Transmural Repolarization Gradients Research Articles

Shark Fin Electrocardiogram in the Intensive Care Unit.

Shark Fin Electrocardiogram in the Intensive Care Unit.

Analyzing the Role of Repolarization Gradients in Post-infarct Ventricular Tachycardia Dynamics Using Patient-Specific Computational Heart Models.

Aims: Disease-induced repolarization heterogeneity in infarcted myocardium contributes to VT arrhythmogenesis but how apicobasal and transmural (AB-TM) repolarization gradients additionally affect post-infarct VT dynamics is unknown. The goal of this study is to assess how AB-TM repolarization gradients impact post-infarct VT dynamics using patient-specific heart models.Method: 3D late gadolinium-enhanced cardiac magnetic resonance images were acquired from seven post-infarct patients. Models representing the patient-specific scar and infarct border zone distributions were reconstructed without (baseline) and with repolarization gradients along both the AB-TM axes. AB only and TM only models were created to assess the effects of each ventricular gradient on VT dynamics. VTs were induced in all models via rapid pacing.Results: Ten baseline VTs were induced. VT inducibility in AB-TM models was not significantly different from baseline (p>0.05). Reentry pathways in AB-TM models were different than baseline pathways due to alterations in the location of conduction block (p<0.05). VT exit sites in AB-TM models were different than baseline VT exit sites (p<0.05). VT inducibility of AB only and TM only models were not significantly different than that of baseline (p>0.05) or AB-TM models (p>0.05). Reentry pathways and VT exit sites in AB only and TM only models were different than in baseline (p<0.05). Lastly, repolarization gradients uncovered multiple VT morphologies with different reentrant pathways and exit sites within the same structural, conducting channels.Conclusion: VT inducibility was not impacted by the addition of AB-TM repolarization gradients, but the VT reentrant pathway and exit sites were greatly affected due to modulation of conduction block. Thus, during ablation procedures, physiological and pharmacological factors that impact the ventricular repolarization gradient might need to be considered when targeting the VTs.

Arrhythmogenic Mechanisms in Hypokalaemia: Insights From Pre-clinical Models.

Potassium is the predominant intracellular cation, with its extracellular concentrations maintained between 3. 5 and 5 mM. Among the different potassium disorders, hypokalaemia is a common clinical condition that increases the risk of life-threatening ventricular arrhythmias. This review aims to consolidate pre-clinical findings on the electrophysiological mechanisms underlying hypokalaemia-induced arrhythmogenicity. Both triggers and substrates are required for the induction and maintenance of ventricular arrhythmias. Triggered activity can arise from either early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). Action potential duration (APD) prolongation can predispose to EADs, whereas intracellular Ca2+ overload can cause both EADs and DADs. Substrates on the other hand can either be static or dynamic. Static substrates include action potential triangulation, non-uniform APD prolongation, abnormal transmural repolarization gradients, reduced conduction velocity (CV), shortened effective refractory period (ERP), reduced excitation wavelength (CV × ERP) and increased critical intervals for re-excitation (APD–ERP). In contrast, dynamic substrates comprise increased amplitude of APD alternans, steeper APD restitution gradients, transient reversal of transmural repolarization gradients and impaired depolarization-repolarization coupling. The following review article will summarize the molecular mechanisms that generate these electrophysiological abnormalities and subsequent arrhythmogenesis.

The role of β-adrenergic system remodeling in human heart failure: A mechanistic investigation

β-adrenergic receptor antagonists (β-blockers) are extensively used to improve cardiac performance in heart failure (HF), but the electrical improvements with these clinical treatments are not fully understood. The aim of this study was to analyze the electrophysiological effects of β-adrenergic system remodeling in heart failure with reduced ejection fraction and the underlying mechanisms. We used a combined mathematical model that integrated β-adrenergic signaling with electrophysiology and calcium cycling in human ventricular myocytes. HF remodeling, both in the electrophysiological and signaling systems, was introduced to quantitatively analyze changes in electrophysiological properties due to the stimulation of β-adrenergic receptors in failing myocytes. We found that the inotropic effect of β-adrenergic stimulation was reduced in HF due to the altered Ca2+ dynamics resulting from the combination of structural, electrophysiological and signaling remodeling. Isolated cells showed proarrhythmic risk after sympathetic stimulation because early afterdepolarizations appeared, and the vulnerability was greater in failing myocytes. When analyzing coupled cells, β-adrenergic stimulation reduced transmural repolarization gradients between endocardium and epicardium in normal tissue, but was less effective at reducing these gradients after HF remodeling. The comparison of the selective activation of β-adrenergic isoforms revealed that the response to β2-adrenergic receptors stimulation was blunted in HF while β1-adrenergic receptors downstream effectors regulated most of the changes observed after sympathetic stimulation. In conclusion, this study was able to reproduce an altered β-adrenergic activity on failing myocytes and to explain the mechanisms involved. The derived predictions could help in the treatment of HF and guide in the design of future experiments.

