Repolarization Time Research Articles

Local areas of earlier repolarization cause epicardial repolarization heterogeneity in patients with apparently idiopathic ventricular fibrillation

Abstract Background Sudden cardiac arrest is often due to ventricular fibrillation (VF). In 5–10% of cases, no cause can be identified despite extensive cardiac examination, hence the designation idiopathic VF. Early repolarization with down sloping ST segments has been previously identified in patients with idiopathic VF. Early repolarization may increase repolarization heterogeneity with steep local repolarization time gradients, and thus form a substrate for idiopathic VF. Purpose To study the presence of local earlier repolarization and increased repolarization dispersion in idiopathic VF patients with noninvasive electrocardiographic imaging (ECGI). Methods A validated, non-commercial, potential-based formulation of ECGI was performed in 17 patients with idiopathic VF and 10 controls with no structural or electrical abnormalities. The ECGI measurement consisted of a body surface potential map with 184–256 electrodes in combination with a CT scan to obtain the torso and heart geometries. ECGI provided local epicardial repolarization times (RT) and RT isochrones. We determined the 1st (RT1%) and 99th percentile (RT99%) of RTs, the total epicardial RT dispersion (ERD: RT99%-RT1%), and the mean RT. Heart-rate corrected QT (QTc), TpTe intervals, and presence of the ER pattern were determined from the 12-lead ECG. All metrics were normalized to the body-surface Q. Results QTc and TpTe did not differ between the two groups (P=0.40 and P=0.83, respectively, Figure 1, panel A). One (10%) control subject and three (17.6%) idiopathic VF patients showed an ER pattern on the 12-lead ECG, with a down sloping ST segment only in 2/4 of the latter. With ECGI, the mean RT was similar between the groups (P=0.31), but the ERD was significantly increased in patients with idiopathic VF (P=0.01, figure 1, panel B). Moreover, RT1% was significantly lower in idiopathic VF patients in comparison to the controls (P=0.002), whereas the RT99% did not differ significantly (P=0.40). Subgroup analysis between ER positive and negative patients did not yield significantly different RT results. Conclusion Noninvasive ECGI, in contrast to the 12-lead ECG, revealed a wider range of epicardial RTs in patients with idiopathic VF, implying increased repolarization heterogeneity. This heterogeneity is caused by areas of earlier repolarization. Our data indicate the value of noninvasively diagnosing these repolarization abnormalities, and suggest promising potential value of the 1st percentile of RT to identify idiopathic VF patients with true early repolarization. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Figure 1

Determinants of reperfusion arrhythmias: action potential duration versus dispersion of repolarization.

The role of a border zone in arrhythmogenesis is not fully understood. In this study we evaluated independent contributions of action potential duration (APD) and dispersion of repolarization (DOR) across the normal/ischemic border to the development of ventricular tachycardia and/or fibrillation (VT/VF). Ischemia-reperfusion episodes were induced in anesthetized rats by transient coronary occlusion. Unipolar electrograms were recorded from ischemic and perfused areas using a 64-lead array to obtain activation times (ATs), repolarization times (RTs), activation-repolarization intervals (ARIs, a surrogate for APD) and dispersion of repolarization (DOR, as a difference between the earliest and latest RTs). Pinacidil (0.3 mg/kg) and glibenclamide (2 mg/kg) were applied to reduce DOR and to clamp APD at a lower and upper levels, respectively. In the control animals, APD shortened in the ischemic zone, DOR increased to 9 ± 3 ms, and VT/VF developed at reperfusion (6 out of 10). Pre-occlusion application of glibenclamide prolonged APD in the ischemic and perfused zones, decreased DOR to 5 ± 2 ms and did not affect VT/VF development (4 out of 11). Post-occlusion infusion of pinacidil shortened APD in the perfused zone, decreased DOR to 6 ± 3 ms and VT/VF incidence (2 out of 11). Extrasystolic burden at reperfusion was associated with VT/VF incidence in logistic regression analysis (β = 1.182, 95%CI 1.008 - 1.386, p = 0.04) and was lesser (p < 0.01) in the pinacidil group as compared to the control and glibenclamide groups. In conclusion, the results of this study suggest that the APDs in the perfused zone were a superior arrhythmogenic factor in respect to DOR in the present ischemia-reperfusion model.

Catheter ablation of atrial fibrillation results in significant QTc prolongation in the postoperative period.

