Repolarization Characteristics Research Articles

Arginine-assembly as NO nano-donor prevents the negative feedback of macrophage repolarization by mitochondrial dysfunction for cancer immunotherapy

Repolarizing the tumor-associated macrophages (TAMs) towards the antitumoral M1-like phenotype has been a promising approach for cancer immunotherapy. However, the anti-cancer immune response is severely limited mainly by the repolarized M1-like macrophages belatedly returning to the M2-like phenotype (i.e., negative feedback). Inspired by nitric oxide (NO) effectively preventing repolarization of inflammatory macrophages in inflammatory diseases, herein, we develop an arginine assembly, as NO nano-donor for NO generation to prevent the negative feedback of the macrophage repolarization. The strategy is to first apply reversible tagging of hydrophobic terephthalaldehyde to create an arginine nano-assembly, and then load a toll-like receptor 7/8 agonist resiquimod (R848) (R848@Arg). Through this strategy, a high loading efficiency of 40 % for the arginine and repolarization characteristics for TAMs can be achieved. Upon the macrophage repolarization by R848, NO can be intracellularly generated from the released arginine by the upregulated inducible nitric oxide synthase. Mechanistically, NO effectively prevented the negative feedback of the repolarized macrophage by mitochondrial dysfunction via blocking oxidative phosphorylation. Notably, R848@Arg significantly increased the tumor inhibition ratio by 3.13-fold as compared to the free R848 by maintaining the M1-like phenotype infiltrating into tumor. The Arg-assembly as NO nano-donor provides a promising method for effective repolarization of macrophages.

Formation of a border ischemic zone depends on plasma potassium concentration.

Extracellular potassium concentration might modify electrophysiological properties in the border zone of ischemic myocardium. We evaluated the depolarization and repolarization characteristics across the ischemic-normal border under [K+] variation. Sixty-four-lead epicardial mapping was performed in 26 rats ([K+] 2.3-6.4mM) in a model of acute ischemia/reperfusion. The animals with [K+] < 4.7mM (low-normal potassium) had an ischemic zone with ST-segment elevation and activation delay, a border zone with ST-segment elevation and no activation delay, and a normal zone without electrophysiological abnormalities. The animals with [K+] >4.7mM (normal-high potassium) had only the ischemic and normal zones and no transitional area. Activation-repolarization intervals and local conduction velocities were inversely associated with [K+] in linear regression analysis with adjustment for the zone of myocardium. The reperfusion extrasystolic burden (ESB) was greater in the low-normal as compared to normal-high potassium animals. Ventricular tachycardia/fibrillation incidence did not differ between the groups. In patch-clamp experiments, hypoxia shortened action potential duration at 5.4mM but not at 1.3mM of [K+]. IK(ATP) current was lower at 1.3mM than at 5.4mM of [K+]. We conclude that the border zone formation in low-normal [K+] was associated with attenuation of IK(ATP) response to hypoxia and increased reperfusion ESB.

The Heart of Rett Syndrome: A Quantitative Analysis of Cardiac Repolarization.

Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

Comparison of immediate changes of repolarization parameters after left bundle branch area pacing and traditional biventricular pacing in heart failure patients.

Comparison of immediate changes of repolarization parameters after left bundle branch area pacing and traditional biventricular pacing in heart failure patients.

Electrocardiographic measures of repolarization heterogeneity are not predictive for Torsades de Pointes among undifferentiated patients with prolonged QTc: Acase control study.

Torsades de Pointes (TdP) is a potentially lethal polymorphic ventricular tachydysrhythmia associated with and caused by prolonged myocardial repolarization. However, prediction of TdP is challenging. We sought to determine if electrocardiographic myocardial repolarization heterogeneity is necessary and predictive of TdP. We performed a case control study of TdP at a large urban hospital. We identified cases based on a hospital center electrocardiogram(ECG) database search for tracings from 1/2005 to 6/2019 with heart rate corrected QT (QTc) > 500, QRS < 120, and heart rate (HR) < 60, and a subsequent natural language search of electronic health records for the terms: TdP, polymorphic ventricular tachycardia, sudden cardiac death, and relevant variants. Controls were drawn in a 2:1 ratio to cases from a similar pool of ECGs, and matching for QTc, heart rate, sex, and age. We abstracted historical, laboratory, and ECG data using detailed written instructions and an electronic database. We included a second blinded data abstractor to test data abstraction and manual ECG measurement reliability. We used General Electric (GE) QT Guard software for automated repolarization measurements. We compared groups using unpaired statistics. We included 75 cases and 150 controls. The number of current QTc prolonging medications and serum electrolytes were substantially the same between the two groups. We found no significant difference in measures of QT or T wave repolarization heterogeneity. Electrocardiographic repolarization heterogeneity is not greater in otherwise unselected patients with QTc prolongation who suffer TdP and does not appear predictive of TdP. However, previous observations suggest specific repolarization characteristics may be useful for defined patient subgroups at risk for TdP.