Abstract 14985: Presence of Repolarization Gradients Reverses Post-infarct Ventricular Tachycardia Exit and Entrance Sites in Personalized Digital Hearts

Introduction: Post-infarct ventricular tachycardias (VT) arise due to structural remodeling (scarring). Physiological repolarization gradients (apicobasal and transmural) exist in the human heart, but the effects on post-infarct VT dynamics are unknown. Hypothesis: We hypothesized that incorporation of repolarization gradients in personalized digital hearts of post-infarct patients impacts VT exit sites without altering the location of the VTs. Methods: 3D late-gadolinium enhanced CMR images were acquired from 7 post-infarct patients. Personalized image-based computational heart models (digital hearts) representing scar and infarct border zone distributions were constructed. Apicobasal (AB) and transmural (TM) repolarization gradients were incorporated using a validated method (Fig A). VTs were induced at baseline (no repolarization gradient) via rapid pacing in the right ventricular apex, using two pacing cycle lengths, mimicking non-invasive programmed stimulation. Pacing protocols that induced baseline VTs were repeated under AB and TM conditions. Results: Ten VTs were induced in baseline digital hearts. 8 AB VTs and 8 TM VTs were induced; the remaining 2 VTs for both AB and TM digital hearts could not be induced. 5/8 induced AB VTs had VT exit sites matching baseline VT exit sites; the remaining 3/8 AB VTs had reversed VT exit and entrance sites from the corresponding baseline VTs (Fig B, VT 1 &amp; 2). 4/8 induced TM VTs had exit sites that matched those at baseline; the remaining TM VTs had exit and entrance sites reversed from those of baseline VTs (Fig B, VT 1, 2 &amp; 3). All 8 AB VTs and 8 TM VTs had the same location as corresponding baseline VTs. Conclusion: AB and TM repolarization gradients can act to reverse VT entrance and exit sites without changing VT location. Thus, incorporation of physiological repolarization gradients into personalized digital hearts may not impact VT ablation targeting but may affect accurate prediction of VT exit or entrance sites.

\u03b2-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle

Long QT syndrome (LQTS) is an inherited or drug induced condition associated with delayed repolarization and sudden cardiac death. The cardiac potassium channel, IKr, and the adrenergic-sensitive cardiac potassium current, IKs, are two primary contributors to cardiac repolarization. This study aimed to elucidate the role of β-adrenergic (β-AR) stimulation in mediating the contributions of IKr and IKs to repolarizing the human left ventricle (n = 18). Optical mapping was used to measure action potential durations (APDs) in the presence of the IKs blocker JNJ-303 and the IKr blocker E-4031. We found that JNJ-303 alone did not increase APD. However, under isoprenaline (ISO), both the application of JNJ-303 and additional E-4031 significantly increased APD. With JNJ-303, ISO decreased APD significantly more in the epicardium as compared to the endocardium, with subsequent application E-4031 increasing mid- and endocardial APD80 more significantly than in the epicardium. We found that β-AR stimulation significantly augmented the effect of IKs blocker JNJ-303, in contrast to the reduced effect of IKr blocker E-4031. We also observed synergistic augmentation of transmural repolarization gradient by the combination of ISO and E-4031. Our results suggest β-AR-mediated increase of transmural dispersion of repolarization, which could pose arrhythmogenic risk in LQTS patients.

Ventricular stimulus site influences dynamic dispersion of repolarization in the intact human heart.

The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RVendo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1-S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site (30-ms difference during RVendo pacing, 25-ms during LVendo, and 48-ms during LVepi; 50th quantile, P < 0.01). Basal LVepi pacing resulted in a significant transmural gradient of RT (77 ms, 50th quantile: P < 0.01), due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling (mean slope -1.36 ± 1.9 and -0.71 ± 0.4, respectively). Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic.

