Magnitude Of Alternans Research Articles

218 Action Potential Alternans in the Ageing Ovine Atria

BackgroundThe incidence of atrial fibrillation (AF) has a steep relationship with age. AF prevalence in persons aged over 85 exceeds 15% in European cohorts. The basis for the exaggerated vulnerability...

Heart rate variability and alternans formation in the heart: The role of feedback in cardiac dynamics

A beat-to-beat alternation in the action potential duration (APD) of myocytes, i.e. alternans, is believed to be a direct precursor of ventricular fibrillation in the whole heart. A common approach for the prediction of alternans is to construct the restitution curve, which is the nonlinear functional relationship between the APD and the preceding diastolic interval (DI). It was proposed that alternans appears when the magnitude of the slope of the restitution curve exceeds one, known as the restitution hypothesis. However, this restitution hypothesis was derived under the assumption of periodic stimulation, when there is a dependence of the DI on the immediate preceding APD (i.e. feedback). However, under physiological conditions, the heart rate exhibits substantial variations in time, known as heart rate variability (HRV), which introduces deviations from periodic stimulation in the system. In this manuscript, we investigated the role of HRV on alternans formation in isolated cardiac myocytes using numerical simulations of an ionic model of the cardiac action potential. We used this model with two different pacing protocols: a periodic pacing protocol with feedback and a protocol without feedback. We show that when HRV is incorporated in the periodic pacing protocol, it facilitated alternans formation in the isolated cell, but did not significantly change the magnitude of alternans. On the other hand, in the case of the pacing protocol without feedback, alternans formation was prevented, even in the presence of HRV.

Detection and evaluation of ventricular repolarization alternans: An approach to combined ECG, thoracic impedance, and beat-to-beat heart rate variability analysis

Background and objectiveBeat-to-beat alteration in ventricles repolarization reflected by alternans of amplitude and/or shape of ECG S-T,T segment (TWA) is known as phenomena related with risk of severe arrhythmias leading to sudden cardiac death. Technical difficulties have caused limited its usage in clinical diagnostics. Possibilities to register and analyze multimodal signals reflecting heart activity inspired search for new technical solutions. First objective of this study was to test whether thoracic impedance signal and beat-to-beat heart rate reflect repolarization alternans detected as TWA. The second objective was revelation of multimodal signal features more comprehensively representing the phenomena and increasing its prognostic usefulness. Materials and methodsECG, and thoracic impedance signal recordings made during 24h follow-up of the patients hospitalized in acute phase of myocardial infarction were used for investigation. Signal morphology variations reflecting estimates were obtained by the principal component analysis-based method. Clinical outcomes of patients (survival and/or rehospitalization in 6 and 12 months) were compared to repolarization alternans and heart rate variability estimates. ResultsRepolarization alternans detected as TWA was also reflected in estimates of thoracic impedance signal shape and variation in beat-to-beat heart rate. All these parameters showed correlation with clinical outcomes of patients. The strongest significant correlation showed magnitude of alternans in estimates of thoracic impedance signal shape. ConclusionsThe features of ECG, thoracic impedance signal and beat-to-beat variability of heart rate, give comprehensive estimates of repolarization alternans, which correlate, with clinical outcomes of the patients and we recommend using them to improve diagnostic reliability.

Cardiomyocyte Calcium Handling Dysfunction at High Stimulation Frequencies; Increase in Post-Myocardial Infarction Heart Failure and Decrease by Exercise Training

Ca2+ transient alternans, ie incomplete 1:2 Ca2+ transients, have been linked to contractile dysfunction at high heart rates in heart failure (HF). We investigated the effect of post-myocardial infarction (MI) HF and the therapeutic effect of exercise training on cardiomyocyte Ca2+ handling during increased electrical twitch-stimulation frequencies, in coronary artery-ligated Wistar rats. 4-weeks post-surgery, aerobic exercise training was initiated, with sham-operated (SHAM) and sedentary MI HF rats as controls. MI HF was confirmed by reduced exercise capacity, pathologic cardiomyocyte hypertrophy, and reduced cardiomyocyte contraction and Ca2+ transient amplitude (all 20-40%; p 0.05 vs MI HF), but it shifted the occurrence of Ca2+ transient alternans to higher twitch-stimulation frequencies (median frequency SHAM: 4Hz, MI HF 2Hz, MI HF after exercise training 4Hz; p<0.05). Finally, Ca2+ transient alternans magnitude (difference 1:2 Ca2+ transient) increased in MI HF cardiomyocytes (25-50% in MI HF vs 10-20% in SHAM; p<0.05); exercise training partly corrected this (20-30%; p<0.05 vs MI HF). In conclusion, exercise training partly reversed cardiomyocyte Ca2+ handling abnormalities observed during increasing twitch-stimulation frequencies in post-MI HF. This suggests a mechanism for improving reserve capacity and reducing arrhythmia susceptibility.