Arrhythmogenic right ventricular cardiomyopathy – evolution of electrocardiographic markers during long-term follow-up prior to ascertainment of diagnosis

Abstract Background Depolarization and repolarization abnormalities are part of the diagnostic Task Force Criteria of 2010 (TFC2010) for arrhythmogenic right ventricular cardiomyopathy (ARVC). These abnormalities are thought to be progressive but have also been described as dynamic and sometimes reversible. Evolution of ECG abnormalities prior to clinical ARVC diagnosis is poorly studied. Objective To assess the evolution of ECG depolarization and repolarization characteristics in patients with ARVC prior to diagnosis and to identify markers of disease progression at a preclinical stage. Methods 353 patients with definite ARVC from Sweden, Denmark, the Netherlands and Canada with at least one 12-lead digital ECG (65% males, 67% probands, 56% mutation carriers, median age at diagnosis 42 [IQR 29–53] years and median age at first ECG 44 [30–55] years) were included. Digital ECGs were extracted from regional ECG archives. ECGs with left bundle branch block, ventricular pacing or recorded either prior to 15 years of age or after heart transplantation were excluded. Remaining 6,871 ECGs were digitally processed and automatically analysed using the Glasgow algorithm. Median values for overall QRS duration, terminal activation delay (TAD) in lead V1 as well as amplitudes of QRS-T-components in precordial leads per patient per year were used for analyses and graphically represented using Lowess smoothing with cubic splines (Figure 1). Blue lines indicate smoothed conditional mean with 95% confidence interval (shadow). Time “0” (red line) indicates the time when TFC2010 were fulfilled for definite diagnosis. A database of 18,564 anonymized digital ECGs (58% males, median age at latest ECG 41 years [IQR 32–52]) who were in contact with health care during 2020–2021 was processed using the same exclusion criteria and signal-processing methodology as in the ARVC group and used as a reference (black line). Results TAD in lead V1 and overall QRS duration demonstrated a significant increase years before ARVC diagnosis, and significant reductions were seen in QRS-T voltages measured as R wave amplitude, QRS amplitude (the absolute sum of R wave and S wave), and T wave amplitude (Table 1 and Figure 1). The changes were seen in all precordial leads, not only the right-sided, and visually diverging from the controls. Conclusion Development of the ARVC ECG phenotype started several years before diagnosis and continued afterwards. QRS duration and TAD increased, QRS voltages decrease, and T wave amplitude decreased eventually leading to T wave inversion. These changes might be visually assessed but also measured with available ECG software. These findings may be clinically useful in the screening and follow-up of ARVC relatives. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Governmental funding of clinical research (ALF), Region Ostergotland, Sweden.The Swedish Heart-Lung Foundation.

Repolarization indicates electrical instability in ventricular arrhythmia originating from papillary muscle.

Cardiac arrhythmia originating from the papillary muscle (PM) can trigger ventricular fibrillation (VF) and cause sudden cardiac death even in the absence of structural heart disease. Most premature ventricular contractions, however, are benign and hitherto difficult to distinguish from a potentially fatal arrhythmia. Altered repolarization characteristics are associated with electrical instability, but electrophysiological changes which precede degeneration into VF are still not fully understood. Ventricular arrhythmia (VA) was induced by aconitine injection into PMs of healthy sheep. To investigate mechanisms of degeneration of stable VA into VF in structurally healthy hearts, endocardial high-density and epicardial mapping was performed during sinus rhythm (SR) and VA. The electrical restitution curve, modelling the relation of diastolic interval and activation recovery interval (a surrogate parameter for action potential duration), is steeper in VA than in non-arrhythmia (ventricular pacing and SR). Steeper restitution curves reflect electrical instability and propensity to degenerate into VF. Importantly, we find the parameter repolarization time in relation to cycle length (RT/CL) to differentiate self-limiting from degenerating arrhythmia with high specificity and sensitivity. RT/CL may serve as a simple index to aid differentiation between self-limiting and electrically instable arrhythmia with the propensity to degenerate to VF. RT/CL is independent of cycle length and could easily be measured to identify electrical instability in patients.