BackgroundThe corrected QT interval (QTc) is a measure of ventricular repolarization time, and a prolonged QTc increases risk for malignant ventricular arrhythmias. Pulmonary vein isolation (PVI) may increase QTc but its effects have not been well studied.ObjectiveDetermine the incidence, risk factors, and outcomes of patients presenting for PVI in sinus and atrial fibrillation with postoperative QTc prolongation in a large cohort.MethodsWe performed a single-center retrospective study of consecutive atrial fibrillation ablations. QTc durations using Bazett correction were obtained from electrocardiograms at different postoperative intervals and compared to preoperative QTc. We studied clinical outcomes including clinically significant ventricular arrhythmia and death. A multivariable model was used to identify factors associated with clinically significant QTc prolongation, defined as ΔQTc ≥60 ms or new QTc duration ≥500 ms.ResultsA total of 352 PVIs were included in this study. We observed a statistically significant increase in mean QTc compared to baseline (446.3 ± 37.8 ms) on postoperative day (POD)0 (471.7 ± 38.2 ms, P < .001) and at POD1 (456.5 ± 35.0 ms, P < .001). There was no significant difference at 1 month (452.4 ± 33.5 ms, P = .39) and 3 months (447.3 ± 40.0 ms, P = .78). Sixty-six patients (19.2%) developed ΔQTc ≥60 ms or QTc ≥500 ms on POD0, with 4.1% persisting past 90 days. Female sex (odds ratio [OR] = 1.82, 95% confidence interval [CI] =1.01–3.29, P = .047) and history of coronary artery disease (OR = 2.16, 95% CI = 1.03–4.55, P = .042) were independently predictive of QTc prolongation ≥500 ms or ΔQTc ≥60 ms. There were no episodes of clinically significant ventricular arrhythmia or death attributable to arrhythmia.ConclusionQTc duration increased significantly immediately post-PVI and returned to baseline by 1 month. PVI did not provoke significant ventricular arrhythmias in our cohort.

Transient Acquired QT Interval Prolongation After Administration of Intravenous Ondansetron

A 62-year-old man with a history of stable ischemic heart disease presented to the emergency room with nausea, vomiting, and chest pain at rest. The chest pain was atypical in nature; it did not respond to nitroglycerin and did not worsen with exertion. He took only aspirin, metoprolol, and ramipril at home. The patient was normotensive and normoxemic. Serial high-sensitivity troponin test results were normal, and other bloodwork (including calcium and magnesium levels) was unremarkable, with the exception of a serum potassium level of 2.4 mmol/L. His presenting electrocardiogram (ECG; Fig. 1A ) showed sinus rhythm with a right bundle branch block and a mildly prolonged QTc interval (450 msec using Bazett’s formula1Bazett H. An analysis of the time-relations of electrocardiograms.Heart. 1920; 7: 353-370Google Scholar). However, conduction delays prolong the QRS interval, which affects the length of the QT interval without significant impact on the repolarization duration. Bogossian’s formula can correct the QTc interval in the presence of bundle branch blocks, and this yielded a normal QTc interval of 302 msec.2Bogossian H. Linz D. Heijman J. et al.QTc evaluation in patients with bundle branch block.Int J Cardiol Heart Vasc. 2020; 30: 100636PubMed Google ScholarFigure 1Electrocardiogram showing (A) sinus rhythm with a right bundle branch block (bbb) and mildly prolonged QTc interval; (B) ST changes with profound QTc interval prolongation; and (C) partial resolution of the ST changes.View Large Image Figure ViewerDownload Hi-res image Download (PPT) During his time in the emergency room, he experienced nausea and was given 4 mg of ondansetron intravenously. He was also given 40 mmol of KCl orally for his hypokalemia. Fifteen minutes later, the patient had a mild recurrence of atypical chest discomfort at rest, and another ECG Fig. 1B) was performed. This showed nonspecific ST changes with profound QTc interval prolongation, using both Bogossian’s formula (562 msec) and Bazett’s formula (628 msec). In addition to QTc interval prolongation, there was a dramatic difference in T wave morphology, including prolongation of the Tpeak–Tend interval. Ten minutes later, an ECG (Fig. 1C) and blood work were repeated, which showed a serum potassium level of 3 mmol/L, and partial resolution of the ST changes. The patient was not given any further QT-prolonging medication, and he was subsequently diagnosed with noncardiac chest pain after undergoing normal stress myocardial perfusion imaging. Severe hypokalemia is a known cause of QT interval prolongation.3Yelamanchi V.P. Molnar J. Ranade V. Somberg J.C. Influence of electrolyte abnormalities on interlead variability of ventricular repolarization times in 12-lead electrocardiography.Am J Ther. 2001; 8: 117-122Crossref PubMed Scopus (35) Google Scholar However, this patient’s initial ECG demonstrates a normal (by Bogossian’s formula) or only modestly prolonged (by Bazett’s formula) QTc interval. Subsequent administration of IV ondansetron resulted in profound transient QTc interval prolongation relative to this patient’s baseline, and marked changes in T wave morphology. It has been previously described that intravenous ondansetron administration can lead to QT interval prolongation and T wave changes. Our patient had a history of ischemic heart disease; the presence of structural heart disease increases the risk for acquired QT interval prolongation. Such prolongations of the QTc and Tpeak–Tend intervals are associated with increased risk of Torsades de Pointes and sudden cardiac death, with the risk increasing proportionally to QTc interval duration.4Thomas S. Behr E. Pharmacologic treatment of acquired QT prolongation and torsades de pointe.Br J Clin Pharmacol. 2016; 81: 420-427Crossref PubMed Scopus (67) Google Scholar, 5Hafermann M. Namdar R. Seibold G. et al.Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study.Drug Healthc Patient Saf. 2011; 3: 53-58PubMed Google Scholar, 6Tse G. Gong M. Meng L. et al.Predictive value of Tpeak-Tend indices for adverse outcomes on acquired QT prolongation: a meta-analysis.Front Physiol. 2018; 9: 1226Crossref PubMed Scopus (18) Google Scholar These images demonstrate the importance of cautious administration of QT interval–prolonging medications, particularly in the presence of other risk factors for QT interval prolongation such as hypokalemia and underlying structural heart disease, even if the baseline QTc interval is not markedly prolonged.Novel Teaching Points•Proper assessment of the QT interval is important in the setting of a bundle branch block, as widening of the QRS will cause subsequent QT interval prolongation without significant impact on the duration of repolarization.•Bogossian’s formula is an alternative method for calculating the QT interval in the setting of a bundle branch block. However, no single formula is perfect for QTc interval calculation in every situation.•Caution is needed when prescribing medications that prolong the QT interval, especially for patients with an underlying predilection for QT interval prolongation.