Frequency Analysis of Atrial Action Potential Alternans

Background— Few clinical indices identify the propensity of patients to atrial fibrillation (AF) when not in AF. Repolarization alternans has been shown to indicate AF vulnerability, but is limited in its sensitivity to detect changes in action potential (AP) duration (APD), which may be subtle. We hypothesized that spectral analysis would be a more sensitive and robust marker of AP alternans and thus a better clinical index of individual propensity to AF than APD alternans. Methods and Results— In 31 patients (12 persistent AF, 15 paroxysmal AF, 4 controls with no AF), we recorded left (n=27) and right (n=6) atrial monophasic APs during incremental pacing from cycle length 500 ms (120 beats per minute) to AF onset. Alternans was measured by APD and spectral analysis. At baseline pacing (median cycle length [1st, 3rd quartiles], 500 ms [500, 500]), APD alternans was detected in only 7 of 27 AF patients (no controls), whereas spectral AP alternans was detected in 18 of 27 AF patients (no controls; P =0.003); AP alternans was more prevalent in persistent than paroxysmal AF, and absent in controls ( P =0.018 APD; P =0.042 spectral). Spectral AP alternans magnitude at baseline was highest in persistent AF, with modest rate-dependent amplification, followed by paroxysmal AF, with marked rate dependence, and undetectable in controls until just before induced AF. Conclusions— Spectral AP alternans near baseline rates can identify patients with, versus those without, clinical histories and pathophysiological substrates for AF. Future studies should examine whether the presence of spectral AP alternans during sinus rhythm may obviate the need to actually demonstrate AF, such as on ambulatory ECG monitoring.

Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a+/− hearts

Reductions in cardiac action potential wavelength, and the consequent wavebreak, have been implicated in arrhythmogenesis. Tachyarrhythmias are more common in the Brugada syndrome, particularly following pharmacological challenge, previously modelled using Scn5a+/− murine hearts. Propagation latencies and action potential durations (APDs) from monophasic action potential recordings were used to assess wavelength changes with heart rate in Langendorff-perfused wild-type (WT) and Scn5a+/− hearts. Recordings were obtained from right (RV) and left (LV) ventricular, epicardial and endocardial surfaces during incremental pacing, before and following flecainide or quinidine challenge. Conduction velocities (θ′), action potential wavelengths (λ′= APD ×θ′), and their corresponding alternans depended non-linearly upon diastolic interval (DI). Maximum θ′ was lower in Scn5a+/− RV epicardium than endocardium. Flecainide further reduced θ′, accentuating this RV conduction block. Quinidine reduced maximum θ′ in WT and caused earlier conduction failure in the RV of both Scn5a+/− and WT. Use of recovery wavelengths (λ′0= DI ×θ′) rather than DI, provided novel λ restitution plots of λ′ against λ′0, which sum to a basic cycle distance permitting feedback analysis. λ′ restitution gradient better correlated with alternans magnitude than either APD or θ restitution gradient. The large differences in θ′ and APD restitution contrasted with minor differences in maximum λ′ between epi- and endocardia of untreated hearts, and quinidine-treated WT hearts. Strikingly, all regions and conditions converged to a common instability point, implying a conserved relationship. Flecainide or quinidine decreased the pacing rates at which this occurred, through reducing basic cycle distance, in the Scn5a+/− RV epicardium, directly predictive of its arrhythmic phenotype.

