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(Circulation Research. 2004;94:1083.)
© 2004 American Heart Association, Inc.

Cellular Biology

Role of Calcium Cycling Versus Restitution in the Mechanism of Repolarization Alternans

Etienne J. Pruvot, Rodolphe P. Katra, David S. Rosenbaum, Kenneth R. Laurita

From the Heart and Vascular Research Center and the Department of Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio.

Correspondence to Kenneth R. Laurita, PhD, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Rammelkamp, 6th Floor, Cleveland, OH 44109-1998. E-mail klaurita{at}metrohealth.org

	Abstract

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T-wave alternans, a powerful marker of arrhythmic events, results from alternation in action potential duration (APD). The underlying cellular mechanism of APD alternans is unknown but has been attributed to either intracellular calcium (Ca²⁺) cycling or membrane ionic currents, manifested by a steep slope of cellular APD restitution. To address these mechanisms, high-resolution optical mapping techniques were used to measure action potentials and Ca²⁺ transients simultaneously from hundreds of epicardial sites in the guinea pig model of pacing-induced T-wave alternans (n=7). The pacing rates (ie, alternans threshold) at which T-wave (369±11 bpm), APD (369±21 bpm), and Ca²⁺ (371±29 bpm) alternans first appeared were comparable. Importantly, the site of origin of APD alternans and Ca²⁺ alternans consistently occurred together near the base of the left ventricle, not where APD restitution was steepest. In addition, APD and Ca²⁺ alternans were remarkably similar both spatially and temporally during discordant alternans. In conclusion, the mechanism underlying T-wave alternans in the intact heart is more closely associated with intracellular Ca²⁺ cycling rather than APD restitution.

Key Words: electrophysiology • T-wave alternans • repolarization • Ca²⁺ cycling • optical mapping

	Introduction

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Although we^1,2 and others^3–7 have shown that T-wave alternans in most circumstances results from alternation of cardiac repolarization at the cellular level, the mechanisms responsible for cellular alternans are not well understood. One hypothesis states that repolarization alternans arises when the heart rate exceeds the capacity of myocytes to cycle intracellular Ca²⁺.^4–6,8–11 To maintain homeostasis, the amount of Ca²⁺ released from the sarcoplasmic reticulum (SR) to initiate contraction must be equaled by the amount of Ca²⁺ reclaimed from the cytosol by SR Ca²⁺-ATPase (SERCA). When one or more of the Ca²⁺ cycling proteins are impaired, the amount of released Ca²⁺ can only be fully reclaimed on an alternating beat basis, giving rise to alternation of free cytosolic Ca²⁺ levels. This, in turn, can cause alternans of membrane voltage (ie, repolarization) via several electrogenic Ca²⁺-sensitive sarcolemmal currents. Reduced SERCA expression¹² or interventions that decrease the function of SR Ca²⁺ release channels (Ryanodine receptors)⁹ have been shown to promote both intracellular Ca²⁺ alternans and action potential duration (APD) alternans (APD-ALT). Most studies, however, have focused on the mechanisms responsible for APD and intracellular Ca²⁺ alternans in single cell^6,8,9,11 and tissue samples.^4,5,12 The relationship between the emergence of alternans at the cellular level, ECG T-wave alternans, and arrhythmogenesis is not well understood.

A second hypothesis states that APD-ALT occurs when the slope of the APD restitution curve is >1, as determined by the kinetics of membrane currents.^7,13–15 The slope of the APD restitution curve seems to play a critical role in APD-ALT and wavebreak.^13,15–17 Several experimental^16,17 and theoretical studies^13,18 have shown that a slope >1 promotes alternans, whereas a slope <1 prevents it. Assuming this hypothesis is true, the threshold at which alternans first appears (ie, theoretical alternans threshold) can be calculated from the APD and diastolic interval (DI) when the restitution curve slope equals 1.

To date, no study has directly compared the relevance of cellular restitution and intracellular Ca²⁺ handling with the mechanism of repolarization alternans at the level of the whole heart. The guinea pig model of T-wave alternans^1,2 includes a ventricular gradient of APD restitution that follows a base-to-apex pattern similar to the APD gradient, where longer APD, steeper restitution kinetics, and lower theoretical alternans threshold occur toward the base of the right ventricle (RV).^19,20 Therefore, this model provides an opportunity to determine the relationship, if any, between the development of repolarization alternans and cellular restitution properties. Moreover, we used a novel method for simultaneously recording action potentials and Ca²⁺ transients²¹ to investigate the role of intracellular Ca²⁺ and APD restitution in the mechanism of repolarization alternans.

