Amplitude Of Alternans Research Articles

Alternans of repolarization and depolarization in ventricular myocytes

Several studies suggest that repolarization alternans play an important role in initiation of ventricular arrhythmias. While alternans of duration of repolarization, i.e. of action potential duration (APD), has been extensively investigated, little is known about alternans of amplitude of action potentials (APA). The purpose of our study was to examine the relationship between APD and APA alternans and to determine potential mechanisms of APA alternans. Transmembrane potentials were recorded using glass micro‐electrodes in swine ventricular tissue (n=8). From 51 trials we observed that the incidence of APD alternans was 33% of all action potentials recorded for cycle lengths &*8804; 290 ms. Alternans of APA occurred 50% of times when APD alternans occurred and were concordant (long action potentials were also tall) 98% times. Incidence of APD alternans along with APA alternans was 78% with 96% concordance. These results show that occurrence of APA alternans is not rare. Alternans of APA were accompanied by alternans of |dv/dt|max 77 % of times, suggesting that sodium current may underlie alternans of APA. The potential effect of alternans of depolarization phase of the action potential on conduction suggests that this may also play a role in loss of electrical stability.Supported by the American Heart Association (Great Rivers Affiliate) and the National Science Foundation (CBET 07350).

Reply to “Letter to the editor: ‘Depolarization and repolarization alternans in an anesthetized canine ischemia model’”

Letters to the EditorReply to “Letter to the editor: ‘Depolarization and repolarization alternans in an anesthetized canine ischemia model’”David Gordon, Alan H. Kadish, Jeffrey J. Goldberger, and Jason NgDavid GordonBluhm Cardiovascular Institute and Feinberg School of Medicine at Northwestern University, Chicago, Illinois, Alan H. KadishBluhm Cardiovascular Institute and Feinberg School of Medicine at Northwestern University, Chicago, Illinois, Jeffrey J. GoldbergerBluhm Cardiovascular Institute and Feinberg School of Medicine at Northwestern University, Chicago, Illinois, and Jason NgBluhm Cardiovascular Institute and Feinberg School of Medicine at Northwestern University, Chicago, IllinoisPublished Online:01 Feb 2010https://doi.org/10.1152/ajpheart.01180.2009MoreSectionsPDF (28 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat reply: We thank Dr. J. E. Madias (3) for his perceptive comments on our article, “High-resolution electrical mapping of depolarization and repolarization alternans in an ischemic dog model” (1). Our response to his queries are as follows. The first query was, “Since electrical alternans (EA) was also seen before ischemia, is it not a contradiction that the presence, and not the amplitude, of EA is predictive of ventricular fibrillation (VF)?” The results of our study suggest that there may be a critical amount of area with EA that is necessary for spontaneous VF to develop. Although there were low-level alternans during the preischemic period, none of the dogs had alternans prevalence above the cutoffs determined in our receiver-operator characteristic curve analysis for the respective measurements. This is consistent with the fact that none of the dogs spontaneously developed VF during the preischemia period.His second query was, “Could the methodology used be implemented in standard ECGs or Holter monitorings?” The answer is yes. This methodology can be used to quantify alternans amplitude and provide an amplitude-to-error ratio in standard ECGs and Holter recordings. It would have the potential advantage of a higher time resolution than the spectral or modified moving average techniques. However, the trade-off is the lack of noise reduction with this technique. It would have to be determined what amplitude-to-error ratios are necessary for our method to have predictive value when analyzing microvolt alternans in standard ECGs or Holter recordings.Dr. Madias points out an interesting observation in his third query: the presence of S-wave alternans in Fig 3. Alternans in the S wave was commonly seen in the signals that had clear S waves. As alluded to in our limitation section, the S wave of the unipolar electrogram likely includes both a late depolarization and an early repolarization component. Therefore, it is unclear whether the S-wave alternans is a result of depolarization or repolarization alternans. This feature of the S wave may be an interesting topic for further study.Regarding Dr. Madias's questions and comments about correlation between waveform amplitude and alternans amplitude and the use of scaling, all the electrograms were scaled by the peak-to-peak QRS to account for amplitude differences in the electrograms that may be due to nonphysiological reasons such as differences in electrode contact quality. All measurements were made off the scaled electrograms. The ST/T wave was not scaled separately from the QRS, but this method as shown in Dr. Madias's article (2) may be useful for future analysis of the T wave since it is likely that there is at least some correlation between waveform amplitude and alternans amplitude. We thank Dr. Madias for this suggestion.DISCLOSURESNo conflicts of interest are declared by the author(s).REFERENCES1. Gordon D, Kadish AH, Koolish D, Taneja T, Ulphani J, Goldberger JJ, Ng J. High-resolution electrical mapping of depolarization and repolarization alternans in an ischemic dog model. Am J Physiol Heart Circ Physiol. (November 13, 2009). doi: 10.1152/ajpheart.00914.2009.Google Scholar2. Madias JE. A proposal for a T-wave alternans index. J Electrocardiol 40: 479–481, 2007.Crossref | PubMed | ISI | Google Scholar3. Madias JE. Letter to the editor: “Depolarization and repolarization alternans in an anesthetized canine ischemia model”. Am J Physiol Heart Circ Physiol. doi: 10.1152/ajpheart.01097.2009.Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. Ng, 676 N. St. Clair, Suite 1790, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, IL 60611 (e-mail: [email protected]). Download PDF Previous Back to Top FiguresReferencesRelatedInformation More from this issue > Volume 298Issue 2February 2010Pages H729-H729 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.01180.2009History Published online 1 February 2010 Published in print 1 February 2010 Metrics