Why Is There an Increased Risk for Sudden Cardiac Death in Patients With Early Repolarization Syndrome?

The last two decades have changed the viewpoint on early repolarization syndrome (ERS). The prevalence of the early repolarization pattern is variable and ranges between 3-24% depending upon age, gender, and criteria used for J-point upliftment from baseline (0.05mV vs. 1 mV). While this pattern was previously linked with a benign result, multiple recent investigations have found a link between early repolarization and Sudden Cardiac Death (SCD) by causing life-threatening arrhythmias like Ventricular tachycardia/Ventricular fibrillation, a condition known as early repolarization syndrome. The syndrome falls under a broader bracket of J wave syndromes, which can be caused by early repolarization or depolarization abnormalities. The characteristics of early repolarization that are considered high risk for Sudden Cardiac Death include the amplitude of J-point upliftment from baseline ( > 0.2 mV), Inferior-lateral location of Early Repolarization pattern, and horizontal and downsloping ST-segment. Patients with symptomatic early repolarisation patterns on ECG are more likely to have repeated cardiac episodes. Implantable Cardioverter-Defibrillator (ICD) implantation and isoproterenol are the recommended treatments in symptomatic patients. On the other hand, asymptomatic patients with early repolarization patterns are prevalent and have a better outcome. Risk categorization is still obscure in asymptomatic early repolarization patterns. This traditional review outlines the known knowledge of pathophysiology behind the increased risk of sudden cardiac death, risk stratification of patients with ERS, and the treatment guidelines for patients with ERS. Further prospective studies are recommended to elucidate the exact mechanism for ventricular arrhythmogenesis in ERS patients and to risk stratifying asymptomatic patients with ERS.

Seasonal changes of electrophysiological heterogeneities in the rainbow trout ventricular myocardium.

IntroductionThermal adaptation in fish is accompanied by morphological and electrophysiological changes in the myocardium. Little is known regarding seasonal changes of spatiotemporal organization of ventricular excitation and repolarization processes. We aimed to evaluate transmural and apicobasal heterogeneity of depolarization and repolarization characteristics in the rainbow trout in-situ ventricular myocardium in summer and winter conditions.MethodsThe experiments were done in summer-acclimatized (SA, 18°C, n = 8) and winter-acclimatized (WA, 3°C, n = 8) rainbow trout (Oncorhynchus mykiss). 24 unipolar electrograms were recorded with 3 plunge needle electrodes (eight lead terminals each) impaled into the ventricular wall. Activation time (AT), end of repolarization time (RT), and activation-repolarization interval (ARI, a surrogate for action potential duration) were determined as dV/dt min during QRS-complex, dV/dt max during T-wave, and RT-AT difference, respectively.ResultsThe SA fish demonstrated relatively flat apicobasal and transmural AT and ARI profiles. In the WA animals, ATs and ARIs were longer as compared to SA animals (p≤0.001), ARIs were shorter in the compact layer than in the spongy layer (p≤0.050), and within the compact layer, the apical region had shorter ATs and longer ARIs as compared to the basal region (p≤0.050). In multiple linear regression analysis, ARI duration was associated with RR-interval and AT in SA and WA animals. The WA animals additionally demonstrated an independent association of ARIs with spatial localization across the ventricle.ConclusionCold conditions led to the spatial redistribution of repolarization durations in the rainbow trout ventricle and the formation of repolarization gradients typically observed in mammalian myocardium.

