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Am J Physiol Heart Circ Physiol 288: H2878-H2886, 2005. First published January 21, 2005; doi:10.1152/ajpheart.01165.2004
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Chronic nicotine in hearts with healed ventricular myocardial infarction promotes atrial flutter that resembles typical human atrial flutter

Mizuho Miyauchi, Zhilin Qu, Yasushi Miyauchi, Sheng-Mei Zhou, Hui Pak, William J. Mandel, Michael C. Fishbein, Peng-Sheng Chen, and Hrayr S. Karagueuzian

Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, and Department of Pathology and Laboratory Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California

Submitted 18 November 2004 ; accepted in final form 5 January 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The potential of chronic nicotine exposure for atrial fibrillation (AF) and atrial flutter (AFL) in hearts with and without chronic myocardial infarction (MI) remains poorly explored. MI was created in dogs by permanent occlusion of the left anterior descending coronary artery, and dogs were administered nicotine (5 mg·kg–1·day–1 sc) for 1 mo using osmotic minipumps. High-resolution epicardial (1,792 bipolar electrodes) and endocardial Halo catheters were used to map activation during induced atrial rhythms. Nicotine promoted inducible sustained AFL at a mean cycle length of 134 ± 10 ms in all MI dogs (n = 6) requiring pacing and electrical shocks for termination. No AFL could be induced in MI dogs (n = 6), control (non-MI) dogs (n = 3) not exposed to nicotine, and dogs with no MI and exposed to nicotine (n = 3). Activation maps during AFL showed a single reentrant wavefront in the right atrium that rotated either clockwise (60%) or counterclockwise (40%) around the crista terminalis and through the isthmus. Ablation of the isthmus prevented the induction of AFL. Nicotine caused a significant (P < 0.01) but highly heterogeneous increase in atrial interstitial fibrosis (2- to 10-fold increase in left and right atria, respectively) in the MI group but only a 2-fold increase in the right atrium in the non-MI group. Nicotine also flattened (P < 0.05) the slope of the epicardial monophasic action potential duration (electrical restitution) curve of both atria in the MI but not in non-MI dogs. Two-dimensional simulation in an excitable matrix containing an isthmus and nicotine's restitutional and reduced gap junctional coupling (fibrosis) parameters replicated the experiments. Chronic nicotine in hearts with MI promotes AFL that closely resembles typical human AFL. Increased atrial interstitial fibrosis and flattened electrical restitution are important substrates for the AFL.

atrial flutter; restitution; myocardial infarction; remodeling; reentry; nicotine

THE INCIDENCE OF ATRIAL FLUTTER (AFL) increases significantly in patients with heart failure and in smokers with chronic obstructive pulmonary disease (COPD) (10). In fact, COPD was found to be an independent predictor of AFL (10). AFL carries significant potential risk as it is associated with increased mortality (30). Epidemiological studies have shown that smoking promotes coronary heart disease and myocardial infarction (MI) and is a major cause of COPD in the United States (29). These findings raise the possibility that a causal link might exist between nicotine, a major constituent of tobacco smoke and an agent thought to be the culprit of cardiac arrhythmias (1), and AFL in patients with MI. This hypothesis, however, has not been tested previously. Over 46 million Americans smoke cigarettes or use over-the-counter nicotine products (patches and gum) to satisfy their nicotine addiction (33). The purpose of this study was to test the nicotine hypothesis of AFL in hearts with healed MI.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Surgical preparation. This study protocol was approved by the Institutional Animal Care and Use Committee of Cedars-Sinai Medical Center and followed the guidelines of the American Heart Association. Mongrel dogs of either sex, weighing between 21 and 29 kg, were anesthetized (7.4 mg/kg propofol followed by inhalation of 1.5–3.0% isoflurane). In one group (n = 6), a left thoracotomy was performed through the fifth intercostal space, and MI was created by ligating the left anterior descending coronary artery just distal to the first diagonal branch (MI group) (17). In the second group (n = 6), MI was created, and two subcutaneous miniosmotic pumps (2ML4, Alzet) were implanted, with each loaded with 2 g nicotine base (MI + nicotine group). In two dogs, only one pump (2 g) of nicotine base was loaded in the pump. These doses of nicotine are expected to deliver 2.5–5 mg·kg–1·day–1 of nicotine, a dose that corresponds to the daily intake of nicotine by heavy smokers (26, 27). Because similar electrophysiological and fibrotic changes developed with the two doses, the results were pooled. In the third group (n = 3), a thoracotomy was performed, and two nicotine-loaded pumps were implanted subcuteneously as in the MI group (sham + nicotine). A fourth group (n = 3) received no surgery and no nicotine (control group). One month after the surgery, all dogs were anesthetized as before and studied in the open-chest state (17).