Off-site control of repolarization alternans in cardiac fibers

Repolarization alternans, a beat-to-beat alternation in action potential duration, has been putatively linked to the onset of cardiac reentry. Anti-alternans control strategies can eliminate alternans in individual cells by exploiting the rate dependence of action potential duration. The same approach, when applied to a common measuring/stimulating site at one end of a cardiac fiber, has been shown to have limited spatial efficacy. As a first step toward spatially distributed electrode control systems, we investigated "off-site" control in canine Purkinje fibers, in which the recording and control sites are different. We found experimentally that alternans can be eliminated at, or very near, the recording site, and that varying the location of the recording site along the fiber causes the node (the location with no alternans) to move along the fiber in close proximity to the recording site. Theoretical predictions based on an amplitude equation [B. Echebarria and A. Karma, Chaos 12, 923 (2002)] show that those findings follow directly from the wave nature of alternans: the most unstable mode of alternans along the fiber is a wave solution of a one-dimensional Helmholtz equation with a node position that only deviates slightly from the recording site by an amount dependent on electrotonic coupling. Computer simulations using a Purkinje fiber model confirm these theoretical and experimental results. Although off-site alternans control does not suppress alternans along the entire fiber, our results indicate that placing the node away from the stimulus site reduces alternans amplitude along the fiber, and may therefore have implications for antiarrhythmic strategies based on alternans termination.

Effect of Sodium Homeostasis on Action Potential Duration Alternans in Cardiac Ventricular Cells

Beat-to-beat alternation of action potential (AP) duration (alternans) is a precursor of fatal cardiac arrhythmias. The effect of the time course of intracellular Ca2+ transient on AP duration (APD) alternans was studied extensively, and the Na+/Ca2+ exchanger (INCX) was identified as a major coupling link between Ca2+ alternans and APD alternans. However, the role of Ca2+ -independent factors such as the Na+/K+ pump (INaK) in the coupling between the Ca2+ and AP subsystems has been overlooked.We used computational models of AP and Ca2+ cycling in guinea-pig and canine myocytes to study effects of rate-dependent Na+ homeostasis on APD and the Ca2+ transient. We found that rate-dependent Na+ accumulation increases both the amplitude and frequency range of APD alternans in the guinea-pig, but decreases the amplitude of APD alternans in canine cells. The mechanism is as follows: in canine, Ca2+ and APD alternans are concordant (large Ca2+ is accompanied by long APD) and APD prolongation is due to inward INCX enhancement at a late phase of the AP. INaK enhancement by Na+ accumulation blunts the effect of INCX and decreases APD alternans amplitude. In the guinea pig, alternans are discordant (large Ca2+ transient with short APD) due to enhanced Ca2+ -dependent inactivation of L-type Ca2+ current and increased Ca2+-dependent slow delayed rectifier IKs at high Ca2+. Additional APD shortening by INaK increases the amplitude of the discordant alternans.In conclusion, INaK enhancement due to Na+ accumulation decreases the amplitude of concordant APD-Ca2+ alternans and increases the amplitude of discordant APD-Ca2+ alternans. This mechanistic insight is relevant to arrhythmogenesis in heart failure where INCX is upregulated and INaK downregulated, amplifying APD alternans in larger mammals (canine) and possibly humans.