0173 : Mechanisms behind the pro-arrhythmogenic state induced by exposure to chronic intermittent hypoxia

Obstructive sleep apnea (OSA) is now recognized as a major risk factor for cardiovascular disorders including ventricular arrhythmias and sudden cardiac death. We have demonstrated that intermittent hypoxia (IH), a major component of OSA, increases the incidence of myocardial ischemiarelated ventricular fibrillation. The aim of the present study was to investigate the mechanisms behind the arrhythmogenic effects of IH. Wistar rats were exposed to IH (60-sec cycles alternating 21 and 5% FiO2, 8h/day) or normoxia (similar air-air cycles) during 14 days. Arterial blood pressure and ECG were recorded for power spectral analysis and ECG interval measurement. Hearts were removed, perfused in Langendorff mode and paced at 300 bpm. Epicardial and endocardial monophasic action potentials were recorded and action potential duration at 50% repolarization (APD50) was measured. Mean arterial blood pressure was significantly increased by IH exposure. Rats exposed to IH exhibited higher low-frequency (LF) power, lower high-frequency (HF) power and higher LF/HF ratio of heart rate and blood pressure variability, indicative of a systemic sympathetic activation. This was corroborated by a significant increase in circulating norepinephine levels. IH exposure also resulted in a significant increase in QTc and Tpeak- Tend intervals, indicative of increased spatial and transmural dispersion of repolarization and associated with an increased vulnerability to ischemic ventricular arrhythmias. The increase in the transmural repolarization gradient was associated with a significantly longer endocardial APD50 in IH-exposed rats (49.07 ± 2.19 ms) compared to normoxia-exposed rats (41.29 ± 0.62 ms, p<0.01) while epicardial APD50 did not differ. Thus, chronic exposure to intermittent hypoxia, such as that occurring during OSA, promotes a pro-arrhythmogenic state characterized by sympathoactivation and alterations in ventricular repolarization. The author hereby declares no conflict of interest

The Role of Transmural Repolarization Gradient in the Inversion of Cardiac Electric Field: Model Study of ECG in Hypothermia.

The changes in ventricular repolarization gradients lead to significant alterations of the electrocardiographic body surface T waves up to the T wave inversion. However, the contribution of a specific gradient remains to be elucidated. The objective of the present investigation was to study the role of the transmural repolarization gradient in the inversion of the body surface T wave with a mathematical model of the hypothermia-induced changes of ventricular repolarization. By means of mathematical simulation, we set the hypothermic action potential duration (APD) distribution on the rabbit ventricular epicardium as it was previously experimentally documented. Then the parameters of the body surface potential distribution were tested with the introduction of different scenarios of the endocardial and epicardial APD behavior in hypothermia resulting in the unchanged, reversed or enlarged transmural repolarization gradient. The reversal of epicardial repolarization gradients (apicobasal, anterior-posterior and interventricular) caused the inversion of the T waves regardless of the direction of the transmural repolarization gradient. However, the most realistic body surface potentials were obtained when the endocardial APDs were not changed under hypothermia while the epicardial APDs prolonged. This produced the reversed and increased transmural repolarization gradient in absolute magnitude. The body surface potentials simulated under the unchanged transmural gradient were reduced in comparison to those simulated under the reversed transmural gradient. The simulations demonstrated that the transmural repolarization gradient did not play a crucial role in the cardiac electric field inversion under hypothermia, but its magnitude and direction contribute to the T wave amplitude.

Transient outward potassium channel: a heart failure mediator.

Transient outward K(+) current (Ito) plays a crucial role in shaping the early phase of repolarization and setting the plateau voltage level of action potential. As a result, it extensively affects membrane current flow in the plateau window. A great body of evidence illustrates a transmural gradient of I to within ventricular wall with much higher density in epicardial than endocardial myocytes, which is important for the physiological ventricular repolarization. In heart failure (HF), this gradient is diminished due to a greater reduction of I to in epicardial myocytes. This attenuates the transmural gradient of early repolarization, facilitating conduction of abnormal impulses originated in the epicardium. In addition, I to reduction prolongs action potential duration and increases intercellular Ca(2+), thus affecting Ca(2+) handling and the excitation-contraction coupling. Furthermore, increased intercellular Ca(2+) could activate CaMKII and calcineurin whose role in cardiac hypertrophy and HF development has been well established. Based on the impact of I to reduction on electrical activity, signal conduction, calcium handling and cardiac function, restoration of I to is likely a potential therapeutic strategy for HF. In this review, we summarize the physiological and pathological role of cardiac I to channel and the potential impact of I to restoration on HF therapy with an emphasis of recent novel findings.

