Spatial Dispersion Of Repolarization Research Articles

Targeted activation of human ether-à-go-go-related gene channels rescues electrical instability induced by the R56Q+/- long QT syndrome variant.

Long QT syndrome type 2 (LQTS2) is associated with inherited variants in the cardiac human ether-à-go-go-related gene (hERG) K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant and its phenotypic rescue by using the Type 1 hERG activator, RPR260243. The above approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean action potential duration (APD90). However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of APD90 during rate transitions, and increases the incidence of 2:1 block. During paired S1-S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness. Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.

Human atrial fibrillation and genetic defects in transient outward currents: mechanistic insights from multi-scale computational models.

Previous studies have linked dysfunctional Ito arising from mutations to KCND3-encoded Kv4.3 and KCND2-encoded Kv4.2 to atrial fibrillation. Using computational models, this study aimed to investigate the mechanisms underlying pro-arrhythmic effects of the gain-of-function Kv4.3 (T361S, A545P) and Kv4.2 (S447R) mutations. Wild-type and mutant Ito formulations were developed from and validated against experimental data and incorporated into the Colman et al. model of human atrial cells. Single-cell models were incorporated into one- (1D) and two-dimensional (2D) models of atrial tissue, and a three-dimensional (3D) realistic model of the human atria. The three gain-of-function mutations had similar, albeit quantitatively different, effects: shortening of the action potential duration; lowering the plateau membrane potential, abbreviating the effective refractory period (ERP) and the wavelength (WL) of atrial excitation at the tissue level. Restitution curves for the WL, the ERP and the conduction velocity were leftward shifted, facilitating the conduction of atrial excitation waves at high excitation rates. The mutations also increased lifespan and stationarity of re-entry in both 2D and 3D simulations, which further highlighted a mutation-induced increase in spatial dispersion of repolarization. Collectively, these changes account for pro-arrhythmic effects of these Kv4.3 and Kv4.2 mutations in facilitating AF. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Safe electrophysiologic profile of the neprilysin-inhibitor sacubitril in combination with different antiarrhythmic drugs

Abstract Background Observational clinical data suggest a direct effect of sacubitril on cardiac electrophysiology. However, data concerning the impact of combination of sacubitril with antiarrhythmic drug therapy is sparse. Purpose We aimed at characterizing the electrophysiologic effects of a combination therapy of sacubitril with the class III-drug sotalol and the class IB-agent mexiletine in a sensitive, experimental whole-heart model. Methods and results 25 isolated rabbit hearts were retrogradely perfused. Hearts were treated with mexiletine (25 μM, 13 hearts) or sotalol (100 μM, 12 hearts) after generating baseline data. Eight endo- and epicardial monophasic action potentials and ECG recordings demonstrated an abbreviation of action potential duration (APD90, −21 ms, p<0.01) and no significant changes of QT interval (+10ms, p=ns) after administration of mexiletine. Spatial dispersion of repolarization (SDR) remained stable after mexiletine treatment (+6 ms, p=ns) whereas effective refractory periods (ERP) were significantly prolonged (+80 ms, p<0.01). Sotalol prolonged cardiac repolarization (APD90: +1 ms, p=ns; QT: +24 ms, p<0.01) and amplified spatial dispersion (+19 ms, p<0.01) without changing ERP (+8 ms, p=ns). Additional treatment with sacubitril (5 μM) led to a significant reduction of APD90 (−12 ms, p<0.01), QT interval (−20 ms, p<0.01) and ERP (−23 ms, p<0.01) in the presence of a stable SDR (−4 ms, p=ns) in the mexiletine group. In the sotalol group, additional administration of sacubitril abbreviated APD90 (−9 ms, p<0.05) and QT interval (−13 ms, p<0.01) and reduced ERP (−18 ms, p<0.01) without affecting SDR (−3 ms, p=ns). Ventricular vulnerability was assessed by a predefined pacing protocol employing premature extra stimuli and burst stimulation. After lowering the potassium concentration, 30 episodes of torsade de pointes tachycardia were observed after sotalol treatment (vs. 0 episodes under baseline, p<0.05). Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (8 episodes, p<0.05) in the sotalol-group. No proarrhythmic effect was observed after mexiletine treatment (8 episodes vs. 3 episodes under baseline conditions, p=ns). Additional sacubitril treatment did not increase ventricular vulnerability (32 episods, p=ns). Conclusion Sacubitril in combination with antiarrhythmic drugs demonstrates a safe electrophysiologic profile. In class IB- and class III-pretreated hearts, sacubitril abbreviates cardiac repolarization duration and effective refractory periods without changing spatial dispersion of repolarization. Thereby, sacubitril reduces the occurrence of torsade de pointes-tachycardia in antiarrhythmic pretreated hearts. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Deutsche Stiftung für Herzforschung (to G.F.)

