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. 2009 Oct 21;97(8):2179-90.
doi: 10.1016/j.bpj.2009.07.054.

Electrotonic coupling between human atrial myocytes and fibroblasts alters myocyte excitability and repolarization

Mary M Maleckar  1 , Joseph L Greenstein, Wayne R Giles, Natalia A Trayanova
Affiliations

Electrotonic coupling between human atrial myocytes and fibroblasts alters myocyte excitability and repolarization

Mary M Maleckar et al. Biophys J. .

Abstract

Atrial fibrosis has been implicated in the development and maintenance of atrial arrhythmias, and is characterized by expansion of the extracellular matrix and an increased number of fibroblasts (Fbs). Electrotonic coupling between atrial myocytes and Fbs may contribute to the formation of an arrhythmogenic substrate. However, the role of these cell-cell interactions in the function of both normal and diseased atria remains poorly understood. The goal of this study was to gain mechanistic insight into the role of electrotonic Fb-myocyte coupling on myocyte excitability and repolarization. To represent the system, a human atrial myocyte (hAM) coupled to a variable number of Fbs, we employed a new ionic model of the hAM, and a variety of membrane representations for atrial Fbs. Simulations elucidated the effects of altering the intercellular coupling conductance, electrophysiological Fb properties, and stimulation rate on the myocyte action potential. The results demonstrate that the myocyte resting potential and action potential waveform are modulated strongly by the properties and number of coupled Fbs, the degree of coupling, and the pacing frequency. Our model provides mechanistic insight into the consequences of heterologous cell coupling on hAM electrophysiology, and can be extended to evaluate these implications at both tissue and organ levels.

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Figures

Figure 1
Figure 1
A schematic representation of FMC. (A) A hAM (myo) is coupled to a number n of identical Fbs via an ohmic gap junctional conductance (Ggap) of 0.5 or 8 nS. The membrane capacitance of the myocyte (Cm, myo) is 50 pF, and the membrane capacitance of each Fb (Cm, Fb) is 6.3 pF. (B) Equivalent circuit model of FMC, where Rm represents the membrane resistance of a single cell. Fbs are represented by either an RC circuit (Passive model) or an Active membrane model with Vrest, Fb either −47.8 mV (Active 1) or −31.4 mV (Active 2). Er is the reversal potential.
Figure 2
Figure 2
AP of a hAM coupled to two Passive or Active 1 Fbs for Low Ggap (0.5 nS) as compared to noncoupled hAM. (A) hAM AP; arrow indicates differences in RMP. (B) Detail of hAM AP during the first 20 ms. (C) INa during the first 10 ms of the AP. (D) The transmembrane potential of a coupled Fb, VFb. (E) The gap junctional current, Igap. (F) The sum of outward K+ currents in the hAM, IK.
Figure 3
Figure 3
AP of a hAM coupled to two Passive or Active 1 Fbs for High Ggap (8.0 nS) as compared to noncoupled hAM. (A) hAM AP; arrow indicates differences in RMP. (B) Detail of hAM AP during the first 20 ms. (C) INa during the first 10 ms of the AP. (D) The transmembrane potential of a coupled Fb, VFb. (E) The gap junctional current, Igap. (F) The sum of outward K+ currents in the hAM, IK.
Figure 4
Figure 4
AP of a hAM coupled to 2 Active 1 or Active 2 Fbs for Low Ggap (0.5 nS) as compared to noncoupled hAM. (A) hAM AP; arrow indicates differences in RMP. (B) Detail of hAM AP during the first 20 ms. (C) INa during the first 10 ms of the AP. (D) The transmembrane potential of a coupled Fb, VFb. (E) The gap junctional current, Igap. (F) The sum of outward K+ currents in the myocyte, IK.
Figure 5
Figure 5
AP of a hAM coupled to two Active 1 or Active 2 Fbs for High Ggap (8.0 nS) as compared to noncoupled hAM. (A) hAM AP; arrow indicates differences in RMP. (B) Detail of hAM AP during the first 20 ms. (C) INa during the first 10 ms of the AP. (D) The transmembrane potential of a coupled Fb, VFb. (E) The gap junctional current, Igap. (F) The sum of outward K+ currents in the myocyte, IK.
Figure 6
Figure 6
Effect of pacing rate on hAM AP and excitability. Panel I: AP of a hAM paced at 1 or 4 Hz and coupled to two Active 1 (middle) or Active 2 (right) Fbs via High Ggap (8.0 nS), as compared to noncoupled controls (left). (A) AP of the noncoupled control, Vmyo. (B) INa of control. (C) AP of coupled hAM,Vmyo (Active 1). (D) INa of coupled hAM (Active 1). (E) Gap junctional current, Igap (Active 1). (F) AP of coupled hAM,Vmyo (Active 2). (G) INa of coupled hAM (Active 2). (H) Gap junctional current, Igap (Active 2). Panel II: Effect of hAM coupling to one to three Active 1 (top) or Active 2 (bottom) Fbs at a Ggap of 0.0–16.0 nS on INa,peak for pacing rates of 1, 2, and 4 Hz (left, middle, and right, respectively).
Figure 7
Figure 7
Effects of coupling between a hAM and one or three Active 1 or Active 2 Fbs on AP characteristics for several rates of stimulation (basic cycle lengths of 250, 375 500, 750, 1000, and 2000 ms). Results for both Low (left panel: A, C, E, G, and I) and High (right panel: B, D, F, H, and J) Ggap are shown. Asterisks (∗) represent cases of failed excitation in A and B; these cases are omitted from C–J. (A and B) RMP. (C and D) APA. (E and F) APD30. (G and H) APD60. (I and J) APD90.
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