Repolarization characteristics indicate electrical instability in ventricular arrhythmia originating from papillary muscle

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK (German Center for Cardiovascular Research) Introduction Cardiac arrhythmia originating from the papillary muscle can trigger ventricular fibrillation and cause sudden cardiac death even in the absence of structural heart disease. Yet, no clinical parameters are known to reflect the propensity of arrhythmia to degenerate into ventricular fibrillation. Purpose We aimed at identification of parameters associated with degeneration of ventricular arrhythmia into ventricular fibrillation. Methods Ventricular arrhythmia was induced by aconitine injection into the papillary muscle of healthy sheep (n = 12) in an open-chest model. Endocardial high-density-mapping and epicardial mapping were performed. We determined repolarization time and activation-recovery-interval according to the Wyatt method. Results During focal arrhythmia faster conduction occurred in longitudinal and basal direction than transversal and apical direction. The electrical restitution curve, modelling relation of diastolic interval and activation-recovery-interval, is steeper in aconitine-induced ventricular arrhythmia than in ventricular pacing or sinus rhythm. Steeper restitution curves reflect electrical instability and propensity to degenerate into ventricular fibrillation. The repolarization-related parameters activation-recovery interval and repolarization time exhibit higher heterogeneity per beat in ventricular arrhythmia preceding degeneration into ventricular fibrillation. Repolarization time in relation to cycle length (RT/CL), which can easily be measured during electrophysiological procedures, differentiates self-limiting from degenerating arrhythmia with high specificity and sensitivity. Conclusion In structurally normal ovine hearts, the ratio of repolarization and cycle length (RT/CL) in ventricular arrhythmia and greater dispersion of repolarization are indicators of subsequent degeneration into ventricular fibrillation. While dispersion of repolarization is not easily acquired in clinical routine, a simple index (RT/CL) may be sufficient to differentiate between self-limiting and electrically instable arrhythmia with propensity to degenerate to ventricular fibrillation. Abstract Figure. Repolarization in VA model

Psoriatic arthritis is associated with myocardial repolarization dysregulation as assessed by the QTc interval and the Tp-e/QTc ratio

Aim: An increased risk of arrhythmia has been shown in patients with psoriatic arthritis (PsA). Tp-e interval and Tp-e/QT ratio are considered useful markers for the assessment of myocardial repolarization heterogeneity. In present study we aim to investigate the characteristics of ventricular repolarization on the basis of QTc interval and Tp-e/QTc ratio in patients PsA. Methods: This cross-sectional observational study included patients with psoriatic arthritis who were over 18 years of age. A control group was created with healthy volunteers. The diagnosis of psoriatic arthritis were done according to the CASPAR criteria. QT interval, corrected QT (QTc), Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were measured from the 12-lead electrocardiograms(ECG) of the PsA patients and control group. Results: The study population consisted of 82 patients with PsA and 82 healthy volunteers. According to electrocardiographic parameters the heart rate was similar in both groups, but QT, QTc, Tp-e intervals; Tp-e /QT and Tp-e/ QTc ratios were significantly higher in the PsA group. The median Tp-e/QTc ratio of the patients with PsA was significantly higher than the median Tp-e/QTc ratio of the control group (0.21 (0.20-0.25) vs. 0.18 (0.17-0.19, P<0.001). The correlation analysis showed a weak correlation between Tp-e/QTc ratio and CRP value (r=0.197, P=0.012). Conclusions: This is the first study to demonstrate the prolongation of the Tp-e/QTc ratio in patients with PsA. Prospective clinical studies to observe clinical importance of this finding particularly with regard to the arrhythmias and sudden death may be more valuable.

Precordial T-Wave Inversions in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy Who Present with the Initial Features of Right Ventricular Outflow Tract Arrhythmia.

Precordial T-wave inversion (TWI) is an important diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aimed to characterize the initial repolarization features of definite ARVC in patients who first presented with right ventricular outflow tract ventricular arrhythmia (RVOT-VA) and TWI. Patients who presented with RVOT-VA and TWI ≥ V2 were retrospectively assessed. The initial characteristics of repolarization between patients with and without a final diagnosis of definite ARVC during follow-up were compared. TWI ≥ V2 was observed in 61 of 553 patients (mean age: 44.1 ± 14.7 years; 14 men) with RVOT-VAs. After an average follow-up time of 54.9 ± 33.7 months, 31 (50.8%) patients were classified into the definite ARVC group and 30 (49.2%) into the non-definite ARVC group. The disappearance of precordial TWI ≥ V2 was observed in eight (13.1%) patients after the elimination of RVOT-VAs. In a multivariate analysis of the initial electrocardiogram features, only fragmented QRS [odds ratio (OR): 15.45, 95% confidence interval (CI): 1.61-148.26, p = 0.02] and precordial V2 TpTe interval (OR: 1.03, 95% CI: 1.01-1.06, p = 0.02) could independently predict definite ARVC during longitudinal follow-up. An initial V2 TpTe cutoff value > 88.5 ms could predict the final diagnosis of definite ARVC, with a sensitivity and specificity of 74.2% and 78.6%, respectively. Despite the high risk of ARVC in RVOT-VAs and TWI ≥ V2, "normalization" of TWI was observed after ventricular arrhythmia elimination in 13.1% of the patients. Fragmented QRS and longer V2 TpTe interval were associated with definite ARVC during longitudinal follow-up.

