Repolarization Dynamics Research Articles

Biological therapy safety in chronic inflammatory arthropathy patients.

The marketing of biological therapies transformed the treatment of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. But there is still concern about patient safety and management in daily clinical practice. The aim of this study was to estimate risk factors of the adverse effects in a cohort of Spanish patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. A single institution, descriptive, retrospective, cohort study was developed from January 2009 to December 2016. Patients diagnosed with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis on biological therapies were included. Undesirable events affecting patients during biological therapy, their clinical implications and the use of health resources related to adverse effects were collected. Three hundred and sixty-two patients corresponding to 478 biological therapy lines were analysed. It implied 1192 years of monitoring. There were 57 adverse effects per 100 biological patient- years and 4.8 serious adverse effects per 100 biological patient-years. The only significant factor for a likely serious adverse effect was having a Charlson Index ≥10, OR of 6.2 (CI 95%: 3.4-11.1, p<0.001). Around 15 % of patients with adverse effects were admitted to hospital and 25% received attention at the Emergency Department. Over half of the patients with arthropathies on biological therapy can suffer adverse effect during treatment but only 8.5% of these effects are serious. Special vigilance must be paid to patients with a higher number of comorbidities because they are more likely to experience serious adverse effects.

Long-Term Microgravity Exposure Increases ECG Repolarization Instability Manifested by Low-Frequency Oscillations of T-Wave Vector.

Ventricular arrhythmias and sudden cardiac death during long-term space missions are a major concern for space agencies. Long-duration spaceflight and its ground-based analog head-down bed rest (HDBR) have been reported to markedly alter autonomic and cardiac functioning, particularly affecting ventricular repolarization of the electrocardiogram (ECG). In this study, novel methods are developed, departing from previously published methodologies, to quantify the index of Periodic Repolarization Dynamics (PRD), an arrhythmic risk marker that characterizes sympathetically-mediated low-frequency oscillations in the T-wave vector. PRD is evaluated in ECGs from 42 volunteers at rest and during an orthostatic tilt table test recorded before and after 60-day –6° HDBR. Our results indicate that tilt test, on top of enhancing sympathetic regulation of heart rate, notably increases PRD, both before and after HDBR, thus supporting previous evidence on PRD being an indicator of sympathetic modulation of ventricular repolarization. Importantly, long-term microgravity exposure is shown to lead to significant increases in PRD, both when evaluated at rest and, even more notably, in response to tilt test. The extent of microgravity-induced changes in PRD has been associated with arrhythmic risk in prior studies. An exercise-based, but not a nutrition-based, countermeasure is able to partially reverse microgravity-induced effects on PRD. In conclusion, long-term exposure to microgravity conditions leads to elevated low-frequency oscillations of ventricular repolarization, which are potentiated following sympathetic stimulation and are related to increased risk for repolarization instabilities and arrhythmias. Tested countermeasures are only partially effective in counteracting microgravity effects.

The Effect of Emotional Valence on Ventricular Repolarization Dynamics Is Mediated by Heart Rate Variability: A Study of QT Variability and Music-Induced Emotions.

BackgroundEmotions can affect cardiac activity, but their impact on ventricular repolarization variability, an important parameter providing information about cardiac risk and autonomic nervous system activity, is unknown. The beat-to-beat variability of the QT interval (QTV) from the body surface ECG is a non-invasive marker of repolarization variability, which can be decomposed into QTV related to RR variability (QTVrRRV) and QTV unrelated to RRV (QTVuRRV), with the latter thought to be a marker of intrinsic repolarization variability.AimTo determine the effect of emotional valence (pleasant and unpleasant) on repolarization variability in healthy volunteers by means of QTV analysis.Methods75 individuals (24.5 ± 3.2 years, 36 females) without a history of cardiovascular disease listened to music-excerpts that were either felt as pleasant (n = 6) or unpleasant (n = 6). Excerpts lasted about 90 s and were presented in a random order along with silent intervals (n = 6). QTV and RRV were derived from the ECG and the time-frequency spectrum of RRV, QTV, QTVuRRV and QTVrRRV as well as time-frequency coherence between QTV and RRV were estimated. Analysis was performed in low-frequency (LF), high frequency (HF) and total spectral bands.ResultsThe heart rate-corrected QTV showed a small but significant increase from silence (median 347/interquartile range 31 ms) to listening to music felt as unpleasant (351/30 ms) and pleasant (355/32 ms). The dynamic response of QTV to emotional valence showed a transient phase lasting about 20 s after the onset of each musical excerpt. QTV and RRV were highly correlated in both HF and LF (mean coherence ranging 0.76–0.85). QTV and QTVrRRV decreased during listening to music felt as pleasant and unpleasant with respect to silence and further decreased during listening to music felt as pleasant. QTVuRRV was small and not affected by emotional valence.ConclusionEmotional valence, as evoked by music, has a small but significant effect on QTV and QTVrRRV, but not on QTVuRRV. This suggests that the interaction between emotional valence and ventricular repolarization variability is mediated by cycle length dynamics and not due to intrinsic repolarization variability.

