Action Potential Duration Restitution Research Articles

Ventricular fibrillation mechanisms and cardiac restitutions: An investigation by simulation study on whole-heart model

BackgroundThe action potential duration (APD) and the conduction velocity (CV) restitution have been reported to be important in the maintenance and conversion of ventricular fibrillation (VF), whose mechanisms remain poorly understood. Multiple-wavelet and/or mother-rotor have been regarded as the main VF mechanisms, and APD restitution (APDR) and CV restitution (CVR) properties are involved in the mutual conversion or transition between VF and ventricular tachycardia (VT). Methods and resultsThe effects of APDR (both its slope and heterogeneity) and CVR on VF organization and conversion were examined using a “rule-based” whole-heart model. The results showed that different organizations of simulated VF were manifestations of different restitution configurations. Multiple-wavelet and mother-rotor VF mechanisms could recur in models with steep and heterogeneous APDR, respectively. Suppressing the excitability either decreased or increased the VF complexity under the steep or shallow APDR, respectively. The multiple-wavelet VF changed into a VT in response to a flattening of the APDR, and the VT degenerated into a mother-rotor VF due to the APDR heterogeneity. ConclusionsOur results suggest that the mechanisms of VF are tightly related to cardiac restitution properties. From a viewpoint of the “rule-based” whole-heart model, our work supports the hypothesis that the synergy between APDR and CVR contributes to transitions between multiple-wavelet and mother-rotor mechanisms in the VF.

Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber.

Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.

Contrasting Effects of HMR1098 on Arrhythmogenicity in a Langendorff‐Perfused Phase‐2 Myocardial Infarction Rabbit Model

The stability of dynamic factors has been reported to play a role in the antiarrhythmic actions of adenosine triphosphate (ATP)-sensitive potassium channel (KATP) opener in phase-2 myocardial infarction (MI) hearts. In the situation of the downregulation of KATP, the effects of KATP blocker (HMR1098) on the dynamic factors and electrophysiological changes during phase-2 MI remain unclear. Dual voltage and intracellular Ca(2+) (Cai) optical mapping was performed in nine Langendorff-perfused hearts 4-5 hours after coronary artery ligation and five control hearts. Electrophysiology studies, including action potential duration (APD) restitution, conduction velocity (CV), inducibility of ventricular fibrillation (VF), VF dominant frequency, APD and Cai alternans, and Cai decay, were performed. The same protocol was repeated in the presence of HMR1098 (10 μm) after the baseline studies. HMR1098 significantly prolonged APD and effective refractory period to prevent sustained VF in five of nine MI hearts and two of five control hearts compared to none at baseline in both groups. On the other hand, HMR1098 steepened APD restitution slope to enhance spatially concordant alternans in both groups. In the phase-2 MI group, HMR1098 steepened CV restitution slope and enhanced spatially discordant alternans (SDA), which might account for a decreased pacing threshold of VF induction during HMR1098 infusion in phase-2 MI hearts. In phase-2 MI hearts, HMR1098 has contrasting effects on arrhythmogenesis, suppressing reentry and VF persistence but facilitating VF inducibility. The mechanism is the intensified induction of SDA because of the steepened APD and CV restitution slopes.

Select Articles Published on the Topic of Arrhythmia and Electrophysiogy in 2013

Select Articles Published on the Topic of Arrhythmia and Electrophysiogy in 2013

How does β-adrenergic signalling affect the transitions from ventricular tachycardia to ventricular fibrillation?