B-PO05-013 A CASE STUDY: HIGH RESOLUTION OPTICAL MAPPING OF A 19 YEAR OLD MALE VICTIM OF SUDDEN CARDIAC DEATH DURING A MARATHON

Sudden cardiac death due to ventricular fibrillation impacts 50 000 athletes per year. The most common finding at autopsy amongst young adults is sudden cardiac death with unexplained origins due to the absence of structural cardiac disease. A case study to investigate the electrophysiological properties in a male of 19 years old after suffering a fatal sudden cardiac arrest during a marathon event. A coronary-perfused left ventricular preparation was imaged using high resolution optical mapping of both epicardial and endocardial surfaces using a voltage-sensitive dye, Di-4-ANEPPS. Activation time, repolarization time and action potential duration were assessed during paced activity through the His bundle and endocardial and epicardial surfaces. Conduction system activation origins were identified as distant endocardial origins during His bundle pacing. Short-coupled S1S2S3S4 pacing was used to determine effective refractory period (ERP). Pacing protocols were repeated in the presence of isoprenaline (ISO) at 100nM, 500nM and 1μM to mimic stress conditions. No structural abnormalities were identified at the macroscopic level. At pacing cycle lengths of 667ms, a total myocardial activation time of 63ms was observed. Negligible changes were found in the presence of isoprenaline at all tested concentrations (up to 64ms). However, the latency of activation of conduction system activation origins following His pacing was shortened by ISO from 61ms to 42ms, 44ms and 16ms for 100nM, 500nM and 1μM. At short cycle length (250ms) His pacing, considerable AT latency reduction from 146ms to 43ms was observed under ISO at 100nM, but insensitive to further increases of ISO concentration. Local APD and RT gradients at His pacing origins were greatly enhanced by ISO (from 3ms/mm & 3ms/mm to 40ms/mm & 41 ms/mm) at short cycle lengths. The ERP of the His was up to 55ms shorter than endocardial pacing. Origins of ectopic activity coincided with His paced responses and frequency increased with ISO. The cardiac conduction system showed a greater dynamic range of excitability under short cycle length and isoprenaline stresses compared to the myocardium and likely underlie local repolarization gradients at Purkinje termini.