High-resolution electrical mapping of depolarization and repolarization alternans in an ischemic dog model

Cardiac electrical alternans have been associated with spontaneous ventricular arrhythmias during myocardial ischemia. The study aims were to use a new algorithm to measure depolarization and repolarization alternans from epicardial electrograms in an ischemia model and to evaluate which features are predictive of ventricular fibrillation (VF). The left anterior descending coronary artery was occluded in 21 dogs, of which 6 developed spontaneous VF. Four seconds of unipolar epicardial electrograms was recorded before and 5 min after occlusion from an 8 x 14-electrode plaque placed on the anterior left ventricle. Alternans amplitudes were estimated with a triangular wave-fitting algorithm and for each unipolar electrogram for various measurements of the QRS and ST-T wave amplitude. The root mean square error was computed for each fit. Receiver-operator characteristic curves were used to determine whether prevalence of alternans having estimated alternans amplitude-to-error ratio (A/E) above a given threshold could distinguish the dogs who had and did not have spontaneous VF. The prevalence of alternans after ischemia was highly predictive of VF when measured both during depolarization (sensitivity of 83% and specificity of 87%) and during repolarization (sensitivity of 100% and specificity of 73%). The optimal alternans A/E ranged from 1 to 4. There were no differences in the level of discordance or alternans amplitude between dogs who developed VF versus dogs who did not. The prevalence of alternans in the ventricles may be the key risk factor for developing VF during myocardial ischemia when short-term recordings are used.

Are the T-Wave Alternans Amplitude “Zones” Related to T-Wave Amplitude “Zones” in ECG Ambulatory Recordings?

Are the T-Wave Alternans Amplitude “Zones” Related to T-Wave Amplitude “Zones” in ECG Ambulatory Recordings?

Relationship between extracellular T-wave height, T-wave alternans amplitude, and tissue action potential alternans: a 1-dimensional computer modeling study

T-wave alternans (TWA) is a useful marker of cardiac instability, but not much is known about the factors that affect its measurement, such as electrode placement. We used a 1-dimensional myocardial fiber computer model of alternans to investigate the effect of electrode position on TWA measurement. Results demonstrated that TWA amplitude and T-wave amplitude change proportionally if both recording electrodes are symmetrically moved toward or away from the tissue. However, TWA amplitude and T-wave amplitude change out of proportion to one another when one electrode is moved while the other electrode remains stationary. These disproportionate changes result from beatwise alternation in the asymmetric potential field around the tissue. In summary, nonlinear changes in tissue repolarization during alternans result in nonlinear changes in T-wave amplitude and TWA amplitude.

A novel method to quantify contribution of electrical restitution to alternans of repolarization in cardiac myocytes: A simulation study

There is evidence that alternans of repolarization, i.e. a beat to beat alternation in the action potential duration (APD), is a precursor to ventricular fibrillation. Electrical restitution is considered important in predicting the onset of alternans in cardiac myocytes. Restitution predicts action potential duration (APD) based on the preceding diastolic interval (DI). Determining how much restitution contributes to alternans is not possible with existing methods. We used mathematical models and control of DI using a novel pacing protocol to quantify DI dependent contribution to alternans. Using the canine ventricular model (CVM), we paced at one end of the simulated tissue and found the DI dependent contribution as a rate of increase in the amplitude of alternans as a function of tissue length. Through manipulation of different ionic currents, we compared the new method with standard and dynamic restitution to quantify the contribution of different ionic currents towards DI independent and dependent components. When the L‐type calcium current was altered, we found non‐conformal changes between standard restitution and our method at a controlled DI value of 30 msec. These results suggest that the new method allows for unmasking of features of mechanisms of alternans not seen with current methods.Supported by grant CBET 0730450 from the National Science Foundation.