Congenital long QT syndrome and concomitant early repolarization pattern: A benign association or an ICD-worthy one?

The seminal studies performed by Antzelevitch and colleagues1–6 have provided the fundamental basis for the current understanding of early repolarization/J-wave syndromes. The J wave is thought to reflect a transmural repolarization gradient resulting from the early outward current and is dictated by a higher prominence of transient outward current (Ito) in epicardial tissue than in the endocardium.3,5 Early repolarization (ER) has been defined as an elevated J point, terminal slurring of the QRS complex, and possible ST-segment elevation.

Early Repolarization: A Rare Primary Arrhythmic Syndrome and Common Modifier of Arrhythmic Risk

Despite longstanding beliefs, early repolarization is not always a benign electrocardiographic observation. Its association with increased arrhythmic events has been observed in 2 strikingly different groups of individuals, retrospectively in young subjects with idiopathic ventricular fibrillation and in long-term cohort studies from the general population. This form of primary electrical disease is now referred to as the early repolarization syndrome and has mechanistically been demonstrated to occur secondary to a transmural gradient of early cellular repolarization, resulting in the presence of an ST-elevation pattern and J-waves merged within or offset from the terminal QRS complex. In addition to creating a milieu of increased arrhythmic risk in isolation, an increasing number of studies have highlighted that the presence of early repolarization and J-waves may provide a baseline electrical substrate that modifies the risk of malignant arrhythmias in other clinical settings, such as acute myocardial ischemia. The challenge ahead lies in discerning when early repolarization may represent an ominous ECG marker, as opposed to a benign entity.

Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in guinea-pig heart

Endocardial pacing instituted to treat symptomatic bradycardia may nevertheless promote tachyarrhythmia in some pacemaker-implanted patients. We sought to determine the contributing electrophysiological mechanisms. Left ventricular (LV) monophasic action potential duration (APD(90)) and effective refractory periods were determined in perfused guinea-pig hearts along with volume-conducted ECG recordings during epicardial and endocardial stimulations. Consistent with electrotonic modulation of repolarization, APD(90) at a given (either epicardial or endocardial) recording site tended to be longer while pacing from the ipsilateral LV site as compared to stimulations applied at the opposite side of ventricular wall. As a result, the intrinsic transmural repolarization gradient was amplified during endocardial pacing while being significantly reduced upon epicardial stimulations. The maximum slope of APD(90) restitution was greater upon endocardial than epicardial pacing. The excitability was found to recur at earlier repolarization time point at endocardium than epicardium, thereby contributing to increased endocardial critical intervals for re-excitation. Premature extrasystolic beats could have been elicited at shorter coupling stimulation intervals and propagated with greater transmural conduction delay upon endocardial than epicardial stimulations. Endocardial site exhibited lower ventricular fibrillation thresholds and greater inducibility of tachyarrhythmia upon extrasystolic stimulations as compared to epicardium. Arrhythmic susceptibility in guinea-pig heart is greater during endocardial than epicardial pacing because of greater transmural APD(90) dispersion, steeper electrical restitution slopes, greater critical intervals for LV re-excitation and slower transmural conduction of the earliest premature ectopic beats. Further studies are warranted to determine whether these effects may contribute to proarrhythmia in paced human patients.