Myocardial repolarization time, J-point to T-peak and T-peak to T-end intervals, have different heart rate dependency and autonomic nerve interference in healthy prepubertal children

Objective: The JT interval of the myocardial repolarization time can be divided into Jpoint to T-peak interval (JTp) and T-peak to T-end interval (Tpe). It is well known that the JT interval is dependent on the heart rate, but little is known regarding heart rate dependence for JTp and Tpe. The aim of the present study was to clarify the heart rate dependence of JTp and Tpe and to elucidate the interference of autonomic nervous activity with these parameters. Methods: We evaluated 50 prepubertal children (mean age: 6.4 ± 0.5 years; male:female, 22:28) without heart disease. JTp, Tpe, and the preceding RR intervals were measured using 120 consecutive beats (lead CM5). First, the relationships between the RR interval and JTp and Tpe were evaluated by Pearson's correlation coefficient. Second, to evaluate autonomic interference with JTp and Tpe, the degree of coherence between RR interval variability and JTp or Tpe variability was calculated using spectral analysis. Results: Significant positive correlations were observed between the RR interval and JTp (y = 0.116x + 105.5; r = 0.594, p < 0.001) and between the RR interval and Tpe (y = 0.037x + 44.7; r = 0.432, p < 0.001). Tpe variability had a lower degree of coherence with RR interval variability (range: 0.039–0.5 Hz) than with JTp variability (0.401 [interquartile range, 0.352–0.460] vs. 0.593 [0.503–0.664], respectively; p < 0.001). Conclusions: Tpe had lower heart rate dependence and a lower degree of autonomic nervous interference than did JTp.

Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias.

The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset.

Noninvasive unipolar electrogram T-wave upslope is an accurate marker of local refractoriness in explanted hearts with drug-induced repolarization dispersion

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): French National Research Agency Matthijs Cluitmans is supported by a Veni grant from the Netherlands Organization for Scientific Research Background The relationship between T-wave morphology in local unipolar electrograms (UEGs) as mapped with noninvasive electrocardiographic imaging (ECGI) and local repolarization time (RT) has not been validated in pronounced RT dispersion. Purpose To study the time of upslope of the T-wave (Tup) in epicardial UEGs mapped with ECGI as a marker of time of local refractoriness (trefr, a surrogate for RT) in intact hearts with RT dispersion. Methods Six pig hearts were Langendorff-perfused with selective perfusion of the LAD artery and submersed in a torso-shaped tank containing 256 electrodes on the torso surface (panel A). RT was prolonged in the non-LAD regions by infusing dofetilide (‘Dof’) and shortened in the LAD region using pinacidil (‘Pin’). Tup was determined in both invasive UEGs (recorded with epicardial electrodes) and in noninvasive UEGs (reconstructed with ECGI). Programmed stimulation was used to determine trefr, defined as the shortest coupling interval with capture. Both metrics were determined relative to the common pacing spike. Results In all six hearts, selective dofetilide and pinacidil infusion resulted in delayed trefr and Tup in the non-LAD region, and shortened invasive trefr and noninvasive Tup in the LAD region, respectively (panel B and C). Over all 59 observations, Tup showed high agreement with trefr (values close to line of identity, panel D) with strong correlation (r = 0.91). This finding was independent of T-wave polarity (positive, negative or biphasic). Conclusion The moment of steepest upslope of the T-wave in a noninvasively reconstructed UEG accurately reflects end of local refractoriness in intact hearts, in case of pronounced RT dispersion. Under these circumstances, when local RT is defined by moment of re-excitability (allowing to link it to conduction block and re-entry), ECGI T-wave upslope can be taken as a truthful marker for local RT. Abstract Figure. Results

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

His resynchronization therapy produces more physiological ventricular repolarisation compared with biventricular pacing

