John Asta

Spatiotemporal Frequency Analysis of Ventricular Fibrillation in Explanted Human Hearts

Ventricular fibrillation (VF) is a medical condition that occurs due to rapid and irregular electrical activity of heart. If undiagnosed or untreated, VF leads to sudden cardiac death. VF has been studied by researchers for over 100 years to elucidate the mechanism that maintains VF, and thus to arrive at therapeutic options. VF is a nonstationary process, and it manifests into variations in the waveform morphology, phase, and frequency dynamics of the surface electrograms. Dominant frequency analysis (DF maps) and phase maps are two widely used complementary approaches in assessing the evolution of VF process. These techniques are applied to electrograms or fluorescence signals obtained with voltage-sensitive dyes. In spite of VF being a nonstationary process, most of the existing literature limits frequency analysis to a segmented, time-averaged spectral analysis, where valuable information on the instantaneous temporal evolution of the spectral characteristics is lost. In order to resolve this issue, in this paper, we present a joint time-frequency approach that is suited for VF analysis and demonstrate the application of instantaneous mean frequency (IMF) in interpreting VF episodes. Human VF sources are rarely anatomically stable and are migratory. Traditional DF techniques fail in tracking this migratory behavior. IMF, on the other hand, can deal with these migratory sources and conduction blocks better than DF approaches. Results of the analysis using the electrograms of 204 VF segments obtained from 13 isolated human hearts (explanted during cardiac transplantation) indicate that in 81% of the VF segments, there were significant changes in the spatiotemporal evolution of the frequency, suggesting that IMF provides better mechanistic insight of these signals. The IMF tool presented in this paper demonstrates potential for applications in tracking frequency patterns, conduction blocks, and arriving at newer therapies to modulate VF.

Effect of global ischemia and reperfusion during ventricular fibrillation in myopathic human hearts

The effect of lack of global coronary perfusion on myocardial activation rate, wavebreak, and its temporal progression during human ventricular fibrillation (VF) is not known. We tested the hypothesis that global myocardial ischemia decreases activation rate and spatiotemporal organization during VF in myopathic human hearts, while increasing wavebreak, and that a short duration of reperfusion can restore these spatiotemporal changes to baseline levels. The electrograms were acquired during VF in a human Langendorff model using global mapping consisting of two 112-electrode arrays placed on the epicardium and endocardium simultaneously. We found that global myocardial ischemia results in slowing of the global activation rate (combined endo and epi), from 4.89+/-0.04 Hz. to 3.60+/-0.04 Hz. during the 200 s of global ischemia (no coronary flow) (P<0.01) in eight myopathic hearts. Two minutes of reperfusion contributed to reversal of the slowing with activation rate value increasing close to VF onset (4.72+/-0.04 Hz). In addition, during the period of ischemia, an activation rate gradient between the endocardium (3.76+/-0.06 Hz) and epicardium (3.45+/-0.06 Hz) was observed (P<0.01). There was a concomitant difference in wavebreak index (that provides a normalized parameterization of phase singularities) between the epicardium (11.29+/-2.7) and endocardium (3.25+/-2.7) during the 200 s of ischemia (P=0.02). The activation rate, gradient, and wavebreak changes were reversed by short duration (2 min) of reperfusion. Global myocardial ischemia of 3 min leads to complex spatiotemporal changes during VF in myopathic human hearts; these changes can be reversed by a short duration of reperfusion.

Regional frequency variation during human ventricular fibrillation

Quantifying the regional frequency variation in ventricular fibrillation (VF) may lead to focal strategies in treating human VF. We hypothesized that during human VF there are quantifiable regional frequency variations in the ventricles and they relate to underlying fixed myocardial substrate. In eight myopathic human hearts, we studied 35 VF episodes. The electrograms during VF were acquired simultaneously from the epicardium and endocardium using 2 electrode arrays each consisting of 112 electrodes. Regional characterization was performed using a ratio parameter derived from the dominant frequency analysis of the electrograms. The findings were related to the anatomical substrate using bipolar voltage maps. The results of the analysis indicate that LV had a larger dominant frequency (DF) span than RV (p=0.0111) while there was no significant difference (p=0.1488) in the DF span between LV freewall (FW) and septum (SE). Correlation of areas of abnormal myocardium with the dominant frequency feature matched only in 50% of the cases indicating that ion channel heterogeneity and time-varying physiological factors may play an important role in maintaining VF.