Vulnerability to atrial arrhythmias. Vulnerability to atrial arrhythmias was tested by progressive rapid atrial pacing, starting at a cycle length (CL) of 300 ms, until loss of 1:1 atrial capture (17).

High-density epicardial mapping. Induced atrial arrhythmias were mapped epicardially using 1,792 bipolar electrodes with 1-mm interelectrode distance distributed equally over four plaques of 1.5 x 2.7 cm each (Unemap, Uniservices) (17). Two plaques were sutured side by side on the right atrial (RA) free wall (RAFW) and the crista terminalis (CT) region. The third was sutured on the left atrial (LA) free wall (LAFW), and the fourth was sutured in the isthmus area encompassing the inferior vena cava (IVC) and the tricuspid annulus (TA).

Endocardial mapping. In two of the MI dogs treated with nicotine, we performed simultaneous epicardial (1,792 electrodes) and endocardial mapping using a 7-Fr deflectable transvenous catheter with 20 electrodes spaced at 2 x 8 x 2-mm intervals (Halo catheter, Cordis Webster). The catheter was positioned around the TA under fluoroscopic guidance.

Atrial monophasic action potentials and electrical restitution. Dynamic monophasic action potentials duration (MAPD) restitution curves to 90% repolarization were constructed from the RA and LA during progressively rapid pacing as described previously (17). The time interval between the maximum change in voltage over time of the monophasic action potential upstroke and the time to 90% repolarization was plotted against its preceding diastolic interval (DI) at all pacing cycle lengths [CLs; 400, 350, 300, 250, 200, 190, 180, and 170 ms in 10-ms decrements until loss of 1:1 atrial capture (dynamic restitution)]. Curve fitting of the dynamic MAPD restitution relation was achieved using Origin 5.0 (Microcal Sofware). The fit was optimized by adjusting the parameters of the exponential function to find the highest degree of freedom adjusted r2 coefficient (17). In each dog of all four groups, recordings were made from two to three different epicardial sites in each atrium, and MAPD restitution curves from these sites were plotted. The mean value of the slope of the MAPD restitution curves from theses sites was taken to represent the mean value of the MAPD restitution slope of each atrial chamber in each dog.

Effective refractory period. The RA and LA epicardial effective refractory periods (ERP) were measured using the S1S2 protocol during regular pacing at a CL of 400 ms. The current strength for both S1 and S2 was twice the diastolic threshold. In each dog, two to three sites from both atria were sampled. The mean value of the ERP from these sites was taken to represent the mean value of the ERP of each atrial chamber in each dog for all four groups (17).

Radiofrequency catheter. A conventional 7-Fr ablation catheter was inserted from the right femoral vein, and the tip of the catheter was positioned in the isthmus under fluoroscopic guidance. Radiofrequency energy (30W, 30–60 s) was applied to cause a linear lesion in the isthmus.

Histopathological analysis. In each dog, two to five atrial tissue samples were taken from both atria. The fixed tissue samples were stained with Masson trichrome to quantify the amount of atrial fibrosis. Fifteen to twenty areas of 0.3 x 0.4 mm and 2 mm apart were analyzed in each slide. With the use of a grid, each area was divided into 100 squares, and the number of collagen points (blue stain) at the 100 intersection points in the grid was scored as 1 (present) or 0 (absent). Results are expressed as the ratio (in %) occupied by fibrosis to the total atrial area examined (14).