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation BACKGROUND Biventricular pacing (BVP) is known to shorten activation time in patients with heart failure and left bundle branch block (LBBB) but its effects on repolarisation are not well studied. His bundle pacing (HBP) can correct LBBB to deliver cardiac resynchronization therapy (HBP-CRT), producing more physiological ventricular activation time and pattern than BVP. It is not known whether this translates to more physiological repolarisation, and if so whether the effect is mediated through its effects on activation. PURPOSE We measured the effects of HBP-CRT and BVP on left ventricular repolarisation using non-invasive epicardial mapping (ECGI). METHODS Patients were recruited in two groups. 1) Patients scheduled for clinically indicated BVP procedures for heart failure with LBBB, 2) Individuals with narrow QRS, normal ventricular function and intact conduction systems. Using non-invasive electrocardiographic imaging, we identified patients with LBBB in whom HBP shortened ECGI-derived left ventricular (LV) activation time by &amp;gt;10ms. We compared the effects of HBP and BVP on ECGI-derived dispersion of LV repolarisation times and activation-recovery intervals (a surrogate for action potential duration). RESULTS 21 patients in whom HBP shortened LV activation time by &amp;gt;10ms and an equal number of individuals with narrow intrinsic QRS were recruited. LV repolarisation dispersion was reduced by HBP-CRT (-42.0 ms, 95% confidence interval (CI): -52.3 to -31.7 ms, p &amp;lt;0.001) but not by BVP (11.9 ms, 95% CI: -6.24 to 30.1 ms, p = 0.182). The mean within-patient change in LV repolarisation dispersion from BVP to HBP-CRT was -56.5 ms (95% CI: -70.5 to -42.5 ms, p &amp;lt; 0.001). LV repolarisation dispersion with HBP-CRT was not different from individuals with narrow intrinsic QRS (2.75 ms, 95% CI: -16.2 to 21.7 ms, p = 0.981). The magnitude of reduction in LV repolarisation dispersion with HBP-CRT from intrinsic LBBB appeared similar to the magnitude of LV activation time shortening (-54.9 ms, 95% CI: -68.2 to -41.6 ms, p &amp;lt; 0.001). However, LV activation-recovery interval dispersion was also reduced by HBP-CRT (-44.3 ms, 95% CI: -69.2 to -19.3 ms, p &amp;lt; 0.001). Repolarisation mapping demonstrated normalisation of repolarisation pattern by HBP-CRT. CONCLUSIONS HBP-CRT can normalise repolarisation dispersion, producing more physiological repolarisation compared with BVP, which does not resolve the repolarisation abnormality of LBBB. HBP-CRT improves repolarisation through both activation resynchronization and modulation of action-potential duration. If these acute results translate to longer term outcomes, HBP-CRT may reduce the risk of ventricular arrhythmias in heart failure with LBBB to a greater extent than BVP. Abstract Figure. Epicardial Repolarisation Maps

Dynamic spatial dispersion of repolarization is present in regions critical for ischemic ventricular tachycardia ablation.

BackgroundThe presence of dynamic substrate changes may facilitate functional block and reentry in ventricular tachycardia (VT).ObjectiveWe aimed to study dynamic ventricular repolarization changes in critical regions of the VT circuit during sensed single extrastimulus pacing known as the Sense Protocol (SP).MethodsTwenty patients (aged 67 ± 9 years, 17 male) underwent VT ablation. A bipolar voltage map was obtained during sinus rhythm (SR) and right ventricular SP pacing at 20 ms above ventricular effective refractory period. Ventricular repolarization maps were constructed. Ventricular repolarization time (RT) was calculated from unipolar electrogram T waves, using the Wyatt method, as the dV/dtmax of the unipolar T wave. Entrainment or pace mapping confirmed critical sites for ablation.ResultsThe median global repolarization range (max-min RT per patient) was 166 ms (interquartile range [IQR] 143–181 ms) during SR mapping vs 208 ms (IQR 182–234) during SP mapping (P = .0003 vs intrinsic rhythm). Regions of late potentials (LP) had a longer RT during SP mapping compared to regions without LP (mean 394 ± 40 ms vs 342 ± 25 ms, P < .001). In paired regions of normal myocardium there was no significant spatial dispersion of repolarization (SDR)/10 mm2 during SP mapping vs SR mapping (SDR 11 ± 6 ms vs 10 ± 6 ms, P = .54). SDR/10 mm2 was greater in critical areas of the VT circuit during SP mapping 63 ± 29 ms vs SR mapping 16 ± 9 ms (P < .001).ConclusionVentricular repolarization is prolonged in regions of LP and increases dynamically, resulting in dynamic SDR in critical areas of the VT circuit. These dynamic substrate changes may be an important factor that facilitates VT circuits.

Parameter variations in personalized electrophysiological models of human heart ventricles.

The objectives of this study were to evaluate the accuracy of personalized numerical simulations of the electrical activity in human ventricles by comparing simulated electrocardiograms (ECGs) with real patients' ECGs and analyzing the sensitivity of the model output to variations in the model parameters. We used standard 12-lead ECGs and up to 224 unipolar body-surface ECGs to record three patients with cardiac resynchronization therapy devices and three patients with focal ventricular tachycardia. Patient-tailored geometrical models of the ventricles, atria, large vessels, liver, and spine were created using computed tomography data. Ten cases of focal ventricular activation were simulated using the bidomain model and the TNNP 2006 cellular model. The population-based values of electrical conductivities and other model parameters were used for accuracy analysis, and their variations were used for sensitivity analysis. The mean correlation coefficient between the simulated and real ECGs varied significantly (from r = 0.29 to r = 0.86) among the simulated cases. A strong mean correlation (r > 0.7) was found in eight of the ten model cases. The accuracy of the ECG simulation varied widely in the same patient depending on the localization of the excitation origin. The sensitivity analysis revealed that variations in the anisotropy ratio, blood conductivity, and cellular apicobasal heterogeneity had the strongest influence on transmembrane potential, while variation in lung conductivity had the greatest influence on body-surface ECGs. Futhermore, the anisotropy ratio predominantly affected the latest activation time and repolarization time dispersion, while the cellular apicobasal heterogeneity mainly affected the dispersion of action potential duration, and variation in lung conductivity mainly led to changes in the amplitudes of ECGs and cardiac electrograms. We also found that the effects of certain parameter variations had specific regional patterns on the cardiac and body surfaces. These observations are useful for further developing personalized cardiac models.

