Heart rate and autonomic biomarkers distinguish convulsive epileptic vs. functional or dissociative seizures.

OBJECTIVE: 20-40% of individuals whose seizures are not controlled by anti-seizure medications exhibit manifestations comparable to epileptic seizures (ES), but there are no EEG correlates. These events are called functional or dissociative seizures (FDS). Due to limited access to EEG-monitoring and inconclusive results, we aimed to develop an alternative diagnostic tool that distinguishes ES vs. FDS. We evaluated the temporal evolution of ECG-based measures of autonomic function (heart rate variability, HRV) to determine whether they distinguish ES vs. FDS. METHODS: The prospective study includes patients admitted to the University of Rochester Epilepsy Monitoring Unit. Participants are 18-65 years old, without therapies or co-morbidities associated with altered autonomics. A habitual ES or FDS is recorded during admission. HRV analysis is performed to evaluate the temporal changes in autonomic function during the peri­ictal period (150-minutes each pre-/post-ictal). We determined if autonomic measures distinguish ES vs. FDS. RESULTS: The study includes 53 ES and 46 FDS. Temporal evolution of HR and autonomics significantly differ surrounding ES vs. FDS. The pre-to-post-ictal change (delta) in HR differs surrounding ES vs. FDS, stratified for convulsive and non-convulsive events. Post-ictal HR, total autonomic (SDNN & Total Power), vagal (RMSSD & HF), and baroreflex (LF) function differ for convulsive ES vs. convulsive FDS. HR distinguishes non-convulsive ES vs. non-convulsive FDS with ROC>0.7, sensitivity>70%, but specificity<50%. HR-delta and post-ictal HR, SDNN, RMSSD, LF, HF, and Total Power each distinguish convulsive ES vs. convulsive FDS (ROC, 0.83-0.98). Models with HR-delta and post-ictal HR provide the highest diagnostic accuracy for convulsive ES vs. convulsive FDS: 92% sensitivity, 94% specificity, ROC 0.99). SIGNIFICANCE: HR and HRV measures accurately distinguish convulsive, but not non-convulsive, events (ES vs. FDS). Results establish the framework for future studies to apply this diagnostic tool to more heterogeneous populations, and on out-of-hospital recordings, particularly for populations without access to epilepsy monitoring units.

Monitoring Pulse Rate in the Background Using Front Facing Cameras of Mobile Devices.

We propose a novel framework to passively monitor pulse rate during the time spent by users on their personal mobile devices. Our framework is based on passively capturing the user's pulse signal using the front-facing camera. Signal capture is performed in the background, while the user is interacting with the device as he/she normally would, e.g., watch movies, read emails, text, and play games. The framework does not require subject participation with the monitoring procedure, thereby addressing the well-known problem of low adherence with such procedures. We investigate various techniques to suppress the impact of spontaneous user motion and fluctuations in ambient light conditions expected in non-participatory environments. Techniques include traditional signal processing, machine learning classifiers, and deep learning methods. Our performance evaluation is based on a clinical study encompassing 113 patients with a history of atrial fibrillation (Afib) who are passively monitored at home using a tablet for a period of two weeks. Our results show that the proposed framework accurately monitors pulse rate, thereby providing a gateway for long-term monitoring without relying on subject participation or the use of a dedicated wearable device.

Assessment of facial video-based detection of atrial fibrillation across human complexion.

Background: Early self-detection of atrial fibrillation (AF) can help delay and/or prevent significant associated complications, including embolic stroke and heart failure. We developed a facial video technology, videoplethysmography (VPG), to detect AF based on the analysis of facial pulsatile signals. Objective: The purpose of this study was to evaluate the accuracy of a video-based technology to detect AF on a smartphone and to test the performance of the technology in AF patients across the whole spectrum of skin complexion and under various recording conditions. Methods: The performance of video-based monitoring depends on a set of factors such as the angle and the distance between the camera and the patient's face, the strength of illumination, and the patient's skin tone. We conducted a clinical study involving 60 subjects with a confirmed diagnosis of AF. A continuous electrocardiogram was used as the gold standard for cardiac rhythm annotation. The VPG technology was fine-tuned on a smartphone for the first 15 subjects. Validation recordings were then done using 7053 measurements collected from the remaining 45 subjects. Results: The VPG technology detected the presence of AF using the video camera from a common smartphone with sensitivity and specificity ≥90%. The ambient level of illumination needs to be ≥100 lux for the technology to deliver consistent performance across all skin tones. Conclusion: We demonstrated that facial video-based detection of AF provides accurate outpatient cardiac monitoring including high pulse rate accuracy and medical-grade performance for AF detection.

Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects.

Perhexiline has been used to treat hypertrophic cardiomyopathy. In addition to its effect on carnitine-palmitoyltransferase-1, it has mixed ion channel effects through inhibition of several cardiac ion currents. Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch-clamp technique, action potential duration (APD) was measured in ventricular trabeculae of human donor hearts, and electrocardiogram effects were evaluated in healthy subjects in a thorough QT (TQT) study. Perhexiline blocked several cardiac ion currents at concentrations within the therapeutic range (150-600 ng/mL) with IC50 for hCav1.2 ∼ hERG < late hNav1.5. A significant APD shortening was observed in perhexiline-treated cardiomyocytes. The TQT study was conducted with a pilot part in 9 subjects to evaluate a dosing schedule that would achieve therapeutic and supratherapeutic perhexiline plasma concentrations on days 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel-designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on ΔΔQTcF, 14.7 milliseconds at therapeutic concentrations and 25.6 milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration-ΔΔQTcF relationship (0.018 milliseconds per ng/mL; 90%CI, 0.0119-0.0237 milliseconds per ng/mL). In contrast, the JTpeak interval was shortened with a negative concentration-JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk.

2021 ISHNE/HRS/EHRA/APHRS collaborative statement on mHealth in Arrhythmia Management: Digital Medical Tools for Heart Rhythm Professionals: From the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society describes the current status of mobile health ("mHealth") technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored.

2021 ISHNE/HRS/EHRA/APHRS Expert Collaborative Statement on mHealth in Arrhythmia Management: Digital Medical Tools for Heart Rhythm Professionals: From the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia-Pacific Heart Rhythm Society.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia-Pacific Heart Rhythm Society describes the current status of mobile health technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mobile health. The promises of predictive analytics but also operational challenges in embedding mobile health into routine clinical care are explored.

Diurnal QT analysis in patients with sotalol after cardioversion of atrial fibrillation.

BACKGROUND: The risk of ventricular arrhythmias in patients on QT prolonging drugs is indicated to be increased early after cardioversion (CV) of atrial fibrillation (AF) to sinus rhythm (SR). Sotalol, used to prevent AF relapse, prolongs cardiac repolarization and corrected QT interval (QTc). A pronounced QTc prolongation is an established marker of pro-arrhythmias. Our objective was to use novel technique to quantify and evaluate the diurnal variation of the QTc interval after elective CV to SR in patients on sotalol or metoprolol. METHODS: Fifty patients underwent twelve-lead Holter recording for 24 hr after elective CV for persistent AF. All patients had the highest tolerable stable dose of sotalol (n = 27) or metoprolol (n = 23). Measurements of QT and RR intervals were performed on all valid beats. RESULTS: A clear diurnal variation of both HR and QTc was seen in both groups, more pronounced in patients on sotalol, where a high percentage of heartbeats with QTc >500 ms was observed, especially at night. Six patients (22%) on sotalol but none on metoprolol had >20% of all heart beats within the 24-hour recording with QTc >500 ms. CONCLUSION: Twenty-four-hour Holter recordings with QT-measurement immediately after CV demonstrated that one in five patients on sotalol had >20% of all heart beats with prolonged QTc >500 ms, especially during night-time. The QTc diurnal variation was retained in patients on ß-blockade or a potent class III anti-arrhythmic drug with ß-blocking properties.

2021 ISHNE/ HRS/ EHRA/ APHRS collaborative statement on mHealth in Arrhythmia Management: Digital Medical Tools for Heart Rhythm Professionals: From the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/ Heart Rhythm Society/ European Heart Rhythm Association/ Asia Pacific Heart Rhythm Society describes the current status of mobile health ("mHealth") technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored.

2021 ISHNE/HRS/EHRA/APHRS Collaborative Statement on mHealth in Arrhythmia Management: Digital Medical Tools for Heart Rhythm Professionals: From the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society describes the current status of mobile health ("mHealth") technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored.

2021 ISHNE / HRS / EHRA / APHRS Collaborative Statement on mHealth in Arrhythmia Management: Digital Medical Tools for Heart Rhythm Professionals: From the International Society for Holter and Noninvasive Electrocardiology / Heart Rhythm Society / European Heart Rhythm Association / Asia Pacific Heart Rhythm Society.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology / Heart Rhythm Society / European Heart Rhythm Association / Asia Pacific Heart Rhythm Society describes the current status of mobile health ("mHealth") technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored.