Auto-Entrainment Risk Assessment in Heart Failure

Risk assessment studies use a suite of nominally independent noninvasive heart rate metrics, often brought together in a statistical model to compute a risk score. The ongoing need to noninvasively identify the higher risk patients requiring more invasive investigations/interventions drives the search for better noninvasive predictive metrics, with increased sensitivity. Many varieties of autoregulatory malfunction occur within the cardiovascular system; thus, it seems a daunting challenge to build predictive models that account for all potential modes of failure. Auto-entrainment (AE) methodology was developed to help address this challenge. AE methodology tests intrinsic capacity to maintain a stable and coherent oscillatory dynamic of autoregulatory control via respiratory entrainment of the blood pressure and heart period. Using cardiovascular death (n=18) at follow-up (1.5 years) as the end point, analysis of AE measurements from 148 patients with heart failure revealed 2 parameters significantly predictive of death. Using logistic regression, the magnitude of systolic pulsus alternans measured during AE had predictive sensitivity of 90% (confidence interval, 62%-100% and specificity of 62% (confidence interval, 49%-74%). The capacity to maintain a stable oscillatory dynamic was measured by the fraction of the total RR-interval spectral power contained within the AE-band. This capacity had predictive sensitivity of 73% (confidence interval, 47%-99%) and specificity of 55% (confidence interval, 43%-66%). AE methodology provides a noninvasive platform to assess the integrity of cardiovascular autoregulatory control systems for risk assessment in heart failure patients.

Nonlinearity between action potential alternans and restitution, which both predict ventricular arrhythmic properties inScn5a+/−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.

Is the T-wave alternans magnitude in apparently healthy subjects and in different subsets of patients with ischaemic heart disease T-wave amplitude dependent? Reply to the letter by J.E. Madias

We thank Dr Madias for his interest in our study on the distribution of T-wave alternans (TWA) magnitude in apparently healthy subjects and in patients with ischaemic heart disease.1In his letter, Dr Madias suggests that TWA magnitude might depend on T-wave amplitude, a very interesting hypothesis that he has been proposing for some years, raising the possibility that adjusting TWA magnitude for T-wave amplitude might result in a TWA index able to …

Is the T-wave alternans magnitude in apparently healthy subjects and in different subsets of patients with ischaemic heart disease T-wave amplitude dependent?

It has been established that T-wave alternans (TWA) is heart rate dependent. Also it has been previously hypothesized that TWA magnitude (TWA-MG) may be T-wave amplitude (TW-AMP) dependent.1Such a speculation is supported by the variation in the TWA-MG in different electrocardiogram (ECG) leads of the same subject, the larger TWA-MG in the ECG precordial among the ECG leads, which are characterized by larger TW-AMP, and the larger TWA-MG in ECGs of patients with bundle branch blocks with large secondary T waves, than in the ones with normal intraventricular conduction. If this hypothesis proves to be valid, adjustment of the different TWA-MG values in a single ECG by the corresponding TW-AMP is in order. Also such adjustment of TWA-MG in serial ECGs or …

Should T-wave alternans magnitude be corrected with T-wave amplitude in the ultra-short-term prediction of life-threatening cardiac arrhythmias?

We appreciate efforts by Dr Madias to develop T-wave alternans (TWA) index based on the theory that TWA magnitude is affected by T-wave amplitude and should, therefore, be corrected.1 He suggested that there may be limitations in correlating TWA magnitude data derived from the J-point to the end of the T-wave with the corresponding peak of the T-wave.2 We could not measure the area under the ECG curve from the J-point to …

Relationship between T-wave alternans magnitude and T-wave amplitude before onset of ventricular tachyarrhythmias during emergent reperfusion in acute coronary syndrome patients: a response

I would like to thank Dr Takasugi and his co-authors for their response to my inquiry regarding a possible relationship between T-wave alternans (TWA) magnitude (TWAM) and the corresponding T-wave amplitude prior to the emergence of ventricular tachyarrhythmias (VTA) in patients undergoing acute coronary interventions, reported in their recent article in the Journal.1 They did not find a ‘significant positive correlation between TWAM and the corresponding T-wave …

Relationship between T-wave alternans magnitude and T-wave amplitude before the onset of ventricular tachyarrhythmias during emergent reperfusion in acute coronary syndrome patients

