Electromechanical Alternans Research Articles

Omecamtiv mecarbil evokes diastolic dysfunction and leads to periodic electromechanical alternans

Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca2+ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure–volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

Prediction of the mechanical response of cardiac alternans by using an electromechanical model of human ventricular myocytes

PurposeAlthough the quantitative analysis of electromechanical alternans is important, previous studies have focused on electrical alternans, and there is a lack quantitative analysis of mechanical alternans at the subcellular level according to various basic cycle lengths (BCLs). Therefore, we used the excitation–contraction (E–C) coupling model of human ventricular cells to quantitatively analyze the mechanical alternans of ventricular cells according to various BCLs.MethodsTo implement E–C coupling, we used calcium transient data, which is the output data of electrical simulation using the electrophysiological model of human ventricular myocytes, as the input data of mechanical simulation using the contractile myofilament dynamics model. Moreover, we applied various loads on ventricular cells for implementation of isotonic and isometric contraction.ResultsAs the BCL was reduced from 1000 to 200 ms at 30 ms increments, mechanical alternans, as well as electrical alternans, were observed. At this time, the myocardial diastolic tension increased, and the contractile ATP consumption rate remained greater than zero even in the resting state. Furthermore, the time of peak tension, equivalent cell length, and contractile ATP consumption rate were all reduced. There are two tendencies that endocardial, mid-myocardial, and epicardial cells have the maximum amplitude of tension and the peak systolic tension begins to appear at a high rate under the isometric condition at a particular BCL.ConclusionsWe observed mechanical alternans of ventricular myocytes as well as electrical alternans, and identified unstable conditions associated with mechanical alternans. We also determined the amount of BCL given to each ventricular cell to generate stable and high tension state in the case of isometric contraction.

Ginsenoside Re prevents angiotensin II-induced gap-junction remodeling by activation of PPARγ in isolated beating rat atria

AimsGinsenoside Re (G-Re), a major ginsenoside in ginseng, has many beneficial pharmacological effects on negative cardiac contractility, electromechanical alternans, antiarrhythmia, angiogenic regeneration and cardiac electrophysiological function. However, effects of G-Re on gap-junction remodeling are unclear. Therefore, this study aimed to investigate the effect of G-Re on angiotensin II (Ang II)-induced downregulation of connexin-40 (CX40) and -43 (CX43) in beating rat left atria. Main methodsIn this study, the isolated perfused beating rat atrial model was used and atrial gap-junction remodeling was induced by Ang II. In vivo hemodynamic experiments were analyzed with a biological recorder. Changes in protein expression were analyzed by western blot. Key findingsG-Re attenuated Ang II-induced abnormal changes in heart rate, MAP, LVESP, LVEDP, +dp/dt max, −dp/dt min, P wave amplitude, P-R interval and P wave length. This indicated a dose-dependent preventive role against Ang II-induced hyper hemodynamics in rats. Atrial activities of p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB) and activator protein 1 (AP-1) were significantly increased by Ang II, as was expression of atrial collagen I and matrix metalloproteinase 2 (MMP2). Atrial CX40 and CX43 expression was downregulated by Ang II. These Ang II-induced atrial effects were blocked by G-Re, as well as rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ (PPARγ), in a dose-dependent manner. However, this inhibition was abolished by the PPARγ inhibitor GW9662. SignificanceG-Re may suppress Ang II-induced downregulation of CX40 and CX43, by activating PPARγ signaling, in isolated perfused beating rat atria.

Calcium alternans is due to an order-disorder phase transition in cardiac cells.

Electromechanical alternans is a beat-to-beat alternation in the strength of contraction of a cardiac cell, which can be caused by an instability of calcium cycling. Using a distributed model of subcellular calcium we show that alternans occurs via an order-disorder phase transition which exhibits critical slowing down and a diverging correlation length. We apply finite size scaling along with a mapping to a stochastic coupled map model, to show that this transition in two dimensions is characterized by critical exponents consistent with the Ising universality class. These findings highlight the important role of cooperativity in biological cells, and suggest novel approaches to investigate the onset of the alternans instability in the heart.