Ventricular tachycardia (VT) and fibrillation (VF) are the most lethal cardiac arrhythmias. The degeneration of VT into VF is associated with the breakup of a spiral wave of the action potential in cardiac tissue. β-Adrenergic (βAR) signalling potentiates the L-type Ca current (ICaL) faster than the slow delayed rectifier potassium current (IKs), which transiently prolongs the action potential duration (APD) and promotes early after depolarizations. In this study, we aimed at investigating how βAR signalling affects the transition from VT to VF. We used a physiologically detailed computer model of the rabbit ventricular myocyte in a two-dimensional tissue to determine how spiral waves respond to βAR activation following administration of isoproterenol. A simplified mathematical model was also used to investigate the underlying dynamics. We found that the spatiotemporal behaviour of spiral waves strongly depends on the kinetics of βAR activation. When βAR activation is rapid, a stable spiral wave turns into small fragments and its electrocardiogram reveals the transition from VT to VF. This is due to the transiently steepened APD restitution induced by the faster activation of ICaL vs. IKs upon sudden βAR activation. The spiral wave may also disappear if its transient wavelength is too large to be supported by the tissue size upon sudden strong βAR activation that prolongs APD transiently. When βAR activation is gradual, a stable spiral wave remains such, because of more limited increase in both APD and slope of APD restitution due to more contemporaneous ICaL and IKs activation. Changes in APD restitution during βAR activation revealed a novel transient spiral wave dynamics; this spatiotemporal characteristic strongly depends on the protocol of isoproterenol application.

Cellular mechanism of cardiac alternans: an unresolved chicken or egg problem

T-wave alternans, a specific form of cardiac alternans, has been associated with the increased susceptibility to cardiac arrhythmias and sudden cardiac death (SCD). Plenty of evidence has related cardiac alternans at the tissue level to the instability of voltage kinetics or Ca(2+) handling dynamics at the cellular level. However, to date, none of the existing experiments could identify the exact cellular mechanism of cardiac alternans due to the bi-directional coupling between voltage kinetics and Ca(2+) handling dynamics. Either of these systems could be the origin of alternans and the other follows as a secondary change, therefore making the cellular mechanism of alternans a difficult chicken or egg problem. In this context, theoretical analysis combined with experimental techniques provides a possibility to explore this problem. In this review, we will summarize the experimental and theoretical advances in understanding the cellular mechanism of alternans. We focus on the roles of action potential duration (APD) restitution and Ca(2+) handling dynamics in the genesis of alternans and show how the theoretical analysis combined with experimental techniques has provided us a new insight into the cellular mechanism of alternans. We also discuss the possible reasons of increased propensity for alternans in heart failure (HF) and the new possible therapeutic targets. Finally, according to the level of electrophysiological recording techniques and theoretical strategies, we list some critical experimental or theoretical challenges which may help to determine the origin of alternans and to find more effective therapeutic targets in the future.

QT restitution properties during exercise in male patients with coronary artery disease.

The hypothesis of action potential duration restitution (APDR) suggests that wave break is mainly determined by the steepness of APDR curve. The purpose of this study was to investigate the QT restitution properties by a noninvasive method, exercise ECG test, in patients with and without left anterior descending coronary artery disease (CAD). Twenty-six male patients were divided into CAD group and control group based on the result of selective coronary angiography (SCA). Exercise tests were performed in each case before the SCA. Sequential QT intervals and preceding TQ intervals were measured, and QT restitution curve (QTRC) was constructed by plotting QT versus TQ intervals. Within the physiological maximal heart rate, the maximal slope of QTRC in the CAD group (1.40 ± 0.41) was greater than that in the control group (0.84 ± 0.20, P = 0.002). The mean slope values of the CAD group was also statistically higher than that in the control group at the same TQ levels when the TQ interval decreased to less than 250 ms (P < 0.05). CAD patients had lower linear correlation coefficients of QT/TQ compared with the control group (0.86 ± 0.04 in the CAD group vs 0.91 ± 0.02 in the control group, P < 0.001). Male patients with left anterior descending CAD had steeper QTRC than those without CAD. QTRC from exercise test ECG may be an effective noninvasive method for estimating the electrophysiological restitution properties of the ventricle.

