Oscillation in cycle length induces transient discordant and steady-state concordant alternans in the heart

Alternans is a beat-to-beat alternation of the cardiac action potential duration (APD) or intracellular calcium (Ca(i)) transient. In cardiac tissue, alternans can be spatially concordant or discordant, of which the latter has been shown to increase dispersion of repolarization and promote a substrate for initiation of ventricular fibrillation. Alternans has been studied almost exclusively under constant cycle length pacing conditions. However, heart rate varies greatly on a beat-by-beat basis in normal and pathological conditions. The purpose of this study was to determine if applying a repetitive but non-constant pacing pattern, specifically cycle length oscillation (CLO), promotes or suppresses a proarrhythmic substrate. We performed computational simulations and optical mapping experiments to investigate the potential consequences of CLO. In a single cell computational model, CLO induced APD and Ca(i) alternans, which became "phase-matched" with the applied oscillation. As a consequence of the phase-matching, in one-dimensional cable simulations, neonatal rat ventricular myocyte monolayers, and isolated adult guinea pig hearts CLO could transiently induce spatial and electromechanical discordant alternans followed by a steady-state of concordance. Our results demonstrated that under certain conditions, CLO can initiate ventricular fibrillation in the isolated hearts. On the other hand, CLO can also exert an antiarrhythmic effect by converting an existing state of discordant alternans to concordant alternans.     

Tracking cardiac electrical instability by computing interlead heterogeneity of T-wave morphology.

Oscillations in T-wave morphology, particularly T-wave alternans (TWA), have been fundamentally linked to increased susceptibility to ventricular fibrillation (VF). We investigated whether the escalation in complexity of T-wave oscillations before VF is attributable to increased spatial heterogeneity of repolarization. Peak interlead T-wave heterogeneity (TWH) was measured by second central moment analysis of T-wave morphology in epicardial electrograms in dogs during left anterior descending coronary artery occlusion. TWH differentiated cases in which myocardial ischemia provoked VF from those without VF (563 +/- 56 vs. 139 +/- 36 microV, P < 0.01). In the former group, progressive, significant increases in TWH above preocclusion baseline (70 +/- 8 microV) began at 2.25 min after the start of occlusion and were associated successively with TWA (at 155 +/- 19 microV), T-wave multupling (at 386 +/- 100 microV), complex oscillatory T-wave forms (at 560 +/- 76 microV), discordant TWA (at 572 +/- 98 microV), and VF at 4.36 +/- 0.14 min. TWH in precordial ECGs in 12 pigs during angioplasty-balloon-induced myocardial ischemia also discriminated animals that experienced VF (from 90 +/- 14 at baseline to 382 +/- 39 microV, P < 0.05) from those without VF (from 96 +/- 17 at baseline to 199 +/- 61 microV, NS). Ischemia-induced changes in ST segment and T-wave amplitude did not predict VF. Heightened spatial heterogeneity of repolarization, as assessed by second central moment analysis of TWH, underlies TWA and increased risk for ischemia-induced VF. Monitoring spatial TWH from precordial leads could prove useful in stratifying risk for life-threatening arrhythmias.     

Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit

T-wave alternans, characterized by a beat-to-beat change in T-wave morphology, amplitude, and/or polarity on the ECG, often heralds the development of lethal ventricular arrhythmias in patients with left ventricular hypertrophy (LVH). The aim of our study was to examine the ionic basis for a beat-to-beat change in ventricular repolarization in the setting of LVH. Transmembrane action potentials (APs) from epicardium and endocardium were recorded simultaneously, together with transmural ECG and contraction force, in arterially perfused rabbit left ventricular wedge preparation. APs and Ca(2+)-activated chloride current (I(Cl,Ca)) were recorded from left ventricular myocytes isolated from normal rabbits and those with renovascular LVH using the standard microelectrode and whole cell patch-clamping techniques, respectively. In the LVH rabbits, a significant beat-to-beat change in endocardial AP duration (APD) created beat-to-beat alteration in transmural voltage gradient that manifested as T-wave alternans on the ECG. Interestingly, contraction force alternated in an opposite phase ("out of phase") with APD. In the single myocytes of LVH rabbits, a significant beat-to-beat change in APD was also observed in both left ventricular endocardial and epicardial myocytes at various pacing rates. APD alternans was suppressed by adding 1 microM ryanodine, 100 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and 100 microM 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). The density of the Ca(2+)-activated chloride currents (I(Cl,Ca)) in left ventricular myocytes was significantly greater in the LVH rabbits than in the normal group. Our data indicate that abnormal intracellular Ca(2+) fluctuation may exert a strong feedback on the membrane I(Cl,Ca), leading to a beat-to-beat change in the net repolarizing current that manifests as T-wave alternans on the ECG.     

Nonlinearity between action potential alternans and restitution, which both predict ventricular arrhythmic properties in Scn5a+/- and wild-type murine hearts

Electrocardiographic QT- and T-wave alternans, presaging ventricular arrhythmia, reflects compromised adaptation of action potential (AP) duration (APD) to altered heart rate, classically attributed to incomplete Na(v)1.5 channel recovery prior to subsequent stimulation. The restitution hypothesis suggests a function whose slope directly relates to APD alternans magnitude, predicting a critical instability condition, potentially generating arrhythmia. The present experiments directly test for such correlations among arrhythmia, APD alternans and restitution. Mice haploinsufficient in the Scn5a, cardiac Na(+) channel gene (Scn5a(+/-)), previously used to replicate Brugada syndrome, were used, owing to their established arrhythmic properties increased by flecainide and decreased by quinidine, particularly in right ventricular (RV) epicardium. Monophasic APs, obtained during pacing with progressively decrementing cycle lengths, were systematically compared at RV and left ventricular epicardial and endocardial recording sites in Langendorff-perfused Scn5a(+/-) and wild-type hearts before and following flecainide (10 μM) or quinidine (5 μM) application. The extent of alternans was assessed using a novel algorithm. Scn5a(+/-) hearts showed greater frequencies of arrhythmic endpoints with increased incidences of ventricular tachycardia, diminished by quinidine, and earlier onsets of ventricular fibrillation, particularly following flecainide challenge. These features correlated directly with increased refractory periods, specifically in the RV, and abnormal restitution and alternans properties in the RV epicardium. The latter variables were related by a unique, continuous higher-order function, rather than a linear relationship with an unstable threshold. These findings demonstrate a specific relationship between alternans and restitution, as well as confirming their capacity to predict arrhythmia, but implicate mechanisms additional to the voltage feedback suggested in the restitution hypothesis.     

Influence of heart rate and sympathetic stimulation on arrhythmogenic T wave alternans

We determined the temporal stability of T wave alternans (TWA) during constant rate stimulation and the dependence of alternans on heart rate (HR) and beta-adrenergic stimulation. Although it is established that exercise can provoke microvolt-level TWA in patients at risk for reentrant ventricular arrhythmias, the mechanisms underlying TWA in humans are not well understood. Specifically, the temporal stability of alternans at any given HR and the influence of HR vs. sympathetic activation on alternans remain unclear. TWA was measured during prolonged fixed-rate atrial pacing at multiple cycle lengths (CLs) in 10 subjects referred for electrophysiological testing and in 14 additional subjects in whom atrial pacing was performed at identical pacing CLs with and without isoproterenol. During constant CL stimulation, TWA amplitude oscillated significantly over time (typically by 10 microV) in a quasiperiodic fashion with periodicity of approximately 2-3 min. Alternans amplitude was strongly dependent on HR but not on adrenergic stimulation. There was a patient-specific threshold HR over which alternans appeared. At higher HR, alternans amplitude increased and oscillations were less prominent. Adrenergic stimulation was required to produce TWA that was not already elicited by moderate elevation of HR in only 2 of 14 (14%) patients. In conclusion, TWA 1) fluctuates spontaneously over 2-3 min and 2) increases monotonically with increased HR (without a major adrenergic contribution in most patients). These data suggest that increased HR rather than sympathetic activation is responsible for arrhythmogenic microvolt-level TWA measured during exercise.     