Erratum: Erratum to: 2021 ISHNE / HRS / EHRA / APHRS Collaborative Statement on mHealth in Arrhythmia Management: Digital Medical Tools for Heart Rhythm Professionals: From the International Society for Holter and Noninvasive Electrocardiology / Heart Rhythm Society / European Heart Rhythm Association / Asia Pacific Heart Rhythm Society.

[This corrects the article DOI: 10.1093/ehjdh/ztab001.].

T-wave and its association with myocardial fibrosis on cardiovascular magnetic resonance examination.

BACKGROUND: Risk stratification in non-ischemic myocardial disease poses a challenge. While cardiovascular magnetic resonance (CMR) is a comprehensive tool, the electrocardiogram (ECG) provides quick impactful clinical information. Studying the relationships between CMR and ECG can provide much-needed risk stratification. We evaluated the electrocardiographic signature of myocardial fibrosis defined as presence of late gadolinium enhancement (LGE) or extracellular volume fraction (ECV) ≥29%. METHODS: We evaluated 240 consecutive patients (51% female, 47.1 ± 16.6 years) referred for a clinical CMR who underwent 12-lead ECGs within 90 days. ECG parameters studied to determine association with myocardial fibrosis included heart rate, QRS amplitude/duration, T-wave amplitude, corrected QT and QT peak, and Tpeak-Tend. Abnormal T-wave was defined as low T-wave amplitude ≤200 µV or a negative T wave, both in leads II and V5. RESULTS: Of the 147 (61.3%) patients with myocardial fibrosis, 67 (28.2%) had ECV ≥ 29%, and 132 (54.6%) had non-ischemic LGE. An abnormal T-wave was more prevalent in patients with versus without myocardial fibrosis (66% versus 42%, p < .001). Multivariable analysis demonstrated that abnormal T-wave (OR 1.95, 95% CI 1.09-3.49, p = .03) was associated with myocardial fibrosis (ECV ≥ 29% or LGE) after adjustment for clinical covariates (age, gender, history of hypertension, and heart failure). Dynamic nomogram for predicting myocardial fibrosis using clinical parameters and the T-wave was developed: https://normogram.shinyapps.io/CMR_Fibrosis/. CONCLUSION: Low T-wave amplitude ≤ 200 µV or negative T-waves are independently associated with myocardial fibrosis. Prospective evaluation of T-wave amplitude may identify patients with a high probability of myocardial fibrosis and guide further indication for CMR.

Autonomic and Cardiac Repolarization Lability in Long QT Syndrome Patients.

OBJECTIVE: Long QT-Syndrome (LQTS) patients are at risk of arrhythmias and seizures. We investigated whether autonomic and cardiac repolarization measures differed based on LQTS genotypes, and in LQTS patients with vs. without arrhythmias and seizures. METHODS: We used 24-h ECGs from LQTS1 (n = 87), LQTS2 (n = 50), and LQTS genotype negative patients (LQTS(-), n = 16). Patients were stratified by LQTS genotype, and arrhythmias/seizures. Heart rate variability (HRV) and QT variability index (QTVI) measures were compared between groups during specific physiological states (minimum, middle, & maximum sympathovagal balance, LF/HF). Results were further tested using logistic regression for each ECG measure, and all HRV measures in a single multivariate model. RESULTS: Across multiple physiological states, total autonomic (SDNN) and vagal (RMSSD, pNN50) function were lower and repolarization dynamics (QTVI) were elevated in LQTS(+), LQTS1, and LQTS2, compared to LQTS(-). Many measures remained significant in the regression models. Multivariate modeling demonstrated that SDNN, RMSSD, and pNN50 were independent markers of LQTS(+) vs. LQTS(-), and SDNN and pNN50 were markers for LQTS1 vs. LQTS(-). During sympathovagal balance (middle LF/HF), RMSSD and pNN50 distinguished LQTS1 vs. LQTS2. LQTS1 patients with arrhythmias had lower total (SDNN) and vagal (RMSSD and pNN50) autonomic function, and SDNN remained significant in the models. In contrast, ECG measures did not differ in LQTS2 patients with vs. without arrhythmias, and LQTS1 and LQTS2 with vs. without seizures. CONCLUSION: Autonomic (HRV) and cardiac repolarization (QTVI) ECG measures differ based on LQTS genotype and history of arrhythmias in LQTS1. SDNN, RMSSD, and pNN50 were each independent markers for LQTS genotype.

Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.

Prenatal and recent methylmercury exposure and heart rate variability in young adults: the Seychelles Child Development Study.