Cardiovascular Predictive Value and Genetic Basis of Ventricular Repolarization Dynamics.

Early prediction of cardiovascular risk in the general population remains an important issue. The T-wave morphology restitution (TMR), an ECG marker quantifying ventricular repolarization dynamics, is strongly associated with cardiovascular mortality in patients with heart failure. Our aim was to evaluate the cardiovascular prognostic value of TMR in a UK middle-aged population and identify any genetic contribution. We analyzed ECG recordings from 55 222 individuals from a UK middle-aged population undergoing an exercise stress test in UK Biobank (UKB). TMR was used to measure ventricular repolarization dynamics, exposed in this cohort by exercise (TMR during exercise, TMRex) and recovery from exercise (TMR during recovery, TMRrec). The primary end point was cardiovascular events; secondary end points were all-cause mortality, ventricular arrhythmias, and atrial fibrillation with median follow-up of 7 years. Genome-wide association studies for TMRex and TMRrec were performed, and genetic risk scores were derived and tested for association in independent samples from the full UKB cohort (N=360 631). A total of 1743 (3.2%) individuals in UKB who underwent the exercise stress test had a cardiovascular event, and TMRrec was significantly associated with cardiovascular events (hazard ratio, 1.11; P=5×10-7), independent of clinical variables and other ECG markers. TMRrec was also associated with all-cause mortality (hazard ratio, 1.10) and ventricular arrhythmias (hazard ratio, 1.16). We identified 12 genetic loci in total for TMRex and TMRrec, of which 9 are associated with another ECG marker. Individuals in the top 20% of the TMRrec genetic risk score were significantly more likely to have a cardiovascular event in the full UKB cohort (18 997, 5.3%) than individuals in the bottom 20% (hazard ratio, 1.07; P=6×10-3). TMR and TMR genetic risk scores are significantly associated with cardiovascular risk in a UK middle-aged population, supporting the hypothesis that increased spatio-temporal heterogeneity of ventricular repolarization is a substrate for cardiovascular risk and the validity of TMR as a cardiovascular risk predictor.

Determining Coefficients in an Expansion of the Electric Energy of A2ВХ4 Group Crystals According to Polarization by Studying the Dynamics of Repolarization via Harmonic Analysis

Coefficients of the expansion of electrical energy $${{W}_{c}}$$ in the ferroelectric phase near phase transition temperature $${{T}_{c}}$$ are determined from an even power series according to polarization $${{P}_{c}}$$ by studying the dynamics of repolarization in A2BX4 group crystals according to the Landau–Ginzburg–Devonshire theory. Experimental results are compared to the theoretical concepts of the Landau–Ginzburg–Devonshire theory describing dependences $${{W}_{c}}({{P}_{c}})$$ in static.

Restitution and adaptation measurements for the estimate of short-term cardiac action potential memory: comparison of five human ventricular models.