Simulation studies. Computer simulations were carried in a two-dimensional (2-D) tissue using a modified Luo-Rudy model (15). Simulation in a 2-D tissue was accomplished using the Luo-Rudy phase 1 formulation modified by Zeng et al. (35) and Courtemanche et al. (3). The following differential equation was used

(1)

where Vij is the membrane potential of the (i,j)th cell and Cm = 1 µF/cm3 and is the membrane capacitance. Dyi,j + 1/2 is the local diffusion constant in the longitudinal direction between the (i + 1,j)th cell and the (i,j)th cell; Dyi,j + 1/2 is the local diffusion in the transverse direction between the (i,j + 1)th cell and the (i,j)th cell. Iion is the current density, which was the summation of the following ion currents: Na+ current (INa), slow inward Ca2+ current (Isi), slow component of the delayed rectifier K+ current (IKs), fast component of the delayed rectifier K+ current (IKr), transient outward K+ current (Ito), inward rectifier K+ current (IK1), plateau current (IKp), and background current (Ib). INa, Isi, IK1, IKp, and Ib are from the phase I Luo and Rudy formulation (15). IKs and IKr are from Zeng et al. (35) and Ito is from Courtemanche et al. (3) formulations, respectively. We used {Delta}x = {Delta}y = 0.015 cm, and the tissue size was 7.5 x 4.5 cm. The coupling between cells was uniform except in the CT area, for which we used the following formula (24):

(2)

where {xi}xij and {xi}yij are random numbers uniformly distributed in [0,1].Dx0 = Dy0 = 0.8 cm2/s and is the uniform diffusion strength; {gamma}x and {gamma}y are two parameters representing the strength of coupling in the x and y directions, respectively. When {gamma}x > 1 or {gamma}y > 1, cell uncoupling occurs. Rapid pacing (site S in Fig. 8) was used to induce arrhythmias. We used the advanced numerical method to integrate Eq. 1 (24). MI + nicotine-induced flattening of the slope of the electrical restitution was achieved by reducing the maximum conductance () of Ito, IKr, IK1, and L-type calcium currents consistent with voltage-clamp data on nicotine's effect on isolated atrial myocyctes (25, 31, 32).



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  		Fig. 8. Two-dimensional computer simulation. A: APD restitution curves for the control, MI, and MI + Nic groups. B: pseudo-ECG (PECG) for the three cases showing the effects of rapid pacing. AF, atrial fibrillation; A-flutter, AFL; t, time. C: snapshots during pacing (top) and 2 s after the cessation of pacing (bottom). Note that during pacing, target waves are present at the site of the stimulus (site S in E), which undergoes short-lived breakup in control but is maintained in MI. A single spiral is formed in the case of MI + Nic that circles around the CT area through the isthmus (D). E: schematic of the tissue model. The open circle is the IVC and the shaded area is the CT; below the IVC is the isthmus region. SAN, sinoatrial node region.

 
The parameters used in Fig. 8 are as follows. Control parameters were Na = 16 mS/cm2, si = 0.05 mS/cm2, to = 0.05 mS/cm2,Ks = 0.5 mS/cm2, Kr = 0.0725 mS/cm2, and K1 = 0.5 mS/cm2. CT area and isthmus parameters were Na = 14.5 mS/cm2 and {tau}j -> 1.5{tau}j where {tau}j is the time constant of recovery from inactivation from INa. {gamma}x = 0.9 and {gamma}y = 0.6 in the CT area. For MI parameters, two changes were made from control: Kr = 0.065 mS/cm2 and Dx0 = Dy0 = 0.4 cm2/s (50% reduction in gap junction conductance). For the MI + nicotine case, the following changes were made from control: Na = 12 mS/cm2, si = 0.03 mS/cm2 (40% reduction), to = 0.025 mS/cm2 (50% reduction), Kr = 0.04 mS/cm2 (45% reduction), and K1 = 0.2 mS/cm2 (60% reduction); Dx0 = Dy0 = 0.4 cm2/s. Na = 9.6 mS/cm2, and {tau}j -> 3.5{tau}j in the CT area and isthmus. {gamma}x = 1.75 and {gamma}y = 1.6 in the CT area.

Nicotine plasma levels. Arterial nicotine levels were determined by the National Medical Services (Willow Grove, PA) using gas chromatographic methods (34).