Stretch Activated Channel Activation can Promote or Suppress Cardiac Alternans

Alternans has been linked to the onset of ventricular fibrillation and ventricular tachycardia, leading to life-threatening arrhythmias. Experimentally electromechanical alternans can be either concordant (Long/Short APD corresponds to a Large/Small Ca transient on alternate beats) or discordant (Long/Short APD corresponds to a Small/Large Ca transient). Our previous studies have shown that these phenomena depend on the underlying instability mechanisms (voltage driven or Ca driven) and bi-directional coupling between voltage and Ca cycling. The Large Ca transients also cause larger contractions which can activate mechanically (or stretch) activated currents (SACs). Here, we show how SAC activation can feed back to alter cardiac alternans, using a physiologically detailed rabbit AP and Ca cycling model coupled with SAC (either as Cl current or nonselective cation current). We found that (1) SAC suppresses electromechanically concordant alternans, because SAC shortens longer APD more than the shorter APD and limits the difference between successive APDs, (2) SAC enhances electromechanically discordant alternans, because SAC shortens the Short APD more than Long APD which amplifies the difference of two successive APDs. Qualitatively similar results were found for Cl-selective and non-selective cation current (and also Ca-activated K current). These results suggest that mechano-electric feedback can play an important role in development and stability of cardiac alternans.

Are SR Ca content fluctuations or SR refractoriness the key to atrial cardiac alternans?: insights from a human atrial model

Despite the important role of electromechanical alternans in cardiac arrhythmogenesis, its molecular origin is not well understood. The appearance of calcium alternans has often been associated to fluctuations in the sarcoplasmic reticulum (SR) Ca loading. However, cytosolic calcium alternans observed without concurrent oscillations in the SR Ca content suggests an alternative mechanism related to a dysfunction in the dynamics of the ryanodine receptor (RyR2). We have investigated the effect of SR release refractoriness in the appearance of alternans, using a mathematical model of a single human atrial cell, based on the model by Nygren et al. (30), where we modified the dynamics of the RyR2 and of SR Ca release. The genesis of calcium alternans was studied stimulating the cell for different periods and values of the RyR2 recovery time from inactivation. At fast rates cytosolic calcium alternans were obtained without concurrent SR Ca content fluctuations. A transition from regular response to alternans was also observed, changing the recovery time from inactivation of the RyR2. This transition was found to be hysteretic, so for a given set of parameters different responses were observed. We then studied the relevance of RyR2 refractoriness for the generation of alternans, reproducing the same protocols as in recent experiments. In particular, restitution of Ca release during alternans was studied with a S1S2 protocol, obtaining a different response if the S2 stimulation was given after a long or a short release. We show that the experimental results can be explained by RyR2 refractoriness, arising from a slow RyR2 recovery from inactivation, stressing the role of the RyR2 in the genesis of alternans.

GW24-e0582 The role and mechanism of late sodium current in the development of electromechanical alternans and arrhythmia in heart failure

ObjectivesHeart failure is associated with electromechanical alternans that often heralds the development of malignant arrhythmias and sudden death, but the exact mechanism is unclear. Our previous studies have shown that...

Spatiotemporal Evolution and Prediction of [Ca2+]i and APD Alternans in Isolated Rabbit Hearts