Repolarization heterogeneity and rate dependency in a canine rapid pacing model of heart failure

BackgroundRepolarization heterogeneity and rate dependency have long been established as factors contributing to arrhythmogenic risk. However, there are conflicting observations regarding the nature and extent of ventricular repolarization heterogeneity that complicate understanding of arrhythmogenic mechanisms. To explore these disparate findings, we studied ventricular repolarization heterogeneity and rate dependency in a canine, rapid pacing model of heart failure. Methods and ResultsWe studied ventricular repolarization heterogeneity and rate dependency in 10 canine hearts (5 normal and 5 after 1 month of rapid pacing at 240 beats per minute) by analyzing 64 body surface electrocardiograms, 64 epicardial, and 190 intramural plunge electrograms. We estimated mean ventricular depolarization and repolarization times from R- and T-wave peaks of the root-mean-square electrocardiogram (body surface) and local depolarization and repolarization times using activation-recovery interval (ARI) methods from recordings obtained during a range of fixed rate pacing. In addition, we estimated local epicardial and transmural gradients of ARIs to assess cardiac locations of greatest spatial repolarization heterogeneity. We compared changes in repolarization at different rates between normal and heart failure hearts. Findings documented prolongation of repolarization, repolarization rate dependency, and increased repolarization gradients in the heart failure hearts compared with control as observed from body surface, epicardial, and transmural measurements. Maximum local epicardial and intramural ARI gradients were comparable both in heart failure and control hearts. Intramural ARI distributions tended to be more irregular in the heart failure hearts compared with the systematic epicardium to endocardium ARI increase observed in control animals. ConclusionsThis study documented prolongation of repolarization, increase in both epicardial and transmural repolarization gradients, and irregularity of transmural distribution in a rapid pacing canine model of heart failure compared with control animals. The findings support previously published results of increased repolarization heterogeneity and repolarization prolongation observed in rapid pacing models of heart failure. New findings are the irregularity of transmural heterogeneity and the ability of noninvasive root-mean-square electrocardiogram R-T intervals to estimate mean ventricular repolarization duration in the setting of rapid pacing models of heart failure. These findings suggest increased arrhythmogenic risk in this model and potentially in patients with heart failure.

Refractory dispersion promotes conduction disturbance and arrhythmias in a Scn5a +/− mouse model

Accentuated right ventricular (RV) gradients in action potential duration (APD) have been implicated in the arrhythmogenicity observed in Brugada syndrome in studies assuming that ventricular effective refractory periods (VERPs) vary in concert with APDs. The present experiments use a genetically modified mouse model to explore spatial heterogeneities in VERP that in turn might affect conduction velocity, thereby causing arrhythmias. Activation latencies, APDs and VERPs recorded during programmed S1S2 protocols were compared in RV and left ventricular (LV) epicardia and endocardia of Langendorff-perfused wild-type (WT) and Scn5a +/− hearts. Scn5a +/− and WT hearts showed similar patterns of shorter VERPs in RV than LV epicardia, and in epicardia than endocardia. However, Scn5a +/− hearts showed longer VERPs, despite shorter APD90s, than WT in all regions examined. The pro- and anti-arrhythmic agents flecainide and quinidine increased regional VERPs despite respectively decreasing and increasing the corresponding APD90s particularly in Scn5a +/− RV epicardia. In contrast, Scn5a +/− hearts showed greater VERP gradients between neighbouring regions, particularly RV transmural gradients, than WT (9.1 ± 1.1 vs. 5.7 ± 0.5 ms, p < 0.05, n = 12). Flecainide increased (to 21 ± 0.9 ms, p < 0.05, n = 6) but quinidine decreased (to 4.5 ± 0.5 ms, p < 0.05, n = 6) these gradients, particularly across the Scn5a +/− RV. Finally, Scn5a +/− hearts showed greater conduction slowing than WT following S2 stimuli, particularly with flecainide administration. Rather than arrhythmogenesis resulting from increased transmural repolarization gradients in an early, phase 2, reentrant excitation mechanism, the present findings implicate RV VERP gradients in potential reentrant mechanisms involving impulse conduction slowed by partial refractoriness.