Statistical analysis. Multiple comparisons among the different groups were obtained using ANOVA. A nonpaired t-test was used to evaluate the significance between two groups when ANOVA showed a significant difference.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Atrial arrhythmias. Atrial pacing at CLs of 200–150 ms induced sustained AFL at a mean CL of 134 ± 10 ms in all six MI dogs exposed to chronic nicotine administration. The induced AFL had the characteristic sawtooth appearance on ECG lead II (Fig. 1). The AFL lasted for >30 min, requiring cardioversion for termination with electrical shocks applied across both atria. Atrial pacing at CLs slightly shorter (114 ± 9 ms) than the CL of the AFL abruptly terminated the AFL (Fig. 1). The ability to prematurely capture the AFL with subsequent termination indicates the presence of an excitable gap in the AFL circuit. A total of 34 episodes of typical AFL (i.e., sawtooth appearing on the ECG) was induced in all six MI dogs (4–7 episodes in each dog). In contrast, however, no AFL could be induced in any of the dogs in the remaining three groups. Nonsustained AF could, however, be induced in these three groups, the duration of which was significantly (P < 0.05) longer in the MI (29 ± 21 s) compared with control (9.1 ± 2.7 s) and sham + chronic nicotine (2.5 ± 3.7 s) groups.



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  		Fig. 1. Initiation (A) and termination (C) of sustained atrial flutter (AFL) in a dog with chronic myocardial infarction (MI) exposed to nicotine (Nic). Note the sawtooth appearance of the AFL (B). In A–C, ECG II is the surface lead II electrocardiogram, RA is the right atrial bipolar electrogram, Stim is a stimulus artifact, and CL is cycle length.

 
Epicardial mapping of the AFL. Figure 2 shows the dynamic atrial activation pattern during sinus, paced, and induced sustained AFL in a dog with MI and exposed to chronic nicotine. During sinus rhythm (Fig. 2A), the activation propagates from the upper toward the lower RA and fully activated the entire RA without undergoing conduction block. The IVC-TV isthmus area and the LA were then activated some 25 ms after the onset of the sinus beat. During RA pacing from the left side of the sinus node (Fig. 2B), the activation wavefront, after activating the left side in the RAFW (left side-pointing arrows in Fig. 2B) also propagated in a SVC-IVC direction, as is the case during the sinus beat. During AFL, however (Fig. 2C), a reentrant activation was observed in the RA. The activation first propagated in the SVC-IVC direction with a line of conduction block, along the CT (downward arrows in Fig. 2C). Propagation then proceeded across the isthmus, activating the LA. The wavefront then propagates upward in the IVC-SVC direction through the region of initial block (upward arrows in Fig. 2C), completing reentrant cycle. The reentrant cycle then repeated itself. We also constructed an isochronal map during AFL. Figure 3 illustrates an example with selected electrograms. During AFL, the activation in the SVC-IVC direction was blocked across the crista (Fig. 3A) and then propagated through the isthmus (Fig. 3B) and the LA (Fig. 3C). Activation then proceeded in the IVC-SVC direction along the crista, completing a full rotation. The electrograms around the line of functional conduction block showed double potentials (Fig. 3D) consistent with recordings made in the center of the reentrant circuit seen both in dogs (7) and in humans with common AFL (21). The double potentials represent sequential activations when the reentrant wavefront passes on either side of the line of conduction block, as shown in Fig. 3D, electrograms q, r, s, and t. The mean length of the line of functional conduction block in the six dogs was 1.46 ± 0.5 cm. The induced AFL was clockwise in 20 episodes (60%) with a positive sawtooth and counterclockwise in 14 episodes (40%) with a negative sawtooth on lead II ECG, mimicking the common type of AFL in humans (Fig. 4).



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  		Fig. 2. Atrial activation snap shots during sinus beat (A), during a right atrial paced beat at a CL of 300 ms (B), and during induced sustained AFL (C) in a dog with MI and exposed to Nic. When an activation is registered, each dot (representing an electrode) first illuminates in red, orange, yellow, green, light blue, and then dark blue before fading to white, representing the resting state. The persistence of each color is 5 ms. (See text for details.) RAFW and LAFW, right atrial and left atrial free wall, respectively.

