Author + information
- Received May 31, 2005
- Revision received August 18, 2005
- Accepted September 8, 2005
- Published online March 21, 2006.
- Eugene Patterson, PhD⁎,⁎ (, )
- Ralph Lazzara, MD, FACC⁎,
- Bela Szabo, MD, PhD⁎,
- Hong Liu, PhD†,
- David Tang, MS†,
- Yu-Hua Li, PhD†,
- Benjamin J. Scherlag, PhD, FACC⁎ and
- Sunny S. Po, PhD, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Eugene Patterson, 6E103 ET CARI, 1200 Everett Drive, Oklahoma City, Oklahoma 73104
Objectives The hypothesis that an increased or prolonged Ca2+transient during an abbreviated action potential can give rise to early afterdepolarizations (EADs) and triggered arrhythmia by enhanced forward sodium-calcium (Na-Ca) exchange was examined.
Background Because pulmonary veins have the shortest action potential of any cardiac tissue, we examined this hypothesis in canine pulmonary vein sleeves during interventions further shortening the action potential and increasing the calcium transient.
Methods Extracellular bipolar electrode, intracellular microelectrode, and isometric force (a surrogate marker for the Ca2+transient) recordings were obtained from superfused canine pulmonary veins.
Results An elevation and prolongation of the terminal phase of repolarization (EADs) were observed during interventions increasing contractile force; isoproterenol or norepinephrine (3.2 × 10−11to 3.2 × 10−7M), hypothermia, and pacing (post-extrasystolic potentiation, post-pacing pause). The EAD formation was prevented by ryanodine (10 μM) or reversed by transiently increasing [Ca2+]ofrom 1.35 to 5 mM (inhibition of forward Na-Ca exchange). Pacing-induced EADs were enhanced by re-introduction of normal Tyrode solution (Na+= 130 mM) after substitution of 30 mM NaCl with 30 mM LiCl (stimulation of forward Na-Ca exchange). With norepinephrine or isoproterenol (3.2 × 10−8M) + acetylcholine (10−7M) (to enhance the Ca2+transient and further shorten the abbreviated action potential, respectively), tachycardia-pause initiated arrhythmia (1,132 ± 153 beats/min) lasting >1 s was observed. Rapid firing was prevented by either suppression of the Ca2+transient (ryanodine) or transiently increasing [Ca2+]o.
Conclusions The data show EAD formation in superfused canine pulmonary veins, enhanced by an increased Ca2+transient and increased Na-Ca exchange current. With subsequent shortening of the action potential with acetylcholine, tachycardia-pause triggers rapid firing within the PV sleeve.
Rapid focal excitation originating within left atrial myocardial extensions into the pulmonary veins (PVs) is the initiator for atrial fibrillation (AF) in the great majority of patients presenting for electrophysiological study (1). Focal firing >500/min has been reported (1,2). Coupling intervals of PV-derived premature beats are short, and refractory periods as brief as 60 ms have been reported (3).
The ionic mechanisms for focal firing have not been clarified. Studies of isolated PV myocytes and multicellular PV preparations disclose action potentials of brief duration (4–8) and excitation during repolarization described as early afterdepolarizations (EADs) (5–7). These observations conform with clinical findings of brief refractory periods and short coupling intervals for excitation originating within PVs (3). These EADs contrast with previously studied EADs associated with prolonged repolarization (9–11). Although local re-excitation may also result from circus movement (re-entry) (12–15) or phase II re-entry (16), these mechanisms cannot be operative in isolated myocytes. The brief action potential duration (APD) and the short coupling interval for spontaneous excitation during repolarization led us to examine the hypothesis that triggered excitation could result from forward sodium-calcium (Na-Ca) exchange (NCX) and an inward current (INCX) activated by the elevated [Ca2+]i, a circumstance favored by accelerated repolarization and enhancement/delay of the Ca2+transient. The brief APDs of PV myocytes provide an intrinsic vulnerability to “Ca2+transient triggering” under conditions exaggerating temporal asynchrony between repolarization and the Ca2+transient.
We manipulated by experimental interventions the duration of repolarization, the amplitude and duration of the Ca2+transient, and NCX in superfused canine PV tissue preparations. Membrane voltage, triggering, and contractile force (an index of [Ca2+]iduring the Ca2+transient) were measured to establish an association between an enhanced Ca2+transient, increased inward INCXand EAD formation, and arrhythmia formation.