A novel method to correct repolarization time estimation from unipolar electrograms distorted by standard filtering.

Reliable patient-specific ventricular repolarization times (RTs) can identify regions of functional block or afterdepolarizations, indicating arrhythmogenic cardiac tissue and the risk of sudden cardiac death. Unipolar electrograms (UEs) record electric potentials, and the Wyatt method has been shown to be accurate for estimating RT from a UE. High-pass filtering is an important step in processing UEs, however, it is known to distort the T-wave phase of the UE, which may compromise the accuracy of the Wyatt method. The aim of this study was to examine the effects of high-pass filtering, and improve RT estimates derived from filtered UEs. We first generated a comprehensive set of UEs, corresponding to early and late activation and repolarization, that were then high-pass filtered with settings that mimicked the CARTO filter. We trained a deep neural network (DNN) to output a probabilistic estimation of RT and a measure of confidence, using the filtered synthetic UEs and their true RTs. Unfiltered ex-vivo human UEs were also filtered and the trained DNN used to estimate RT. Even a modest 2Hz high-pass filter imposes a significant error on RT estimation using the Wyatt method. The DNN outperformed the Wyatt method in 62.75% of cases, and produced a significantly lower absolute error (p=8.99E-13), with a median of 16.91ms, on 102 ex-vivo UEs. We also applied the DNN to patient UEs from CARTO, from which an RT map was computed. In conclusion, DNNs trained on synthetic UEs improve the RT estimation from filtered UEs, which leads to more reliable repolarization maps that help to identify patient-specific repolarization abnormalities.

Tracking Acoustic and Electrophysiological Changes Associated with CKD-induced Cardiac and Valvular Remodeling in a Mouse Model

Objective: Patients with chronic kidney disease (CKD) are at a higher risk of developing heart and valvular diseases than the general population. Non-invasive screening methods are needed to identify cardiovascular abnormalities in this population. In this study, we use a diet-induced CKD mouse to study AV and cardiac remodeling. We hypothesize that structural differences in AV and cardiac remodeling occur in CKD mice, and can be identified through phonocardiogram (PCG) and electrocardiogram (ECG) signals. Methods: Eight-week old C57BL/6J mice were assigned to the following groups: 1) control group, fed a normal chow diet for 12 weeks, and 2) CKD group, fed a chow containing 0.2% adenine, with normal (0.6%) phosphorus for 6 weeks to induce CKD, and 3) CKD+high phosphate (HP) group, fed CKD inducing diet for 6 weeks, and then fed for 6 weeks with a 0.2% adenine/1.8% phosphorus diet to induce cardiovascular calcification. PCG and ECG signals were recorded weekly and echocardiogram parameters were recorded at the experimental end-point. Results: The HP diet induced aortic valve calcification in the CKD+HP group. CKD and CKD+HP group had increased end-diastolic volume, which is indicative of left ventricular hypertrophy. Changes in ECG parameters indicate that CKD groups have delayed cardiac repolarization time, an early ECG marker associated with arrhythmias. PCG signals indicate the presence of a systolic and diastolic murmur in the CKD+HP group, a characteristic of both valve disease and cardiac dysfunction. Conclusions: We demonstrate that the diet-induced CKD mouse model can be used to study valve and cardiac remodeling, and ECG and PCG signals can noninvasively track valve and cardiac changes. Future studies will determine the adequacy of using these signals to predict cardiovascular diseases.