Nocturnal low glucose detection in healthy elderly from one-lead ECG using convolutional denoising autoencoders

Hypoglycemia is a condition caused by low blood glucose levels, mainly affecting people with diabetes. Low levels of blood glucose can be dangerous, causing multiple complications over time. Hypoglycemia affects the repolarization characteristics of the heart. This study presents a personalized, deep learning-based approach that enables nocturnal hypoglycemia detection using raw electrocardiogram (ECG) signals, recorded with non-invasive, wearable devices. The study was carried out in a calorimeter room during 24–36 h monitoring on twenty-five, healthy, elderly participants. The results of this study (accuracy of ≈90%) provide evidence for the feasibility of a non-invasive, ECG-based hypoglycemia alarming system. Moreover, leveraging an unsupervised method (i.e. convolutional denoising autoencoder) and visualizing the ECG heartbeats in the embeddings space, clear heartbeats clusters grouped by glucose levels could be determined, showing that specific patterns in the input heartbeats are indeed glucose discriminative and the autoencoder could successfully capture those patterns.

Repolarization Predictors of Fetal Long QT Syndrome.

BackgroundDiagnosis of fetal long QT syndrome (LQTS) using fetal magnetocardiography (fMCG) is straightforward in cases of overt QTc prolongation accompanied by LQTS rhythms; however, cases of isolated QTc prolongation can be challenging.ObjectiveThe purpose of this study was to characterize repolarization in normal and phenotype-positive LQTS fetuses with the goal of using additional parameters of repolarization to improve the accuracy of fMCG diagnosis of LQTS.MethodsfMCG recordings were taken from 37 phenotype-positive fetuses with confirmed LQTS and 132 normal controls. The normal fetuses were grouped into those with T and U waves and those with only T waves. We compared the repolarization characteristics of normal fetuses with only T waves with those of LQTS fetuses. We also compared the repolarization characteristics of normal fetuses with T and U waves with those of LQTS fetuses with 2-component T waves.ResultsLate-peaking T waves were strongly associated with LQTS (35/37 [95%]). No normal fetuses showed both QTc prolongation (QTc >500 ms) and a late-peaking T wave. U waves were seen in 11 normal fetuses (8%) and resulted in waveforms that often mimicked those of the 19 LQTS fetuses with 2-component T waves. However, in normal fetuses the polarities of the T and U waves were the same, whereas in LQTS fetuses with 2-component T waves the polarities of the components usually were opposite.ConclusionA late-peaking T wave in association with QTc prolongation is a distinctive, reliable indicator of fetal LQTS. U waves confound assessment of QTc; however, normal U waves usually can be distinguished from LQTS T waves based on polarity.

Novel use of repolarization parameters in electrocardiographic imaging to uncover arrhythmogenic substrate

BackgroundMeasuring repolarization characteristics is challenging and has been reserved for experienced physicians. In electrocardiographic imaging (ECGI), activation-recovery interval (ARI) is used as a measure of local cardiac repolarization duration. We hypothesized that repolarization characteristics, such as local electrogram morphology and local and global dispersion of repolarization timing and duration could be of significance in ECGI. ObjectiveTo further explore their potential in arrhythmic risk stratification we investigated the use of novel repolarization parameters in ECGI. Materials and methodsWe developed and compared methods for T-peak and T-end detection in reconstructed potentials. All methods were validated on annotated reconstructed electrograms (EGMs). Characteristics of the reconstructed EGMs and epicardial substrate maps in IVF patients were analyzed by using data recorded during sinus rhythm. The ECGI data were analyzed for EGM morphology, conduction, and repolarization. ResultsWe acquired ECGI data from 8 subjects for this study. In all patients we evaluated four repolarization parameters: Repolarization time, T-wave area, Tpeak-Tend interval, and T-wave alternans. Most prominent findings were steep repolarization time gradients in regions with flat EGMs. These regions were also characterized by low T-wave area and large differences in Tpeak-Tend interval. ConclusionsMeasuring novel repolarization parameters in reconstructed electrograms acquired with ECGI is feasible, can be done in a fully automated manner and may provide additional information on underlying arrhythmogenic substrate for risk stratification. Further studies are needed to investigate their potential use and clinical application.