Male dogs (n = 50) were anesthetized with intravenous sodium pentobarbital. The heart was excised and placed into Tyrode solution containing (mM): NaCl, 130; KCl, 4.0; MgCl2, 1.0; NaHCO3, 20; NaH2PO4, 1.0; glucose, 5.5; and CaCl2, 1.35, bubbled with 95% oxygen: 5% CO2(pH, 7.40 to 7.45). Preparations containing the PV antrum, the visible PV myocardial sleeve, and 3 to 5 mm of the PV distal to the visible sleeve were excised and dissected free of residual adipose and visceral tissues. The preparations were cut lengthwise and pinned for superfusion of the endocardial surface (20 ml/min).
Up to three bipolar electrograms (0.10 mm diameter Teflon-coated silver wires, 1 mm apart) and an intracellular glass microelectrode (3 M KCl, 10 to 30 MΩ) were recorded on a Gould Windograf recorder. The preparation was paced at 2× to 3× diastolic threshold using 2-ms duration stimuli.
The preparation was superfused with a solution containing (mM): NaCl, 135; KCl, 4.5; MgCl2, 2.5, glucose, 5.0; N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), 5.0; Na2HPO4, 1.0; aspartic acid, 1.0; CaCl2, 2.5, pH adjusted to 7.45 with 5 mM NaOH. The atrial end was mounted in a clamp containing a bipolar pacing electrode, and the distal vein was attached to a Grass FT-01 force transducer. Resting tension was adjusted to achieve maximal isometric force, recorded with a Grass polygraph.
On removal of the heart from the anesthetized dog (n = 12), the proximal circumflex artery was cannulated and perfused with oxygenated Tyrode solution containing 5 μM 4-(4-ditetradecylaminostyryl)-N-methylpyridinium (ANEPPS) at 35° for 20 min. The anterior descending artery and ventricular branches of the circumflex artery were ligated to enhance atrial perfusion. The preparation was pinned securely to the bottom of the tissue bath, but no drugs or special methods were used to prevent contraction because interventions to limit contraction would alter the Ca2+transient and change the very physiological process that we were studying. The PV sleeve is very thin (<1 mm) and fails to produce vigorous contraction, as shown in the contraction studies, where force generation is very small.
Optical mapping was designed and implemented in accordance with fluorescence characteristics of di-4-ANEPPS, using a charge-coupled device-based digital detector. Comprehensive measurements showed a wide dynamic range (12-bit digitization) and a high temporal resolution (approximately 2 ms). With a 20 × 20-mm field, the system offers spatial resolution of 128 × 128 pixels, 0.156 mm/pixel. With a smaller field, a higher spatial resolution (0.11 mm/pixel) is achieved.
Correctable image distortions or variations are minimized before analysis. These image distortions are usually caused by system components such as vignetting or illumination inhomogeneities. A flat field correction was performed on each of the original digital images. The image pixel values therefore reflect accurately the strength of the fluorescence signal.
Data are expressed as the mean ± the standard error. Differences between two groups were determined with the Student test for paired or unpaired determinations, as appropriate. Differences within a group were determined by analysis of variance for repeated measures as appropriate. The Student-Newman-Keuls test was used to determine differences between individual groups when significance was identified by analysis of variance.
Cells within the visible myocardial sleeve, extending 3 to 10 mm from the PV os, had reduced resting potentials (−74 ± 2 mV vs. −79 ± 1 mV, p = 0.008), action potential amplitudes (95 ± 2 mV vs. 102 ± 2 mV, p = 0.009), and APDs at both 50% and 90% of repolarization (58 ± 2 ms and 138 ± 2 ms vs. 76 ± 3 ms and 152 ± 4 ms respectively, p = 0.007 and p = 0.005) compared with adjacent left atrial muscle (n = 76 and 78, respectively) from 43 experimental preparations (left superior PVs, n = 25; right superior PVs, n = 18). Myocardial cells in the vein distal (3 to 5 mm) to the visible sleeve were depolarized (−64 ± 4 mV, p = 0.01), with reduced action potential amplitudes (78 ± 3 mV, p = 0.02) and APDs at both 50% and 90% of repolarization (42 ± 6 ms and 111 ± 7 ms; p = 0.01 and p = 0.005, respectively) (n = 36) compared with PV cells in the visible sleeve. Only microelectrode impalements obtained from the visible PV sleeve are included in the remaining results section.