Drug-Induced Arrhythmia

Prolongation of the QTc interval has been associated with proarrhythmia resulting from a potentially fatal form of polymorphic ventricular tachycardia called torsades de pointes (TdP). Genetic forms of the long-QT syndrome (LQTS) associated with high arrhythmic risk have been causally related to mutations in ion channels responsible for the cardiac action potential; genetic factors associated with milder degrees of QTc prolongation and arrhythmic risk have also been described. Acquired forms of QTc prolongation and proarrhythmia, particularly related to drug therapy, are frequently related to drug effects on the same ion channels involved in genetic forms of LQTS. As is true for genetic forms of LQTS, there is a wide spectrum of potential drug effects on the QTc interval ranging from trivial to potentially lethal. Drug-induced QTc prolongation is a complicated phenomenon related not just to the properties or dose of a particular drug but also to drug-drug interactions and a variety of patient factors, including age, gender, the presence and severity of underlying heart disease, and genetic predisposition. Additionally, drug effects on other ion channels, including blockade of sodium channels (causing prolongation of the QRS interval rather than the QTc interval), are an important cause of drug-induced proarrhythmia. The purpose of this review is to summarize the available data related to acquired forms of LQTS, with particular focus on drug-related LQTS and proarrhythmia. A brief summary is presented here of genetic LQTS because the relevant genes and proteins form the basis for an understanding of the causes of acquired LQTS, and in any given patient, the QTc is determined by genetic, substrate, and environmental factors. Emphasis is placed on practical strategies for clinicians, with the goal of minimizing the risk of dangerous proarrhythmia related to the use of both cardiac and noncardiac drugs with the potential for QTc prolongation. Genetic …

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 ± 5 vs. epi: 147 ± 4 ms; P < 0.05). During epicardial stimulation, this gradient reversed (epi: 162 ± 4 vs. endo: 148 ± 6 ms; P < 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall.

Response to Selvaraj and Nair

HomeCirculation ResearchVol. 107, No. 3Response to Selvaraj and Nair Free AccessReplyPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReplyPDF/EPUBResponse to Selvaraj and Nair Alexey V. Glukhov, Vadim V. Fedorov and Igor R. Efimov Alexey V. GlukhovAlexey V. Glukhov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail (Glukhov, Fedorov, Efimov) Search for more papers by this author , Vadim V. FedorovVadim V. Fedorov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail (Glukhov, Fedorov, Efimov) Search for more papers by this author and Igor R. EfimovIgor R. Efimov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail (Glukhov, Fedorov, Efimov) Search for more papers by this author Originally published6 Aug 2010https://doi.org/10.1161/CIRCRESAHA.110.224733Circulation Research. 2010;107:e10We thank Drs Selvaraj and Nair for the opportunity to discuss the clinical relevance of our recent findings in explanted human hearts and to bridge the gap between clinical and basic electrophysiology research methodologies. Using the basic science methodology of optical mapping, which is not yet available in clinical electrophysiological laboratories, we have recently found that end-stage heart failure results in anatomically heterogeneous repolarization remodeling in humans.1 In this human study, we have used a measure of intrinsic repolarization properties that is commonly accepted in basic studies, action potential duration (APD),2–4 which is the basis for activation–recovery interval (ARI) and a close approximation of the functional refractory period (RP) used in clinical studies.5 Mapping APD dispersion is methodologically challenging in clinical settings, unlike basic research laboratories.A repolarization map is simply an algebraic sum of the activation map and the map of APD. APD map has become an important characteristic because it represents intrinsic repolarization properties, which are less dependent on activation sequence and more dependent on local functional state, cell–cell coupling, and gene expression responsible for repolarizing currents. Thus, APD dispersion is a frequently used measure for estimation of repolarization remodeling. We are surprised that the authors of the letter found this approach “an artificial measurement with no physiological significance,” given that it was introduced to cardiac electrophysiology by Thomas Lewis6 in 1925 and, since that time, has been used by numerous groups.2–5In our early studies,7,8 we have demonstrated that APD base-to-apex gradient governs repolarization and RP pattern in the guinea pig heart, because activation is relatively fast, and therefore the conduction delay is significantly shorter compared to global APD gradient. But, if activation were relatively slow, it may indeed influence the repolarization sequence and dispersion. In our present study,1 activation sequence during endocardial pacing, which represents normal excitation, was similar in all hearts, with activation time ranging from 45 to 70 ms. Our findings are in agreement with the observation of Taggart et al,5 who demonstrated the absence of the ARI dispersion in patients measured during routine coronary artery surgery using plunge needle electrodes. To address the question of Drs Selvaraj and Nair, we constructed maps of repolarization (data are not shown because of editorial limitations for Letters). Contrary to their hypothesis, repolarization pattern to a significant degree is determined by APD maps in these hearts during endocardial pacing. In a nonfailing heart with 150-ms intrinsic transmural APD gradient (range from 380 to 530 ms), 50-ms transmural activation slightly delayed epicardial repolarization and thus produced 122-ms transmural repolarization gradient, which was governed by APD distribution pattern. In a failing heart with 35-ms transmural APD gradient (range from 435 to 470 ms), 69-ms heterogeneous transmural activation significantly delayed both midmyocardial and subepicardial repolarization and resulted in 40-ms repolarization gradient (range from 485 to 525 ms), which was still governed by APD pattern.However, in general, we agree that dispersion of repolarization depends on the activation sequence, which indeed could be distorted in failing hearts by scars, regions of ischemia, remodeling, and fibrosis. In our Limitations section, we have discussed the fact that we selected regions of the left ventricles without these structural abnormalities to focus on intrinsic repolarization remodeling. Moreover, this study provided assessment of repolarization in relatively small samples of tissue, which cannot predict global dispersion of repolarization of the whole heart. Unfortunately, we still do not have a methodology to map repolarization in the entire heart in 3D. But optical mapping is a promising first step in this direction. Our follow-up study focuses on this issue.9Alexey V. GlukhovVadim V. FedorovIgor R. Efimov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail [email protected]Sources of FundingSupported by NIH grant R01 HL085369.DisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.