	Materials and Methods

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Experimental Preparation
Experiments were carried out in accordance with the United States Public Health Service guidelines for the care and use of laboratory animals. Adult guinea pig breeders (n=7, 800 to 1000 g) were anesthetized with pentobarbital sodium (30 mg/kg IP), and their hearts were rapidly excised and perfused as Langendorff preparations with oxygenated (95% O₂ and 5% CO₂) Tyrode solution containing (in mmol/L) NaCl 121.7, NaHCO₃ 20.0, MgSO₄ 1.18, KCl 4.81, dextrose 5.0, and CaCl₂ 1.25 (pH 7.40, 32°C).²¹ Hearts were first stained by direct coronary perfusion for 10 minutes with the voltage-sensitive indicator di-4-ANEPPS (Molecular Probes) at a final concentration of 15 µmol/L and then for 45 minutes with the Ca²⁺-sensitive indicator indo 1-AM (Molecular Probes) at a final concentration of 5 µmol/L.²¹ In all experiments, a low concentration of 2,3-butanedione monoxime (5 mmol/L) was used to reduce motion artifact without altering substantially intracellular Ca²⁺ handling²² or cellular electrophysiology.²¹ The mapping field was carefully positioned over the left descending coronary artery.

Multisite Dual-Voltage Calcium Imaging
To selectively distinguish membrane voltage (Vm) from intracellular Ca²⁺ signals, it was essential to use dyes that avoid overlap in emission spectra. Therefore, we developed a system for simultaneous intracellular Ca²⁺ and Vm imaging. Excitation light for di-4-ANEPPS (515±5 nm) was obtained from a 200-W quartz tungsten halogen light source, and excitation light for indo-1 (365±25 nm) was obtained from a 200-W mercury arc lamp light source. Both were directed to the same position on the heart with separate liquid light guides.²¹ A dichroic mirror placed between tandem lens passed light of longer wavelengths to an emission filter (>695 nm) and photodiode array and reflected light of shorter wavelengths to a second emission filter (485±5 nm) and photodiode array.²¹ Both photodiode arrays were carefully aligned with an accuracy of 35 µm to assure recordings from similar locations.²¹ Signals recorded from each array and ECG signals were multiplexed and digitized with 12-bit precision at a sampling rate of 1 kHz/channel. For the present study, an optical magnification of x1.24 resulted in a total mapping field of 14x14 mm, with 0.9 mm spatial resolution between sites.

Stimulation Protocol
Bipolar stimulation was performed at twice diastolic threshold using two Teflon-coated silver electrodes separated by 1 mm. Electrodes were carefully inserted into the myocardium near the apex of the left ventricle (LV) to reproduce as close as possible normal propagation (ie, from endocardium to epicardium and from apex to base). Alternans was induced by periods (30 seconds) of rapid pacing from the apex of the LV separated by resting periods of 30 seconds, during which preparations were allowed to recover at a pacing cycle length of 400 ms. Simultaneous Ca²⁺ and Vm signals were recorded for 10 seconds at the end of rapid pacing, which started at a pacing cycle length of 300 ms (200 bpm) and was decreased by 10 ms until 1/1 capture was lost or until ventricular fibrillation ensued. All measurements were made during steady-state alternans. In two of the seven experiments, this protocol was repeated while pacing from a different location (base of the LV).

Restitution Protocols
In a subset of experiments, standard and dynamic APD restitutions were measured simultaneously from each recording site by introducing a single premature stimulus (S₂) after a 40-beat drive train (S₁) at the basic cycle length of 400 ms (ie, standard restitution)¹⁹ and by plotting APD as a function of DI measured during periods of rapid pacing used to promote alternans (ie, dynamic restitution).^7,18,23

Data Analysis
Activation time and repolarization time were measured as described previously.^1,2 Ca²⁺ alternans (CaF-ALT) was defined as the difference in the net amplitude of the large and small Ca²⁺ transient, expressed as a percent of the average net amplitude of two consecutive beats. APD-ALT and CaF-ALT were considered to be present when absolute differences in consecutive beats were 4 ms and >10%, respectively. These threshold values gave us a reliable measure of alternans spatially and temporally across all experiments. An epicardial region was considered alternating when at least 10 neighboring sites fulfilled criteria for APD-ALT or CaF-ALT. Concordant alternans was defined as one or more regions in phase, fulfilling criteria for APD-ALT or CaF-ALT, and spatially discordant alternans as two or more regions but in opposite phase, ie, one region showed a long-short APD or a large-small CaF amplitude pattern (positive difference) whereas another region showed a short-long APD or a small-large CaF amplitude pattern (negative difference).