PO-709-07 THE IMPACT OF MULTI-DIRECTIONAL PACING ON THE DISTRIBUTION OF LATE SIGNAL ACTIVATION, ACTIVATION SLOWING AND REPOLARIZATION GRADIENTS IN RELATION TO VENTRICULAR TACHYCARDIA IN A PORCINE INFARCT MODEL

In ventricular tachycardia (VT) ablation electrograms with late or decremental activation properties have emerged as a target in substrate ablation, and spatial dispersion of repolarization has been shown to correlate with areas of late potentials and critical VT sites. Multi-directional pacing has been demonstrated to reveal a greater area of activation slowing in infarct related VT. The optimal strategy to identify key sites of arrhythmogenesis substrate mapping is not established.

Safe electrophysiologic profile of dexmedetomidine in different experimental arrhythmia models

Previous studies suggest an impact of dexmedetomidine on cardiac electrophysiology. However, experimental data is sparse. Therefore, purpose of this study was to investigate the influence of dexmedetomidine on different experimental models of proarrhythmia. 50 rabbit hearts were explanted and retrogradely perfused. The first group (n = 12) was treated with dexmedetomidine in ascending concentrations (3, 5 and 10 µM). Dexmedetomidine did not substantially alter action potential duration (APD) but reduced spatial dispersion of repolarization (SDR) and rendered the action potentials rectangular, resulting in no proarrhythmia. In further 12 hearts, erythromycin (300 µM) was administered to simulate long-QT-syndrome-2 (LQT2). Additional treatment with dexmedetomidine reduced SDR, thereby suppressing torsade de pointes. In the third group (n = 14), 0.5 µM veratridine was added to reduce the repolarization reserve. Further administration of dexmedetomidine did not influence APD, SDR or the occurrence of arrhythmias. In the last group (n = 12), a combination of acetylcholine (1 µM) and isoproterenol (1 µM) was used to facilitate atrial fibrillation. Additional treatment with dexmedetomidine prolonged the atrial APD but did not reduce AF episodes. In this study, dexmedetomidine did not significantly alter cardiac repolarization duration and was not proarrhythmic in different models of ventricular and atrial arrhythmias. Of note, dexmedetomidine might be antiarrhythmic in acquired LQT2 by reducing SDR.

Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of torsades de pointes in the chronic atrioventricular block dog

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and torsades de pointes (TdP, defined as ≥5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic atrioventricular block (CAVB) dog by dofetilide (IKr blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (≥3 TdPs/10 min) CAVB dogs underwent one mapping experiment and were observed for 10 min from the start of dofetilide infusion (0.025 mg/kg, 5 min). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARIs) on the intracardiac EGM, using the formula: [Formula: see text]. The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion before first 1) sEB (occurrence at 100 ± 35 s), 2) mEB (224 ± 96 s), and 3) non-self-terminating TdP (454 ± 298 s). STVARI increased from 2.15 ± 0.32 ms at BL to 3.73 ± 0.99 ms* before the first sEB and remained increased without further significant progression to mEB (4.41 ± 0.45 ms*) and TdP (5.07 ± 0.84 ms*) (*P < 0.05 compared with BL). SDR3D did not change from 31 ± 11 ms at BL to 43 ± 13 ms before sEB but increased significantly before mEB (68 ± 7 ms*) and to TdP (86 ± 9 ms*+) (+P < 0.05 compared with sEB). An increase in STV contributes to the initiation of sEB, whereas an increase in SDR is important for the perpetuation of non-self-terminating TdPs.NEW & NOTEWORTHY This study compared two well-established electrophysiological parameters, being temporal and spatial dispersion of repolarization, and provided new insights into their interplay in the arrhythmogenesis of torsades de pointes arrhythmias. Although it confirmed that an increase in temporal dispersion of repolarization contributes to the initiation of single ectopic beats, it showed that an increase in spatial dispersion of repolarization is important for the perpetuation of non-self-terminating torsades de pointes arrhythmias.

Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model.

IntroductionTorsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.MethodsDofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.ResultsIVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate).ConclusionIn CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

Beneficial electrophysiologic effects of sacubitril in different arrhythmia syndromes

Abstract Background Previous studies report conflicting data regarding anti- or proarrhythmic effects of sacubitril. The aim of the presents study was to assess the impact of sacubitril in different arrhythmia models. Methods and results In 12 isolated rabbit hearts, sacubitril was infused in rising concentrations (3, 5, 10μM) after obtaining baseline data. In 12 further hearts, erythromycin was administered to simulate long QT syndrome-2 (LQT2). Other 12 hearts were perfused with veratridine to mimic long QT syndrome-3 (LQT3). Both LQT groups were treated with sacubitril (5μM). Ventricular vulnerability was assessed by a pacing protocol. AV-blocked bradycardic hearts were perfused with a hypokalemic solution to trigger torsade de pointes (TdP). In further 13 hearts, AF was induced by a combination of acetylcholine and isoproterenol (ACH/ISO) and sacubitril (5μM) was added afterwards. With sacubitril, action potential duration (APD) was abbreviated whereas spatial dispersion of repolarization (SDR) remained stable. In both LQT groups, APD and SDR were increased. Infusion of sacubitril reduced APD and SDR in the LQT2-group (APD: −21 ms, p&amp;lt;0.05; SDR: −8 ms, p=ns) and did not alter APD but reduced SDR in the LQT3-group (APD: +2 ms, p=ns; SDR: −9 ms, p&amp;lt;0.05). Ventricular vulnerability was not altered by sacubitril. No TdP were observed with sacubitril treatment or under baseline conditions in any group. Erythromycin provoked 43 episodes of TdP (p&amp;lt;0.05). Additional treatment with sacubitril significantly suppressed TdP (3 episodes, p&amp;lt;0.05). With veratridine, 16 episodes of TdP (p=0.07) occurred. Further treatment with sacubitril did not reduce TdP (10 episodes, p=ns) significantly. Infusion of ACH/ISO led to an increased inducibility of atrial fibrillation (31 vs. 7 episodes). Additional infusion of sacubitril increased atrial ERP (+21ms, p&amp;lt;0.05) and reduced inducibility of AF (9 episodes). Conclusion Sacubitril abbreviated APD and was not proarrhythmic. SDR is a major pathomechanism of TdP and was reduced by sacubitril in both LQT groups. Thereby, sacubitril exhibits antiarrhythmic effects in LQT2 and may be beneficial in LQT3. Furthermore, sacubitril suppressed AF by prolonging aERP. Our results indicate beneficial effects of sacubitril on cardiac electrophysiology. Funding Acknowledgement Type of funding source: None

PREDICTORS OF RISK IN PATIENTS WITH CORONARY AND NON-CORONARY HEART DISEASES AND VENTRICULAR EXTRASYSTOLES, DEPENDING ON HEART RHYTHM TURBULENCE

Purpose. This investigation examines changes in the parameters of heart rate turbulence and spatial dispersion of repolarization in persons with ventricular extrasystoles (VE), depending on constellation with stable angina (SA), post inflammation myocardial fibrosis (PIMF), including the effects of hypertension (AH), compared with patients without organic pathology with diagnosis of neurocirculatory dystonia (NCD). Material and methods. Thirty patients were examined in the following distribution of diagnoses: SA, PIMF, NCD and AH, which occurred in combination with other pathologies. All patients underwent a standard examination plan and Holter ECG monitoring (HM ECG) with analysis of electrocardiographic changes and assessment of turbulence onset parameters and T peak-T end interval dispersion of repolarization phase. VE and supraventricular extrasystoles (SVE) were diagnosed in all patients according to HM ECG. For statistical analysis we used the determination of the sample mean, the standard error of the mean, determined the significance of differences in quantitative parameters using the zero hypothesis for the paired t-test Student for normal distribution and t-criterion Wilkoxon at distribution other than normal. Results. When analyzing changes in turbulence onset and “Tpeak-Tend” (TpTe) intervals, a favorable distribution of TpTe (65.0+6.19 vs. 90.43+2.77ms, p 0%) under conditions of structural pathology of the heart. Conclusion. Analysis of the distribution of TpTe indicates a smaller effect of functional pathology in reducing the value of TpTe (p 0%).