A Quantitative Comparison of the Behavior of Human Ventricular Cardiac Electrophysiology Models in Tissue

Numerical integration of mathematical models of heart cell electrophysiology provides an important computational tool for studying cardiac arrhythmias, but the abundance of available models complicates selecting an appropriate model. We study the behavior of two recently published models of human ventricular action potentials, the Grandi-Pasqualini-Bers (GPB) and the O'Hara-Virág-Varró-Rudy (OVVR) models, and compare the results with four previously published models and with available experimental and clinical data. We find the shapes and durations of action potentials and calcium transients differ between the GPB and OVVR models, as do the magnitudes and rate-dependent properties of transmembrane currents and the calcium transient. Differences also occur in the steady-state and S1–S2 action potential duration and conduction velocity restitution curves, including a maximum conduction velocity for the OVVR model roughly half that of the GPB model and well below clinical values. Between single cells and tissue, both models exhibit differences in properties, including maximum upstroke velocity, action potential amplitude, and minimum diastolic interval. Compared to experimental data, action potential durations for the GPB and OVVR models agree fairly well (although OVVR epicardial action potentials are shorter), but maximum slopes of steady-state restitution curves are smaller. Although studies show alternans in normal hearts, it occurs only in the OVVR model, and only for a narrow range of cycle lengths. We find initiated spiral waves do not progress to sustained breakup for either model. The dominant spiral wave period of the GPB model falls within clinically relevant values for ventricular tachycardia (VT), but for the OVVR model, the dominant period is longer than periods associated with VT. Our results should facilitate choosing a model to match properties of interest in human cardiac tissue and to replicate arrhythmia behavior more closely. Furthermore, by indicating areas where existing models disagree, our findings suggest avenues for further experimental work.

18 Metabolically Compromised Murine PGC-1B(-/-) Hearts Show Decreased action Potential Duration and Increased Arrhythmia with Adrenergic Challenge

IntroductionThe incidence of ventricular arrhythmia is predicted to rise due to obesity and diabetes. Disorders in the peroxisome proliferator-activated receptor-γ co-activators, PGC-1α and PGC-1β, are associated with both conditions. Homozygous...

Piceatannol facilitates conduction block and ventricular fibrillation induction in ischemia-reperfused rabbit hearts with pacing-induced heart failure

BackgroundPiceatannol, a hydroxystilbene natural product, has been reported to exert antiarrhythmic action via INa inhibition and slow INa inactivation in ischemia-reperfused (IR) rat hearts. The present study aimed to clarify the proarrhythmic property of piceatannol during regional IR injury in failing rabbit hearts. MethodsHeart failure (HF) was induced by rapid right ventricular pacing for 4weeks. The IR model was created by coronary artery ligation for 30min, followed by reperfusion for 15min in vivo. Simultaneous voltage and intracellular Ca2+ (Cai) optical mapping was then performed in isolated Langendorff-perfused hearts (n=11 in each HF and control group). Action potential duration (APD) restitution, arrhythmogenic alternans and VF inducibility were evaluated by a dynamic pacing protocol. Conduction velocity was measured along lines across the IR and non-IR zones during pacing. Piceatannol (10μM) was administered after baseline studies. ResultsIn the HF group, piceatannol decreased conduction velocity, induced rate-dependent regional inhomogeneity of conduction delay and wavelength shortening, slowed Cai decay, and facilitated arrhythmogenic alternans instead of APD prolongation to increase VF inducibility. In the control group, the proarrhythmic effects of piceatannol on APD restitution, arrhythmogenic alternans and conduction delay were offset by its antiarrhythmic effects (APD and wavelength prolongation), resulting in a neutral effect on VF inducibility. ConclusionsPiceatannol (10μM) is proarrhythmic in failing rabbit hearts with regional IR injury. The increased VF inducibility by piceatannol in HF suggests that its undesirable effects are more pronounced than its benefits in failing hearts.