Action potential duration (APD) alternans can be accompanied by alternans in intracellular calcium transients ([Ca(2+) ]i ), leading to electromechanical alternans. Electromechanical alternans is considered a substrate for ventricular fibrillation. Although some techniques have been developed to predict APD alternans, the onset of [Ca(2+) ]i alternans has never been predicted. Simultaneous mapping of voltage and calcium was performed in 8 Langendorff-perfused rabbit hearts. APD, [Ca(2+) ]i amplitude (CaA) and duration (CaD) alternans were induced using a perturbed downsweep protocol. Local onset of alternans (B(onset) ) was defined as the cycle length (BCL) at which at least 10% of the RV exhibited alternans. We observed that the local onset of CaA alternans always occurred first, followed by APD and then CaD alternans. We constructed APD, CaD, and CaA restitution portraits for 2 regions of the heart defined at B(onset) : the 1:1alt region, which developed alternans, and the 1:1 region, which did not. Our results also show that the slopes S12 Max and SDyn were higher in 1:1alt region (SDyn = 0.99 ± 0.04 vs 0.73 ± 0.06; S12 Max = 0.95 ± 0.13 vs 0.65 ± 0.1, P < 0.05) prior to onset of CaD alternans, while S12 and S12 Max were significantly higher in the 1:1alt region (S12 = 0.59 ± 0.19 vs 0.19 ± 0.02; S12 Max = 1.09 ± 0.1 vs 0.61 ± 0.08, P < 0.05) prior to onset of CaA alternans. We successfully applied the restitution portrait technique to the prediction of [Ca(2+) ]i (both CaA and CaD) alternans. The slopes of the APD/CaD/CaA restitution portrait are definitive indicators of APD, CaD, and CaA alternans.

Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts

Selective glycolytic inhibition (GI) promotes electromechanical alternans and triggered beats in isolated cardiac myocytes. We sought to determine whether GI promotes triggered activity by early afterdepolarization (EAD) or delayed afterdepolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Ca(i)(2+)) fluorescent optical maps and single cell glass microelectrode recordings were made from the left ventricular (LV) epicardium of isolated Langendorff-perfused adult (∼4 mo) and aged (∼24 mo) rat hearts. GI was induced by replacing glucose with 10 mM pyruvate in oxygenated Tyrode's. Within 20 min, GI slowed Ca(i)(2+) transient decline rate and shortened action potential duration in both groups. These changes were associated with ventricular fibrillation (VF) in the aged hearts (64 out of 66) but not in adult hearts (0 out of 18; P < 0.001). VF was preceded by a transient period of focal ventricular tachycardia caused by EAD-mediated triggered activity leading to VF within seconds. The VF was suppressed by the ATP-sensitive K (K(ATP)) channel blocker glibenclamide (1 μM) but not (0 out of 7) by mitochondrial K(ATP) block. The Ca-calmodulin-dependent protein kinase II (CaMKII) blocker KN-93 (1 μM) prevented GI-mediated VF (P < 0.05). Block of Na-Ca exchanger (NCX) by SEA0400 (2 μM) prevented GI-mediated VF (3 out of 6), provided significant bradycardia did not occur. Aged hearts had significantly greater LV fibrosis and reduced connexin 43 than adult hearts (P < 0.05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of K(ATP) channels CaMKII and NCX.

Ginsenoside Re suppresses electromechanical alternans in cat and human cardiomyocytes

Ginseng botanicals are increasingly used as complementary or alternative medicines for a variety of cardiovascular diseases, yet little is known about their cellular actions in cardiac muscle. Electromechanical alternans (EMA) is a proarrhythmic cardiac abnormality that results from disturbances of intracellular Ca(2+) homeostasis. This study sought to determine whether a purified ginsenoside extract of ginseng, Re, exerts effects to suppress EMA and to gain insight into its mechanism of action. Alternans was induced by electrically pacing cardiomyocytes at room temperature. Re (> or = 10 nM) reversibly suppressed EMA recorded from cat ventricular and atrial myocytes and Langendorff-perfused cat hearts. In cat ventricular myocytes, Re reversibly suppressed intracellular Ca(2+) concentration ([Ca(2+)](i)) transient alternans. Re exerted no significant effects on baseline action potential configuration or sarcolemmal L-type Ca(2+) current (I(Ca,L)), Na(+) current, or total K(+) conductance. In human atrial myocytes, Re suppressed mechanical alternans and exerted no effect on I(Ca,L). In cat ventricular myocytes, Re increased [Ca(2+)](i) transient amplitude and decreased sarcoplasmic reticulum (SR) Ca(2+) content, resulting in an increase in fractional SR Ca(2+) release. In SR microsomes isolated from cat ventricles, Re had no effect on SR Ca(2+) uptake. Re increased the open probability of ryanodine receptors (RyRs), i.e., SR Ca(2+)-release channels, isolated from cat ventricles and incorporated into planar lipid bilayers. We concluded that ginsenoside Re suppresses EMA in cat atrial and ventricular myocytes, cat ventricular muscle, and human atrial myocytes. The effects of Re are not mediated via actions on sarcolemmal ion channels or action potential configuration. Re acts via a subcellular mechanism to enhance the opening of RyRs and thereby overcome the impaired SR Ca(2+) release underlying EMA.