 


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  		Fig. 3. Isochronal activation maps and selected bipolar atrial electrograms during induced sustained AFL in a dog with MI exposed to Nic. Two plaques are located side by side on the RAFW (A and E), one on the isthmus (B), and the fourth on the LAFW (C). Reentry proceeds in the superior vena cava (SVC)-inferior vena cava (IVC) direction (sites a–d), blocks across the crista terminalis (CT; dark line in D), and then proceeds in the IVC-SVC direction (sites e–h; arrows in A and D). Electrograms in D are recorded on the CT and show double potentials (downward arrows). These double potentials represent activation on either side of the line of functional block (electrograms q, r, s, and t) and disappear at sites u and v, where no conduction block occurs. E: gross anatomy of the heart showing plaque location. RAA, right atrial appendage.

 


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  		Fig. 4. Endocardial mapping during AFL in a dog with MI and nicotine using a Halo catheter positioned around the CT. A: clockwise reentrant AFL at a CL of 136 ms and a positive sawtooth pattern on ECG lead II. B: during AFL with a counterclockwise reentry in the same dog showing a negative sawtooth pattern on ECG lead II. Next to each set of electrograms (1–10), a schematic diagram shows the locations of the Halo electrodes. CS, coronary sinus; RAA, RAA bipolar electrogram.

 
Endocardial mapping of the AFL. We also mapped the RA endocardium with a Halo catheter during sustained AFL (Fig. 4). Clockwise, with a positive sawtooth on the ECG (Fig. 4A), and counterclockwise, with a negative sawtooth on the ECG (Fig. 4B), rotations around the CT were observed during the AFL, consistent with functional conduction block across the crista.

Catheter ablation. In two MI dogs, we ablated the isthmus by radiofrequency energy. Pacing before the ablation induced AFL in both dogs (Fig. 5A). However, after the ablation of the isthmus, AFL could no longer be induced in either dog (Fig. 5B). Macroscopic examination showed grossly visible black (burned) area in the isthmus (Fig. 5).



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  		Fig. 5. Prevention of inducible AFL in a dog with MI and nicotine by radiofrequency ablation of the isthmus area. A: gross anatomic appearance of the isthmus area [white arrows before and after ablation (in B); darkened area pointed by arrows]. Ablation of the isthmus prevents induction of AFL; instead, a short run (<2 s) of repetitive atrial activity is induced. Abbreviations are as in Fig. 1. RV, right ventricle; LV, left ventricle.

 
Electrical restitution and refractoriness. Figure 6 shows representative RA and LA restitution curves in all four groups. The maximum slope of the MAPD restitution curve was significantly (P < 0.05) higher in both atria in the MI group compared with the remaining three groups (Table 1). Nicotine exposure in the MI dogs caused a significant (P < 0.05) flattening of the maximum slope of the MAPD restitution curve of both atria compared with other three groups (Table 1). Nicotine exposure in the sham-operated dogs had no significant effect on the restitution curve in both atria (Table 1). No significant differences in the ERP of the RA and LA could be detected among the four groups (Table 1).



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  		Fig. 6. Monophasic action potential duration (APD) restitution curves to 90% repolarization (APD90) of the RA and LA in control, sham-operated + Nic, MI, and MI + Nic dogs. Note the flattening of the slope of the restitution curve in MI dogs exposed to nicotine. DI, diastolic interval (in ms).

 

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  		Table 1. Atrial electrical restitution, refractoriness, and fibrosis

 
Histopathological analysis. Nicotine exposure in the MI dogs caused significant (P < 0.01) and highly heterogeneous interstitial fibrosis in both atria. The increase was significantly higher in the RA, up to 10-fold higher than the LA (2-fold; Fig. 7, C and D). Bundles of myofibers in the MI + nicotine atria were packed less tightly than in control animals and were separated by thick layers of fibrous tissue, indicating reactive rather than replacement fibrosis. In contrast to normal collagenous structures, which have an "organoid" parallel arrangement of relatively broad bands of collagen fibers, abnormal interstitial fibrosis consisted of haphazardly arranged, disorganized, fine collagen fibers. Nicotine caused an only 2-fold increase in RA fibrosis and had no significant effect on the LA in sham-operated dogs with no MI (Table 1). The MI was exclusively confined to the left ventricle (LV) with no atrial involvement. The mean infarct size was 14 ± 6% of the LV in the MI group and 15 ± 8% in the MI + nicotine group [not significant (NS)]. Atrial chamber size was not significantly different in all four groups.