In the basal state (1.0 Hz), early repolarization is very rapid and the terminal phase of repolarization of the PV sleeve action potential is slowed (Fig. 1A,top left). Interventions amplifying isometric force augmented the delay in repolarization and generated an inflection to a distinctly slowed rate of repolarization that can be characterized as an EAD (Fig. 1A, bottom right). The EAD formation became prominent, and the take-off potential moved to more positive voltages after pacing interventions and catecholamines, interventions shown to increase contractile force.
Three pacing algorithms were examined to increase the Ca2+transient: 1) bigeminal pacing, 2) single premature beats, and 3) a prolonged pause after a rapid pacing train. Each intervention increased force generation and enhanced EAD formation. The EAD formation with bigeminal pacing is shown in Figure 1. The APD90(an index for the magnitude of EAD formation because no inflection point may be present under control conditions) observed after a 2-s pause after 30 s of bigeminal pacing increased from 168 ± 12 ms to 312 ± 21 ms (p = 0.0009 vs. control) (n = 15). Isometric force was more than doubled (168 ± 12 dynes vs. 483 ± 45 dynes, p = 0.008) (n = 5). Other pacing interventions increasing both APD90and isometric force included: 1) premature beats and 2) rapid pacing trains (Figs. 1B and 1C). Both an increased pause duration after a pacing train and an increased pacing train duration increased isometric force and APD90(Figs. 1B and 1C, Table 1).Although APD90was used to quantitate EAD formation, consistent changes in the EAD inflection point were observed, moving toward depolarization in association with APD90prolongation (Fig. 1, Table 1).
Isometric force and APD prolongation with catecholamines
Norepinephrine and isoproterenol produced concentration-dependent prolongation of APD90(Fig. 2A).At 3.2 × 10−8M, isometric force was increased four-fold to five-fold with further increases after pacing interventions prolonging APD90(Table 2).Although both catecholamines increased APD90/EAD formation, spontaneous triggering (single beats only) was observed in only 3 of 10 preparations. Single beats (coupling interval = 122 ± 18 ms) arose after pacing-induced pauses (take-off potential = −52 ± 6 mV). Rapid repetitive rhythms were never observed with catecholamines alone. In addition to single beats arising from EADs, there were late-coupled beats arising from delayed afterdepolarizations (DADs) (coupling interval = 225 ± 45 ms) observed in 6 of 10 isoproterenol-treated and 3 of 10 norepinephrine-treated preparations (Fig. 3C).
Role of NCX in EAD formation
Substitution of 30 mM NaCl with 30 mM LiCl (15 min) promoted reverse NCX and Ca2+loading of the sarcoplasmic reticulum, with enhanced EAD formation after a re-introduction of normal Tyrode solution (Na+= 130 mM). The take-off potential for EADs was more positive (−57 ± 3 mV to −52 ± 3 mV, p = 0.035), and APD90was prolonged. The EAD formation was quickly suppressed by a rapid, transient increase in [Ca2+]ofrom 1.35 to 5 mM (n = 5) (Fig. 4A),established by rapid addition of 100 μl 0.73 M calcium chloride during superfusion (20 ml/min).
Diltiazem, in half-log increments every 10 min from 3.2 × 10−9to 10−6M, failed to alter pause-dependent EAD formation after a premature beat (123 ± 7 ms to 142 ± 7 ms) or a 10-beat pacing train (1-s pause) (199 ± 8 ms) (n = 6). In the presence of 10−6M diltiazem, EAD formation was suppressed by a rapid, transient increase in [Ca2+]ofrom 1.35 to 5 mM.
Ryanodine (10 μM for 10 min before re-introduction of normal Tyrode solution) suppressed pause-dependent APD90prolongation associated with premature beats and rapid pacing (Table 1) and catecholamines (Table 2). Examples of suppression of pause-dependent and norepinephrine-induced EAD formation by ryanodine are shown in Figure 4C.