APD restitution was fit to a single exponential to compare restitution kinetics characteristics between recording sites. The following parameters of APD restitution were calculated at each recording site: (1) APD_b, the baseline APD; (2) , the time constant of a single exponential fit; (3) the DI and APD values, where slope equals 1 on the restitution curve^13,16; and (4) the theoretical alternans pacing rate threshold, defined as [1000/(APD+DI)]x60, where APD and DI values are taken from where slope equals 1 on the restitution curve.^13,16

Statistics
Nonparametric tests were used to assess differences between paired and unpaired samples, respectively. P<0.05 was considered significant. Linear regression analysis was used to evaluate possible association between variables.

	Results

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Spatial and Temporal Relationships Between APD and Intracellular Ca²⁺ Alternans
Figure 1A shows representative examples of the ECG, action potential, and CaF transients recorded simultaneously at three different pacing rates. During baseline pacing (150 bpm), the ECG, APD, and CaF amplitude were stable over time and no alternans was observed. At a pacing rate of 375 bpm, subtle beat-to-beat alternans in APD, CaF amplitude, and T-wave amplitude was observed. An additional increase in pacing rate (461 bpm) resulted in pronounced alternans of APD, CaF amplitude, and ECG T wave. In all experiments, long APDs were always associated with CaF transient of large amplitude and short APD with CaF transient of small amplitude (ie, concordant electromechanical alternans). Figure 1B displays the averaged magnitude of APD-ALT and CaF-ALT across the entire mapping field as a function of pacing rate for one representative experiment. By gradually increasing the pacing rate, an exponential increase in both APD-ALT and CaF-ALT occurred simultaneously at 340 bpm. In this example, the threshold pacing rate for APD-ALT and CaF-ALT was 353 bpm. The heart rate threshold for inducing APD-ALT and CaF-ALT in all experiments was similar (Table), suggesting that the development of beat-to-beat APD-ALT closely coincides with the development of CaF-ALT.

View larger version (27K): [in this window] [in a new window]   Figure 1. ECG, Vm, and CaF recordings at 3 different pacing rates (A). The number below each Vm and CaF recording represents APD (ms) and normalized CaF amplitude (%), respectively. The development of T-wave alternans was closely paralleled by APD-ALT and CaF-ALT. At 150 bpm (left), all signals were stable over time, and no alternans was observed. At 375 bpm (middle), subtle beat-to-beat alternans was observed, which was further increased at a pacing rate of 461 bpm. B, Representative experiment showing that the magnitude of APD-ALT and CaF-ALT increased as a function of pacing rate.

View this table: [in this window] [in a new window]   Table 1. Comparison of APD-ALT, CaF-ALT, and T-Wave ALT Thresholds

For each experiment, we determined the spatial relationship between APD-ALT and CaF-ALT measured simultaneously from multiple sites across the anterior epicardial surface. In a representative example, at a pacing rate of 375 bpm (Figure 2, top), both APD-ALT and CaF-ALT were concordant in space and originated at the base of the LV, away from the apical stimulation site. In separate experiments, the site of alternans onset also occurred at the LV base, even when pacing from the base of the LV. At a faster pacing rate, APD-ALT and CaF-ALT increased in magnitude and spread toward regions that were not previously alternating (ie, RV base and apex). In these regions, the cycle length at which alternans occurred was shorter (10 to 20 ms) compared with the site of alternans onset (LV base). Importantly, as pacing rate was increased (461 bpm, Figure 2, bottom), both APD-ALT and CaF-ALT became discordant in space, where neighboring regions alternated in opposite phase. The entire mapping field displayed beat-to-beat alternans in APD and CaF amplitude with bands of zero alternans separating regions in opposite phase (ie, node).