This computational study refines our recently published pacing protocol to measure short-term memory (STM) of cardiac action potential (AP), and apply it to five numerical models of human ventricular AP. Several formulations of electrical restitution (ER) have been provided over the years, including standard, beat-to-beat, dynamic, steady-state, which make it difficult to compare results from different studies. We discuss here the notion of dynamic ER (dER) by relating it to its steady-state counterpart, and propose a pacing protocol based on dER to measure STM under periodically varying pacing cycle length (CL). Under high and highly variable-pacing rate, all models develop STM, which can be measured over the entire sequence by means of dER. Short-term memory can also be measured on a beat-to-beat basis by estimating action potential duration (APD) adaptation after clamping CL constant. We visualize STM as a phase shift between action potential (AP) parameters over consecutive cycles of CL oscillations, and show that delay between CL and APD oscillation is nearly constant (around 92 ms) in the five models, despite variability in their intrinsic AP properties. dER, as we define it and together with other approaches described in the study, provides an univocal way to measure STM under extreme cardiac pacing conditions. Given the relevance of AP memory for repolarization dynamics and stability, STM should be considered, among other usual biomarkers, to validate and tune cardiac AP models. The possibility of extending the method to in vivo cellular and whole organ models can also be profitably explored.

Abstract 102: Molecular, Cellular and Systemic Mechanism of Nonlinear Dynamic Patterns of Ventricular Repolarization and Spontaneous Arrhythmic Sudden Death in Non-ischemic Heart Failure

Introduction: Sudden cardiac death (SCD) is the leading cause of death in USA. Heart failure (HF) confers high SCD risk, but most SCD victims do not have HF or well-defined genetic abnormalities. The underlying mechanisms are poorly understood, precluding the design of more effective strategies for risk stratification and therapy. We previously showed that distinct non-linear patterns of cardiac repolarization strongly and independently predict SCD in HF patients [PMID: 27044982]. We also showed in a unique guinea pig HF model that increased levels of mitochondrial reactive oxygen species (mROS) drive spontaneous SCD, even before HF onset [PMID: 29898892]. Herein, we further dissect the underlying mechanisms. Hypothesis: Increased mROS levels in pressure overloaded hearts reduce K+ currents, destabilize the resting membrane potential, increase repolarization lability and cause SCD. Methods: Guinea pigs were randomized to Sham, aortic banding (AC), or AC with daily brief low-dose β-adrenergic stress (ACi) with and without in vivo mROS scavenger MitoTEMPO (ACi+MT). We performed time series analyses on recordings of: (1) 24-hour ECG QT interval in freely ambulating animals before sacrifice at 4 weeks; (2) pressure-volume and electrophysiology (EP) in excised perfused hearts; and (3) duration of action potential (APd), calcium transient (CaTd) and sarcomere shortening (SSd) in isolated LV myocytes. Results: About 50% of ACi animals had SCD by 4 weeks. Increased QT entropy in ACi (at 1 week) predicted SCD over followup, similar to HF patients. Compared to Sham and ACi+MT, LV myocytes isolated from AC and ACi had reduced inward (IK1) and delayed slow (IKs) and rapid (IKr) rectifier currents; and increased beat-to-beat lability in APd, CaTd and SSd. The late Na and L-type Ca currents were similar between models. Acute exposure to isoproterenol (Iso) and carbachol (CCh) increased lability in LV myocytes compared to Iso or CCh alone. Conclusions: High mROS levels reduce repolarization reserve in LV myocytes and contribute, at least in part, to the non-linear dynamics of ventricular repolarization (reflected by high QT entropy), leading to spontaneous arrhythmic SCD. These findings provide important new mechanistic insight with direct clinical implications.

Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts.

Cardiac electrophysiology and Ca2+ handling change rapidly during the fight-or-flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight-or-flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) while optically mapping cardiac action potentials and intracellular Ca2+ transients in innervated mouse and rabbit hearts. Despite similar heart rate and Ca2+ handling responses between mouse and rabbit hearts, we found notable species differences in spatio-temporal repolarization dynamics during SNS. Species-specific computational models revealed that these electrophysiological differences allowed for enhanced Ca2+ handling (i.e. enhanced inotropy) in each species, suggesting that electrophysiological responses are fine-tuned across species to produce optimal cardiac fight-or-flight responses. Sympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca2+ handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca2+ transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff-perfused rabbit and mouse hearts. Dual optical mapping with voltage- and Ca2+ -sensitive dyes allowed for analysis of spatio-temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9±5.1ms at t=0s vs. 60.6±4.1ms at t=15s, P<0.05) followed by shortening (46.5±9.1ms at t=60s, P=NS vs. t=0). We determined the biphasic APD response in mouse was partly due to dynamic changes in HR during SNS and was exacerbated by β-adrenergic activation. Simulations with species-specific cardiac models revealed that transient APD prolongation in mouse allowed for greater and more rapid CaT responses, suggesting more rapid increases in contractility; conversely, the rabbit heart requires APD shortening to produce optimal inotropic responses. Thus, while the cardiac fight-or-flight response is highly conserved between species, the underlying mechanisms orchestrating these effects differ significantly.