Action Potential Dynamics Explain Arrhythmic Vulnerability in Human Heart Failure: A Clinical and Modeling Study Implicating Abnormal Calcium Handling

The purpose of this study was to determine whether abnormalities of calcium cycling explain ventricular action potential (AP) oscillations and cause electrocardiogram T-wave alternans (TWA). Mechanisms explaining why heart failure patients are at risk for malignant ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) are unclear. We studied whether oscillations in human ventricular AP explain TWA and predict VT/VF, and used computer modeling to suggest potential cellular mechanisms. We studied 53 patients with left ventricular ejection fraction 28 +/- 8% and 18 control subjects. Monophasic APs were recorded in the right ventricle (n = 62) and/or left ventricle (n = 9) at 109 beats/min. Alternans of AP amplitude, computed spectrally, had higher magnitude in study patients than in controls (p = 0.03), particularly in AP phase II (p = 0.02) rather than phase III (p = 0.10). The AP duration and activation restitution (n = 11 patients) were flat at 109 beats/min and did not explain TWA. In computer simulations, only reduced sarcoplasmic reticulum calcium uptake explained our results, causing calcium oscillations, AP amplitude alternans, and TWA that were all abolished by calcium clamping. On prospective follow-up for 949 +/- 553 days, 17 patients had VT/VF. The AP amplitude alternans predicted VT/VF (p = 0.04), and was 78% concordant with simultaneous TWA (p = 0.003). Patients with systolic dysfunction show ventricular AP amplitude alternans that prospectively predicted VT/VF. Alternans in AP amplitude, but not variations in AP duration or conduction, explained TWA at < or =109 beats/min. In computer models, these findings were best explained by reduced sarcoplasmic reticulum calcium uptake. Thus, in heart failure patients, in vivo AP alternans may reflect cellular calcium abnormalities and provide a mechanistic link with VT/VF.

Optimal mechano-electric stabilization of cardiac alternans

Alternation of normal action-potential morphology in the myocardium is a condition with a beat-to-beat oscillation in the length of the electric wave which is linked through electromechanical coupling to the cardiac muscle contraction, and is believed to be the first manifestation of the onset of life threatening ventricular arrhythmias and sudden cardiac death. In this work, the effects of electrical and mechanical stimuli are utilized in alternans annihilation problem. Electrical stimuli that alter the action-potential morphology are represented by a pacer located at the domain's boundary, while mechanical stimuli are distributed within the spatial domain and affect the action potential by altering intracellular calcium kinetics. Alternation of action potential is described by the small amplitude of alternans parabolic partial differential equation (PDE). Spatially uniform unstable steady state of the alternans amplitude PDE is stabilized by optimal control methods through boundary and spatially distributed actuation. Mixed boundary and spatially distributed actuation is manipulated by a linear quadratic regulator (LQR) in the full-state-feedback control structure and in a compensator design with a finite-dimensional Luenberger-type observer, and it achieves exponential stabilization in a finite size tissue cable length. The proposed control problem formulation and the performance and robustness of the closed-loop system under the proposed linear controller are evaluated through simulations.

Optimal boundary control of cardiac alternans

AbstractAlternation of normal electrical activity in the myocardium is believed to be linked to the onset of life‐threatening ventricular arrhythmias and sudden cardiac death. In this paper, a spatially uniform unstable steady state of small amplitude of alternans described by parabolic partial differential equations (PDEs) is stabilized by boundary optimal control methods. A finite dimensional linear quadratic regulator (LQR) is utilized in both a full‐state‐feedback control structure and in a compensator design with the Luenberger observer, and it achieves global stabilization in a finite size tissue cable length. The ability to realize such control algorithm is analyzed based on the structure of the amplitude of alternans equation and the control methodology applied. Copyright © 2008 John Wiley &amp; Sons, Ltd.