View larger version (67K): [in this window] [in a new window]   Figure 2. Contour maps of APD-ALT and CaF-ALT paced from the apex of the LV. At a pacing rate of 375 bpm (top), both APD-ALT and CaF-ALT originated near the LV base, away from the apical pacing site. At 461 bpm (bottom), APD-ALT and CaF-ALT increased in magnitude and exhibited a similar pattern of discordance in space.

Table 1 shows similar pacing rate thresholds between spatially discordant APD-ALT and CaF-ALT in all experiments (P=NS). In a subset of experiments, similar results were observed for a pacing site located at the LV base. In summary, these data show that beat-to-beat APD and CaF amplitude were closely associated spatially both during concordant and discordant alternans and that the site of alternans onset was independent of pacing location.

Site of Repolarization Alternans Onset
Interestingly, the sites showing the first signs of APD-ALT or CaF-ALT were not randomly distributed across the mapping field but consistently occurred toward the base of the LV, independent of pacing site. We defined the region where alternans first appeared as the alternans-prone site, in contrast to regions where alternans occurred at faster pacing rates (ie, alternans-resistant site). Figure 3 shows representative examples of the ECG (top), action potentials, and APD time series from the alternans-prone site (middle) and an alternans-resistant site (bottom). At a pacing rate of 375 bpm, the alternans-prone site displayed a subtle but visible beat-to-beat alternation in DI and APD. The time series below the action potential traces undoubtedly showed alternation in beat-to-beat APD of 10 ms. In contrast, the alternans-resistant site displayed no visible alternans, further illustrated by the lack of beat-to-beat APD-ALT in the time series shown below the traces. Note as well the subtle alternation in the amplitude of the ECG T wave also evident in the corresponding time series.

View larger version (18K): [in this window] [in a new window]   Figure 3. Representative examples of ECG (top), action potentials, and APD time series from the alternans-prone site (middle) and an alternans-resistant site (bottom) from the RV base. The alternans-prone site displayed a subtle beat-to-beat alternation in DI, APD, and APD time series that was not visible at the alternans-resistant site. Importantly, both sites displayed APD-ALT at a faster pacing rate (461 bpm). Note that the peak of the short AP at the alternans-prone site appeared to raise slightly above the longer AP.

Role of APD Restitution in Repolarization Alternans
To investigate the mechanism of alternans onset, standard and dynamic restitution curves were compared between the alternans-prone site and an alternans-resistant site near the RV base in a subset of experiments. Figures 4A and 4B show standard restitution curves from two representative examples. In both experiments, the alternans-prone site () is characterized by a shorter baseline APD value (APD_b), shallower kinetics (ie, longer ), shorter DI at slope of 1, and higher theoretical alternans heart rate threshold (HR_alt) compared with the alternans-resistant site (. The alternans heart rate threshold measured experimentally from the LV base (369±21 bpm, Table) was on average higher by 60 bpm than the theoretical value (HR_alt, 290 to 331 bpm) determined from the restitution curves. Similarly, the DI at which alternans occurred at the LV base (34±3 ms) was longer by 10 ms than the predicted value based on the standard restitution curve (22 to 24 ms, Figure 4). These data suggest a lack of causal relationship between APD-ALT and kinetics of APD restitution as assessed by the standard restitution protocol.

View larger version (29K): [in this window] [in a new window]   Figure 4. APD restitution curves from 2 representative experiments (A and B). APD restitution curves were fitted to a single exponential from a site where alternans onset was earliest () and delayed (. Arrows depict the location of the point of a slope of 1 used to calculate the theoretical alternans pacing rate threshold (HRalt), defined as [1000/(APD+DI)]x60, where APD and DI values are taken from where slope equals 1 on the restitution curve. In both experiments, the alternans-prone site was characterized by shorter baseline APD (APDb), longer restitution time course (), shorter DI at a slope of 1, and higher HRalt compared with the alternans-resistant site.