AB31-4: Dysfunction of calcium subsystem including CaMKII signaling pathway cause electromechanical alternans in guinea pig and dog myocyte models

AB31-4: Dysfunction of calcium subsystem including CaMKII signaling pathway cause electromechanical alternans in guinea pig and dog myocyte models

Arrhythmogenic Effects of Arsenic Trioxide in Patients With Acute Promyelocytic Leukemia and an Electrophysiological Study in Isolated Guinea Pig Papillary Muscles

Arsenic trioxide (As(2)O (3)) is a new promising regimen for patients with a relapse of acute promyelocytic leukemia (APL), but causes life-threatening arrhythmias. This study aimed to investigate the incidence and mechanism of arrythmogenesis caused by As(2)O(3). Standard 12-lead ECGs were monitored throughout As(2)O(3) therapy in 20 APL patients. As(2)O (3) (0.15 mg/kg) significantly prolonged the corrected QT interval (QTc: 445+/-7 to 517+/-17 ms, means+/-SE, p<0.01), and also increased the QTc dispersion and transmural dispersion of repolarization. Non-sustained ventricular tachycardias and torsades de pointes occurred in 4 and 1 patients, respectively. The action potentials and isometric contraction were measured in guinea pig papillary muscles during As(2)O (3) perfusion (350 micromol/L). The action potential duration was prolonged (APD(90): 150+/-11 to 195+/-12 ms at 60 min, p<0.01, n=5) and perfusion of As(2)O(3) in a low K(+) solution with a low stimulation rate augmented the prolongation of APD, and provoked early after-depolarizations and triggered activities. The prolonged exposure to As(2)O(3) induced muscle contracture, aftercontractions, triggered activities and electromechanical alternans. Tetrodotoxin or butylated hydroxytoluene partially prevented the As(2)O(3)-induced prolongation of APD. The prolonged QTc and spatial heterogeneity are responsible for the As(2)O(3)-induced ventricular tachyarrhythmias. In addition to prolongation of the APD, cellular Ca(2+) overload and lipid peroxidation might contribute to the electrophysiological abnormalities caused by As(2)O(3).

Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes.

Subcellular Ca(2+) signalling during normal excitation-contraction (E-C) coupling and during Ca(2+) alternans was studied in atrial myocytes using fast confocal microscopy and measurement of Ca(2+) currents (I(Ca)). Ca(2+) alternans, a beat-to-beat alternation in the amplitude of the [Ca(2+)](i) transient, causes electromechanical alternans, which has been implicated in the generation of cardiac fibrillation and sudden cardiac death. Cat atrial myocytes lack transverse tubules and contain sarcoplasmic reticulum (SR) of the junctional (j-SR) and non-junctional (nj-SR) types, both of which have ryanodine-receptor calcium release channels. During E-C coupling, Ca(2+) entering through voltage-gated membrane Ca(2+) channels (I(Ca)) triggers Ca(2+) release at discrete peripheral j-SR release sites. The discrete Ca(2+) spark-like increases of [Ca(2+)](i) then fuse into a peripheral 'ring' of elevated [Ca(2+)](i), followed by propagation (via calcium-induced Ca(2+) release, CICR) to the cell centre, resulting in contraction. Interrupting I(Ca) instantaneously terminates j-SR Ca(2+) release, whereas nj-SR Ca(2+) release continues. Increasing the stimulation frequency or inhibition of glycolysis elicits Ca(2+) alternans. The spatiotemporal [Ca(2+)](i) pattern during alternans shows marked subcellular heterogeneities including longitudinal and transverse gradients of [Ca(2+)](i) and neighbouring subcellular regions alternating out of phase. Moreover, focal inhibition of glycolysis causes spatially restricted Ca(2+) alternans, further emphasising the local character of this phenomenon. When two adjacent regions within a myocyte alternate out of phase, delayed propagating Ca(2+) waves develop at their border. In conclusion, the results demonstrate that (1) during normal E-C coupling the atrial [Ca(2+)](i) transient is the result of the spatiotemporal summation of Ca(2+) release from individual release sites of the peripheral j-SR and the central nj-SR, activated in a centripetal fashion by CICR via I(Ca) and Ca(2+) release from j-SR, respectively, (2) Ca(2+) alternans is caused by subcellular alterations of SR Ca(2+) release mediated, at least in part, by local inhibition of energy metabolism, and (3) the generation of arrhythmogenic Ca(2+) waves resulting from heterogeneities in subcellular Ca(2+) alternans may constitute a novel mechanism for the development of cardiac dysrhythmias.