Action potential duration dispersion and alternans in simulated heterogeneous cardiac tissue with a structural barrier

Structural barriers to wave propagation in cardiac tissue are associated with a decreased threshold for repolarization alternans both experimentally and clinically. Using computer simulations, we investigated the effects of a structural barrier on the onset of spatially concordant and discordant alternans. We used two-dimensional tissue geometry with heterogeneity in selected potassium conductances to mimic known apex-base gradients. Although we found that the actual onset of alternans was similar with and without the structural barrier, the increase in alternans magnitude with faster pacing was steeper with the barrier--giving the appearance of an earlier alternans onset in its presence. This is consistent with both experimental structural barrier findings and the clinical observation of T-wave alternans occurring at slower pacing rates in patients with structural heart disease. In ionically homogeneous tissue, discordant alternans induced by the presence of the structural barrier arose at intermediate pacing rates due to a source-sink mismatch behind the barrier. In heterogeneous tissue, discordant alternans occurred during fast pacing due to a barrier-induced decoupling of tissue with different restitution properties. Our results demonstrate a causal relationship between the presence of a structural barrier and increased alternans magnitude and action potential duration dispersion, which may contribute to why patients with structural heart disease are at higher risk for ventricular tachyarrhythmias.     

Spatially discordant alternans in cardiomyocyte monolayers

Repolarization alternans is a harbinger of sudden cardiac death, particularly when it becomes spatially discordant. Alternans, a beat-to-beat alternation in the action potential duration (APD) and intracellular Ca (Cai), can arise from either tissue heterogeneities or dynamic factors. Distinguishing between these mechanisms in normal cardiac tissue is difficult because of inherent complex three-dimensional tissue heterogeneities. To evaluate repolarization alternans in a simpler two-dimensional cardiac substrate, we optically recorded voltage and/or Cai in monolayers of cultured neonatal rat ventricular myocytes during rapid pacing, before and after exposure to BAY K 8644 to enhance dynamic factors promoting alternans. Under control conditions (n = 37), rapid pacing caused detectable APD alternans in 81% of monolayers, and Cai transient alternans in all monolayers, becoming spatially discordant in 62%. After BAY K 8644 (n = 28), conduction velocity restitution became more prominent, and APD and Cai alternans developed and became spatially discordant in all monolayers, with an increased number of nodal lines separating out-of-phase alternating regions. Nodal lines moved closer to the pacing site with faster pacing rates and changed orientation when the pacing site was moved, as predicted for the dynamically generated, but not heterogeneity-based, alternans. Spatial APD gradients during spatially discordant alternans were sufficiently steep to induce conduction block and reentry. These findings indicate that spatially discordant alternans severe enough to initiate reentry can be readily induced by pacing in two-dimensional cardiac tissue and behaves according to predictions for a predominantly dynamically generated mechanism.     

Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension

Pulmonary hypertension provokes right heart failure and arrhythmias. Better understanding of the mechanisms underlying these arrhythmias is needed to facilitate new therapeutic approaches for the hypertensive, failing right ventricle (RV). The aim of our study was to identify the mechanisms generating arrhythmias in a model of RV failure induced by pulmonary hypertension. Rats were injected with monocrotaline to induce either RV hypertrophy or failure or with saline (control). ECGs were measured in conscious, unrestrained animals by telemetry. In isolated hearts, electrical activity was measured by optical mapping and myofiber orientation by diffusion tensor-MRI. Sarcoplasmic reticular Ca(2+) handling was studied in single myocytes. Compared with control animals, the T-wave of the ECG was prolonged and in three of seven heart failure animals, prominent T-wave alternans occurred. Discordant action potential (AP) alternans occurred in isolated failing hearts and Ca(2+) transient alternans in failing myocytes. In failing hearts, AP duration and dispersion were increased; conduction velocity and AP restitution were steeper. The latter was intrinsic to failing single myocytes. Failing hearts had greater fiber angle disarray; this correlated with AP duration. Failing myocytes had reduced sarco(endo)plasmic reticular Ca(2+)-ATPase activity, increased sarcoplasmic reticular Ca(2+)-release fraction, and increased Ca(2+) spark leak. In hypertrophied hearts and myocytes, dysfunctional adaptation had begun, but alternans did not develop. We conclude that increased electrical and structural heterogeneity and dysfunctional sarcoplasmic reticular Ca(2+) handling increased the probability of alternans, a proarrhythmic predictor of sudden cardiac death. These mechanisms are potential therapeutic targets for the correction of arrhythmias in hypertensive, failing RVs.     

Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca(2+) transient (CaT). Because of experimental difficulty in independently controlling the Ca(2+) and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca(2+) release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current (I(Kr)) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans) while I(Kr) enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and I(Kr) enhancement as a possible antiarrhythmic intervention.     

The need for studies to evaluate the reproducibility of the T-wave alternans (TWA), and the rationale for a correction index of the TWA

Sudden cardiac death (SCD) due to various cardiomyopathies is currently prevented by the implantation of an automated cardioverter/defibrillator (ICD). ICD impalntation in patients who are not survivors of SCD, or have not suffered potentially lethal ventricular arrhythmias, are based on the presence of cardiomyopathy with a reduced left ventricular ejection fraction. The bulk of patients who are considered suitable for an ICD implantation and receive such devices, do not experience device therapy shocks at follow-up ("false positives"), thus creating a climate of uncertainty among patients and physicians about the soundness of our current eligibility criteria for ICDs. In addition the cost of inappropriate ICDs is staggering, and the undue exposure of "false positive" patients to complications, and hardships is disconcerting. T-wave alternans (TWA) has emerged as a possible "risk detection of SCD" technology, but its reproducibility has not been tested. Peripheral edema (extracardiac) or other cardiac mechanisms, unrelated to the degree of SCD risk, alter the amplitude, and other attributes, of the T-waves. Since TWA may be T-wave amplitude-, or other T-wave attributes-dependent (this is still a speculation), a need may be emerging for its correction by the T-wave amplitude (TWA index); such an index may enhance the reproducibility, and evaluate the true sensitivity, specificity and predictive accuracy of the TWA in detecting future victims of SCD.     

Dynamic origin of spatially discordant alternans in cardiac tissue

Alternans, a condition in which there is a beat-to-beat alternation in the electromechanical response of a periodically stimulated cardiac cell, has been linked to the genesis of life-threatening ventricular arrhythmias. Optical mapping of membrane voltage (V_m) and intracellular calcium (Ca_i) on the surface of animal hearts reveals complex spatial patterns of alternans. In particular, spatially discordant alternans has been observed in which regions with a large-small-large action potential duration (APD) alternate out-of-phase adjacent to regions of small-large-small APD. However, the underlying mechanisms that lead to the initiation of discordant alternans and govern its spatiotemporal properties are not well understood. Using mathematical modeling, we show that dynamic changes in the spatial distribution of discordant alternans can be used to pinpoint the underlying mechanisms. Optical mapping of V_m and Ca_i in paced rabbit hearts revealed that spatially discordant alternans induced by rapid pacing exhibits properties consistent with a purely dynamical mechanism as shown in theoretical studies. Our results support the viewpoint that spatially discordant alternans in the heart can be formed via a dynamical pattern formation process which does not require tissue heterogeneity.     