We greatly appreciate Dr Madias’ remarks on our recent study demonstrating the usefulness of continuous T-wave alternans (TWA) monitoring in ultra-short-term prediction of impending life-threatening ventricular tachyarrhythmias (VTA) during emergent reperfusion therapy in acute coronary syndrome (ACS) patients.1 He raised an interesting question, namely, was there a relationship between the increase in TWA and the possible increase in T-wave amplitude prior to the occurrence of VTA?2 This question is based on his theory that TWA magnitude is affected …

Action Potential Amplitude Alternans and Conduction Block in Human Hearts

A critical requirement for arrhythmogenesis in myopathic hearts is the establishment of functional conduction block, which leads to both the initiation and the maintenance of reentrant excitation. We studied diseased left ventricular trabecular muscle (n 2) using a combined floating microelectrode and optical mapping technique to characterize the mechanism of conduction block in human hearts. Figure 1 shows trabecular muscle that is being paced (120 beats per minute [BPM]) via a Purkinje fibre. The spread of activation is in the longitudinal plane parallel to myocyte fibre orientation seen in the top image of Figure 1 (A), with 2:1 conduction block seen distally on the dominant frequency (DF) map. The amplitude ratio demonstrates that amplitude alternans occurs proximal to the region of block, with the magnitude of alternans increasing closer to the region of block. At the region of block, fibre anisotropy was observed where the fibre orientation changes from longitudinal to transverse (B) with minimal fibrosis (C, picrosirius red stain). Figure 2 reports microelectrode recordings from 3 sites: A, B (3 mm away from A), and C (6 mm away from A). With increasing activation rates from 60, 150, and 200, to 300 beats per minute, progressive conduction

Application of Wavelet Based Denoising for T-Wave Alternans Analysis in High Resolution ECG Maps

T-wave alternans (TWA) allows for identification of patients at an increased risk of ventricular arrhythmia. Stress test, which increases heart rate in controlled manner, is used for TWA measurement. However, the TWA detection and analysis are often disturbed by muscular interference. The evaluation of wavelet based denoising methods was performed to find optimal algorithm for TWA analysis. ECG signals recorded in twelve patients with cardiac disease were analyzed. In seven of them significant T-wave alternans magnitude was detected. The application of wavelet based denoising method in the pre-processing stage increases the T-wave alternans magnitude as well as the number of BSPM signals where TWA was detected. Keywords: T-wave alternans, wavelet denoising, stress test, arrhythmia, sudden cardiac death

Na+ channel distribution and electrophysiological heterogeneities in guinea pig ventricular wall

We sought to explore the distribution pattern of Na(+) channels across ventricular wall, and to determine its functional correlates, in the guinea pig heart. Voltage-dependent Na(+) channel (Na(v)) protein expression levels were measured in transmural samples of ventricular tissue by Western blotting. Isolated, perfused heart preparations were used to record monophasic action potentials and volume-conducted ECG, and to measure effective refractory periods (ERPs) and pacing thresholds, in order to assess excitability, electrical restitution kinetics, and susceptibility to stimulation-evoked tachyarrhythmias at epicardial and endocardial stimulation sites. In both ventricular chambers, Na(v) protein expression was higher at endocardium than epicardium, with midmyocardial layers showing intermediate expression levels. Endocardial stimulation sites showed higher excitability, as evidenced by lower pacing thresholds during regular stimulation and downward displacement of the strength-interval curve reconstructed after extrasystolic stimulation compared with epicardium. ERP restitution assessed over a wide range of pacing rates showed greater maximal slope and faster kinetics at endocardial than epicardial stimulation sites. Flecainide, a Na(+) channel blocker, reduced the maximal ERP restitution slope, slowed restitution kinetics, and eliminated epicardial-to-endocardial difference in dynamics of electrical restitution. Greater excitability and steeper electrical restitution have been associated with greater arrhythmic susceptibility of endocardium than epicardium, as assessed by measuring ventricular fibrillation threshold, inducibility of tachyarrhythmias by rapid cardiac pacing, and the magnitude of stimulation-evoked repolarization alternans. In conclusion, higher Na(+) channel expression levels may contribute to greater excitability, steeper electrical restitution slopes and faster restitution kinetics, and greater susceptibility to stimulation-evoked tachyarrhythmias at endocardium than epicardium in the guinea pig heart.