Effects of Endothelin-1 Chronic Stimulation on Electrical Restitution, Beat-to-beat Variability of Repolarization, and Ventricular Arrhythmogenesis

Chronically elevated levels of endothelin-1 (ET-1) have been detected in several cardiovascular diseases. In this study, we investigated the chronic effects of ET-1 on the electrophysiological characteristics expected to influence the genesis and maintenance of ventricular arrhythmia (VA). Rabbits were randomized to ET-1 (ET-1 group) or 0.9% saline (control group) for 2 weeks. The S1-S2 protocol and S1-S1 dynamic pacing were performed to assess the action potential duration restitution (APDR) and to induce APD alternans or VA in 4 sites of Langendorff-perfused rabbit hearts. The beat-to-beat variability of repolarization was quantified as short-term variability and long-term variability. Compared with the control group, chronic ET-1 administration significantly prolonged QT intervals, APD at 90% repolarization (APD₉₀), and effective refractory period (ERP), steepened the maximum slopes of the APDR curve, decreased the ERP/APD₉₀ ratio, and increased the spatial dispersions of APD₉₀, ERP, and maximum slopes (P < 0.05 for all). Moreover, chronic ET-1 administration markedly increased the short-term variability and long-term variability (P < 0.01 for all). APD alternans occurred in both groups, but the threshold of APD alternans was decreased at all sites in the ET-1 group (P < 0.01 for all). We also observed that chronic ET-1 stimulation significantly increased the incidence and duration of the VA episodes. These results suggest that chronic stimulation with ET-1 facilitated VA by steepening the APDR curve and increasing the spatial dispersion of APDR and beat-to-beat variability of repolarization.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts

Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity. The purpose of this study was to define the influence of selective block of INa-L on EAD- and DAD-mediated triggered ventricular tachycardia (VT) and ventricular fibrillation (VF) in intact hearts using (GS967), a selective and potent (IC50 = 0.13 ± 0.01 μM) blocker of INa-L. VT/VF were induced either by local aconitine injection (50 μg) in the left ventricular muscle of adult (3-4 months) male rats (N = 21) or by arterial perfusion of 0.1 mM hydrogen peroxide (H2O2) in aged male rats (24-26 months, N = 16). The left ventricular epicardial surface of the isolated-perfused hearts was optically mapped using fluorescent voltage-sensitive dye, and microelectrode recordings of action potentials were made adjacent to the aconitine injection site. The suppressive and preventive effects of GS967 (1 μM) against EAD/DAD-mediated VT/VF were then determined. Aconitine induced VT in all 13 hearts studied. Activation map (N = 6) showed that the VT was initiated by a focal activity arising from the aconitine injection site (cycle length [CL] 84 ± 12) that degenerated to VF (CL 52 ± 8 ms) within a few seconds. VF was maintained by multifocal activity with occasional incomplete reentrant wavefronts. Administration of GS967 suppressed the VT/VF in 10 of 13 hearts (P < .001). Preexposure to GS967 for 15 minutes before aconitine injection prevented initiation of VT/VF in 5 of 8 additional hearts (P < .02). VF reoccurred within 10 minutes on washout of GS967. Microelectrode recordings (N = 7) showed that VT/VF was initiated by EAD- and DAD-mediated triggered activity at CL of 86 ± 14 ms (NS from VT CL) that preceded the VF. GS967 shortened APD, flattened the slope of the dynamic APD restitution curve, and reduced APD dispersion from 42 ± 12 ms to 8 ± 3 ms (P < .01). H2O2 perfusion in eight fibrotic aged hearts promoted EAD-mediated focal VT/VF, which was suppressed by GS967 in five hearts (P < .02). The selective INa-L blocker GS967 effectively suppresses and prevents aconitine and oxidative stress-induced EADs, DADs, and focal VT/VF. Suppression of EADs, DADs, and reduction of APD dispersion make GS967 a potentially useful antiarrhythmic drug in conditions of enhanced INa-L.