View larger version (62K): [in this window] [in a new window]   Figure 5. APD gradient was oriented from the RV base to the LV free wall, orthogonal to the LAD (A). The onset of APD-ALT and CaF-ALT (hatched area) consistently occurred at the LV base (n=7), independent of pacing site. Alternans onset did not occur where APD was longest (ie, at the RV base), nor where APD was shortest (ie, toward LV free wall). Similar results were observed in all experiments (B). At a baseline pacing rate of 150 bpm, APD at the alternans-prone site (LV base, hatched area) was significantly shorter by 8 ms than APD at the alternans-resistant site from the RV base. C, Contour map of , a measure of standard APD restitution kinetics, from the same representative experiment as in A. Faster kinetics (ie, smaller ) were observed toward the RV, where APD was longer, and slower kinetics (ie, longer ) were observed toward the LV free wall, where APD was shorter. Note that the alternans-prone site (hatched area) was not located where standard APD restitution kinetics were steepest (ie, RV) but originated where restitution kinetics were shallower. D, Plot of as a function of APD-ALT magnitude from the same representative experiment as in A and C. No relationship could be established between the time course of APD restitution and APD-ALT magnitude (R2=0.06).

To further investigate the mechanism of alternans, we compared the spatial pattern of alternans onset with baseline APD gradients. In general, APD gradients were oriented from the RV base to the LV free wall, orthogonal to the LAD artery, as shown in Figure 5A. Interestingly, alternans did not start where APD was longest, ie, at the base of the RV, nor where APD was shortest, ie, toward the LV free wall. In fact, alternans consistently started at the base of the LV, where APD values tended to be intermediate (Figure 5A, hatched area). Figure 5B shows that for all experiments (n=7), mean baseline APD at the alternans-prone site was significantly smaller than at the alternans-resistant site at the RV base (211±8 versus 219±8 ms, respectively; P<0.01). Similarly, we compared the pattern of alternans onset with the time course of standard APD restitution, as described by in the same representative experiment shown in Figure 5A. As expected, followed the APD gradient, with steeper kinetics (ie, smaller ) toward the RV and shallower kinetics (ie, longer ) toward the LV free wall. Interestingly, the site of earliest alternans was not located where APD restitution kinetics were steepest (ie, RV) but occurred where standard restitution kinetics were shallow (ie, toward the base of the LV). Figure 5D shows a plot of from the standard restitution curve as a function of APD-ALT magnitude in the same representative example in Figures 5A and 5C. APD-ALT magnitude was measured at a pacing rate (400 bpm) at which the anterior epicardial surface showed alternans that was only concordant in space. Assuming that standard APD restitution kinetics govern alternans in the intact heart, one would expect that would be smallest (ie, steep kinetics) where APD-ALT is largest and that would be largest (ie, shallow kinetics) where APD-ALT is smallest. As indicated by the low correlation coefficient (R²=0.06), no relationship could be established between the time course of standard APD restitution and APD-ALT magnitude.

Figure 6A shows dynamic restitution curves from the alternans-prone site (LV base) and alternans-resistant site (RV base). Interestingly, both sites showed similar kinetics, with a time constant () of 100 ms and a DI of 30 ms, reaffirming that susceptibility of a cell to alternans is not determined by its restitution properties. Figure 6B shows that the measured alternans threshold (DI, 34±3 ms) is significantly smaller than the predicted alternans threshold based on the dynamic restitution curves for each experiment (DI, 54±8 ms). Taken together, these data suggest that in the intact heart, there is no causal relationship between APD-ALT and APD restitution kinetics in its broad definition (ie, standard and dynamic).

View larger version (25K): [in this window] [in a new window]   Figure 6. A, Dynamic restitution curves from the alternans-prone site (LV base) and alternans-resistant site (RV base) in the same subset of experiments shown in Figures 4 and 5. Interestingly, both sites showed similar kinetics, with a time constant on the order of 100 ms and a DI of 30 ms. B, Measured DI at which alternans was first observed at the alternans-prone site (LV base) is significantly shorter (P<0.05, n=6) than predicted DI measured from dynamic restitution.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The present study shows that the mechanisms underlying T-wave alternans in the intact heart are more closely associated with intracellular Ca²⁺ cycling rather than APD restitution (ie, standard and dynamic). We also found that alternans of both APD and intracellular Ca²⁺ consistently originated at the base of the LV and were unrelated to APD restitution kinetics in the intact heart.