Repolarization of Ferroelectric Superlattices BaZrO3/BaTiO3

With the use of the modified Sawyer-Tower scheme and Merz technique, studies were conducted on the repolarization characteristics of ferroelectric (BaZrO3/BaTiO3) superlattices on monocrystalline MgO substrate. Studies of temperature changes in the dielectric hysteresis loops indicated a sufficiently smooth decrease in spontaneous polarization compared with homogeneous barium titanate near the phase transition temperature of the superlattice. Experimental studies of switched currents have shown that the switching processes in the synthesized superlattices are implemented in two stages: activation motion (“creep” mode) and non-activation motion (slip mode). The presence of the activation switching stage and the numerical estimates show that with high probability, the movement of domain boundaries accomplishes the processes of switching in the studied superlattice. The threshold field separating the stated stages decreases with increasing temperature up to the Curie point of the superlattice, similar to the coercive field. Detection of the non-strictly exponential dependence of the switching current on the reverse field strength in the activation stage was modulated by the dependence with the power-law exponent for the applied electric field. Both techniques indicate that the studied superlattices have a small internal displacement field directed from the superlattice to the substrate.

Advantages and pitfalls of noninvasive electrocardiographic imaging

BackgroundWith increasing clinical use of Electrocardiographic Imaging (ECGI), it is imperative to understand the limits of this technique. The objective of this study is to evaluate a potential-based ECGI approach for activation and repolarization mapping in sinus rhythm. MethodLangendorff-perfused pig hearts were suspended in a human-shaped torso tank. Electrograms were recorded with a 108-electrode sock and ECGs with 256 electrodes embedded in the tank surface. Left bundle branch block (LBBB) was developed in 4 hearts through ablation, and repolarization abnormalities in another 4 hearts through regional perfusion of dofetilide and pinacidil. Electrograms were noninvasively reconstructed and reconstructed activation and repolarization features were compared to those recorded. ResultsVisual consistency between ECGI and recorded activation and repolarization maps was high. While reconstructed repolarization times showed significantly more error than activation times quantitatively, patterns were reconstructed with a similar level of accuracy. The number of epicardial breakthrough sites was underestimated by ECGI and these were misplaced (>20 mm) in location. Likewise, ECGI reconstructed activation maps demonstrated artificial lines of block resulting from a W-shaped QRS waveform that were not present in recorded maps. Nevertheless, ECGI allowed identification of regions of abnormal repolarization reasonably accurately in terms of size, location and timing. ConclusionsThis study validates a potential-based ECGI approach to noninvasively image activation and recovery in sinus rhythm. Despite inaccuracies in epicardial breakthroughs and lines of conduction block, other important clinical features such as regions of abnormal repolarization can be accurately derived making ECGI a valuable clinical tool.

Repolarization variability independent of heart rate during sympathetic activation elicited by head-up tilt.

The fraction of repolarization variability independent of RR interval variability is of clinical interest. It has been linked to direct autonomic nervous system (ANS) regulation of the ventricles in healthy subjects and seems to reflect the instability of the ventricular repolarization process in heart disease. In this study, we sought to identify repolarization measures that best reflect the sympathetic influences on the ventricles independent of the RR interval. ECG was recorded in 46 young subjects during supine and then following 45 degrees head-up tilt. RR intervals and five repolarization features (QTend, QTpeak, RTend, RTpeak, and TpTe) were extracted from the ECG recordings. Repolarization variability was separated into RR-dependent and RR-independent variability using parametric spectral analysis. Results show that LF power of TpTe is independent of RR in both supine and tilt, while the LF power of QTend and RTend independent of RR and respiration increases following tilt. We conclude that TpTe is independent of RR and is highly affected by respiration. QTend and RTend LF power might reflect the sympathetic influences on the ventricles elicited by tilt. Graphical abstract.