Isometric force and prolongation of APD with hypothermia
Graded hypothermia (32°C to 38°C), increased the duration and magnitude of force development and increased APD (Table 3,Fig. 4B). Further increases in force development, APD, and EAD formation became apparent after pauses produced by a premature beat or after pacing trains. Ryanodine suppressed APD prolongation associated with hypothermia (Table 3).
Combined norepinephrine/isoproterenol + acetylcholine administration
Acetylcholine (10−7M) partially reversed the increase in PV isometric force after isoproterenol or norepinephrine (Table 2, Fig. 2B), but did not eliminate EAD formation (Fig. 2C). After acetylcholine was added, triggered arrhythmias were sustained (Fig. 3A and 3B), lasting >1 s in 26 of 30 preparations and >15 s in 156 of 296 episodes. The longest episode lasted 12 min 33 s. Rapid repetitive rhythms were triggered: 1) by a stimulated beat after a prolonged pause, subsequent to a rapid pacing train (43%), or 2) by a late DAD (cycle length, 218 ± 13 ms) subsequent to rapid non-sustained firing (<1 s) initiated by an early premature stimulus (57%). With reduced acetylcholine concentrations and less APD shortening, triggering was less common (Fig. 3C). Both ryanodine administration and a rapid, transient increase in [Ca2+]ofrom 1.35 to 5 mM (n = 6) prevented triggered firing.
The rapid, repetitive firing (59 ± 13 ms cycle length) originated from reduced take-off potentials (−62 ± 6 mV) and showed variable conduction block to other sites, with premature beats capturing multiple recording sites without capturing the site of focal firing (Fig. 3B). Triggered arrhythmia terminated with an EAD (Fig. 3D). The earliest activation site during arrhythmia was always within the proximal as opposed to the distal PV sleeve, as verified by optical mapping (Fig. 5).A concentric pattern of activation indicated a focal rather than a re-entrant mechanism (Fig. 5). We did not detect an excitable gap and double potentials (along a line of block) as previously described for re-entrant arrhythmias arising subsequent to an early premature beat introduced in the presence of acetylcholine alone (12).
The EADs associated with prolonged repolarization have been attributed to two mechanisms. Each mechanism is critically dependent on delayed repolarization and prolongation of phase 2 of repolarization (plateau). One mechanism implicated in EADs originating at membrane voltages near the plateau ascribes the depolarizing (positive) shift in membrane voltage to reactivation of ICaL, triggering a secondary release of Ca2+from the sarcoplasmic reticulum and secondary contraction (aftercontraction) (9,10). The second mechanism is responsible for EADs generated at membrane voltages negative to ICaLactivation, and attributes EADs to Ca2+-activated inward current (INCX) caused by a secondary “spontaneous” Ca2+release from the sarcoplasmic reticulum (11). With both mechanisms, EADs are intimately associated with aftertransients and aftercontractions. In the present experiments, aftercontractions were not observed in association with EADs that did not generate triggered action potentials; a second contraction was observed only after a non-stimulated/triggered action potential. This finding and the observation of a direct relationship between EAD amplitude and triggering versus the amplitude of the contractile force of the primary contraction are the major findings indicating that the mechanism of EAD formation in PV myocytes is directly linked to the primary Ca2+transient. The link to an enhanced primary Ca2+transient distinguishes the present proposed mechanism from mechanisms of EAD formation associated with prolonged APDs. This mechanism is also distinct from delayed afterdepolarizations, which have also been shown to be attributable to a “spontaneous” release of Ca2+under conditions of Ca2+loading (17) and augmented Ca2+sparks (18). The elimination of EADs and triggering by ryanodine and their suppression by transient elevation of [Ca2+]osupport a role for sarcoplasmic reticulum Ca2+release and INCX(19). The failure of diltiazem to prevent EADs denies a direct role for acute ICa-Las a mechanism.
EAD formation in the canine PV: a physiologic event?