Ambulatory ECG-based T-wave alternans and heart rate turbulence can predict cardiac mortality in patients with myocardial infarction with or without diabetes mellitus

ABSTRACT: BACKGROUND: Many patients who survive a myocardial infarction (MI) remain at risk of sudden cardiac death despite revascularization and optimal medical treatment. We used the modified moving average (MMA) method to assess the utility of T-wave alternans (TWA) and heart rate turbulence (HRT) as risk markers in MI patients with or without diabetes mellitus (DM). METHODS: We prospectively enrolled 248 consecutive patients: 96 with MI (post-MI patients); 77 MI with DM (post-MI + DM patients); 75 controls without cardiovascular disease (group control). Both TWA and HRT were measured on ambulatory electrocardiograms (AECGs). HRT was assessed by two parameters [BOX DRAWINGS LIGHT HORIZONTAL] turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO [GREATER-THAN OR EQUAL TO]0% and TS [LESS-THAN OR EQUAL TO]2.5 ms/R-R interval were met. The endpoint was cardiac mortality. RESULTS: TWA values differed significantly between MI and controls. Post-MI + DM patients had higher TWA values than post-MI patients (58 [PLUS-MINUS SIGN] 21 muV VS 52 [PLUS-MINUS SIGN] 18 muV, P = 0.029). Impaired HRT--increased TO and decreased TS were observed in MI patients with or without DM. During follow-up of 578 [PLUS-MINUS SIGN] 146 days, cardiac death occurred in ten patients and three of them suffered sudden cardiac death (SCD). Multivariate analysis determined that a HRT-positive outcome [HR (95% CI): 5.01, 1.33--18.85; P = 0.017], as well as the combination of abnormal TWA ([GREATER-THAN OR EQUAL TO]47 muV) and positive HRT had significant association with the endpoint [HR (95% CI): 9.08, 2.21--37.2; P = 0.002)]. CONCLUSION: This study indicates that AECGs-based TWA and HRT can predict cardiac mortality in MI patients with or without DM. Combined analysis TWA and HRT may be a convenient and useful method of identifying patients at high risk for cardiovascular death.     

Cardiac alternans in embryonic mouse ventricles

T-wave alternans, an important arrhythmogenic factor, has recently been described in human fetuses. Here we sought to determine whether alternans can be induced in the embryonic mouse hearts, despite its underdeveloped sarcoplasmic reticulum (SR) and, if so, to analyze the response to pharmacological and autonomic interventions. Immunohistochemistry confirmed minimal sarcoplasmic-endoplasmic reticulum Ca-ATPase 2a expression in embryonic mouse hearts at embryonic day (E) 10.5 to E12.5, compared with neonatal or adult mouse hearts. We optically mapped voltage and/or intracellular Ca (Ca(i)) in 99 embryonic mouse hearts (dual mapping in 64 hearts) at these ages. Under control conditions, ventricular action potential duration (APD) and Ca(i) transient alternans occurred during rapid pacing at an average cycle length of 212 +/- 34 ms in 57% (n = 15/26) of E10.5-E12.5 hearts. Maximum APD restitution slope was steeper in hearts developing alternans than those that did not (2.2 +/- 0.6 vs. 0.8 +/- 0.4; P < 0.001). Disabling SR Ca(i) cycling with thapsigargin plus ryanodine did not significantly reduce alternans incidence (44%, n = 8/18, P = 0.5), whereas isoproterenol (n = 14) increased the incidence to 100% (P < 0.05), coincident with steepening APD restitution slope. Verapamil abolished Ca(i) transients (n = 9). Thapsigargin plus ryanodine had no major effects on Ca(i)-transient amplitude or its half time of recovery in E10.5 hearts, but significantly depressed Ca(i)-transient amplitude (by 47 +/- 8%) and prolonged its half time of recovery (by 18 +/- 3%) in E11.5 and older hearts. Embryonic mouse ventricles can develop cardiac alternans, which generally is well correlated with APD restitution slope and does not depend on fully functional SR Ca(i) cycling.     

