Multiple mechanisms of spiral wave breakup in a model of cardiac electrical activity

It has become widely accepted that the most dangerous cardiac arrhythmias are due to re- entrant waves, i.e., electrical wave(s) that re-circulate repeatedly throughout the tissue at a higher frequency than the waves produced by the heart's natural pacemaker (sinoatrial node). However, the complicated structure of cardiac tissue, as well as the complex ionic currents in the cell, has made it extremely difficult to pinpoint the detailed mechanisms of these life-threatening reentrant arrhythmias. A simplified ionic model of the cardiac action potential (AP), which can be fitted to a wide variety of experimentally and numerically obtained mesoscopic characteristics of cardiac tissue such as AP shape and restitution of AP duration and conduction velocity, is used to explain many different mechanisms of spiral wave breakup which in principle can occur in cardiac tissue. Some, but not all, of these mechanisms have been observed before using other models; therefore, the purpose of this paper is to demonstrate them using just one framework model and to explain the different parameter regimes or physiological properties necessary for each mechanism (such as high or low excitability, corresponding to normal or ischemic tissue, spiral tip trajectory types, and tissue structures such as rotational anisotropy and periodic boundary conditions). Each mechanism is compared with data from other ionic models or experiments to illustrate that they are not model-specific phenomena. The fact that many different breakup mechanisms exist has important implications for antiarrhythmic drug design and for comparisons of fibrillation experiments using different species, electromechanical uncoupling drugs, and initiation protocols.Comment: 128 pages, 42 figures (29 color, 13 b&w

DYNAMICS OF ACTION POTENTIAL DURATION: EFFECTS ON RESTITUTION AND REPOLARIZATION ALTERNANS

The presented studies investigate dynamics of action potential duration (APD) tobetter understand the underlying mechanism for repolarization alternans.We recorded trans-membrane potentials (TMP) in canine endocardial muscle tissueusing standard glass microelectrode under the control of an explicit diastolic interval (DI)control pacing protocol, i.e. feedback protocol. During sequential sinusoidal DI activation,the trajectory of APD dynamics has multiple values of APD correspondent to the sameDI, i.e. restitution is a bi-modal relationship. Our results indicate that: 1) there is a delay,similar to hysteresis, of change in APD responding to change in DI, 2) and the timecourse of the delay is asymmetric for fast or slow pacing history. The alternans wasobserved during constant DI pacing, i.e. the DI preceding each APD was invariant orchanged within a limited range. This finding suggests that alternans of APD do not needthe oscillation of preceding DI, i.e. DI dependent restitution is not a necessary conditionfor the alternans. This result implies that DI independent component exists in themechanism of the alternans. Nonetheless, the amplitude of alternans was statisticallylarger during constant pacing cycle length (PCL) pacing than that during constant DIpacing, even though both PCL and DI pacing trials used similar average activation rate.These results also demonstrate the ability of the feedback protocol to analyze the memoryeffects and dissect different components in the mechanism of alternans.Two computational models, Luo-Rudy dynamics (LRD) and cardiac ventricle model(CVM) were used to study the hysteresis in restitution. By perturbing membrane current:L-type calcium current, rapid and slow potassium rectifier, and intracellular calciumtransfer rate in sarcoplasmic reticulum (SR) and using sinusoidal DI pacing sequence, weshowed that the asymmetric calcium current across the membrane and its interaction withcalcium buffer in SR during increasing and decreasing DI phase plays an important rolein the hysteresis. CVM was used to study the alternans during constant DI pacing.However CVM failed to replicate the alternans that occurred in the experiments. Thisresult implies that CVM lacks the electrophysiological kinetics related to alternans thatwas shown in our experiment

HYSTERESIS IN REPOLARIZATION OF CARDIAC ACTION POTENTIALS: EFFECTS OF SPATIAL HETEROGENEITY AND SLOW REPOLARIZATION CURRENTS

Repolarization alternans, i.e. beat-to-beat variation of repolarization of action potential, is proposed as a predictor of life-threatening arrhythmias. Restitution relates repolarization duration with its previous relaxation time, i.e. diatstolic interval (DI), and is considered a dominant mechanism for alternans. Previously, we observed that different repolarization durations at the same DI during decelerating and accelerating pacing, i.e. restitution displays hysteresis, which is a measure of “cardiac memory”. Objective of the current study was to investigate in the pig 1) the mechanism for a previously observed hysteresis type phenomenon, where alternans, once started at higher heart rate, persists even when heart rate decreases below its initiating rate, 2) regional differences in expression of hysteresis, i.e. memory in restitution in the heart, and 3) changes in restitution and memory during manipulation of an important repolarization current, the slow delayed rectifier, IKs. Action potentials were recorded in pig ventricular tissues using microelectrodes. Regional differences were explored in endocardial and epicardial tissues from both ventricles. DIs were explicitly controlled in real time to separate restitution mechanism from non-restitution related effects. Stepwise protocols were used to explore the existence in hysteresis in alternans threshold, where DIs were held constant for each step and progressively decreased and then increased. Quantification of cardiac memory was achieved by sinusoidally changing DI protocols, which were used to investigate memory changes among myocytes from different regions of the heart and during IKs manipulation. Results show that during stepwise protocol, hysteresis in alternans still existed, which indicates that restitution is not the only mechanism underlying the hysteresis. When comparing hysteresis obtained from sinusoidally oscillatory DIs among different regions, results show memory is expressed differently with endocardium expressing the most and epicardium the least memory. This provides important implications about the location where arrhythmia would initiate. Results also show that measures for hysteresis loops obtained by sinusoidal DI protocols decreased (increased) after enhancement (attenuation) of IKs, suggesting decreased (increased) hysteresis, i.e. memory in restitution. This effect needs to be considered during drug development