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  		Fig. 7. Histological staining with Masson trichrome stain in a control and in a MI + Nic dog. A and B: longitudinal section of the CT (A) and IVC-TV isthmus region (B) in a dog with MI and Nic. Note the abundant interstitial fibrosis in both structures. C and D: higher magnifications of the RAFW, CT, and IVC-TV isthmus, respectively, in control and MI + Nic atria. TV, tricuspid valve.

 
Nicotine plasma levels. After the conclusion of the electrophysiological studies, the mean nicotine arterial plasma levels were 70 ± 57 ng/ml in the MI and 78 ± 64 ng/ml the sham-operated dogs, respectively (NS).

2-D simulation studies. Figure 8 summarizes our simulation results. Figure 8A shows the APD restitution curves for the control, MI, and MI + nicotine groups. In control, the baseline APD is about 150 ms and slope of the APD restitution becomes >1 with a short DI (<50 ms). To account for the slight APD lengthening seen in MI dogs (17), we decreased the maximum conductance of IKr to prolong the APD to around 160 ms. In this case, the slope of the APD restitution curve also increased at short DIs (<68 ms) to reach a maximum of 2, consistent with our experiments. In the control case, rapid pacing caused short-live multiple waves (Fig. 8E). In the MI case, rapid pacing resulted in multiple waves; however, after the cessation of pacing, activity did not cease (Fig. 8C), as was the case in the control experiment. In the case of MI + nicotine, rapid pacing resulted in a single, stable reentrant activation that circulated around the CT and through the isthmus (Fig. 8D).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Novel findings. The initiation of typical, isthmus-dependent, reentrant AFL in dogs with healed MI and exposed to chronic nicotine constitutes a novel finding in this study. Simulation in a 2-D excitable medium replicated the experimental findings.

Nicotine and isthmus-dependent atrial flutter. Lewis (13), in 1913, articulated the criteria for the electrocardiographic diagnosis of AFL, "the restless sawtooth baseline" (i.e., F waves). More recently, AFL was induced in dogs by creating a lesion between the two vena cavas (6, 8) or by inducing sterile pericarditis (23). These animal models provided important insight into the mechanism of AFL. However, unlike human AFL (5, 22), these AFL models were induced by an acute, exogenously introduced direct atrial injury rather than resulting from the "natural" evolution of an underlying heart disease. The critical role of the TV-IVC isthmus in typical human AFL was demonstrated by terminating the AFL by ablating the isthmus (5). The characteristics of the AFL in the present study bear many similarities to typical human AFL. These include 1) isthmus dependency of the single reentrant wavefront in the RA that supports the AFL, 2) the presence of an excitable gap (evidenced by electrically capturing and terminating the AFL, and 3) the presence of functional conduction block across the CT.

Nicotine and atrial fibrosis. It was unexpected to find a nicotine-induced considerable increase in atrial interstitial fibrosis in MI dogs but only a mild increase, namely, a 2-fold increase in the RA, in dogs with no MI. These differential effects of nicotine on atrial fibrosis occurred despite the fact that nicotine blood levels were similar in both groups during the electrophysiological studies and within the range seen in smokers (11). We do not know the reasons for the differential expression pattern of atrial interstitial fibrosis in the MI dogs versus the non-MI dogs. Nicotine-induced interstitial fibrosis had the major characteristic features of new collagen deposits. The collagen filaments were fine and irregular in shape, indicating newly laid filaments. It is known that chronic maternal nicotine exposure also greatly increases collagen expression in fetal monkey lungs (27) through the interaction with nicotinic acetylcholine receptors of the lung fibroblasts (26). Because nicotine modulates growth factor production in fibroblasts (16) and endothelial cells (4), it is tempting to suggest that nicotine's atrial fibrotic effect in MI dogs may be mediated through cardiac fibroblastic growth factors, such as basis fibroblast growth factor and transforming growth factor-{beta}1 (TGF-{beta}1) (18). Because growth factors become elevated during MI, it is conceivable that nicotine's enhanced profibrotic effects develops primarily in dogs with MI and only mildly in dogs without MI because the MI may provide an added background levels of growth factors, causing a considerable amplification in collagen expression (12, 18, 28).