Inward (forward) INCXis enhanced by high [Ca2+]Iand negative membrane voltages; conversely, inward INCXis diminished by high [Ca2+]o. The present experiments show a relationship between isometric force and slow terminal repolarization in PV cells, dependent on inward INCX. Interventions increasing PV isometric force augment the magnitude and duration of the terminal action potential, taking the form of an EAD (schematic shown in Fig. 6).Conversely, inhibition of sarcoplasmic reticulum Ca2+release by ryanodine attenuated both isometric force and EADs. The data indicate that inward INCXactivated by elevated [Ca2+]Iduring the Ca2+transient generates EADs in PVs, enabled by weak repolarizing currents opposing terminal repolarization, including: reduced IK1(7,8), inactivated Ito, deactivated IKr, and activation failure of IKs. Contribution of other Ca2+-activated inward currents to EADs, i.e., Ca2+-activated Cl−current, is not excluded by our experiments. The observations suggest that EADs in PVs are a physiological phenomenon as previously described in rat ventricular trabeculae (20). In both rat ventricle and canine PVs, a slow phase of repolarization (EAD) is observed in conjunction with early repolarization and a late inward current synchronous with contraction. In rat ventricle (20) as in the present studies, EADs were suppressed by an increase in [Ca2+]oand increased with a reintroduction of normal Tyrode solution after exposure to reduced [Na+]o.
Acetylcholine-induced action potential abbreviation
Although pacing interventions produced dramatic EADs after catecholamines, single triggered extrasystoles were observed infrequently; repetitive firing was never observed. Activation of IK-Achby acetylcholine (21) and the resultant decrease in APD (22) was an absolute requirement enabling repetitive triggering in the present studies. With combined catecholamines + acetylcholine, rapid firing could be induced in the PVs by pacing protocols enhancing isometric force and EADs. The inability to capture the focus with premature stimuli, as well as the observation of 2:1 or variable conduction block to other PV sites, is consistent with a rapid, focal rhythm or an extremely small re-entrant circuit.
Muscarinic receptor activation by acetylcholine decreases beta-adrenergic-stimulated cyclic adenosine monophosphate formation (23) and myocardial contractility, limiting the increase in the Ca2+transient by catecholamines and reducing inward INCXas reflected by the diminution of adrenergic-enhanced EADs by acetylcholine. A further contribution of outward IK-Achduring late repolarization also would inhibit EAD formation and triggering. Although acetylcholine produces diverse electrophysiologic actions, the net effect was to promote triggering.
Proposed arrhythmogenic mechanism
We propose that the abbreviated APD within PVs determines that peak Ca2+transient occurs during late repolarization. The [Ca2+]ithus remains elevated at a time when the membrane potential is negative to the equilibrium potential for NCX, activating inward INCX(Fig. 6). Interventions that further abbreviate repolarization and augment the Ca2+transient enhance EADs and promote triggering. Unlike previously described EAD mechanisms associated with APD prolongation, the present proposed mechanism is critically dependent on accelerated repolarization. Only an enhanced primary Ca2+transient is necessary for triggering, without any need for time-dependent re-activation of ICaL(9,10) or a secondary spontaneous release of Ca2+from the sarcoplasmic reticulum (11). The EADs also may be promoted by a paucity of Ik1within PV cells (7,8) and a failure to activate time-dependent IKs.
A similar mechanism has been proposed for the early AF recurrence in canine atria treated with acetylcholine (24). Increased atrial contractility and triggered beats re-initiating AF were observed with the first beat after AF termination. The investigators attributed late-phase APD prolongation and extrasystoles to rate-induced Ca2+loading with an enhanced Ca2+transient after a prolonged pause. As in the present studies, ryanodine suppresses extrasystole formation.
We used contractile force as a surrogate indicator of relative changes in the Ca2+transient. Although a temporally delayed (and therefore imperfect) indicator of [Ca2+]i, the method estimates the magnitude of the Ca2+transient while avoiding buffering of [Ca2+]iby a fluorescent indicator. Further experiments using direct determination of the Ca2+transient will be necessary to better understand the coupling of intracellular Ca2+and NCX as an arrhythmia mechanism.