Role of APD Restitution in Repolarization Alternans
Heterogeneity of standard APD restitution across the epicardial surface of the Langendorff-perfused guinea pig model has been well characterized.¹⁹ In general, standard APD restitution follows a base-to-apex pattern similar to the APD gradient, where longer APD, steeper kinetics, and lower theoretical alternans threshold (ie, HR at a slope of 1) occur toward the base of the RV.^19,20 The slope of the APD restitution curve is believed to be mechanistically related to APD-ALT and wavebreak.^13,15–17 Several experimental^16,17 and theoretical studies^13,18 have shown that a slope >1 promotes alternans, whereas a slope <1 prevents it. Our study is the first to report that both APD and intracellular Ca²⁺ alternans consistently originated at the base of the LV, independent of pacing site. It is therefore possible that the base of the LV has unique restitution properties, making it prone to APD-ALT and, hence, Ca²⁺ alternans. If restitution kinetics govern APD-ALT, one would expect alternans to originate first toward the RV, where standard restitution kinetics are greatest and baseline APD is longest. However, we found that restitution characteristics at the alternans-prone site did not exhibit the steepest kinetics nor the longest DI at a slope of 1. Likewise, alternans onset did not occur where APD was longest (ie, base of the RV), nor where APD was shortest (ie, apex of the heart), but alternans of both intracellular Ca²⁺ and APD consistently began together at the base of the LV, where APD was intermediate. In addition, the measured alternans threshold was significantly higher than the predicted threshold based on standard restitution. We also analyzed the relationship between alternans and dynamic restitution, which takes into account pacing history (ie, memory). Interestingly, measured DI at which alternans was first observed was significantly shorter than the predicted DI at a slope of 1, measured from dynamic restitution curves reaffirming the poor relationship between repolarization alternans and APD restitution.

Our findings share some similarities with previous studies showing a poor relationship between restitution kinetics and APD-ALT.^5,7,24 Banville et al⁷ observed stable alternans in the intact heart at rates where the slope of the APD restitution curve <1. In addition, Saitoh et al⁵ reported that transient APD-ALT in muscle fibers was dependent on intracellular Ca²⁺ cycling rather than on the recovery of membrane currents, as measured by APD restitution. Our study extends their findings to stable alternans in the intact heart, which, unlike transient alternans, is proven to increase risk of arrhythmic events.^1,2,25

Assuming that APD restitution slope >1 promotes alternans whereas slope <1 prevents it,^13,16–18 the theoretical alternans threshold can be calculated from the APD and diastolic interval values where the slope equals 1 (see the Materials and Methods section for details). However, it is well established clinically^3,26 and experimentally²⁷ that increasing the baseline pacing rate at which restitution is measured moves the APD restitution downward and leftward. This is, in turn, produces multiple theoretical alternans thresholds, which may preclude the use of restitution (a measure accessible during clinical electrophysiology study^3,26) as a simple means to clinically determine alternans threshold. Taken together, these data suggest a lack of causal relationship between APD-ALT and APD restitution kinetics in the intact heart. However, cardiac memory or electronic effects may account for this discrepancy.^5,24 Interestingly, we have found that calcium cycling also seems to play a role in short-term cardiac memory, which, in turn, can modulate the alternans heart rate threshold.²⁸ In addition, using theoretical models, it has been shown that short-term memory may be caused by factors other than calcium cycling, such as K⁺ current deactivation.²⁹

Finally, APD restitution and intracellular Ca²⁺ cycling are not mutually exclusive causes of APD alternans, because one may affect the other. However, in different experimental conditions that affect APD restitution and intracellular Ca²⁺ cycling differentially (eg, sympathetic tone, different [Ca²⁺]₀, and temperature), one or the other mechanism may dominate. It is also important to emphasize that APD restitution can provide a useful approach for understanding alternans but additional investigation of calcium cycling proteins must be pursued to ascertain the underlying cellular mechanisms.