Resolving Myocardial Activation With Novel Omnipolar Electrograms

Background—With its inherent limitations, determining local activation times has been the basis of cardiac mapping for over a century. Here, we introduce omnipolar electrograms that originate from the natural direction of a travelling wave and from which instantaneous conduction velocity amplitude and direction can be computed at any single location without first determining activation times. We sought to validate omnipole-derived conduction velocities and explore potential application for localization of sources of arrhythmias. Methods and Results—Electrograms from omnipolar mapping were derived and validated using 4 separate models and 2 independent signal acquisition methodologies. We used both electric signals and optical signals collected from monolayer cell preparations, 3-dimensional constructs built with cardiomyocytes derived from human embryonic stem cells, simultaneous optical and electric mapping of rabbit hearts, and in vivo pig electrophysiology studies. Conduction velocities calculated from omnipolar electrograms were compared with wavefront propagation from optical and electric-mapping studies with a traditional local activation time–based method. Bland–Altman analysis revealed that omnipolar measurements on optical data were in agreement with local activation time methods for wavefront direction and velocity within 25 cm/s and 30°, respectively. Similar agreement was also found on electric data. Furthermore, mathematical operations, such as curl and divergence, were applied to omnipole-derived velocity vector fields to locate rotational and focal sources, respectively. Conclusions—Electrode orientation–independent cardiac wavefront trajectory and speed at a single location for each cardiac activation can be determined accurately with omnipolar electrograms. Omnipole-derived vector fields, when combined with mathematical transforms may aid in real-time detection of cardiac activation sources.

Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF.

Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and energetically expensive. The objective of the present study is to determine the effects of dichloroacetate (DCA), a glucose oxidation stimulator, on cardiac contractile dysfunction following ischemia-induced VF. Male Sprague-Dawley rat hearts were Langendorff perfused in Tyrodes buffer. Once stabilized, hearts were subjected to 15 min of global ischemia and 5 min of aerobic reperfusion in the presence or absence of DCA. At the 6th min of reperfusion, VF was induced electrically, and terminated. Left ventricular (LV) pressure was measured using a balloon. Pretreatment with DCA significantly improved post-VF left ventricular developed pressure (LVDP) and dp/dtmax. In DCA-pretreated hearts, post-VF lactate production and pyruvate dehydrogenase (PDH) phosphorylation were significantly reduced, indicative of stimulated glucose oxidation, and inhibited anaerobic glycolysis by activation of PDH. Epicardial NADH fluorescence was increased during global ischemia above preischemic levels, but decreased below preischemia levels following VF, with no differences between nontreated controls and DCA-pretreated hearts, whereas DCA pretreatment increased NADH production in nonischemic hearts. With exogenous fatty acids (FA) added to the perfusion solution, DCA pretreatment also resulted in improvements in post-VF LVDP and dp/dtmax, indicating that the presence of exogenous FA did not affect the beneficial actions of DCA. In conclusion, enhancement of PDH activation by DCA mitigates cardiac contractile dysfunction following ischemia-induced VF.

Non-linear image registration for correction of motion artifacts during optical imaging of human hearts

Optical imaging of cardiac electrical activity can be used to elucidate patho-physiological mechanisms of cardiac arrhythmias. However, cardiac motion during optical imaging causes significant error in electrophysiological measurements such as action potential duration. In particular, cardiac tissue in fibrillation introduces highly non-linear imaging artifacts. We present a novel approach that uses non-linear image registration to correct for in-plane cardiac motion, particularly of non-linear origin found during cardiac arrhythmias. The algorithm is performed entirely post-acquisition and does not require a complicated optical setup. It is computationally fast, and available as open source. The algorithm was tested with images acquired from five excised dilated myopathic human hearts and the results show that the image registration method significantly reduces both non-linear and linear motion-related artifacts in both sinus rhythm and ventricular fibrillation. This algorithm corrects for non-linear imaging artifacts caused by cardiac motion that are impossible to correct using linear registration methods.