Control of Electrical Alternans in Canine Cardiac Purkinje Fibers

Alternation in the duration of consecutive cardiac action potentials (electrical alternans) may precipitate conduction block and the onset of arrhythmias. Consequently, suppression of alternans using properly timed premature stimuli may be antiarrhythmic. To determine the extent to which alternans control can be achieved in cardiac tissue, isolated canine Purkinje fibers were paced from one end using a feedback control method. Spatially uniform control of alternans was possible when alternans amplitude was small. However, control became attenuated spatially as alternans amplitude increased. The amplitude variation along the cable was well described by a theoretically expected standing wave profile that corresponds to the first quantized mode of the one-dimensional Helmholtz equation. These results confirm the wavelike nature of alternans and may have important implications for their control using electrical stimuli.

Mechanism of Repolarization Alternans Has Restitution of Action Potential Duration Dependent and Independent Components

Investigation of relationship between diastolic-interval (DI)-dependent restitution of action potential duration (APD) and alternans of APD has produced conflicting results. We used a novel pacing protocol to determine the role of restitution in alternans by minimizing changes in DI preceding each activation. Transmembrane potentials were recorded from right ventricular endocardial tissue isolated from five dogs. We used three pacing sequences: (i) The tissue was paced at a constant DI for 100 beats. (ii) The DIs were changed randomly between two sequences of constant DI. (iii) Each constant DI trial was followed by constant cycle length trial where pacing cycle length was equal to average cycle length during previous constant DI trial. Alternans of APD occurred even when DIs preceding each activation were invariant. Slopes of restitution during constant DI pacing were both negative and positive and were much larger than unity. Alternans amplitude during constant cycle length pacing was larger than during constant DI, 32.2 +/- 12.3 versus 7.5 +/- 2.8 msec, P < 0.01. Random perturbation of DI decreased alternans amplitude during constant DI pacing from 14.7 +/- 4.8 to 10.5 +/- 3.4 msec, P < 0.01. Our results indicate that mechanism of repolarization alternans has restitution-dependent and restitution-independent components. However, our results also provide direct evidence that shows that DI-dependent restitution of APD is not a necessary mechanism for the alternans to exist. Ability to pace with explicit control of DI provides a novel approach to dissect mechanisms of alternans into restitution-dependent and restitution-independent effects.

Dynamic and not static change in ventricular repolarization is a substrate of ventricular arrhythmia on chronic ischemic myocardium.

The restitution mechanism has been the focus of attention as the possible mechanism behind ventricular fibrillation (VF). However, its contribution in chronic ischemic heart has not been established. We investigated chronic ischemic dogs with occlusion of left anterior descending artery. Sixty unipolar electrograms were simultaneously recorded from an entire cardiac surface. Activation-recovery intervals (ARIs) and QRST deflection area (AQRST) were measured during constant atrial pacing. The ischemic dogs were divided into two groups, five dogs in VF(+) group or seven dogs in VF(-) group, according to VF occurrence by programmed electrical stimulation. When investigating ARI dispersions on an epicardium, there was no difference between VF(+) and VF(-) groups. The relationship between ARIs and diastolic intervals was quantified as an electrical restitution curve. The slopes of the ARI restitution curve for the anterior left ventricle in VF(+) dogs were significantly steeper than those of VF(-) dogs. The amplitude of AQRST alternans were significantly greater in VF(+) dogs than VF(-) dogs. Combined observation of steep restitution slopes and increased electrical alternans supported the restitution mechanism as being involved in the arrhythmia. Dynamic restitution properties and not static single-beat ARI dispersion may play an important role in the VF arrhythmia in the chronic ischemic heart.

Contribution of IKr to rate-dependent action potential dynamics in canine endocardium.