Intracellular Ca²⁺ Cycling as a Mechanism of Repolarization Alternans
Another original finding in our study is that both APD and intracellular Ca²⁺ alternans consistently originated at the base of the LV, independent of pacing site. At the alternans threshold, APD and intracellular Ca²⁺ were both concordant in space and confined to a relatively small region near the LV base. Spatial heterogeneity of intrinsic cellular function may play a role in the preferential onset of alternans toward the base of the LV. Electrophysiological properties^19,20 and contractility³⁰ are known to follow a base-to-apex gradient across the heart. In particular, the base of the heart displays a weaker contraction and slower relaxation³⁰ as well as Ca²⁺ transients of longer duration^20,31 and smaller amplitude³¹ compared with the apex. Such heterogeneity of Ca²⁺ handling may provide insights into the cellular mechanisms of alternans. For example, a smaller amplitude of Ca²⁺ release near the base of the heart is indicative of weaker Ca²⁺-induced Ca²⁺ release. Both mechanical and repolarization alternans have been associated with alternans of Ca²⁺ release by the SR on a beat-to-beat basis.^4,5,8,12,15 L-type Ca²⁺ blockers, which affect membrane current and Ca²⁺-induced Ca²⁺ release, decreased but did not prevent mechanical alternans.¹⁰ In contrast, pharmacological compounds preventing the release of Ca²⁺ from the SR (eg, Ryanodine and caffeine) abolished both APD and intracellular Ca²⁺ alternans.¹⁰ Recently, reduced SERCA expression¹² or interventions that decrease Ryanodine receptor function, such as reducing the open probability or availability of glycolytic ATP,⁹ have been shown to promote both intracellular Ca²⁺ and APD alternans. Most studies, however, have focused on the mechanisms responsible for APD and intracellular Ca²⁺ alternans in single cell^6,8,9,11 and tissue samples.^4,5,12 Because our measurements were made from the anterior epicardial surface of the LV and RV, the earliest site of alternans onset could have occurred elsewhere. However, APD and Ca²⁺ alternans thresholds were similar to the ECG T-wave alternans threshold (Table), suggesting that the alternans observed first at the LV base reflected the earliest site of onset. In conclusion, our data suggest that Ca²⁺-induced Ca²⁺ release may also play a role in the onset of alternans in the intact heart and, moreover, that the base of the LV has unique Ca²⁺-handling properties rendering this region prone to alternate first.

We always observed concordant electromechanical alternans during spatially concordant and discordant alternans. This finding is similar to experiments performed by Choi et al²⁰ in the intact guinea pig heart and by Rubenstein et al⁶ in single cells, both of which were performed at near-physiological temperatures. Orchard et al⁸ have shown that the Na⁺-Ca²⁺ exchange current is involved in promoting APD-ALT. However, discordant electromechanical alternans has been reported when experiments were run at room temperature.^6,32 Interestingly, the Na⁺-Ca²⁺ exchange current is reduced at room temperature more than other ionic membrane currents.⁶ Thus, it is possible that other Ca²⁺-sensitive currents (I_Ca,L and I_Ks) dominate at low temperature, resulting in electromechanical discordant alternans. We occasionally noticed a peculiar pattern at very rapid pacing rates where the peak of the short AP upstroke appeared to raise slightly above the longer AP upstroke (Figure 3). The mechanisms of this is not clear but may be related to supernormal excitability, where the takeoff potential is slightly higher than resting potential but still lower than the potential at which sodium channels inactivate.³³

Our observation of a close spatial and temporal association between intracellular Ca²⁺ and APD during alternans is in good agreement with previous studies performed in nonischemic²⁰ and ischemic preparations.³⁴ It is important to mention, however, that the onset of alternans may be different during regional ischemia. The close temporal and spatial association between APD and intracellular Ca²⁺ reported in the present study suggests that Ca²⁺ cycling may also play a role in the pathogenesis of discordant alternans. When the pacing rate is increased, intracellular Ca²⁺ rises to a new steady-state level.^12,20 Increasing intracellular Ca²⁺ has been shown to promote cell uncoupling independent of intracellular H⁺.³⁵ A decrease in coupling between regions or cells may also enhance spatial heterogeneity of electrophysiological properties² and slow impulse propagation across the heart,³⁶ each of which has been shown to lower alternans threshold² and enhance discordant alternans.^2,13,14,18 However, additional studies are required to elucidate the role played by intracellular Ca²⁺ in spatially discordant alternans.

	Acknowledgments

 
This work was supported by The Fondation Suisse de Bourses en Médecine et Biologie, the Fondation Vaudoise de Cardiologie, and NIH grants R01HL68877 (to K.R.L.) and R01HL54807 (to D.S.R.).

	Footnotes

 
Original received May 2, 2003; resubmission received December 29, 2003; revised resubmission received February 23, 2004; accepted March 2, 2004.

	References

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