.H.).

Disclosures

No conflicts of interest, financial or otherwise, are declared by the authors.

Author Contributions

H.T., K.H., and X.K. conceived and designed research; J.E. and P.U. performed experiments; J.E., P.U., and X.K. analyzed data; J.E., P.L.S., A.K., B.K.P., H.T., K.H., and X.K. interpreted results of experiments; J.E. and P.L.S. prepared figures; K.H., H.T., and X.K. drafted manuscript; J.E., P.U., P.L.S., A.K., and B.K.P., edited and revised manuscript; J.E., P.U., P.L.S., A.K., B.K.P., H.T., K.H., and X.K. approved final version of manuscript.

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