Nicotine and electrical restitution. Nicotine is known to exerts multiple effects on atrial ion channels by blocking outward potassium currents (25, 31, 32) and exerts variable effects on inward currents (INa and L-type calcium current) depending on its concentration (25). The net effect of nicotine may thus vary, ranging from no net change to shortening or lengthening of the APD depending on the underlying channel profile (density/conductance) in the remodeled atria (34). Alternatively, nicotine's flattening effect of the MAPD restitution may not result from direct ion channel effect but rather from the inability of the highly fibrotic right atrial tissue (increased stiffness) to distend (i.e., stretch) at short DIs. Decreased stretch may decrease MAPD shortening and thus prevent attainment of ultrashort DIs, causing a flat electrical restitution curve (2). The absence of atrial fibrosis in the MI alone group permits stretch to develop during rapid pacing (i.e., during dynamic electrical restitution curve construction), causing shortening of the APD and thus the attainment of ultrashort DIs. The highly fibrotic atria in the nicotine group may not distend and thus be unable to produce action at very short DIs.

The presence of a flat electrical restitution curve prevents wavefront breakup, whereas the partial electrical uncoupling caused by the considerable increase in RA fibrosis promotes slow conduction (20) that increases the excitable gap interval during the flutter. The coexistence of these two electrophysiological properties lead to a stable reentrant flutter with an excitable gap in dogs with chronic MI exposed to nicotine.

Simulation results. In MI dogs, longer AF duration may be caused by an increased slope (>1) of the atrial electrical restitution curve (17) and by increased junctional resistance leading to decreased gap junctional connexin43 that develops in the atria of dogs with chronic MI (19). These effects are known to promote wavebreak, leading to multiple wavelets and AF (9, 19, 20). However, in the MI dogs exposed to nicotine, the flattening of the slope of the MAPD restitution curve (<1) prevents wavebreak and allows reentry to remain stable (9). Furthermore, the nicotine-induced considerable increase in RA fibrosis promotes conduction slowing and conduction block across the CT leading to reentry formation and an increase in the excitable gap of the reentry circuit (19, 20). These effects (conduction block and increased excitable gap) cause the reentrant AFL to be sustained (stable) without termination.

Clinical significance. To our knowledge, this is the first animal counterpart to human typical AFL that develops during the course of a disease. To the extent that this model may be representative of human AFL, the combined development of increased atrial fibrosis and flattened atrial electrical restitution curve might be important etiological factors in the pathogenesis of human typical AFL. These results provide a novel therapeutic target (prevention of fibrosis) to prevent the incidence of fibrosis-based AFL in humans that may afflict a fraction of some 200,000 patients that become stricken with this disease every year in the United States (10).


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported in part by University of California Tobacco-Related Disease Research Program Grant 11RT-0058; the Cedars-Sinai Electrocardiographic Heartbeat Organization; American Heart Association (AHA), Western States Affiliate, Grant 0255937Y; AHA, National Affiliate, Scientist Development Grant 0131017N, National Institutes of Health (NIH) Specialized Center of Research Grant in Sudden Death P50 HL-52319; NIH Grants RO1 HL-66389 and R01 HL-71140; the Cardiac Arrhythmia Research Education Support Group; the Pauline and Harold Price Endowment; and the Piansky Family Trust.


   ACKNOWLEDGMENTS
 
We thank Drs. Tom C. Peter and P. K. Shah for the support and Avile McCullen and Elaine Lebowitz for technical and secretarial assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. S. Karagueuzian, 8700 Beverly Blvd., Davis Research Bldg., Rm. 6066, Los Angeles, CA 90048 (E-mail: Karagueuzian{at}cshs.org)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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