Previous modeling studies have suggested that the rapid component of the delayed rectifier (I(Kr)) may contribute importantly to action potential dynamics during tachycardia. To test this idea experimentally, I(Kr) was measured as the E-4031-sensitive current in isolated canine endocardial myocytes at 37 degrees C using the perforated patch-clamp technique. Command potentials were trains of action potential waveforms recorded at cycle lengths (CLs) of 1000, 500, 320, 170, and 120 ms. Action potential duration (APD) alternans occurred at CLs of 170 and 120 ms. During an action potential, I(Kr) increased gradually to a maximum at -55 to -60 mV. Peak I(Kr) increased initially as CL was shortened from 1000 to 500 ms (from 0.55+/-0.03 to 0.57+/-0.03 pA/pF), but decreased progressively as CL was shortened further (to 0.45+/-0.03 pA/pF at CL=120 ms). Baseline I(Kr) was negligible at CLs of 1000 to 320 ms, but increased to 0.12+/-0.01 pA/pF at a CL of 120 ms. During APD alternans, peak I(Kr) was larger for the short than for the long action potential (0.48+/-0.03 versus 0.46+/-0.03 pA/pF). A computer model of I(Kr) based on these data indicated that increasing I(Kr) suppressed alternans and decreasing I(Kr) increased alternans. In support of the latter result, inhibition of I(Kr) by E-4031 increased the maximal amplitude of alternans. These results indicate that I(Kr) contributes importantly to rate-related alterations of repolarization, including APD alternans. Modifying I(Kr) may be a promising approach to suppressing alternans and thereby preventing ventricular tachyarrhythmias.

Altered atrial electrical restitution and heterogeneous sympathetic hyperinnervation in hearts with chronic left ventricular myocardial infarction: implications for atrial fibrillation.

The substrates for the increased incidence of atrial fibrillation (AF) in hearts with chronic left ventricular myocardial infarction (MI) remain poorly defined. We hypothesized that chronic MI is associated with atrial electrical and neural remodeling that enhances AF vulnerability. We created MI in 8 dogs by permanent occlusion of the left anterior descending (LAD) coronary artery. Seven dogs (3 with thoracotomy) that had no LAD occlusion served as controls. Eight weeks after surgery, the incidence and duration of pacing-induced AF in the open chest anesthetized state were significantly (P<0.05) higher in the MI than in control dogs. Multisite biatrial monophasic action potential (MAP) recordings showed increased heterogeneity of MAP duration (MAPD) and MAPD restitution slope. AF in the MI groups was preceded by significantly higher MAPD (P<0.01) and MAP amplitude (P<0.05) alternans in both atria compared with controls. Epicardial mapping using 1792 bipolar electrodes (1-mm spatial resolution) showed multisite wavebreaks of the paced wavefronts leading to AF in MI but not in control dogs. Multiple wavelets in MI dogs were associated with significantly higher incidence and longer duration of AF compared with control. The density of biatrial tyrosine hydroxylase (TH) and growth-associated protein43 (GAP43) nerves were 5- to 8-fold higher and were more heterogeneous in MI compared with control dogs. Chronic ventricular MI with no atrial involvement causes heterogeneous alteration of atrial electrical restitution and atrial sympathetic hyperinnervation that might provide important substrates for the observed increased AF vulnerability.

Two-photon molecular excitation imaging of Ca2+ transients in Langendorff-perfused mouse hearts.

