Evaluating strict and conventional left bundle branch block criteria using electrocardiographic simulations.

AIMS: Left bundle branch block (LBBB) is a critical predictor of patient benefit from cardiac resynchronization therapy (CRT), but recent studies suggest that one-third of patients diagnosed with LBBB by conventional electrocardiographic (ECG) criteria may have a false-positive diagnosis. In this study, we tested the hypothesis that recently proposed strict LBBB ECG criteria improve specificity in cases of left ventricular hypertrophy (LVH) /dilatation and incomplete LBBB. METHODS AND RESULTS: We developed five heart models based on a healthy male with increasing degrees of LV hypertrophy and/or dilation. With each model, we simulated six conduction types: normal conduction, four increments of delayed initiation of LV activation (incomplete LBBB), and complete LBBB. Simulated ECGs were evaluated for the presence of LBBB by conventional (LV conduction delay and QRSd ≥120 ms) and strict ECG criteria (LV conduction delay, QRSd ≥140 ms men or ≥130 ms women, and mid-QRS notching in at least two of the leads I, aVL, V1, V2, V5, and/or V6). Both conventional and strict LBBB criteria had 100% sensitivity. However, conventional criteria falsely diagnosed LBBB in cases with LVH + LV dilated 10 mm, LVH or LV dilated 10 mm combined with LV initiation ≥6 ms after the right ventricle (RV), and with LV dilated 5 mm combined with LV initiation ≥12 ms after RV (48% specificity). Strict LBBB criteria resulted in no false positives (100% specificity). CONCLUSIONS: New strict LBBB criteria increase the specificity of complete LBBB diagnosis in the presence of LV hypertrophy/dilatation and incomplete LBBB, which is critical for selecting CRT patients.

Comparative analysis of media effects on human induced pluripotent stem cell-derived cardiomyocytes in proarrhythmia risk assessment.

INTRODUCTION: Cardiotoxicity assessment using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) forms a key component of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). A potentially impactful factor on iPSC-CM testing is the presence of serum in the experimental media. Generally, serum-free media is used to most accurately reproduce "free" drug concentration. However, caution is needed; drug solubility and cardiomyocyte electrophysiology could be affected by media formulation, potentially impacting interpretation of drug-induced effects. METHODS: Effects of 25 drugs on properties of spontaneous field potentials in iPSC-CMs were assayed using a high-throughput microelectrode array (MEA) in two media formulations: serum-containing and serum-free. Comparative analysis was conducted on rate-corrected field potential duration (FPDc) and prevalence of arrhythmic events. Further MEA experiments were conducted, varying percentages of serum as well as carbon substrate components. Comparative LC-MS/MS analysis was done on two compounds to evaluate drug concentrations. RESULTS: In serum-free media, 9 drugs prolonged FPDc. In serum-containing, 11 drugs prolonged FPDc. Eighteen drugs induced arrhythmias, 8 of these induced arrhythmias at lower concentrations in serum-containing media. At the highest non-arrhythmic concentrations, 13 of 25 drugs exhibited significant differences in FPDc prolongation/shortening between the media. Increasing fractions of serum in media yielded higher FPDc measurements. LC-MS/MS analysis of moxifloxacin and quinidine showed higher concentrations in serum-containing media. DISCUSSION: The present study highlights media formulation as an important consideration for cardiac safety testing with iPSC-CMs. Results described here suggest that media formulation influences both compound availability and baseline electrophysiological properties. Special attention should be paid to media for future iPSC-CM assays.

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.

Implantable cardiac pacemaker electromagnetic compatibility testing in a novel security system simulator.

This paper describes a novel simulator to perform electromagnetic compatibility (EMC) tests for active implantable medical devices (AIMDs) with electromagnetic fields emitted by security systems. The security system simulator was developed in response to over 100 incident reports over 17 years related to the interference of AIMD's with security systems and the lack of a standardized test method. The simulator was evaluated regarding field homogeneity, signal distortion, and maximum magnetic field strength levels. Small three-axis probes and a three-axis scanning system were designed to determine the spatial and temporal characteristics of the fields emitted by 12 different types of walk through metal detectors (WTMDs). Tests were performed on four implanted pacemakers with a saline phantom and correlated to a newly developed test method performed "in air" (without the phantom). Comparison of the simulator thresholds with tests performed in real WTMDs showed that the simulator is able to mimic the pacemaker interference. The interference thresholds found in the simulator indicate that pulsed magnetic fields are more likely to cause interference in pacemakers than sinusoidal fields. The security system simulator will help biomedical engineers, manufacturers of medical devices, and manufacturers of security systems to identify incompatible combinations of WTMDs and AIMDs early in the development stage.

Calculation of induced current densities and specific absorption rates (SAR) for pregnant women exposed to hand-held metal detectors.