Propofol abolishes torsade de pointes in different models of acquired long QT syndrome

There is conflicting evidence regarding the impact of propofol on cardiac repolarization and the risk of torsade de pointes (TdP). The purpose of this study was to elucidate the risk of propofol-induced TdP and to investigate the impact of propofol in drug-induced long QT syndrome. 35 rabbit hearts were perfused employing a Langendorff-setup. 10 hearts were perfused with increasing concentrations of propofol (50, 75, 100 µM). Propofol abbreviated action potential duration (APD90) in a concentration-dependent manner without altering spatial dispersion of repolarization (SDR). Consequently, no proarrhythmic effects of propofol were observed. In 12 further hearts, erythromycin was employed to induce prolongation of cardiac repolarization. Erythromycin led to an amplification of SDR and triggered 36 episodes of TdP. Additional infusion of propofol abbreviated repolarization and reduced SDR. No episodes of TdP were observed with propofol. Similarly, ondansetron prolonged cardiac repolarization in another 13 hearts. SDR was increased and 36 episodes of TdP occurred. With additional propofol infusion, repolarization was abbreviated, SDR reduced and triggered activity abolished. In this experimental whole-heart study, propofol abbreviated repolarization without triggering TdP. On the contrary, propofol reversed prolongation of repolarization caused by erythromycin or ondansetron, reduced SDR and thereby eliminated drug-induced TdP.

Severe proarrhythmic potential of risperidone compared to quetiapine in an experimental whole-heart model of proarrhythmia

In several case reports, proarrhythmic effects of antipsychotic drugs have been reported. The aim of the present study was to investigate if application of risperidone or quetiapine has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In 24 isolated rabbit hearts, risperidone (5 and 10μM, n=12) or quetiapine (5 and 10μM, n=12) was infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of risperidone as compared with baseline (5μM: +29ms, 10μM: +35ms, p<0.01) accompanied by an increase of action potential duration. Administration of risperidone also significantly increased spatial dispersion of repolarization (5μM: +16ms, 4μM: +19ms; p<0.05) as well as temporal dispersion of repolarization. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 8 of 12 hearts and polymorphic ventricular tachycardia resembling torsade de pointes in 6 of 12 hearts (10μM, 49 episodes). The results were compared with hearts treated with quetiapine (5 and 10μM). Quetiapine led to an increase in QT interval (5μM: +10ms; 10μM: +28ms; p<0.05) and a similar increase of APD90. However, treatment with quetiapine did not result in significant alterations of spatial and temporal dispersion of repolarization. No ventricular arrhythmias were observed in this group. In the present study, quetiapine demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, risperidone led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization.

Microvolt T-wave alternans amplifies spatial dispersion of repolarization in human subjects with ischemic cardiomyopathy

IntroductionIn experimental models, spatial dispersion of repolarization (DOR) due to discordant cellular alternans predisposes to ventricular fibrillation. To test the hypothesis that microvolt T-wave alternans (MTWA) in humans causes spatial DOR, we measured Tpeak-Tend interval (Tpe) and Tpe/QT ratio, electrocardiographic indices of spatial DOR. MethodsMean Tpe and Tpe/QT were compared in ischemic cardiomyopathy patients with positive and negative MTWA studies. ResultsMTWA was positive in 12 and negative in 24 patients. Tpe and Tpe/QT were higher in MTWA+ subjects compared to MTWA- subjects during exercise (64.5±6.8 vs. 54.9±8.7ms, p=0.001 and 0.218±0.03 vs. 0.177±0.02, p=0.001) but not at rest. ConclusionIschemic cardiomyopathy patients have increased Tpe and Tpe/QT when MTWA is induced during exercise, suggesting that MTWA causes increased spatial DOR in humans. Future studies are needed to determine if Tpe and Tpe/QT during exercise might predict increased risk of SCD alone or in combination with measurement of MTWA.

The role of short term memory and conduction velocity restitution in alternans formation.