The present experiments conform to the demonstration that stimulation of ganglionated plexuses adjacent to the PVs in intact animals induces PV firing, in turn inducing AF (6). Recently, it was shown in patients with AF that ablation of nerves in the vicinity of the PVs improves successful elimination of AF (25), supporting a facilitory role for cholinergic and adrenergic input in AF initiated by PV focal firing. Using the same superfused canine PV preparation, local selective autonomic nerve stimulation, with the release of norepinephrine from sympathetic nerve endings and acetylcholine from parasympathetic nerve endings, induced focal firing from the PV sleeve. The triggered firing is dependent on activation of both parasympathetic and sympathetic nerve terminals, as well as an enhanced contractile force development (26). Although the local nerve stimulation may provide a more appropriate physiologic substrate for PV arrhythmia formation, the electrophysiologic bases for EAD formation (sodium-calcium exchange), the dependence of arrhythmia on enhanced rate-dependent EAD formation and contractile force development, and the exclusion of local re-entrant as a primary arrhythmia mechanism (optical mapping) were not performed in the previous published studies, limiting the more precise identification of arrhythmia mechanism allowed in the present studies.
Accelerated early repolarization can also occur in various abnormal conditions including activation of IKATP(ischemia/hypoxia) (27); reduction of INa(Brugada syndrome) (28); activation of outward currents during early repolarization and inward currents during late repolarization (dilatation and stretch) (29); the short QT syndrome (increased Ik) (30), and reduced ICaL(tachycardia remodeling) (31). The inherent deficiency of IK1in PV myocytes, a facilitory element, could occur when myocytes become depolarized to a membrane voltage at which IK1is reduced by rectification (5,8). The Ca2+loading, also a facilitory element, can occur under both physiological and pathophysiological conditions.
The observation of EAD-triggered firing in the present studies does not exclude other mechanisms for PV firing. The EAD-triggered rhythms were often initiated from spontaneous beats observed after a diastolic interval, consistent with a DAD-triggered action potential (Fig. 3B). Although Ifcurrent has been measured in spontaneously firing PV cells, spontaneous firing within intact PV preparations and intact hearts fails to achieve the rapid rates initiating AF in humans, even after catecholamine administration (13).
Honjo et al. (32) have described spontaneous oscillatory beating in rabbit PVs with diastolic depolarization at relatively depolarized membrane voltage initiated by rapid pacing. Ryanodine (0.5 to 2 μM) was used to lock ryanodine channels in the open position to increase [Ca2+]iwith rapid pacing. Experimental manipulations implicated Ca2+release from the sarcoplasmic reticulum, and Ca2+activated INCXand IClin the generation of the oscillatory activity occurring at rates less rapid than observed in present experiments. The present experiments used a larger ryanodine concentration (10 μM) that completely suppressed sarcoplasmic reticulum Ca2+release, preventing the development of the Ca2+transient and associated NCX current.
The fertile potential of the extremely short action potential within PVs to support re-entry has been well recognized and shown by us in the superfused canine PV preparation exposed to acetylcholine (but not adrenergic agonists) (12). It is possible that re-entry is a mechanism to sustain tachyarrhythmias initiated by triggering in this preparation exposed to both acetylcholine and adrenergic agonists, although not elucidated by our experiments using optical mapping. The optical mapping provided convincing data to support a focal mechanism of EAD triggering for the initiation of the rhythm disturbances, and this is supported by the presence of a long diastolic interval preceding the beat that initiated the first ectopic beat. A long diastolic interval allowing a complete recovery of refractoriness within the PV is highly unfavorable for the initiation of re-entry. Certain changes during the sustained tachycardia would oppose the operation of sustained triggering, including the intracellular accumulation of sodium, to reverse Na-Ca exchange with enhancement of K+currents. We also favor sustained triggering as a mechanism in the present experiments because the rhythms are faster (1,132 ± 53 beats/min) than re-entrant arrhythmias documented by optical mapping (832 ± 82 beats/min). Both short (3- to 6-beat duration) and prolonged (more than 15 s in duration) rapid rhythms initiated by rapid pacing followed by a pause frequently terminate with an EAD, as shown in Figure 3D. We cannot, however, exclude a role for re-entry.
The studies were supported by a research grant from the American Heart Association, Heartland Affiliate.
- Abbreviations and Acronyms
- atrial fibrillation
- action potential duration
- early afterdepolarization
- inward current sodium-calcium exchange
- sodium-calcium exchange
- pulmonary vein
- Received May 31, 2005.
- Revision received August 18, 2005.
- Accepted September 8, 2005.
- American College of Cardiology Foundation
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