Deterministic Learning-Based Methodology for Detecting Abnormal Dynamics of Cardiac Repolarization During Ischemia.

This study concentrates on subtle electrocardiogram (ECG) spatiotemporal characteristics in the repolarization phase, and describes a deterministic learning-based methodology for the detection of abnormal cardiac dynamics induced by ischemia. ST-T complex of the surface 12-lead ECG signals are identified and extracted. Cardiac dynamics underlying ST-T complex signals is captured using deterministic learning algorithm. This kind of dynamics information represents the beat-to-beat temporal change of electrophysiological modifications in ventricular repolarization, which is shown to be sensitive to the variance during myocardial ischemia. Cardiodynamicsgram (CDG) is proposed as the three-dimensional graphic representation of cardiac dynamics information. Encouraging evaluation results are achieved on electrocardiograms from public PTB database and hospital patients. Significant correlations are found between the CDG morphology and ischemia. Anormal dynamics of cardiac repolarization during ischemia can be detected using a deterministic learning-based methodology. The extracted cardiac dynamics information within routine ECG is expected to provide early detection for latent ischemia before obvious pathological changes are present in ECG. The proposed techniques can be considered as a complementary tool to the generally accepted ECG method for detection of abnormal dynamics in cardiac repolarization, which are important for identifying patients at risk of myocardial ischemia.

The Role of the Cardioversion Defibrillator in Post Myocardial Infarction Sudden Cardiac Death: A Systematic Review of Clinical Trials and Observational Studies.

Sudden cardiac death (SCD) accounts for approximately half of all the deaths attributed to cardiovascular disease in the United States. Survivors of an acute myocardial infarction (AMI) are at high risk of SCD, largely due to cardiac arrhythmias and severe left ventricular (LV) systolic dysfunction. The implantable cardioverter defibrillator (ICD) or automated implantable cardioverter defibrillator (AICD) is a device that is implantable inside the body, able to perform cardioversion, defibrillation, and (in modern versions) pacing of the heart. According to a study included in our review, patients who received an ICD contributed to an adjusted 44% reduction (hazard ratio [HR] 0.56, 95% CI: 0.32-1.01; P = 0.053) of all-cause mortality compared to those with a comparable baseline. Patients with an ICD implant three months after a myocardial infarction (MI) demonstrated a non-significantly higher mortality than patients who did not receive an ICD. The factors favoring ICD implantation were multiple MIs, increased resting heart rate, occurrence of non-sustained ventricular tachycardia, QRS duration = 120 ms, syncope events, anti-arrhythmic drug treatment (mostly Class III), and an index MI of more than one year. The likelihood of receiving an ICD diminished with the patient’s age. Increased periodic repolarization dynamics were a significant predictor of mortality. It can be concluded that cardioverter defibrillators help reduce not only all-cause mortality but also sudden cardiac death. It is important to note that ICDs are only significant if implanted after a sufficient time-gap post-MI.