The ability to image calcium signals at subcellular levels within the intact depolarizing heart could provide valuable information toward a more integrated understanding of cardiac function. Accordingly, a system combining two-photon excitation with laser-scanning microscopy was developed to monitor electrically evoked [Ca(2+)](i) transients in individual cardiomyocytes within noncontracting Langendorff-perfused mouse hearts. [Ca(2+)](i) transients were recorded at depths </=100 microm from the epicardial surface with the fluorescent indicators rhod-2 or fura-2 in the presence of the excitation-contraction uncoupler cytochalasin D. Evoked [Ca(2+)](i) transients were highly synchronized among neighboring cardiomyocytes. At 1 Hz, the times from 90 to 50% (t(90-50%)) and from 50 to 10% (t(50-10%)) of the peak [Ca(2+)](i) were (means +/- SE) 73 +/- 4 and 126 +/- 10 ms, respectively, and at 2 Hz, 62 +/- 3 and 94 +/- 6 ms (n = 19, P < 0.05 vs. 1 Hz) in rhod-2-loaded cardiomyocytes. [Ca(2+)](i) decay was markedly slower in fura-2-loaded hearts (t(90-50%) at 1 Hz, 128 +/- 9 ms and at 2 Hz, 88 +/- 5 ms; t(50-10%) at 1 Hz, 214 +/- 18 ms and at 2 Hz, 163 +/- 7 ms; n = 19, P < 0.05 vs. rhod-2). Fura-2-induced deceleration of [Ca(2+)](i) decline resulted from increased cytosolic Ca(2+) buffering, because the kinetics of rhod-2 decay resembled those obtained with fura-2 after incorporation of the Ca(2+) chelator BAPTA. Propagating calcium waves and [Ca(2+)](i) amplitude alternans were readily detected in paced hearts. This approach should be of general utility to monitor the consequences of genetic and/or functional heterogeneity in cellular calcium signaling within whole mouse hearts at tissue depths that have been inaccessible to single-photon imaging.

Instability and Spatiotemporal Dynamics of Alternans in Paced Cardiac Tissue

We derive an equation that governs the spatiotemporal dynamics of small amplitude alternans in paced cardiac tissue. We show that a pattern-forming linear instability leads to the spontaneous formation of stationary or traveling waves whose nodes divide the tissue into regions with opposite phase of oscillation of action potential duration. This instability is important because it creates dynamically a heterogeneous electrical substrate for the formation of conduction blocks and the induction of fibrillation if the tissue size exceeds a fraction of the pattern wavelength. We derive an analytical expression for this wavelength as a function of three basic length scales related to dispersion and intercellular electrical coupling.

Ionic mechanism of electrical alternans.

Although alternans of action potential duration (APD) is a robust feature of the rapidly paced canine ventricle, currently available ionic models of cardiac myocytes do not recreate this phenomenon. To address this problem, we developed a new ionic model using formulations of currents based on previous models and recent experimental data. Compared with existing models, the inward rectifier K(+) current (I(K1)) was decreased at depolarized potentials, the maximum conductance and rectification of the rapid component of the delayed rectifier K(+) current (I(Kr)) were increased, and I(Kr) activation kinetics were slowed. The slow component of the delayed rectifier K(+) current (I(Ks)) was increased in magnitude and activation shifted to less positive voltages, and the L-type Ca(2+) current (I(Ca)) was modified to produce a smaller, more rapidly inactivating current. Finally, a simplified form of intracellular calcium dynamics was adopted. In this model, APD alternans occurred at cycle lengths = 150-210 ms, with a maximum alternans amplitude of 39 ms. APD alternans was suppressed by decreasing I(Ca) magnitude or calcium-induced inactivation and by increasing the magnitude of I(K1), I(Kr), or I(Ks). These results establish an ionic basis for APD alternans, which should facilitate the development of pharmacological approaches to eliminating alternans.

Coupling interval from slow to tachycardiac pacing decides sustained alternans pattern.

We discovered that the coupling beat interval from a slow to a tachycardiac pacing period considerably affected the pattern of the beat-to-beat alternation of the tachycardia-induced sustained contractile alternans. We analyzed the relationship between the coupling interval and the pattern and amplitude of the alternans in the isovolumic left ventricle of canine blood-perfused hearts. The alternans pattern and amplitude varied transiently over the first 30-50 beats and became gradually stable over the first minute in all 12 hearts. We discovered that stable alternans, even under the same tachycardiac pacing, had three different strong-weak beat patterns depending on the coupling interval. A relatively short coupling interval produced a representative sustained alternans of the strong and weak beats. A relatively long coupling interval produced a similar sustained alternans but in a reversed order of even- and odd-numbered beats counted from the coupling interval. However, sustained alternans disappeared after 1-3 specific coupling intervals. We conclude that ventricular pacing rate does not solely determine the pattern and amplitude of sustained contractile alternans induced by tachycardia.