INVESTIGATION OF CARDIAC ELECTROPHYSIOLOGY IN HUMAN VENTRICULAR TISSUE

Individuals with cardiomyopathy are at higher risk to die from sudden cardiac arrest than those with non-failing (NF) hearts. This study examined the differences in electrical properties of failing and NF human hearts in terms of cardiac memory through explicit control of diastolic intervals in a sinusoidal fashion, restitution of action potential duration (APD) through standard and dynamic pacing protocols, maximum rate of depolarization and APD alternans. Recordings of transmembrane potentials were made in tissues extracted from patients with heart failure and one donor NF heart. Computational simulations were performed using the O’Hara Rudy model for generating surrogates of control data. Significant differences were seen between left ventricular (LV) tissue and NF LV tissue in tilt, and measures of memory in terms of area and thickness during the sinusoidal 400ms protocol. Minimum delay was also significantly higher in the failing LV during the sinusoidal 150ms protocol. Failing tissues showed a higher restitution slope and prolonged AP which is consistent with previous studies and is hypothesized to contribute to the increased susceptibility to unstable alternans. This study further explored how disease alters the electrical functioning of the heart and why these patients are at a higher risk of ventricular arrhythmia

EFFECTS OF ACUTE STRETCH ON CARDIAC ELECTRICAL PROPERTIES IN SWINE

Stretch is known to result in an electrically less stable ventricular substrate, yet the reported effects of stretch on measured electrophysiological parameters have been inconsistent and even contradictory. The goal of this study was to evaluate the effects of acute mechanical stretch on cardiac electrical features thought to be key in generation of arrhythmia, namely restitution of action potential duration (APD), electrical memory, and onset of alternans. Microelectrodes were used to record intracellular potentials pre, during, and post-stretch from isolated right ventricular tissues from swine. In separate experiments, the effects of two levels of stretch were quantified. Pacing protocols employing explicit diastolic interval (DI) control and cycle length (CL) control were used to obtain measures of restitution of APD, memory, and alternans of APD. Stretching the tissue had varying effects on APD, restitution and memory. Stretch increased APD, restitution slopes and memory by as much as 24, 30 and 53 % in some cases, while it decreased these by up to 18, 37 and 81 % in others. During stretch, alternans of APD were observed in some cases, which occurred at slower rates of activation than before stretch. Histology of tissue samples showed localized changes in orientation of cells relative to the direction of stretch. Our results show that among individual trials, stretch altered the measured electrophysiological properties, sometimes markedly. However, when pooled together, these changes cancelled each other and the averages showed no statistically significant difference after stretch. A potential mechanism that explains this divergent and inconsistent response to stretch is the presence of local, micron level, variation in orientation of myocytes. Upon stretch, these divergent effects likely increase dispersion of repolarization diffusely and might thus be the reason behind the consistently observed increase in arrhythmic substrate after stretch

Action potential restitution and hysteresis in a reaction-diffusion system with pacing rate dependent excitation threshold

We have demonstrated that rate dependent restitution and action potential duration-refractory period hysteresis can be reproduced in a one-dimensional two-variable Chernyak-Starobin-Cohen reaction-diffusion medium with variable excitation threshold. We show that restitution and hysteresis depend on the relationship between pacing period and steady state excitation threshold and also on the rate of excitation threshold adaptation after an abrupt change in pacing period. It was also observed that the onset of action potential duration alternans is determined by the minimal stable wavefront speed, which could be approximated by the analytical critical speed of a stable solitary pulse. This approximation was suitably accurate regardless of the adaptation constant of excitation threshold, its dependence on pacing interval, or magnitude of the slopes of restitution curves

Techniques for ventricular repolarization instability assessment from the ECG

Instabilities in ventricular repolarization have been documented to be tightly linked to arrhythmia vulnera- bility. Translation of the information contained in the repolar- ization phase of the electrocardiogram (ECG) into valuable clinical decision-making tools remains challenging. This work aims at providing an overview of the last advances in the pro- posal and quantification of ECG-derived indices that describe repolarization properties and whose alterations are related with threatening arrhythmogenic conditions. A review of the state of the art is provided, spanning from the electrophysio- logical basis of ventricular repolarization to its characteriza- tion on the surface ECG through a set of temporal and spatial risk markers

EFFECTS OF CALCIUM CHANGES ON HYSTERESIS IN RESTITUTION OF ACTION POTENTIAL DURATION

Sudden cardiac death (SCD) is a leading cause of fatalities. Several methods have been developed to predict instability in myocytes which could lead to SCD. The focus of this study was on altering memory in myocytes, i.e. hysteresis in restitution of action potential duration (APD), by differing levels of calcium. Determination of alteration was implemented by using a diastolic interval (DI) control program that implements a sinusoidal change in DI. Plotting APD versus previous DI, i.e. restitution, produces a hysteresis loop. From these hysteresis loops, five parameters were used to determine measures of memory: area, thickness, overall tilt, max delay and min delay. Calcium levels were then altered with either verapamil or BAPTA-AM. Statistically significant effects were found for the verapamil study, but not for the BAPTA-AM study. Simulations were used to explain significant results. The verapamil findings support clinical studies that have shown verapamil to not have anti-arrhythmic effects. Theory predicts that a decrease in memory would decrease the stability of a system, and perhaps verapamil may not increase stability as hypothesized previously. The results of the BAPTA-AM study were inconclusive, and further investigation is needed before it can be determined that BAPTA-AM has no significant effect on memory