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During the past few years, the development of effective, empirical technologies for treatment of cardiac arrhythmias has exceeded the pace at which detailed knowledge of the underlying biology has accumulated. As a result, although some clinical arrhythmias can be cured with techniques such as catheter ablation, drug treatment and prediction of the risk of sudden death remain fairly primitive. The identification of key candidate genes for monogenic arrhythmia syndromes shows that to bring basic biology to the clinic is a powerful approach. Increasingly sophisticated experimental models and methods of measurement, including stem cell-based models of human cardiac arrhythmias, are being deployed to study how perturbations in several biologic pathways can result in an arrhythmia-prone heart. The biology of arrhythmia is largely quantifiable, which allows for systematic analysis that could transform treatment strategies that are often still empirical into management based on molecular evidence.
Copyright © 2012 Elsevier Ltd. All rights reserved.
The heterogeneities of electrophysiological properties of cardiac tissue are the main factors that control both arrhythmia induction and maintenance. Although the local increase of extracellular potassium ([K(+)](o)) due to coronary occlusion is a well-established metabolic response to acute ischemia, the role of local [K(+)](o) heterogeneity in phase 1a arrhythmias has yet to be determined. In this work, we created local [K(+)](o) heterogeneity and investigated its role in fast pacing response and arrhythmia induction. The left marginal vein of a Langendorff-perfused rabbit heart was cannulated and perfused separately with solutions containing 4, 6, 8, 10, and 12 mM of K(+). The fluorescence dye was utilized to map the voltage distribution. We tested stimulation rates, starting from 400 ms down to 120 ms, with steps of 5-50 ms. We found that local [K(+)](o) heterogeneity causes action potential (AP) alternans, 2:1 conduction block, and wave breaks. The effect of [K(+)](o) heterogeneity on electrical stability and vulnerability to arrhythmia induction was largest during regional perfusion with 10 mM of K(+). We detected three concurrent dynamics: normally propagating activation when excitation waves spread over tissue perfused with normal K(+), alternating 2:2 rhythm near the border of [K(+)](o) heterogeneity, and 2:1 aperiodicity when propagation was within the high [K(+)](o) area. [K(+)](o) elevation changed the AP duration (APD) restitution and shifted the restitution curve toward longer diastolic intervals and shorter APD. We conclude that spatial heterogeneity of the APD restitution, created with regional elevation of [K(+)](o), can lead to AP instability, 2:1 block, and reentry induction.
BACKGROUND - Traditional electrocardiographic (ECG) reference ranges were derived from studies in communities or clinical trial populations. The distribution of ECG parameters in a large population presenting to a healthcare system has not been studied.
OBJECTIVE - The purpose of this study was to define the contribution of age, race, gender, height, body mass index, and type 2 diabetes mellitus to normal ECG parameters in a population presenting to a healthcare system.
METHODS - Study subjects were obtained from the Vanderbilt Synthetic Derivative, a de-identified image of the electronic medical record (EMR), containing more than 20 years of records on 1.7 million subjects. We identified 63,177 unique subjects with an ECG that was read as "normal" by the reviewing cardiologist. Using combinations of natural language processing and laboratory and billing code queries, we identified a subset of 32,949 subjects without cardiovascular disease, interfering medications, or abnormal electrolytes. The ethnic makeup was 77% Caucasian, 13% African American, 1% Hispanic, 1% Asian, and 8% unknown.
RESULTS - The range that included 95% of normal PR intervals was 125-196 ms, QRS 69-103 ms, QT interval corrected with Bazett formula 365-458 ms, and heart rate 54-96 bpm. Linear regression modeling of patient characteristic effects reproduced known age and gender effects and identified novel associations with race, body mass index, and type 2 diabetes mellitus. A web-based application for patient-specific normal ranges is available online at http://biostat.mc.vanderbilt.edu/ECGPredictionInterval.
CONCLUSION - Analysis of a large set of EMR-derived normal ECGs reproduced known associations, found new relationships, and established patient-specific normal ranges. Such knowledge informs clinical and genetic research and may improve understanding of normal cardiac physiology.
Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Cardiac repolarization, the process by which cardiomyocytes return to their resting potential after each beat, is a highly regulated process that is critical for heart rhythm stability. Perturbations of cardiac repolarization increase the risk for life-threatening arrhythmias and sudden cardiac death. Although genetic studies of familial long-QT syndromes have uncovered several key genes in cardiac repolarization, the major heritable contribution to this trait remains unexplained. Identification of additional genes may lead to a better understanding of the underlying biology, aid in identification of patients at risk for sudden death, and potentially enable new treatments for susceptible individuals.
METHODS AND RESULTS - We extended and refined a zebrafish model of cardiac repolarization by using fluorescent reporters of transmembrane potential. We then conducted a drug-sensitized genetic screen in zebrafish, identifying 15 genes, including GINS3, that affect cardiac repolarization. Testing these genes for human relevance in 2 concurrently completed genome-wide association studies revealed that the human GINS3 ortholog is located in the 16q21 locus, which is strongly associated with QT interval.
CONCLUSIONS - This sensitized zebrafish screen identified 15 novel myocardial repolarization genes. Among these genes is GINS3, the human ortholog of which is a major locus in 2 concurrent human genome-wide association studies of QT interval. These results reveal a novel network of genes that regulate cardiac repolarization.
In this paper, we clearly demonstrate that the electric potential and the magnetic field can contain different information about current sources in three-dimensional conducting media. Expressions for the magnetic fields of electric dipole and quadrupole current sources immersed in an infinite conducting medium are derived, and it is shown that two different point dipole distributions that are electrically equivalent have different magnetic fields. Although measurements of the electric potential are not sufficient to determine uniquely the characteristics of a quadrupolar source, the radial component of the magnetic field can supply the additional information needed to resolve these ambiguities and to determine uniquely the configuration of dipoles required to specify the electric quadrupoles. We demonstrate how the process can be extended to even higher-order terms in an electrically silent series of magnetic multipoles. In the context of a spherical brain source model, it has been mathematically demonstrated that the part of the neuronal current generating the electric potential lives in the orthogonal complement of the part of the current generating the magnetic potential. This implies a mathematical relationship of complementarity between electroencephalography and magnetoencephalography, although the theoretical result in question does not apply to the nonspherical case [G. Dassios, Math. Med. Biol. 25, 133 (2008)]. Our results have important practical applications in cases where electrically silent sources that generate measurable magnetic fields are of interest. Moreover, electrically silent, magnetically active moments of higher order can be useful when cancellation due to superposition of fields can occur, since this situation leads to a substantial reduction in the measurable amplitude of the signal. In this context, information derived from magnetic recordings of electrically silent, magnetically active multipoles can supplement electrical recordings for the purpose of studying the physiology of the brain. Magnetic fields of the electric multipole sources in a conducting medium surrounded by an insulating spherical shell are also presented and the relevance of this calculation to cardiographic and encephalographic experimentation is discussed.
BACKGROUND - Atrial fibrillation (AF) is heterogeneous at the clinical and molecular levels. Association studies have reported that common single-nucleotide polymorphisms in KCNE1 and SCN5A may predispose to AF. In this study, we tested the hypothesis that specific AF-associated genotypes confer variation on the appearance of AF assessed by analysis of fibrillatory rate of the atria.