Periodic repolarization dynamics as a risk predictor after myocardial infarction: Prospective validation study

Periodic repolarization dynamics (PRD) is a novel electrocardiographic phenomenon that refers to sympathetic activity-associated low-frequency modulations of cardiac repolarization. Retrospective post-myocardial infarction (MI) studies revealed that increased PRD indicates an increased risk of subsequent death. This is the first prospective study to validate PRD in patients after MI receiving up-to-date treatment. Four hundred fifty-five survivors of MI (age ≤80 years) in sinus rhythm were enrolled. PRD was assessed from 20-minute electrocardiographic recordings (2048 Hz) and prospectively dichotomized at 5.75 deg2. Primary and secondary end points were total mortality and cardiovascular mortality, respectively. Multivariable analyses additionally included Global Registry of Acute Coronary Events score (dichotomized at >140), left ventricular ejection fraction (dichotomized at ≤35%), diabetes mellitus, and deceleration capacity of heart rate (dichotomized at ≤2.5ms). The prognostic power of PRD was evaluated using receiver operating characteristic curve analysis, Cox regression analysis, and the integrated discrimination improvement index. During a median follow-up period of 27 months, 47 patients died. Twenty-three of these deaths were classified as cardiovascular. Increased PRD was significantly associated with both end points, yielding areas under receiver operating characteristic curves of 69.3% (60.2%-77.8%) and 79.1% (69.7%-86.7%) for total mortality and cardiovascular mortality, respectively (P < .001 for both). In multivariable analysis, increased PRD indicated a 2.2- and 9.5-fold risk of total mortality and cardiovascular mortality (P = .024 and P = .003, respectively). Addition of PRD to the models significantly improved the integrated discrimination improvement index for total (P = .047) and cardiovascular mortality (P = .007). PRD is a strong and independent predictor of total mortality and cardiovascular mortality in patients after MI treated with contemporary therapy.

Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart.

AimsAction potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo.Methods and resultsWe developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans.ConclusionCombined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.

Dynamic particularities of the coefficients determination in the crystal Rb2ZnCl4 free energy decomposition according to the polarization by the harmonic analysis method

The values of the energy expansion coefficients in a series of polarization even powers on the base of study of the Rb2ZnCl4 crystal repolarization dynamics according to the theory of Landau-Devonshire are determined. The comparison of experimental results in the dynamics with theoretical concepts of the Landau-Devonshire theory describing dependencies in static is obtained.

Left ventricular activation-recovery interval variability predicts spontaneous ventricular tachyarrhythmia in patients with heart failure

Enhanced beat-to-beat variability of repolarization is strongly linked to arrhythmogenesis and is largely due to variation in ventricular action potential duration (APD). Previous studies in humans have relied on QT interval measurements; however, a direct relationship between beat-to-beat variability of APD and arrhythmogenesis in humans has yet to be demonstrated. This study aimed to explore the beat-to-beat repolarization dynamics in patients with heart failure at the level of ventricular APD. Forty-three patients with heart failure and implanted cardiac resynchronization therapy - defibrillator devices were studied. Activation-recovery intervals as a surrogate for APD were recorded from the left ventricular epicardial lead while pacing from the right ventricular lead to maintain a constant cycle length. During a mean follow-up of 23.6±13.6 months, 11 patients sustained ventricular fibrillation/ventricular tachycardia (VT/VF) and received appropriate implantable cardioverter-defibrillator therapies (antitachycardia pacing or shock therapy). Activation-recovery interval variability (ARIV) was significantly greater in patients with subsequent VT/VF than in those without VT/VF (3.55±1.3 ms vs 2.77±1.09 ms; P=.047). Receiver operating characteristic curve analysis (area under the curve 0.71; P=.046) suggested high- and low-risk ARIV groups for VT/VF. Kaplan-Meier survival analysis demonstrated that the time until first appropriate therapy for VT/VF was significantly shorter in the high-risk ARIV group (P=.028). ARIV was a predictor for VT/VF in the multivariate Cox model (hazard ratio 1.623; 95% confidence interval 1.1-2.393; P=.015). Increased left ventricular ARIV is associated with an increased risk of VT/VF in patients with heart failure.