In vivo studies of Scn5a+/− mice modeling Brugada syndrome demonstrate both conduction and repolarization abnormalities

ObjectivesWe investigate the extent to which the electrocardiographic (ECG) properties of intact Scn5a+/− mice reproduce the corresponding clinical Brugada syndrome phenotype and use this model to investigate the role of conduction and repolarization abnormalities in the arrhythmogenic mechanism. Methods and ResultsThe ECGs were obtained from anesthetized wild-type and Scn5a+/− mice, before and after administration of the known pro- and antiarrhythmic agents flecainide and quinidine. The ECG intervals were measured and their dispersions calculated. Scn5a+/− hearts showed ventricular arrhythmias, ST elevation, and conduction disorders including increased QT dispersion, accentuated by flecainide. Quinidine did not cause ventricular arrhythmias but exerted variable effects on ST segments and worsened conduction abnormalities. ConclusionsThe ECG features in an Scn5a+/− mouse establish it as a suitable model for Brugada syndrome and demonstrate abnormal conduction and repolarization phenomena. Altered QT dispersion, taken to indicate increased transmural repolarization gradients, may be useful in clinical risk stratification.

004 Dispersion of refractoriness promotes arrhythmogenesis in a murine model of Brugada syndrome

<h3>Introduction</h3> Recent experiments have implicated accentuated right ventricular (RV) transmural repolarization gradients in arrhythmogenesis in murine models of Brugada Syndrome. The present experiments investigated for the first time the involvement of heterogeneities in the corresponding ventricular effective refractory periods (VERP), hitherto assumed to vary in concert with action potential duration (APD). <h3>Methods</h3> VERPs and APDs were compared in the right ventricular (RV) and left ventricular (LV), epicardial and endocardial, regions of Langendorff-perfused wild-type (WT) and loss of function <i>Scn5a+/−</i> murine hearts. APDs were obtained during regular pacing and VERPs from a programmed S1S2 protocol, before and following addition of flecainide or quinidine. VERP dispersions were calculated from the difference in VERP between neighbouring cardiac regions. <h3>Results</h3> In contrast to APD values, <i>Scn5a+/−</i> hearts showed longer VERPs than WT. Both showed shorter VERPs in RV than LV epicardium and in the epicardia than endocardia of both LV and RV (Abstract 004 Figure 1). VERP/APD ratios were consistently larger in <i>Scn5a+/−</i> than WT but did not vary significantly between regions, contrasting with expectations from re-entrant arrhythmogenic mechanisms suggested previously for the gain of function, <i>Scn5aΔ/+</i> genotype. However, <i>Scn5a+/−</i> hearts showed greater VERP dispersions, particularly across the RV, than WT. Both flecainide and quinidine increased the regional VERP values particularly in <i>Scn5a+/−</i>. However, flecainide increased but quinidine decreased the VERP dispersions, particularly across the RV in the Scn5a+/− (Abstract 004 Figure 2). This is in direct parallel with the established pro- and anti-arrhythmic effects of flecainide and quinidine experimentally and clinically. <h3>Conclusions</h3> These findings implicate for the first time an involvement of VERP dispersions in the RV in the arrhythmogenesis found in murine <i>Scn5a+/−</i> hearts.