Electrophysiology of Heart Failure Using a Rabbit Model: From the Failing Myocyte to Ventricular Fibrillation

Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we compared the electrical wave propagation in one dimensional cables of healthy and failing cells. The validated cell model was then used to simulate the EP of heart failure in an anatomically accurate biventricular rabbit model. As pacing cycle length decreases, both the normal and failing heart develop T-wave alternans, but only the failing heart shows QRS alternans (although moderate) at rapid pacing. Moreover, T-wave alternans is significantly more pronounced in the failing heart. At rapid pacing, APD maps show areas of conduction block in the failing heart. Finally, accelerated pacing initiated wave reentry and breakup in the failing heart. Further, the onset of VF was not observed with an upregulation of SERCA, a potential drug therapy, using the same protocol. The changes introduced at the cell and tissue level have increased the failing heart’s susceptibility to dynamic instabilities and arrhythmias under rapid pacing. However, the observed increase in arrhythmogenic potential is not due to a steepening of the restitution curve (not present in our model), but rather to a novel blocking mechanism.     

Disrupted Calcium Release as a Mechanism for Atrial Alternans Associated with Human Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (ki_Ca) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca²⁺-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca²⁺ release slope. Iterated map analysis revealed that because SR Ca²⁺ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in ki_Ca were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca²⁺ homeostasis which drives proarrhythmic APD alternans in patients with AF.     

多态T 波区间检测技术的研究

目的:利用小波变换进行T波区间的检测。方法:在23尺度上通过模极大值法定位R波。在24尺度上首先根据R峰以及T波起点和终点的经验值确定起始T波区间。然后对每个心拍在此区间上找到T波的模极大值,根据模极值的个数和正负顺序确定T波波形的形态。由于不同形态的T波对应不同的T波起点和终点的检测方法,实现T波区间的分类检测,提高T波检测的精确度。由于本文算法是作为T波交替检测的前期工作,为了验证算法的准确率,采用了QT数据库中的部分记录进行了仿真,评价实验结果。结果:仿真实验证明了本文算法能正确地分辨出每个T波的形态,并在此基础上得到较为准确的T波区间。结论:本文采用模极大值算法根据T波的不同形态进行T波区间的分类检测,检测结果比较理想,且计算简单,较易实现。     

An improved statistical representation for ECG electrode movement and muscular activity noises in the context of T-wave alternan estimation

Microvolt T-wave alternans (TWA) are recognized as markers for malignant ventricular arrhythmias, leading to sudden cardiac death. Its extraordinary pathological significance and life-critical application demand elaborate modeling approaches and efficient analysis schemes. Accurate statistical model encompassing the dynamics of physiological noises and other outliers is highly significant to detection and estimation of the microvolt signal. The anomalies in parametric values characterizing the distributions of the above random phenomena are apt to incur modeling errors. Recent TWA detection theoretic approaches assume Laplacian noise due to leptokurtic distribution of electrode movement (em) and muscular activity (ma) recordings. The presented statistical analysis shows that the practiced model compromises the asymmetric nature of the probability distributions for em and ma. An analytical model called Biexponential distribution is suggested to realize the leptokurtic as well as the asymmetric nature of the noise characteristics. Comparative analysis is presented using visual inspection method, χ² goodness-of-fit and Monte Carlo simulations. The proposed model achieves a best match of 99.14% and 98.13% for em and ma as compared to a Laplacian fit of 95.20% and 93.84%, respectively. Conversely, the worst fit values for em and ma are found to be 96.32% and 92.45% for Biexponential and 60.47% and 15.18% for Laplacian models, respectively. The augmented degree of freedom is likely to increase the complexity of the already challenging TWA detection problem; however, the proposed model achieves a more realistic representation of the real noise data by closely matching the statistical parameters.     