Epidemiologic evidence of an adverse association between exposure to methylmercury (MeHg) from consuming fish and heart rate variability (HRV) is inconclusive. We aimed to evaluate MeHg exposure in relation to HRV parameters in a large cohort of young adults from a high fish consuming population in the Republic of Seychelles. Main Cohort participants in the Seychelles Child Development Study were evaluated at a mean age of 19 years. Prenatal MeHg exposure was determined in maternal hair growing during pregnancy and recent exposure in participant's hair taken at the evaluation. The evaluation consisted of short (~2 h) and long (overnight) Holter recordings obtained in 514 and 203 participants, respectively. Multivariable analyses examined the association of prenatal and recent MeHg exposure (in separate models) with time-domain and frequency-domain HRV parameters in different physiologic circumstances: supine position, standing position, mental stress when undergoing a mathematics test, sleep, and long recording. Prenatal MeHg exposure was not associated with any of the 23 HRV parameters studied after adjustment for multiplicity. The recent MeHg showed a trend toward significance only for few variables in the primary model. However, after additional adjustment for activity levels, polyunsaturated fatty acids, and multiplicity none were significant after a Bonferroni adjustment. In conclusion, prenatal and recent MeHg exposure had no consistent pattern of associations to support the hypothesis that they are adversely associated with heart rate variability in this study population that consumes large amounts of fish.

Low lead one ratio predicts clinical outcomes in left bundle branch block.

INTRODUCTION: We evaluated the association between a novel electrocardiographic (ECG) marker of late, rightward electrocardiographic forces (termed the lead one ratio [LOR]), and left ventricular ejection fraction (LVEF), myocardial scar, and clinical outcomes in patients with left bundle branch block (LBBB). METHODS AND RESULTS: LOR was calculated in patients with LBBB from a derivation cohort (n = 240) and receiver operator characteristic curves identified optimal threshold values for predicting myocardial scar and LVEF less than 35%. An independent validation cohort of patients with LBBB (n = 196) was used to test the association of LOR with the myocardial scar, LVEF, and the likelihood of death, heart transplant or left ventricular assist device (LVAD) implantation. The optimal thresholds in the derivation cohort were LOR less than 13.7 for identification of scar (sensitivity 55%, specificity 80%), and LOR less than 12.1 for LVEF less than 35% (sensitivity 49%, specificity 80%). In the validation cohort, LOR less than 13.7 was not associated with scar size or presence (P > 0.05 for both). LOR less than 12.1 was associated with lower LVEF (30 [20-40] versus 40 [25-55]%; P = 0.002) and predicted LVEF less than 35% in univariable (odds ratio [OR], 2.2 [1.2-4.1]; P = 0.01) and multivariable analysis (OR, 2.2 [1.2-4.3]; P = 0.02). LOR less than 12.1 was associated with scar presence when patients with nonischemic cardiomyopathy were excluded (OR = 7.2 [1.5-33.2]; P = 0.002). LOR less than 12.1 had an adjusted hazard ratio of 1.53 ([1.05-2.21]; P = 0.03) for death, transplant or LVAD implantation. CONCLUSIONS: In conclusion, ECG LOR less than 12.1 predicts reduced-LV systolic function and poorer prognosis in patients with LBBB.

The ability of the electrocardiogram in left bundle branch block to detect myocardial scar determined by cardiovascular magnetic resonance.

AIMS: We aimed to improve the electrocardiographic 2009 left bundle branch block (LBBB) Selvester QRS score (2009 LBSS) for scar assessment. METHODS: We retrospectively identified 325 LBBB patients with available ECG and cardiovascular magnetic resonance imaging (CMR) with late gadolinium enhancement from four centers (142 [44%] with CMR scar). Forty-four semi-automatically measured ECG variables pre-selected based on the 2009 LBSS yielded one multivariable model for scar detection and another for scar quantification. RESULTS: The 2009 LBSS achieved an area under the curve (AUC) of 0.60 (95% confidence interval 0.54-0.66) for scar detection, and R2 = 0.04, p < 0.001, for scar quantification. Multivariable modeling improved scar detection to AUC 0.72 (0.66-0.77) and scar quantification to R2 = 0.21, p < 0.001. CONCLUSIONS: The 2009 LBSS detects and quantifies myocardial scar with poor accuracy. Improved models with extensive comparison of ECG and CMR had modest performance, indicating limited room for improvement of the 2009 LBSS.

The 43rd International Society for Computerized Electrocardiology ECG initiative for the automated detection of strict left bundle branch block.