Alternans is the periodic beat-to-beat short-long alternation in action potential duration (APD), which is considered to be a precursor of ventricular arrhythmias and sudden cardiac death. In extended cardiac tissue, electrical alternans can be either spatially concordant (SCA, all cells oscillate in phase) or spatially discordant (SDA, cells in different regions oscillate out of phase). SDA gives rise to an increase in the spatial dispersion of repolarization, which is thought to be proarrhythmic. In this paper, we investigated the effect of two aspects of short term memory (STM) (α, τ) and their interplay with conduction velocity (CV) restitution on alternans formation using numerical simulations of a mapping model with two beats of memory. Here, α quantifies the dependence of APD restitution on pacing history and τ characterizes APD accommodation, which is an exponential change of APD over time once basic cycle length (BCL) changes. Our main findings are as follows: In both single cell and spatially coupled homogeneous cable, the interplay between α and τ affects the dynamical behaviors of the system. For the case of large APD accommodation (τ ≥ 290 ms), increase in α leads to suppression of alternans. However, if APD accommodation is small (τ ≤ 250 ms), increase in α leads to appearance of additional alternans region. On the other hand, the slope of CV restitution does not change the regions of alternans in the cable. However, steep CV restitution leads to more complicated dynamical behaviors of the system. Specifically, SDA instead of SCA are observed. In addition, for steep CV restitution and sufficiently large τ, we observed formations of type II conduction block (CB2), transition from type I conduction block (CB1) to CB2, and unstable nodes.

Cardiac late Na⁺ current: proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress.

Myocyte sodium channel current that persists throughout the plateau of the cardiac action potential is referred to as late sodium current (I(Na-L)). The magnitude of I(Na-L) is normally small, but can increase significantly in common acute and chronic pathological settings as a result of inherited and/or acquired Na(+) channelopathies that alter channel opening and closing (ie, gating), location (trafficking), or anchoring and interactions with cytoskeletal proteins. An increase in I(Na-L) reduces repolarization reserve in atrial and ventricular myocytes and prolongs the action potential duration and the QT interval. An enhanced I(Na-L) is a cause of long QT syndrome 3. I(Na-L) may be a cause of afterdepolarizations, triggered arrhythmias, and spontaneous diastolic depolarization-induced automaticity. In addition, enhancement of I(Na-L) increases both the temporal and the spatial dispersion of repolarization in the myocardium and may lead to spatially discordant action potential duration alternans, wavebreak, and reentrant arrhythmias. Positive feedback loops between increases in I(Na-L) and the activity of Ca(2+)/calmodulin-dependent protein kinase II appear to contribute to the genesis of arrhythmias and to certain abnormalities of the ischemic heart. In this review, we discuss some of the more relevant experimental results, clinical findings, and insights from cellular and animal models that highlight the role of I(Na-L) in the genesis of arrhythmias, long QT syndromes, and intracellular Ca(2+) homeostasis.

The effects of nifekalant hydrochloride on the spatial dispersion of repolarization after direct current defibrillation in patients with oral amiodarone and β-blocker therapy

BackgroundAlthough nifekalant hydrochloride (NIF) has been demonstrated to suppress ventricular tachyarrhythmias, especially electrical storms, the mechanism by which it does so is still unclear. We examined the effects of NIF on the spatial dispersion of repolarization (SDR) after implantable cardioverter-defibrillator (ICD) shock. Methods and ResultsIn 35 patients with oral amiodarone and β-blocker therapy, and an ICD, we recorded the 87-lead electrocardiogram during sinus rhythm (CONTROL-1 group) under general anesthesia, and just after the termination of induced ventricular fibrillation (VF) by ICD shock, with or without NIF administration. In all recordings, the corrected QT interval (QTc) was measured in each lead. The dispersion of QTc (QTc-D; maximum QTc minus minimum QTc) was also measured. Compared with that in the CONTROL-1 group, the QTc-D exhibited significant deterioration after ICD shock (61±14 and 90±19ms1/2, respectively; p<0.05). However, after the termination of induced VF by ICD shock with NIF administration, the QTc-D did not differ significantly from that in the CONTROL-1 group (63±20 and 61±14ms1/2, respectively). ConclusionsNIF suppressed the deterioration of the SDR after ICD shock. This might be one of the mechanisms by which NIF suppresses recurrence of ventricular tachyarrhythmia just after ICD shock in patients with oral amiodarone and β-blocker therapy.