基于相关分析方法的非稳态心电T波交替检测研究

目的：研究T波段幅度、形态逐拍交替变化的心电变异现象检测。方法：本研究首先使用Mexican．hat小波检测R峰并对心电信号进行预处理;在提取T波矩阵方面为减少心拍间内差,采用点乘最大法,最大程度地对齐T波;最后基于时域相关分析方法检测T波交替幅度、交替心拍,追踪非稳态心电信号中短暂的交替数据段。结果：利用相关分析法对样本数据所测交替幅度与谱分析法相比更加显著,并且可以检测出谱分析方法无法检测的交替心拍。结论：时域相关分析方法能够更精确地追踪T波交替随时间变化的现象,但其对输入数据要求较高,因此在检测中可以先通过谱分析方法检测为阳性TWA的基础上,再对心电信号进行相关分析,从而确定非稳态交替时间段和更加准确的交替幅度。     

Uncovering the dynamics of cardiac systems using stochastic pacing and frequency domain analyses

Alternans of cardiac action potential duration (APD) is a well-known arrhythmogenic mechanism which results from dynamical instabilities. The propensity to alternans is classically investigated by examining APD restitution and by deriving APD restitution slopes as predictive markers. However, experiments have shown that such markers are not always accurate for the prediction of alternans. Using a mathematical ventricular cell model known to exhibit unstable dynamics of both membrane potential and Ca²⁺ cycling, we demonstrate that an accurate marker can be obtained by pacing at cycle lengths (CLs) varying randomly around a basic CL (BCL) and by evaluating the transfer function between the time series of CLs and APDs using an autoregressive-moving-average (ARMA) model. The first pole of this transfer function corresponds to the eigenvalue (λ_alt) of the dominant eigenmode of the cardiac system, which predicts that alternans occurs when λ_alt≤−1. For different BCLs, control values of λ_alt were obtained using eigenmode analysis and compared to the first pole of the transfer function estimated using ARMA model fitting in simulations of random pacing protocols. In all versions of the cell model, this pole provided an accurate estimation of λ_alt. Furthermore, during slow ramp decreases of BCL or simulated drug application, this approach predicted the onset of alternans by extrapolating the time course of the estimated λ_alt. In conclusion, stochastic pacing and ARMA model identification represents a novel approach to predict alternans without making any assumptions about its ionic mechanisms. It should therefore be applicable experimentally for any type of myocardial cell.     

Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart

Congestive heart failure (CHF) predisposes to ventricular fibrillation (VF) in association with electrical remodeling of the ventricle. However, much remains unknown about the rate-dependent electrophysiological properties in a failing heart. Action potential properties in the left ventricular subepicardial muscles during dynamic pacing were examined with optical mapping in pacing-induced CHF (n=18) and control (n=17) rabbit hearts perfused in vitro. Action potential durations (APDs) in CHF were significantly longer than those observed for controls at basic cycle lengths (BCLs)>1,000 ms but significantly shorter at BCLs<400 ms. Spatial APD dispersions were significantly increased in CHF versus control (by 17-81%), and conduction velocity was significantly decreased in CHF (by 6-20%). In both groups, high-frequency stimulation (BCLs<150 ms) always caused spatial APD alternans; spatially concordant alternans and spatially discordant alternans (SDA) were induced at 60% and 40% in control, respectively, whereas 18% and 82% in CHF. SDA in CHF caused wavebreaks followed by reentrant excitations, giving rise to VF. Incidence of ventricular tachycardia/VFs elicited by high-frequency dynamic pacing (BCLs<150 ms) was significantly higher in CHF versus control (93% vs. 20%). In CHF, left ventricular subepicardial muscles show significant APD shortenings at short BCLs favoring reentry formations following wavebreaks in association with SDA. High-frequency excitation itself may increase the vulnerability to VF in CHF.