Change of short-term memory effect in acute ischemic ventricular myocardium: A computational study

The ionic mechanism of change in short-term memory (STM) during acute myocardial ischemia has not been well understood. In this paper, an advanced guinea pig ventricular model developed by Luo and Rudy was used to investigate STM property of ischemic ventricular myocardium. STM response was calculated by testing the time to reach steady-state action potential duration (APD) after an abrupt shortening of basic cycling length (BCL) in the pacing protocol. Electrical restitution curves (RCs), which can simultaneously visualize multiple aspects of APD restitution and STM, were obtained from dynamic and local S1S2 restitution portrait (RP), which consist of a longer interval stimulus (S1) and a shorter interval stimulus (S2). The angle between dynamic RC and local S1S2 RC reflects the amount of STM. Our results indicated that compared with control (normal) condition, time constant of STM response in the ischemic condition decreased significantly. Meanwhile the angle which reflects STM amount is less in ischemic model than that in control model. By tracking the effect of ischemia on intracellular ion concentration and membrane currents, we declared that changes in membrane currents caused by ischemia exert subtle influences on STM; it is only the decline of intracellular calcium concentration that give rise to the most decrement of STM.

Structural and functional plasticity in long-term cultures of adult ventricular myocytes

Cultured heart cells have long been valuable for characterizing biological mechanism and disease pathogenesis. However, these preparations have limitations, relating to immaturity in key properties like excitation–contraction coupling and β-adrenergic stimulation. Progressive attenuation of the latter is intimately related to pathogenesis and therapy in heart failure. Highly valuable would be a long-term culture system that emulates the structural and functional changes that accompany disease and development, while concurrently permitting ready access to underlying molecular events. Accordingly, we here produce functional monolayers of adult guinea-pig ventricular myocytes (aGPVMs) that can be maintained in long-term culture for several weeks. At baseline, these monolayers exhibit considerable myofibrillar organization and a significant contribution of sarcoplasmic reticular (SR) Ca2+ release to global Ca2+ transients. In terms of electrical signaling, these monolayers support propagated electrical activity and manifest monophasic restitution of action-potential duration and conduction velocity. Intriguingly, β-adrenergic stimulation increases chronotropy but not inotropy, indicating selective maintenance of β-adrenergic signaling. It is interesting that this overall phenotypic profile is not fixed, but can be readily enhanced by chronic electrical stimulation of cultures. This simple environmental cue significantly enhances myofibrillar organization as well as β-adrenergic sensitivity. In particular, the chronotropic response increases, and an inotropic effect now emerges, mimicking a reversal of the progression seen in heart failure. Thus, these aGPVM monolayer cultures offer a valuable platform for clarifying long elusive features of β-adrenergic signaling and its plasticity.

Atrium-Specific Kir3.x Determines Inducibility, Dynamics, and Termination of Fibrillation by Regulating Restitution-Driven Alternans

Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (I(K,ACh-c)) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how I(K,ACh-c) contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of I(K,ACh-c) blockade and Kir3.x downregulation on atrial fibrillation. Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3- or Kcnj5-specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0 to 128.8±16.9 milliseconds; P<0.0001) in atrial cultures during reentry, indicating the presence of I(K,ACh-c). Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0 Hz; P<0.05) and complexity (6.6±7.7 to 0.6±0.8 phase singularities; P<0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of I(K,ACh-c) prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (e.g., >50% reduction in atrial fibrillation inducibility after I(K,ACh-c) blockade). Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with I(K,ACh-c). This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.

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.

Stochastic Cardiac Pacing Increases Ventricular Electrical Stability—A Computational Study

The ventricular tissue is activated in a stochastic rather than in a deterministic rhythm due to the inherent heart rate variability (HRV). Low HRV is a known predictor for arrhythmia events and traditionally is attributed to autonomic nervous system tone damage. Yet, there is no model that directly assesses the antiarrhythmic effect of pacing stochasticity per se. One-dimensional (1D) and two-dimensional (2D) human ventricular tissues were modeled, and both deterministic and stochastic pacing protocols were applied. Action potential duration restitution (APDR) and conduction velocity restitution (CVR) curves were generated and analyzed, and the propensity and characteristics of action potential duration (APD) alternans were investigated. In the 1D model, pacing stochasticity was found to sustain a moderating effect on the APDR curve by reducing its slope, rendering the tissue less arrhythmogenic. Moreover, stochasticity was found to be a significant antagonist to the development of concordant APD alternans. These effects were generally amplified with increased variability in the pacing cycle intervals. In addition, in the 2D tissue configuration, stochastic pacing exerted a protective antiarrhythmic effect by reducing the spatial APD heterogeneity and converting discordant APD alternans to concordant ones. These results suggest that high cardiac pacing stochasticity is likely to reduce the risk of cardiac arrhythmias in patients.