Simultaneous maps of optical action potentials and calcium transients in guinea-pig hearts: mechanisms underlying concordant alternans.

1. The mechanisms underlying electro-mechanical alternans caused by faster heart rates were investigated in perfused guinea-pig hearts stained with RH237 and Rhod-2 AM to simultaneously map optical action potentials (APs) and intracellular free Ca2+ (Ca2+i). 2. Fluorescence images of the heart were focused on two 16 x 16 photodiode arrays to map Ca2+i (emission wavelength (lamdda;em) = 585 +/- 20 nm) and APs (lamdda;em > 715 nm) from 252 sites. Spatial resolution was 0.8 mm x 0.8 mm per diode and temporal resolution 4000 frames s-1. 3. The mean time-to-peak for APs and [Ca2+]i was spatially homogeneous (8.8 +/- 0.5 and 25.6 +/- 5.0 ms, respectively; n = 6). The durations of APs (APDs) and Ca2+i transients were shorter at the apex and progressively longer towards the base, indicating a gradient of ventricular relaxation. 4. Restitution kinetics revealed increasingly longer delays between AP and Ca2+i upstrokes (9.5 +/- 0.4 to 11.3 +/- 0.4 ms) with increasingly shorter S1-S2 intervals, particularly at the base, despite nearly normal peak [Ca2+]i. 5. Alternans of APs and Ca2+i transients were induced by a decrease++ in cycle length (CL), if the shorter CL captured at the pacing site and was shorter than refractory periods (RPs) near the base, creating heterogeneities of conduction velocity. 6. Rate-induced alternans in normoxic hearts were concordant (long APD with large [Ca2+]i) across the epicardium, with a magnitude (difference between odd-even signals) that varied with the local RP. Alternans were initiated by gradients of RP, producing alternans of conduction that terminated spontaneously without progressing to fibrillation.

Functional coupling between glycolysis and excitation-contraction coupling underlies alternans in cat heart cells.