Electric Field-Based Dense Spatial Analysis of Unipolar Electrograms to Map Regional Activation-Repolarization Intervals

Objective: We wanted to develop a new method for processing dense spatially sampled unipolar electrograms, that yields physiological spatial distributions in activation-repolarization intervals.Background: Spatial heterogeneity in repolarization plays an important role in genesis and sustainment of cardiac arrhythmias. Reliable determination of repolarization times at high resolution on electrograms remains a difficult task. Methods: The new method describes the electrical activity on the heart's surface in terms of a physical electric field (E-field). Activation and repolarization times are calculated using an amplitude weighted average on QRS and T-waves. Activation-recovery intervals (ARI) obtained with this E-field method were validated against action potential durations (APD90) from monophasic action potential measurements. Relevance of the method was shown by calculating dense spatial distributions of beat-to-beat variability of repolarization (BVR) in myocardial infarction (MI).Results: E-field waveforms were more spatially homogeneous than the unipolar electrograms. The ARI strongly correlated with the APD90 (r2=0.94; p<0.001). Continuous activation and repolarization patterns were obtained, and the method removes non-physiological sharp spatial gradients obtained by currently adopted methods. Spatial BVR analysis revealed an increase in maximum BVR, spatial variance of BVR and spatial gradient of BVR in the border zone versus remote region of MI (all p<0.01). All BVR values were in pathophysiological range as described in other studies.Conclusion: The E-field method allows for a reliable determination of activation and repolarization times over the whole left ventricle. The new methodology confirmed that the border zone of myocardial infarction is a region with patches of increased variability of repolarization.

Effects of serum vitamin D level on ventricular repolarization in children and adolescents.

Low levels of vitamin D are known to increase cardiovascular mortality due to different risks. We aimed to examine whether low vitamin D levels in children and adolescents cause ventricular repolarization changes. Sixtyseven healthy cases aged between 3.5 and 17 years were included. According to levels of vitamin D, cases were grouped as sufficient (n=44), insufficient (n=13) and deficiency (n=10). Ventricular repolarization parameters were measured manually. Levels of vitamin D were different for cases with insufficiency and deficiency compared to sufficiency ones (102±54.9 vs 24.4±7 ng/ml, p<0.001 and 102±54.9 vs 16.6±8.3 ng/ml, respectively, p<0.001). In the insufficient group the following parameters were different from sufficient group: QTmean (357.8±25.3 vs 332±29.9 ms, p=0.012), JTc (310.8±20.2 vs 331.6±21 ms, p=0.005) and Tpe/QT (0.2±0.02 vs 0.22±0.02, p=0.02). It was found that the level of serum vitamin D correlated with JTc (r=-0.37, p=0.002), Tp-e (r=-0.29, p=0.015) and Tp-e/QT (r=-0.24, p=0.047). In the linear regression analysis, it was found that dropping level of vitamin D below normal was an independent risk factor for prolonged duration of JTc (p=0.015). Decline in vitamin D levels causes ventricular repolarization anomaly. As the decrease in vitamin D levels deepens, repolarization times become longer. These results could indicate that decrease in vitamin D levels can increase sensitivity to ventricular arrhythmias (Tab. 3, Ref. 45). Text in PDF www.elis.sk Keywords: adolescent, arrhythmia, child, vitamin D, ventricular repolarization.

Melatonin Prevents Early but Not Delayed Ventricular Fibrillation in the Experimental Porcine Model of Acute Ischemia.

Antiarrhythmic effects of melatonin have been demonstrated ex vivo and in rodent models, but its action in a clinically relevant large mammalian model remains largely unknown. Objectives of the present study were to evaluate electrophysiological and antiarrhythmic effects of melatonin in a porcine model of acute myocardial infarction. Myocardial ischemia was induced by 40-min coronary occlusion in 25 anesthetized pigs. After ischemia onset, 12 animals received melatonin (4 mg/kg). 48 intramyocardial electrograms were recorded from left ventricular wall and interventricular septum (IVS). In each lead, activation time (AT) and repolarization time (RT) were determined. During ischemia, ATs and dispersion of repolarization (DOR = RTmax − RTmin) increased reaching maximal values by 3–5 and 20–25 min, respectively. Ventricular fibrillation (VF) incidence demonstrated no relations to redox state markers and was associated with increased DOR and delayed ATs (specifically, in an IVS base, an area adjacent to the ischemic zone) (p = 0.031). Melatonin prevented AT increase in the IVS base, (p < 0.001) precluding development of early VF (1–5 min, p = 0.016). VF occurrence in the delayed phase (17–40 min) where DOR was maximal was not modified by melatonin. Thus, melatonin-related enhancement of activation prevented development of early VF in the myocardial infarction model.