Electrophysiological and structural determinants of electrotonic modulation of repolarization by the activation sequence

Spatial dispersion of repolarization is known to play an important role in arrhythmogenesis. Electrotonic modulation of repolarization by the activation sequence has been observed in some species and tissue preparations, but to varying extents. Our study sought to determine the mechanisms underlying species- and tissue-dependent electrotonic modulation of repolarization in ventricles. Epi-fluorescence optical imaging of whole rat hearts and pig left ventricular wedges were used to assess epicardial spatial activation and repolarization characteristics. Experiments were supported by computer simulations using realistic geometries. Tight coupling between activation times (AT) and action potential duration (APD) were observed in rat experiments but not in pig. Linear correlation analysis found slopes of −1.03 ± 0.59 and −0.26 ± 0.13 for rat and pig, respectively (p < 0.0001). In rat, maximal dispersion of APD was 11.0 ± 3.1 ms but dispersion of repolarization time (RT) was relatively homogeneous (8.2 ± 2.7, p < 0.0001). However, in pig no such difference was observed between the dispersion of APD and RT (17.8 ± 6.1 vs. 17.7 ± 6.5, respectively). Localized elevations of APD (12.9 ± 8.3%) were identified at ventricular insertion sites of rat hearts both in experiments and simulations. Tissue geometry and action potential (AP) morphology contributed significantly to determining influence of electrotonic modulation. Simulations of a rat AP in a pig geometry decreased the slope of AT and APD relationships by 70.6% whereas slopes were increased by 75.0% when implementing a pig AP in a rat geometry. A modified pig AP, shortened to match the rat APD, showed little coupling between AT and APD with greatly reduced slope compared to the rat AP. Electrotonic modulation of repolarization by the activation sequence is especially pronounced in small hearts with murine-like APs. Tissue architecture and AP morphology play an important role in electrotonic modulation of repolarization.

Repolarização ventricular em pacientes diabéticos: caracterização e implicações clínicas

Diabetes mellitus is a chronic and very common condition, and there has been lately a considerable increase in its prevalence and incidence. Diabetic patients have increased cardiovascular mortality, in which malignant ventricular arrhythmias seem to be implicated. To study the effects of diabetes on ventricular repolarization parameters responsible for an increased susceptibility to malignant ventricular arrhythmias and/or sudden death. We selected a group of 110 diabetic patients and a group of 110 controls with the same distribution of age, gender and race. We evaluated the following parameters of ventricular repolarization: QT(max), QT(mean), QT(min), QTc(max), QTc(mean), QTc(min), QT and QTc dispersions, T(peak)-T(end) and jT(peak)-jT(end) intervals (D(II), V(2) and V(5)), T(peak)-T(end) and jT(peak)-jT(end) dispersions. The electrocardiograms (ECG) were performed by the same operator and reviewed by the same observers. QT intervals were corrected according to Bazzet's formula. We found significantly higher values of QTc(max) (p < 0.001), QTc(mean) (p < 0.001), QT dispersion (p < 0.001), QTc dispersion (p < 0.001), T(peak)-T(end) dispersion ( p < 0.001), and jT(peak)-jT(end) dispersion (p < 0.001) in diabetic patients than in controls. In diabetic patients, we observed prolonged values of QTc interval (5.5%), QT dispersion (0.9%), QTc dispersion (0%), T(peak)-T(end) interval (7.3%), jT(peak)-jT(end) interval (6.4%), T(peak)-T(end) dispersion (16.4%), and jT(peak)-jT(end) dispersion (12.7%). In the controls there were no prolonged values of any of the parameters. We concluded that diabetes causes prolongation and spatial dispersion of repolarization, and it may contribute to a greater ventricular electrical instability, whose expected clinical expression may be malignant ventricular arrhythmias.