Slowing of the Atrial Flutter Rate During 1:1 Atrioventricular Conduction in Humans and Dogs: An Effect Mediated Through Atrial Pressure and Volume

Atrial Flutter Rate and Atrial Pressure. Introduction: During atrial flutter the effects of 1:1 atrioventricular (AV) conduction on the rate of atrial flutter was studied in 12 patients and 14 dogs.

Fusion of structural and functional cardiac magnetic resonance imaging data for studying Ventricular Fibrillation

Magnetic Resonance Imaging (MRI) techniques such as Current Density Imaging (CDI) and Diffusion Tensor Imaging (DTI) provide a complementing set of imaging data that can describe both the functional and structural states of biological tissues. This paper presents a Joint Independent Component Analysis (jICA) based fusion approach which can be utilized to fuse CDI and DTI data to quantify the differences between two cardiac states: Ventricular Fibrillation (VF) and Asystolic/Normal (AS/NM). Such an approach could lead to a better insight on the mechanism of VF. Fusing CDI and DTI data from 8 data sets from 6 beating porcine hearts, in effect, detects the differences between two cardiac states, qualitatively and quantitatively. This initial study demonstrates the applicability of MRI-based imaging techniques and jICA-based fusion approach in studying cardiac arrhythmias.

Resolving Bipolar Electrogram Voltages During Atrial Fibrillation Using Omnipolar Mapping

Background: Low-voltage–guided substrate modification is an emerging strategy in atrial fibrillation (AF) ablation. A major limitation to contemporary bipolar electrogram (EGM) analysis in AF is the resultant lower peak-to-peak voltage (Vpp) from variations in wavefront direction relative to electrode orientation and from fractionation and collision events. We aim to compare bipole Vpp with novel omnipolar peak-to-peak voltages (Vmax) in sinus rhythm (SR) and AF. Methods and Results: A high-density fixed multielectrode plaque was placed on the epicardial surface of the left atrium in dogs. Horizontal and vertical orientation bipolar EGMs, followed by omnipolar EGMs, were obtained and compared in both SR and AF. Bipole orientation has significant impact on bipolar EGM voltages obtained during SR and AF. In SR, vertical values were on average 66±119% larger than horizontal (P=0.004). In AF, vertical values were on average 31±96% larger than horizontal (P=0.07). Omnipole Vmax values were 99.9±125% larger than both horizontal (99.9±125%; P<0.001) and vertical (41±78%; P<0.0001) in SR and larger than both horizontal (76±109%; P<0.001) and vertical (52±70%; P value <0.0001) in AF. Vector field analysis of AF wavefronts demonstrates that omnipolar EGMs can account for collision and fractionation and record EGM voltages unaffected by these events. Conclusions: Omnipolar EGMs can extract maximal voltages from AF signals which are not influenced by directional factors, collision or fractionation, compared with contemporary bipolar techniques.

Feature-based MRI data fusion for cardiac arrhythmia studies

Current practices in studying cardiac arrhythmias primarily use electrical or optical surface recordings of a heart, spatially limited transmural recordings, and mathematical models. However, given that such arrhythmias occur on a 3D myocardial tissue, information obtained from such practices lack in dimension, completeness, and are sometimes prone to oversimplification. The combination of complementary Magnetic-Resonance Imaging (MRI)-based techniques such as Current Density Imaging (CDI) and Diffusion Tensor Imaging (DTI) could provide more depth to current practices in assessing the cardiac arrhythmia dynamics in entire cross sections of myocardium. In this work, we present an approach utilizing feature-based data fusion methods to demonstrate that complimentary information obtained from electrical current distribution and structural properties within a heart could be quantified and enhanced. Twelve (12) pairs of CDI and DTI image data sets were gathered from porcine hearts perfused through a Langendorff setup. Images were fused together using feature-based data fusion techniques such as Joint Independent Component Analysis (jICA), Canonical Correlation Analysis (CCA), and their combination (CCA+jICA). The results suggest that the complimentary information of cardiac states from CDI and DTI are enhanced and are better classified with the use of data fusion methods. For each data set, an increase in mean correlations of fused images were observed with 38% increase from CCA+jICA compared to the original images while mean mutual information of the fused images from jICA and CCA+jICA increased by approximately three-fold. We conclude that MRI-based techniques present potential viable tools in furthering studies for cardiac arrhythmias especially Ventricular Fibrillation.