Patient-Specific Identification of Atrial Flutter Vulnerability-A Computational Approach to Reveal Latent Reentry Pathways.

Atypical atrial flutter (AFlut) is a reentrant arrhythmia which patients frequently develop after ablation for atrial fibrillation (AF). Indeed, substrate modifications during AF ablation can increase the likelihood to develop AFlut and it is clinically not feasible to reliably and sensitively test if a patient is vulnerable to AFlut. Here, we present a novel method based on personalized computational models to identify pathways along which AFlut can be sustained in an individual patient. We build a personalized model of atrial excitation propagation considering the anatomy as well as the spatial distribution of anisotropic conduction velocity and repolarization characteristics based on a combination of a priori knowledge on the population level and information derived from measurements performed in the individual patient. The fast marching scheme is employed to compute activation times for stimuli from all parts of the atria. Potential flutter pathways are then identified by tracing loops from wave front collision sites and constricting them using a geometric snake approach under consideration of the heterogeneous wavelength condition. In this way, all pathways along which AFlut can be sustained are identified. Flutter pathways can be instantiated by using an eikonal-diffusion phase extrapolation approach and a dynamic multifront fast marching simulation. In these dynamic simulations, the initial pattern eventually turns into the one driven by the dominant pathway, which is the only pathway that can be observed clinically. We assessed the sensitivity of the flutter pathway maps with respect to conduction velocity and its anisotropy. Moreover, we demonstrate the application of tailored models considering disease-specific repolarization properties (healthy, AF-remodeled, potassium channel mutations) as well as applicabiltiy on a clinical dataset. Finally, we tested how AFlut vulnerability of these substrates is modulated by exemplary antiarrhythmic drugs (amiodarone, dronedarone). Our novel method allows to assess the vulnerability of an individual patient to develop AFlut based on the personal anatomical, electrophysiological, and pharmacological characteristics. In contrast to clinical electrophysiological studies, our computational approach provides the means to identify all possible AFlut pathways and not just the currently dominant one. This allows to consider all relevant AFlut pathways when tailoring clinical ablation therapy in order to reduce the development and recurrence of AFlut.

SAFETY OF CHRONIC CARDIAC RYANODINE RECEPTOR MODULATION: A 10-YEAR EXPERIENCE

Cardiac Ryanodine Receptor (RyR-2) is crucial in calcium handling, and dysfunction of this process is now being identified as an essential mechanism in arrhythmias, contractile dysfunction, and heart failure. Data from ex-vivo and animal studies have created significant excitement surrounding RyR-2 modulation as a potential novel therapeutic target in various cardiac conditions. However, much needed clinical trials in humans are currently lacking. Therefore, we evaluate the cardiac safety and effect of chronic use of the RyR-2 modulator Dantrolene on cardiac conduction, repolarization, and LV function. Patients treated with chronic oral dantrolene (> 3 months), for RyR-1 modulation mainly for muscle disorders, over the last 27 years in the Malignant Hyperthermia Clinic at Toronto General Hospital and without known cardiac disease, were screened. We included patients who had an electrocardiogram or echocardiogram performed > 3 months after their chronic oral dantrolene use. We analyzed original echocardiograms for mechanical indices and electrocardiograms for activation and repolarization features. 20 patients (male=15) were included. At the time of the first cardiac test, age was 58±13 years, and therapy duration was 10.6±6 years (after which ECG or echo performed). The median dose was 100 mg (IQR 25-100). All ECGs revealed sinus rhythm, and mean heart rate was 68±14 bpm. Corrected QTc was 421±25ms. All conduction and repolarization parameters were within normal limits (Table 1). Three patients had serial ECGs on and off dantrolene, and those showed no changes when compared to the ones performed while taking dantrolene. Ten patients (50%) had an echocardiogram illustrating normal LV size and function (LVEF 62±3%). No major cardiac events (serious arrhythmia, sudden death, or myocardial infarction) noted during dantrolene therapy. No dose-related QTc prolongation seen. Patients on oral dantrolene who had cardiac testing 10 years after chronic therapy didn't have QRS or QTc prolongation and their LVEF was normal. This suggests that chronic modulation of cardiac RyR-2 with dantrolene is safe. However, prospective crossover studies are needed to confirm these findings.