Abstract 15596: Maturation of Hipsc-cm Electrophysiological and Contractile Function for Enhanced Sensitivity of Cardiac Safety Assays

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have significantly advanced in vitro cardiac safety and disese modeling, yet remain an immature representation of human myocytes. Electrical or mechanical conditioning of hiPSC-CMs facilitates functional maturation, as measured by a positive force-frequency relationship, but current in vitro protocols require 2-4 weeks of conditioning. Using array-based contractility and local electrical stimulation, we detected functionally mature phenotypes and compound responses in hiPSC-CMs after only 48 hours of chronic pacing. To mature cardiomyocytes, hiPSC-CMs were cultured on 24- and 96-well MEA plates with a dedicated stimulation electrodes. Later, hiPSC-CMs were electrically or optically paced at 2Hz for 48 hours. Multimodal measures quantified contractile and electrophysiological responses to varied pacing rates and compound addition. After 48 hours of pacing, hiPSC-CMs displayed shortened repolarization timing compared to before chronic pacing (baseline: 423 +/- 21 ms; matured: 316 +/- 15 ms), without significant beat period changes (baseline: 1255 +/- 40 ms; matured: 1314 +/- 84 ms). Contractile beat amplitude was measured using array-based impedance during spontaneous beating and at increasing pacing rates (1, 1.2, 1.5, 2, and 2.5 Hz). Before chronic pacing, beat amplitude decreased with increasing pacing rate; after chronic pacing, the same wells displayed increased beat amplitudes with increasing pacing rate. The matured wells also showed enhanced sensitivity to positive inotropes, such as isoproterenol, digoxin, omecamtiv mecarbil, and dobutamine. Local extracellular action potentials (LEAP) further revealed altered electrophysiological response to ranolazine, a multichannel blocker. Unpaced control wells exhibited dose-dependent APD90 prolongation in response to ranolazine, whereas matured wells showed no APD90 change. Similar results were seen with 48 hour of optogenetic pacing at 2 Hz. Overall, hiPSC-CMs chronically paced for only 48 hours exhibited more mature functional phenotypes, including a positive force-frequnecy relationship, enhanced ionotrope sensitivity, and altered compound response.

Critical repolarization gradients determine the induction of reentry-based torsades de pointes arrhythmia in models of long QT syndrome

Torsades de pointes arrhythmia is a potentially lethal polymorphic ventricular tachyarrhythmia (pVT) in the setting of long QT syndrome. Arrhythmia susceptibility is influenced by risk factors modifying repolarization. The purpose of this article was to characterize repolarization duration and heterogeneity in relation to pVT inducibility and maintenance. Sotalol was infused regionally or globally in isolated Langendorff blood-perfused pig hearts (N = 7) to create repolarization time (RT) heterogeneities. Programmed stimulation and epicardial activation and repolarization mapping were performed. The role of RT (heterogeneities) was studied in more detail using a computer model of the human heart. pVTs (n = 11) were inducible at a critical combination of RT and RT heterogeneities. The pVT cycle lengths were similar in the short and long RT regions. Short-lasting pVTs were maintained by focal activity while longer-lasting pVTs by reentry wandering along the interface between the 2 regions. Local restitution curves from the long and short RT regions crossed. This was associated with T-wave inversion at coupling intervals at either side of the crossing point. These experimental observations were confirmed by the computer simulations. pVTs are inducible within a critical range of RT and RT heterogeneities and are maintained by reentry wandering along the repolarization gradient. Double potentials localize at the core of the reentrant circuit and reflect phase singularities. RT gradient and T waves invert with short-coupled premature beats in the long RT region as a result of the crossing of the restitution curves allowing reentry initiation.

Dispersion of ventricular repolarization: Temporal and spatial.

Repolarization heterogeneity (RH) is an intrinsic property of ventricular myocardium and the reason for T-wave formation on electrocardiogram (ECG). Exceeding the physiologically based RH level is associated with appearance of life-threatening ventricular arrhythmias and sudden cardiac death. In this regard, an accurate and comprehensive evaluation of the degree of RH parameters is of importance for assessment of heart state and arrhythmic risk. This review is devoted to comprehensive consideration of RH phenomena in terms of electrophysiological processes underlying RH, cardiac electric field formation during ventricular repolarization, as well as clinical significance of RH and its reflection on ECG parameters. The formation of transmural, apicobasal, left-to-right and anterior-posterior gradients of action potential durations and end of repolarization times resulting from the heterogenous distribution of repolarizing ion currents and action potential morphology throughout the heart ventricles, and the different sensitivity of myocardial cells in different ventricular regions to the action of pharmacological agents, temperature, frequency of stimulation, etc., are being discussed. The review is focused on the fact that RH has different aspects – temporal and spatial, global and local; ECG reflection of various RH aspects and their clinical significance are being discussed. Strategies for comprehensive assessment of ventricular RH using different ECG indices reflecting various RH aspects are presented.