METHODS AND RESULTS - Twenty-six nonrelated patients (21 males, mean age 55+/-12 years) with persistent lone AF (median AF duration 5 weeks) not taking class I or III antiarrhythmic drugs were studied. Fibrillatory rate was obtained by spatiotemporal QRST cancellation and time-frequency analysis of the index surface ECG. Genotypes at the AF-associated loci in KCNE1 (S38G) and SCN5A (H558R) were determined by direct DNA sequencing. The atrial fibrillatory rate was 418+/-50 fibrillations per minute (range, 336 to 521) in the study cohort. Carriers of the 38GG KCNE1 genotype (n=13) had significantly lower fibrillatory rates (392+/-36 versus 443+/-49 fibrillations per minute, P0.006) compared to those with GS or SS genotype (n=13). Six patients (23%) with fibrillatory rates >450 fibrillations per minute, all had either the GS or SS genotype (Chi2 P0.008). In contrast, both the heterozygeous and homozygeous SCN5A H558R polymorphism had no effect on fibrillatory rate. There were no significant associations between fibrillatory rate and clinical (age, gender, AF duration, drug treatment) or echocardiographic (left atrial diameter, left ventricular ejection fraction) variables. In multivariable regression analysis, the KCNE1 S38G genotype (SS/GS coded 0, GG coded 1) was the only independent predictor of fibrillatory rate (beta = -0.437, P = 0.006) with a SE of the estimate of 44 fibrillations per minute.
CONCLUSIONS - This study suggests that atrial fibrillatory rate obtained from the surface ECG is at least in part determined by KCNE1 (S38G) genotype, implying that this variant exerts functional effects on atrial electrophysiology. This intermediate ECG phenotype may be useful for elaborating genetic influences on AF mechanisms and identifying subsets of patients for variability in AF susceptibility or response to therapies.
Minimally invasive techniques for electrophysiological cardiac data mapping and catheter ablation therapy have been driven through advancements in computer-aided technologies, including magnetic tracking systems, and virtual and augmented-reality environments. The objective of this work is to extend current cardiac mapping techniques to collect and display data in the temporal domain, while mapping on patient-specific cardiac models. This paper details novel approaches to collecting spatially tracked cardiac electrograms, registering the data with a patient-specific cardiac model, and interpreting the data directly on the model surface, with the goal of giving a more comprehensive cardiac mapping system in comparison to current systems. To validate the system, laboratory studies were conducted to assess the accuracy of navigating to both physical and virtual landmarks. Subsequent to the laboratory studies, an in-vivo porcine experiment was conducted to assess the systems overall ability to collect spatial tracked electrophysiological data, and map directly onto a cardiac model. The results from these experiments show the new dynamic cardiac mapping system was able to maintain high accuracy of locating physical and virtual landmarks, while creating a dynamic cardiac map displayed on a dynamic cardiac surface model.
To fully characterize the mechanisms of defibrillation, it is necessary to understand the response, within the three-dimensional (3D) volume of the ventricles, to shocks given in diastole. Studies that have examined diastolic responses conducted measurements on the epicardium or on a transmural surface of the left ventricular (LV) wall only. The goal of this study was to use optical imaging experiments and 3D bidomain simulations, including a model of optical mapping, to ascertain the shock-induced virtual electrode and activation patterns throughout the rabbit ventricles following diastolic shocks. We tested the hypothesis that the locations of shock-induced regions of hyperpolarization govern the different diastolic activation patterns for shocks of reversed polarity. In model and experiment, uniform-field monophasic shocks of reversed polarities (cathode over the right ventricle is RV-, reverse polarity is LV-) were applied to the ventricles in diastole. Experiments and simulations revealed that RV- shocks resulted in longer activation times compared with LV- shocks of the same strength. 3D simulations demonstrated that RV- shocks induced a greater volume of hyperpolarization at shock end compared with LV- shocks; most of these hyperpolarized regions were located in the LV. The results of this study indicate that ventricular geometry plays an important role in both the location and size of the shock-induced virtual anodes that determine activation delay during the shock and subsequently affect shock-induced propagation. If regions of hyperpolarization that develop during the shock are sufficiently large, activation delay may persist until shock end.
A panoramic cardiac imaging system consisting of three high-speed CCD cameras has been developed to image the surface electrophysiology of a rabbit heart via fluorescence imaging using a voltage-sensitive fluorescent dye. A robust, unique mechanical system was designed to accommodate the three cameras and to adapt to the requirements of future experiments. A unified computer interface was created for this application - a single workstation controls all three CCD cameras, illumination, stimulation, and a stepping motor that rotates the heart. The geometric reconstruction algorithms were adapted from a previous cardiac imaging system. We demonstrate the system by imaging a polymorphic cardiac tachycardia.