Electromechanical alternans was characterized in single cat atrial and ventricular myocytes by simultaneous measurements of action potentials, membrane current, cell shortening and changes in intracellular Ca2+ concentration ([Ca2+]i). Using laser scanning confocal fluorescence microscopy, alternans of electrically evoked [Ca2+]i transients revealed marked differences between atrial and ventricular myocytes. In ventricular myocytes, electrically evoked [Ca2+]i transients during alternans were spatially homogeneous. In atrial cells Ca2+ release started at subsarcolemmal peripheral regions and subsequently spread toward the centre of the myocyte. In contrast to ventricular myocytes, in atrial cells propagation of Ca2+ release from the sarcoplasmic reticulum (SR) during the small-amplitude [Ca2+]i transient was incomplete, leading to failures of excitation-contraction (EC) coupling in central regions of the cell. The mechanism underlying alternans was explored by evaluating the trigger signal for SR Ca2+ release (voltage-gated L-type Ca2+ current, ICa,L) and SR Ca2+ load during alternans. Voltage-clamp experiments revealed that peak ICa,L was not affected during alternans when measured simultaneously with changes of cell shortening. The SR Ca2+ content, evaluated by application of caffeine pulses, was identical following the small-amplitude and the large-amplitude [Ca2+]i transient. These results suggest that the primary mechanism responsible for cardiac alternans does not reside in the trigger signal for Ca2+ release and SR Ca2+ load. beta-Adrenergic stimulation with isoproterenol (isoprenaline) reversed electromechanical alternans, suggesting that under conditions of positive cardiac inotropy and enhanced efficiency of EC coupling alternans is less likely to occur. The occurrence of electromechanical alternans could be elicited by impairment of glycolysis. Inhibition of glycolytic flux by application of pyruvate, iodoacetate or beta-hydroxybutyrate induced electromechanical and [Ca2+]i transient alternans in both atrial and ventricular myocytes. The data support the conclusion that in cardiac myocytes alternans is the result of periodic alterations in the gain of EC coupling, i. e. the efficacy of a given trigger signal to release Ca2+ from the SR. It is suggested that the efficiency of EC coupling is locally controlled in the microenvironment of the SR Ca2+ release sites by mechanisms utilizing ATP, produced by glycolytic enzymes closely associated with the release channel.

Electrical alternans and the onset of rate-induced pulsus alternans during acute regional ischaemia in the anaesthetised pig heart

Electrical alternans and mechanical alternans are both associated with cardiac ischaemia and in the case of electrical alternans there is a strong link with serious ventricular arrhythmia. We elected to investigate the relationship between electrical and mechanical alternans in control and acutely ischaemic myocardium in the intact porcine heart to determine the nature of their interaction and in particular to determine if abnormal mechanical events play a role in arhythmogenesis as has been suggested in non-ischaemic preparations. We used rapid atrial pacing to induce regional mechanical alternans and pulsus alternans before and then at 5-min intervals after the onset of acute ischaemia induced by a 30-min ligation of a diagonal branch of the left anterior descending artery. Regional mechanical activity is measured with epicardial tripodal strain gauges and regional electrical activity is measured using suction-based monophasic action potential electrodes. To test whether alternate stretching of ischaemic segments during pulsus alternans contributed to electrical alternans we simulated pulsus alternans by clamping the proximal aorta on alternate beats. In control areas there was a constant discordant relationship between peak systolic pressure during alternans and action potential duration. In contrast, the ischaemic areas showed electromechanical alternans that was most frequently concordant. Clamping the proximal aorta on alternate beats produced an electrical alternans in control areas but not in the ischaemic area. Pulsus alternans during acute ischaemia is associated with electrical alternans that can be out of phase in control and ischaemic areas. This could increase electrical dispersion which may be pro-arrhythmic.

Regional electromechanical alternans in anesthetized pig hearts: modulation by mechanoelectric feedback.

Electrical and mechanical alternans have often been found to coexist. However, the factors controlling their interdependence are not known. In this study we measure regional electrical and mechanical activity during mechanical alternans to investigate this relationship. Mechanical alternans was induced by rapid atrial pacing in 18 anesthetized, open-chest pigs. Regional segmental contraction and monophasic action potential were measured in three areas of left ventricle using epicardial tripodal strain gauges and suction electrodes. Electrical alternans always accompanied pulsus alternans. The phase of electrical alternans was not related to any measure of regional mechanical activity but did show a constant discordant relation to peak ventricular pressure. This suggested that mechanically dependent changes in action potential duration (mechanoelectric feedback) may be important in modulation electrical alternans. In support of this, pulsus alternans simulated by clamping the proximal aorta on alternate beats was associated with electrical alternans comparable to that produced with rapid atrial pacing. Mechanoelectric feedback modulates regional electrophysiology in the intact heart and may be important in the generation of electrical alternans.