The presence of left bundle branch block (LBBB) is an important predictor of benefit from cardiac resynchronization therapy (CRT). New "strict" electrocardiographic (ECG) criteria for LBBB have been shown to better predict benefit from CRT. The "strict" LBBB criteria include: QRS duration ≥140 ms (men) or ≥130 ms (women), QS- or rS-configurations of the QRS complex in leads V1 and V2, and mid-QRS notching or slurring in ≥2 of leads V1, V2, V5, V6, I and aVL. The "strict" LBBB criteria are not regularly used and most hospital automated ECG systems and physicians still use more conventional LBBB criteria. As part of the 43rd International Society for Computerized Electrocardiology (ISCE) meeting, we conducted an initiative on the automated detection of "strict" LBBB where industry and academic investigators could present their algorithm results on digital 12-lead ECGs with varying QRS morphologies from the MADIT-CRT trial (300 training and 302 test set ECGs that were manually adjudicated for "strict" LBBB presence). The results revealed a 64-82% accuracy, 48-76% sensitivity and 46-87% specificity for automated "strict" LBBB detection from 7 participants. Most mismatches were likely attributed to differences in detection and absence of specific definitions for notches and slurs while differences in QRS duration and S-waves in leads V1 and V2 were less problematic. The full unblinded training and test datasets including all ECG signals are being made available through the Telemetric and Holter ECG Warehouse (THEW) for further exploration.

Challenges in implementing and obtaining acceptance for J-Tpeak assessment as the clinical component of CiPA.

INTRODUCTION: This paper is based on a presentation held at the Annual Safety Pharmacology Society meeting in September 2017, at which challenges for the clinical component of CiPA were presented. FDA has published an automated algorithm for measurement of the J-Tpeak interval on a median beat from a vector magnitude lead derived from a 12-lead ECG. CiPA proposes that J-Tpeak prolongation < 10 ms can be used for drugs with a QTc effect < 20 ms to differentiate between safe and unsafe delayed repolarization and to reduce the level of ECG monitoring in late stage clinical trials. METHODS: We applied FDA's algorithm, complemented with iCOMPAS, to moxifloxacin and dolasetron data from the IQ-CSRC study with 9 subjects on active and 6 on placebo. The effect on QTcF and corrected J-Tpeak (J-Tpeak_c) was analyzed using concentration-effect modeling. RESULTS: There was a good correlation between QTcF and J-Tpeak_c prolongation after oral dosing of 400 mg moxifloxacin with placebo-adjusted, change-from-baseline (ΔΔ) J-Tpeak_c of ~12 ms at concentrations that caused ΔΔQTcF of ~20 ms. On dolasetron, J-Tpeak_c was highly variable, no prolongation was seen and an effect on ΔΔJ-Tpeak_c > 10 ms could be excluded across the observed plasma concentration range. DISCUSSION: In this limited analysis performed on the IQ-CSRC study waveforms using FDA's automated algorithm, J-Tpeak prolongation was observed on moxifloxacin, but not on dolasetron, despite clinical observations of proarrhythmias with both drugs. Challenges for the implementation of the J-Tpeak interval as a replacement or complement to the QTc interval, include to demonstrate that the proposed clinical algorithm using a J-Tpeak threshold of 10 ms, can be used to categorize drugs with a QT effect up to ~20 ms as having low pro-arrhythmic risk.

Baseline adverse electrical remodeling and the risk for ventricular arrhythmia in Cardiac Resynchronization Therapy Recipients (MADIT CRT).

INTRODUCTION: Adverse electrical remodeling (AER), represented here as the sum absolute QRST integral (SAI QRST), has previously been shown to be directly associated with the risk for ventricular arrhythmia (VA). Cardiac resynchronization therapy (CRT) is known to reduce the risk for VA through various mechanisms, including reverse remodeling, and we aimed to evaluate the association between baseline AER and the risk for VA in CRT recipients. METHODS AND RESULTS: The study population comprised 961 CRT-D implanted patients from the MADIT CRT study. The relationship between SAI QRST, VA risk, and VA risk/death was evaluated as a continuous and as a categorical variable-tertiles (T1 ≤ 0.527, T2 0.528-0.766, T3 > 0.766). In a multivariable model, AER was inversely associated with the risk of VA. Each unit increase in SAI QRST was associated with 64% (P  =  0.007) and 54% (P  =  0.003) decrease in the risk of VA and VA/death, respectively. Patients with high SAI QRST (T3) and medium SAI QRST (T2) had 52% (P < 0.001) and 32% (P  =  0.027) reduced risk for VA and 44% (P  =  0.002) and 26% (P  =  0.055) reduced risk for VA/death as compared with patients with low SAI QRST (T1), respectively. CONCLUSION: In CRT implanted patients with mild heart failure, baseline AER was inversely associated with the risk for VA and VA/death; this is a finding that contradicts the relationship previously reported in non-CRT implanted patients. We theorize that CRT may abate the process of AER; however, characterization of this mechanism requires further study.