Principles of Cardiac Electric Propagation and Their Implications for Re-entrant Arrhythmias

The study of clinical electrophysiology essentially comprises examining how electric excitation develops and spreads through the millions of cells that constitute the heart. Given the enormous number of cells in a human heart, there is an extremely large number of possible ways that the heart can behave. We encounter rhythms across the spectrum from the organized and orderly behavior of sinus rhythm through repetitive continuous excitation (via reentry) in structurally defined circuits like atrial flutter and, finally, the complex, dynamic, and disorganized behavior of fibrillation. Despite these myriad possibilities, one can apply a basic understanding of the principles of propagation to predict how cardiac tissue will behave under varied circumstances and in response to various manipulations. In this article, we review the principles of propagation and how these can be used to understand reentry of all degrees of complexity. We use these principles to explain the mechanisms by which antiarrhythmic medications and ablation can terminate and prevent reentry. This article is not intended to be an exhaustive description of the physiology of cardiac propagation, rather, it is meant to capture the essence of propagation with sufficient detail to provide an intuitive feel for the interplay of the physiological features relevant to propagation. The figures and videos used in this article were created using a computational model of cardiac propagation (VisibleEP LLC, Colchester, VT). It is a hybrid between a physics-based and cellular automaton model. The model incorporates the fundamental features of propagation without modeling individual ion channels.1 The model manifests several relevant emergent properties, for example, electrotonic interactions, restitution of action potential duration, and conduction velocity as well as source–sink balance–dependent propagation. ### Cell Excitation A cell becomes excited when the balance of inward and outward currents passes a critical point after which inward currents exceed outward and an action potential ensues. …

Effects of Mechano-Electric Feedback on Scroll Wave Stability in Human Ventricular Fibrillation

Recruitment of stretch-activated channels, one of the mechanisms of mechano-electric feedback, has been shown to influence the stability of scroll waves, the waves that underlie reentrant arrhythmias. However, a comprehensive study to examine the effects of recruitment of stretch-activated channels with different reversal potentials and conductances on scroll wave stability has not been undertaken; the mechanisms by which stretch-activated channel opening alters scroll wave stability are also not well understood. The goals of this study were to test the hypothesis that recruitment of stretch-activated channels affects scroll wave stability differently depending on stretch-activated channel reversal potential and channel conductance, and to uncover the relevant mechanisms underlying the observed behaviors. We developed a strongly-coupled model of human ventricular electromechanics that incorporated human ventricular geometry and fiber and sheet orientation reconstructed from MR and diffusion tensor MR images. Since a wide variety of reversal potentials and channel conductances have been reported for stretch-activated channels, two reversal potentials, −60 mV and −10 mV, and a range of channel conductances (0 to 0.07 mS/µF) were implemented. Opening of stretch-activated channels with a reversal potential of −60 mV diminished scroll wave breakup for all values of conductances by flattening heterogeneously the action potential duration restitution curve. Opening of stretch-activated channels with a reversal potential of −10 mV inhibited partially scroll wave breakup at low conductance values (from 0.02 to 0.04 mS/µF) by flattening heterogeneously the conduction velocity restitution relation. For large conductance values (>0.05 mS/µF), recruitment of stretch-activated channels with a reversal potential of −10 mV did not reduce the likelihood of scroll wave breakup because Na channel inactivation in regions of large stretch led to conduction block, which counteracted the increased scroll wave stability due to an overall flatter conduction velocity restitution.