Predicting Collective Migration of Cell Populations Defined by Varying Repolarization Dynamics

Collective migration of heterogeneous cell populations is an essential aspect of fundamental biological processes, including morphogenesis, wound healing, and tumor invasion. Through experiments and modeling, it has been shown that cells attain front-rear polarity, generate forces, and form adhesions to migrate. However, it remains unclear how the ability of individual cells in a population to dynamically repolarize themselves into new directions could regulate the collective response. We present a vertex-based model in which each deformable cell randomly chooses a new polarization direction after every defined time interval, elongates, proportionally generates forces, and causes collective migration. Our simulations predict that cell types that repolarize at longer time intervals attain more elongated shapes, migrate faster, deform the cell sheet, and roughen the leading edge. By imaging collectively migrating epithelial cell monolayers at high temporal resolution, we found longer repolarization intervals and elongated shapes of cells at the leading edge compared to those within the monolayer. Based on these experimental measurements and simulations, we defined aggressive mutant leader cells by long repolarization interval and minimal intercellular contact. The cells with frequent and random repolarization were defined as normal cells. In simulations with uniformly dispersed leader cells in a normal cell population at a 1:10 ratio, the resulting migration and deformation of the heterogeneous cell sheet remained low. However, when the 10% mutant leaders were placed only at the leading edge, we predicted a rise in the migration of an otherwise normal cell sheet. Our model predicts that a repolarization-based definition of leader cells and their placement within a healthy population can generate myriad modes of collective cell migration, which can enhance our understanding of collective cell migration in disease and development.

Electrocardiographic conduction and repolarization markers associated with sudden cardiac death: moving along the electrocardiography waveform.

The QT interval along with its heart rate corrected form (QTc) are well-established ECG markers that have been found to be associated with malignant ventricular arrhythmogenesis. However, extensive preclinical and clinical investigations over the years have allowed for novel clinical ECG markers to be generated as predictors of arrhythmogenesis and sudden cardiac death. Repolarization markers include the older QTc, QT dispersion and newer Tpeak - Tend intervals, (Tpeak - Tend) / QT ratios, T-wave alternans (TWA), microvolt TWA and T-wave area dispersion. Meanwhile, conduction markers dissecting the QRS complex, such as QRS dispersion (QRSD) and fragmented QRS, were also found to correlate conduction velocity and unidirectional block with re-entrant substrates in various cardiac conditions. Both repolarization and conduction parameters can be combined into the excitation wavelength (λ). A surrogate marker for λ is the index of Cardiac Electrophysiological Balance (iCEB: QT / QRSd). Other markers based on conduction-repolarization are [QRSD x (Tpeak-Tend) / QRSd] and [QRSD x (Tpeak-Tend) / (QRSd x QT)]. Advancement in technology permitted sophisticated electrophysiological analyses such as principal component analysis and periodic repolarization dynamics to further improve risk stratification. This was closely followed by other novel indices including ventricular ectopic QRS interval, the f99 index and EntropyXQT, which integrates mathematical and physical calculations for determining the risk markers. Though proven to be effective in limited patient cohorts, more clinical studies across different cardiac pathologies are required to confirm their validity. As such, this review seeks to encapsulate the development of old and new ECG markers along with their associated utility and shortcomings in clinical practice.

Pharmacological Modulation of Right Ventricular Endocardial-Epicardial Gradients in Brugada Syndrome.

Background We explored the hypothesis that increased cholinergic tone exerts its proarrhythmic effects in Brugada syndrome (BrS) through increasing dispersion of transmural repolarization in patients with spontaneous and drug-induced BrS. Methods BrS and supraventricular tachycardia patients were studied after deploying an Ensite Array in the right ventricular outflow tract and a Cardima catheter in the great cardiac vein to record endo and epicardial signals, respectively. S1-S2 restitution curves from the right ventricular apex were conducted at baseline and after edrophonium challenge to promote increased cholinergic tone. The local unipolar electrograms were then analyzed to study transmural conduction and repolarization dynamics. Results The study included 8 BrS patients (5 men:3 women; mean age, 56 years) and 8 controls patients with supraventricular tachycardia (5 men:3 women; mean age, 48 years). Electrophysiological studies in controls demonstrated shorter endocardial than epicardial right ventricular activation times (mean difference: 26 ms; P<0.001). In contrast, patients with BrS showed longer endocardial than epicardial activation time (mean difference: -15 ms; P=0.001). BrS hearts, compared with controls, showed significantly larger transmural gradients in their activation recovery intervals (mean intervals, 20.5 versus 3.5 ms; P<0.01), with longer endocardial than epicardial activation recovery intervals. Edrophonium challenge increased such gradients in both controls (to a mean of 16 ms [ P<0.001]) and BrS (to 29.7 ms; P<0.001). However, these were attributable to epicardial and endocardial activation recovery interval prolongations in control and BrS hearts, respectively. Dynamic changes in repolarization gradients were also observed across the BrS right ventricular wall in BrS. Conclusions Differential contributions of conduction and repolarization were identified in BrS which critically modulated transmural dispersion of repolarization with significant cholinergic effects only identified in the patients with BrS. This has important implications for explaining the proarrhythmic effects of increased vagal tone in BrS, as well as evaluating autonomic modulation and epicardial ablation as therapeutic strategies.