The finite difference time domain (FDTD) method in combination with a well established frequency scaling method was used to calculate the internal fields and current densities induced in a simple model of a pregnant woman and her foetus, when exposed to hand-held metal detectors. The pregnant woman and foetus were modelled using a simple semi-heterogeneous model in 10 mm resolution, consisting of three different types of tissue. The model is based on the scanned shape of a pregnant woman in the 34th gestational week. Nine different representative models of hand-held metal detectors operating in the frequency range from 8 kHz to 2 MHz were evaluated. The metal detectors were placed directly on the abdomen of the computational model with a spacing of 1 cm. Both the induced current density and the specific absorption rate (SAR) are well below the recommended limits for exposure of the general public published in the ICNIRP Guidelines and the IEEE C95.1 Standard. The highest current density is 8.3 mA m(-2) and the highest SAR is 26.5 microW kg(-1). Compared to the limits for the induced current density recommended in the ICNIRP Guidelines, a minimum safety factor of 3 exists. Compared to the IEEE C95. 1 Standard, a safety factor of 60 000 for the specific absorption rate was found. Based on the very low specific absorption rate and an induced current density below the recommended exposure limits, significant temperature rise or nerve stimulation in the pregnant woman or in the foetus can be excluded.

Electromagnetic interference of GSM mobile phones with the implantable deep brain stimulator, ITREL-III.

BACKGROUND: The purpose was to investigate mobile phone interference with implantable deep brain stimulators by means of 10 different 900 Mega Hertz (MHz) and 10 different 1800 MHz GSM (Global System for Mobile Communications) mobile phones. METHODS: All tests were performed in vitro using a phantom especially developed for testing with deep brain stimulators. The phantom was filled with liquid phantom materials simulating brain and muscle tissue. All examinations were carried out inside an anechoic chamber on two implants of the same type of deep brain stimulator: ITREL-III from Medtronic Inc., USA. RESULTS: Despite a maximum transmitted peak power of mobile phones of 1 Watt (W) at 1800 MHz and 2 W at 900 MHz respectively, no influence on the ITREL-III was found. Neither the shape of the pulse form changed nor did single pulses fail. Tests with increased transmitted power using CW signals and broadband dipoles have shown that inhibition of the ITREL-III occurs at frequency dependent power levels which are below the emissions of GSM mobile phones. The ITREL-III is essentially more sensitive at 1800 MHz than at 900 MHz. Particularly the frequency range around 1500 MHz shows a very low interference threshold. CONCLUSION: These investigations do not indicate a direct risk for ITREL-III patients using the tested GSM phones. Based on the interference levels found with CW signals, which are below the mobile phone emissions, we recommend similar precautions as for patients with cardiac pacemakers: 1. The phone should be used at the ear at the opposite side of the implant and 2. The patient should avoid carrying the phone close to the implant.

Temperature measurement on neurological pulse generators during MR scans.

According to manufacturers of both magnetic resonance imaging (MRI) machines, and implantable neurological pulse generators (IPGs), MRI is contraindicated for patients with IPGs. A major argument for this restriction is the risk to induce heat in the leads due to the electromagnetic field, which could be dangerous for the surrounding brain parenchyma. The temperature change on the surface of the case of an ITREL-III (Medtronic Inc., Minneapolis, MN) and the lead tip during MRI was determined. An anatomical realistic and a cubic phantom, filled with phantom material mimicking human tissue, and a typical lead configuration were used to imitate a patient who carries an IPG for deep brain stimulation. The measurements were performed in a 1.5 T and a 3.0 T MRI. 2.1 degrees C temperature increases at the lead tip uncovered the lead tip as the most critical part concerning heating problems in IPGs. Temperature increases in other locations were low compared to the one at the lead tip. The measured temperature increase of 2.1 degrees C can not be considered as harmful to the patient. Comparison with the results of other studies revealed the avoidance of loops as a practical method to reduce heating during MRI procedures.

Comparison of the relation between left ventricular anatomy and QRS duration in patients with cardiomyopathy with versus without left bundle branch block.

QRS duration (QRSd) is used to diagnose left bundle branch block (LBBB) and is important to determine cardiac resynchronization therapy eligibility. The same QRSd thresholds established decades ago are used for all patients. However, significant interpatient variability of normal QRSd exists, and individualized QRSd thresholds might improve diagnosis and intervention strategies. Previous work reported left ventricular (LV) mass and papillary muscle location predicted QRSd in healthy subjects, but the relation in diseased ventricles is unknown. The aim of the present study was to determine the association between LV anatomy and QRSd in patients with cardiomyopathy. Patients referred for primary prevention implantable defibrillators (n = 166) received cardiac magnetic resonance imaging, and those with normal conduction (without bundle branch or fascicular block) and LBBB were studied. The LV mass, length, internal diameter, LV end-diastolic volume, septal and lateral wall thicknesses, and papillary muscle location were measured. In patients with normal conduction, LV length (r = 0.35, p <0.001), mass (r = 0.32, p <0.001), diameter (r = 0.20, p = 0.03), and septal wall thickness (r = 0.20, p = 0.03) had positive correlations with QRSd. In patients with LBBB, LV length (r = 0.32, p = 0.03), mass (r = 0.39, p = 0.01), diameter (r = 0.34, p = 0.02), and LV end-diastolic volume (r = 0.32, p = 0.04) had positive correlations with QRSd. Contrary to previous studies in healthy subjects, papillary muscle angle (location) was not associated with QRSd in cardiomyopathy patients with normal conduction or LBBB. In conclusion, increasing LV anatomical measurements were associated with increasing QRSd in patients with cardiomyopathy. Future work should investigate the use of LV anatomical measurements in developing individualized QRSd thresholds for diagnosing conduction abnormalities such as LBBB and identifying candidates for cardiac resynchronization therapy.