Doxorubicin-induced Changes of Ventricular Repolarization Heterogeneity: Results of a Chronic Rat Study

Anthracycline chemotherapy produces cardiac repolarization abnormalities and arrhythmias because of cardiac toxicity of drugs. Ventricular arrhythmogenesis is attributable to increase in repolarization heterogeneity that is characterized by spatial dispersion of repolarization. The purpose of this work was to study the delayed effects of doxorubicin, the most frequently used anthracycline, on repolarization heterogeneity of the ventricular epicardium. Doxorubicin was administered to rats in a cumulative dose of 15 mg/kg (six equal intraperitoneal injections over a period of 2 weeks). Six weeks after the last injection, electrophysiological mapping of the ventricular epicardium was performed by sequential superimposition of a 64-electrode array on the left ventricular base, left ventricular apex, right ventricular base, and right ventricular apex. Activation-recovery intervals (ARIs) were measured. In doxorubicin-treated rats, ARIs were inhomogeneously prolonged, the overall ARI dispersion and local ARI dispersions were increased, and the interregional differences in ARI dispersion were decreased. These data demonstrate that doxorubicin-induced inhomogeneous prolongation of repolarization of the ventricular epicardium results in increasing heterogeneity of ventricular repolarization because of increasing intraregional heterogeneity while interregional differences are lost. Repolarization of the right ventricle is more sensitive to doxorubicin than that of the left one.

RT, RTend and Tpeak-End Intervalby Signal-Averaged Vector 187 Channel High Resolution ECG for Risk Stratification of Brugada Syndrome

Spatial and transmural dispersion of refractoriness have been reported to relate to arrhythmogenesis of Brugada syndrome (BS). Recovery time (RT), RTend and Tpeak-end (Tp-e) was evaluated in Brugada syndrome (BS). The synthesized signals from vector-projected 187-channel ECGs were amplified. Maximum inter-lead difference, mean inter-lead difference of RT, max. and avg. RT, max. and avg. RTend, max. and avg. Tp-e interval, and late potential by vector magnitude ECG were compared were studied in 27 spontaneous type 1 ECG and 14 non-type 1 BS patients. There were no significant differences in max. and avg. RTend interval, max. Tp-e interval, and avg. RT between type 1 and non-type 1 patients. But max. RT was marginally longer in type 1 patients (86.3±20.8 vs. 73.7±20.9 ms, P=0.07). No relation was found between max. and avg. RT and RTend, and max. Tpeak-end to the symptom. However, avg. Tp-e interval was significantly longer in patients with than that in patients without symptom (41.1±15.2 ms vs. 27.6±13.7 ms, P=0.028). Late potentials were positive in 87.5% (7/8) in 8 patients with symptom, and in 50% (16/32) in patients without symptom P=0.1074). Conclusions: Spatial dispersion of repolarization may relate to the typical ECG manifestation of BS and not spatial and transmural dispersion of repolarization but conduction disturbance may relate to the arrhythmic events.

The Effect of Air Pollution on Spatial Dispersion of Myocardial Repolarization in Healthy Human Volunteers

We tested the hypothesis that exposure to concentrated ambient particles (CAP) and/or ozone (O(3)) would increase dispersion of ventricular repolarization. Elevated levels of air pollution are associated with cardiac arrhythmias through mechanisms yet to be elucidated. Each of 25 volunteers (18 to 50 years of age) had four 2-h exposures to 150 μg/m(3) CAP; 120 parts per billion O(3); CAP + O(3); and filtered air (FA). Exposure-induced changes (Δ = 5-min epochs at end-start) in spatial dispersion of repolarization were determined from continuous 12-lead electrocardiographic recording. Spatial dispersion of repolarization assessed by corrected ΔT-wave peak to T-wave end interval increased significantly for CAP + O(3) (0.17 ± 0.03, p < 0.0001) exposure only, remaining significant when factoring FA (CAP + O(3) - FA) as control (0.11 ± 0.04, p = 0.013). The influence on repolarization was further verified by a significant increase in ΔQT dispersion (for CAP + O(3) compared with FA (5.7 ± 1.4, p = 0.0002). When the low-frequency to high-frequency ratio of heart rate variability (a conventional representation of sympathetic-parasympathetic balances) was included as a covariate, the effect estimate was positive for both corrected ΔT-wave peak to T-wave end interval (p = 0.002) and ΔQT dispersion (p = 0.038). When the high-frequency component (parasympathetic heart rate modulation) was included as a covariate with corrected ΔT-wave peak to T-wave end interval, the effect estimate for high frequency was inverse (p = 0.02). CAP + O(3) exposure alters dispersion of ventricular repolarization in part by increasing sympathetic and decreasing parasympathetic heart rate modulation. Detection of changes in repolarization parameters, even in this small cohort of healthy individuals, suggests an underappreciated role for air pollutants in urban arrhythmogenesis.