P4845Periodic Repolarization Dynamics as risk predictor in patients with moderate to severe aortic stenosis

P4845Periodic Repolarization Dynamics as risk predictor in patients with moderate to severe aortic stenosis

Fibrosis and wall thickness affect ventricular repolarization dynamics in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by ventricular repolarization abnormalities and risk of ventricular arrhythmias. Our aim was to study the association between the phenotype and ventricular repolarization dynamics in HCM patients. HCM patients with either the MYBPC3-Q1061X or TPM1-D175N mutation (n=46) and control subjects without mutation and hypertrophy (n=35) were studied with 24-hr ambulatory ECG recordings by measuring time intervals of rate-adapted QT (QTe), maximal QT, and T-wave apex to wave end (TPE) intervals and the QTe/RR slope. Findings were correlated to specified echocardiographic and cardiac magnetic resonance imaging (CMRI) findings. Rate-adapted QTe interval was progressively longer in HCM patients with decreasing heart rates compared to control subjects (p=0.020). The degree of hypertrophy correlated with measured QTe values. HCM patients with maximal wall thickness higher than the mean (20.6mm) had longer maximum QTe and median TPE intervals compared to control subjects and HCM patients with milder hypertrophy (p<0.001 and p=0.014, respectively). HCM patients with late gadolinium enhancement (LGE) on CMRI had steeper QTe/RR slopes compared to HCM patients without LGE and control subjects (p=0.044 and p=0.001, respectively). LGE was an independent predictor of QTe/RR slope (p=0.023, B=0.043). Dynamics of ventricular repolarization in HCM are affected by hypertrophy and fibrosis. LGE may confer an independent effect on QT dynamics which may increase the arrhythmogenic potential in HCM.

Imbalance of cardiac autonomic nervous activity and increase of ventricular repolarization dynamicity induced by thyroid hormones in hyperthyroidism.

To investigate the effects of thyroid hormones on cardiac autonomic nervous activity and ventricular repolarization dynamicity in hyperthyroidism. 57 consecutive patients first diagnosed of hyperthyroidism (HT group) and 55 age and sex-matched healthy volunteers (Control group) from March 2012 to March 2013 in our center were enrolled. All subjects underwent standard 12‑lead ECG and 24 h Holter recording at baseline. For the HT group, free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were monitored, and after they returned to normal all the examinations were redone. Heart rate variability (HRV) was assessed to determine the cardiac autonomic nervous activity. QTe/RR slope (QT end) and QTp/RR slope (QT apex) were calculated to evaluate the ventricular repolarization dynamicity. The HT patients before treatment had significantly higher LF/HF, QTe/RR slope and QTp/RR slope, and larger QT dispersion than the controls and after treatment (P < 0.05 for all). Correlation analyses revealed that FT3 was positively correlated with QTe/RR and QTp/RR slopes (r = 0.689 and 0.665 respectively, P < 0.001 for both), and similarly in FT4 (r = 0.665 and 0.668 respectively, P < 0.001 for both). While TSH was negatively correlated with QTe/RR and QTp/RR slopes (r = -0.660 and -0.680 respectively, P < 0.001 for both). FT3 and FT4 levels were independent predictors of QTe/RR slopes (P < 0.001, β = 0.007; P = 0.017, β = 0.001, respectively) and QTp/RR slopes (P < 0.001, β = 0.008; P = 0.002, β = 0.001, respectively). High-level thyroid hormones induce the cardiac sympathetic overactivity and increases ventricular repolarization dynamicity, and the impact can be attenuated after euthyroidism restored.