Effect of resistive barrier location on the relationship between T-wave alternans and cellular repolarization alternans: a 1-D modeling study

Structural inhomogeneities in cardiac tissue have been associated with increased cellular repolarization alternans in animal experiments and increased T-wave alternans (TWA) in clinical studies. However, the effect of structural inhomogeneities on the relationship between cellular alternans and TWA has not been thoroughly investigated. We created 1-dimensional multicellular fiber models with and without a resistive barrier in various fiber regions and paced each model to induce cellular alternans. The models demonstrate that a resistive barrier in one fiber region substantially alters cellular repolarization alternans throughout the fiber. A midmyocardial or subepicardial barrier increase both TWA amplitude and maximum cellular alternans magnitude, relative to a fiber without a barrier. In addition, a direct relationship exists between TWA amplitude and maximum cellular alternans magnitude, which was highly dependent on barrier location. These results suggest that the position of a structural inhomogeneity within the myocardium may have substantial effects on dynamic repolarization instability and arrhythmogenicity.

005 Action potential amplitude alternans and ventricular arrhythmia in a rabbit model of heart failure

Introduction In recent large studies abnormal microvolt T-wave alternans has failed to predict arrhythmic events, raising the possibility that it is not specifically associated with a pro-arrhythmic substrate. Although discordant repolarisation alternans has been mechanistically linked to re-entrant ventricular fibrillation (VF) in experimental models and alternans has been demonstrated to occur in pacing-induced heart failure, whether a mechanistic link between alternans and VF in heart failure is unknown. The aim of this study was therefore to examine the occurrence of repolarisation alternans in a rabbit model of heart failure and to investigate the link between alternans and in VF failing hearts. Methods Heart failure was induced by coronary arterial ligation (n=11). Hearts from normal (n=12) and sham-operated rabbits (n=4) were used as controls. Rabbits were killed with an intravenous injection of 200 mg pentobarbital sodium. Hearts were excised and the left coronary artery was cannulated and perfused with oxygenated Tyrode9s solution maintained at pH7.4 and 37 (n=15) or 30°C (n=16). Perfused left ventricular (LV) wedge preparations were dissected, loaded with voltage-sensitive dye and paced from the endocardium. An optical mapping system was used to record transmural optical action potentials (APs) during a progressive reduction in pacing cycle length (CL). Data analysis was performed using custom software employing standard algorithms. Results Repolarisation alternans and ventricular arrhythmia were significantly more common in failing hearts at each temperature. Heart failure was not associated with an increased incidence of transmural discordant alternans. Progressive alternans of AP amplitude was observed during rapid pacing and was associated with both transmural conduction block and inducibility of VF.Abstract 005 Figure 1 A compares alternans of AP duration (APD) and AP amplitude in two failing hearts, one which developed VF during rapid pacing and the other which did not. In both hearts, APD alternans of a similar magnitude was present and in the VF prone heart, APD alternans was accompanied by marked alternans of AP amplitude. By contrast, in the VF resistant heart APD alternans was seen in isolation, without any significant alternans in AP amplitude. The mean magnitude of APD and AP amplitude alternans at the shortest CL captured during rapid pacing protocols as a function of mean pacing cycle length is shown in Figure B. The magnitude of relative AP amplitude alternans is greater than that of APD alternans. Although the magnitude of APD alternans was similar in VF prone and VF resistant hearts, the magnitude of AP amplitude alternans was greater in VF prone hearts. Conclusions For the first time we describe the development of progressive changes in AP amplitude during alternans, and their relation to the development of conduction block. The data suggest an important role for amplitude alternans in the development of arrhythmias in failing hearts.

Letter Regarding “Assessment of Physiological Amplitude, Duration and Magnitude of ECG T‐Wave Alternans”

Letter Regarding “Assessment of Physiological Amplitude, Duration and Magnitude of ECG T‐Wave Alternans”

Response to Dr. Selvaraj's Comments on the “Assessment of Physiological Amplitude, Duration and Magnitude of ECG T‐Wave Alternans”

Response to Dr. Selvaraj's Comments on the “Assessment of Physiological Amplitude, Duration and Magnitude of ECG T‐Wave Alternans”