Kumaraswamy Nanthakumar

Electrogram fractionation in murine HL-1 atrial monolayer model

BACKGROUNDnComplex fractionated atrial electrograms have been suggested as important targets for catheter ablation of atrial fibrillation. The etiology and the mechanism of these signals have not been completely elucidated because of limitations of interpretation of these signals in relation to simultaneously acquired signals in the neighboring atrial tissue.nnnOBJECTIVEnThis study sought to study the origin of electrogram fractionation under the conditions of rotor formation and wave fragmentation, using atrial monolayer preparations.nnnMETHODSnWe performed optical mapping of 45 atrial monolayer preparations using a complementary metal oxide semiconductor (CMOS) Brainvision Ultima camera system (SciMedia-Brainvision, Tokyo, Japan).nnnRESULTSnWe observed stable rotors in 32 of the 45 recordings. The derived bipolar electrograms did not show complex fractionation at the core of the rotor in any of the 32 recordings. We were also able to show that 2 bipolar electrodes placed adjacent to the core of a stable rotor in a zone where there is no wave break will record electrical activity for the majority of the rotors cycle length. In 13 of the 45 recordings, wave break or wave collision events were present. Of these, 8 of 13 recordings showed complex fractionation. In 19 of the 27, simulation of meandering rotors also showed complex fractionation.nnnCONCLUSIONnComplex fractionated electrograms can be recorded at sites of migrating rotors and wave break. No fractionation occurs at the core of a stable rotor. Electrograms that span the rotor cycle length and alternate between 2 bipoles that straddle the core can identify site of a stable rotor.

The Effect of Air Pollution on Spatial Dispersion of Myocardial Repolarization in Healthy Human Volunteers

OBJECTIVESnWe tested the hypothesis that exposure to concentrated ambient particles (CAP) and/or ozone (O(3)) would increase dispersion of ventricular repolarization.nnnBACKGROUNDnElevated levels of air pollution are associated with cardiac arrhythmias through mechanisms yet to be elucidated.nnnMETHODSnEach of 25 volunteers (18 to 50 years of age) had four 2-h exposures to 150 μg/m(3) CAP; 120 parts per billion O(3); CAP + O(3); and filtered air (FA). Exposure-induced changes (Δ = 5-min epochs at end-start) in spatial dispersion of repolarization were determined from continuous 12-lead electrocardiographic recording.nnnRESULTSnSpatial dispersion of repolarization assessed by corrected ΔT-wave peak to T-wave end interval increased significantly for CAP + O(3) (0.17 ± 0.03, p < 0.0001) exposure only, remaining significant when factoring FA (CAP + O(3) - FA) as control (0.11 ± 0.04, p = 0.013). The influence on repolarization was further verified by a significant increase in ΔQT dispersion (for CAP + O(3) compared with FA (5.7 ± 1.4, p = 0.0002). When the low-frequency to high-frequency ratio of heart rate variability (a conventional representation of sympathetic-parasympathetic balances) was included as a covariate, the effect estimate was positive for both corrected ΔT-wave peak to T-wave end interval (p = 0.002) and ΔQT dispersion (p = 0.038). When the high-frequency component (parasympathetic heart rate modulation) was included as a covariate with corrected ΔT-wave peak to T-wave end interval, the effect estimate for high frequency was inverse (p = 0.02).nnnCONCLUSIONSnCAP + O(3) exposure alters dispersion of ventricular repolarization in part by increasing sympathetic and decreasing parasympathetic heart rate modulation. Detection of changes in repolarization parameters, even in this small cohort of healthy individuals, suggests an underappreciated role for air pollutants in urban arrhythmogenesis.

Bipolar ablation for deep intra-myocardial circuits: human ex vivo development and in vivo experience.

AIMSnCurrent conventional ablation strategies for ventricular tachycardia (VT) aim to interrupt reentrant circuits by creating ablation lesions. However, the critical components of reentrant VT circuits may be located at deep intramural sites. We hypothesized that bipolar ablations would create deeper lesions than unipolar ablation in human hearts.nnnMETHODS AND RESULTSnAblation was performed on nine explanted human hearts at the time of transplantation. Following explant, the hearts were perfused by using a Langendorff perfusion setup. For bipolar ablation, the endocardial catheter was connected to the generator as the active electrode and the epicardial catheter as the return electrode. Unipolar ablation was performed at 50 W with irrigation of 25 mL/min, with temperature limit of 50°C. Bipolar ablation was performed with the same settings. Subsequently, in a patient with an incessant septal VT, catheters were positioned on the septum from both the ventricles and radiofrequency was delivered with 40 W. In the explanted hearts, there were a total of nine unipolar ablations and four bipolar ablations. The lesion depth was greater with bipolar ablation, 14.8 vs. 6.1 mm (P < 0.01), but the width was not different (9.8 vs. 7.8 mm). All bipolar lesions achieved transmurality in contrast to the unipolar ablations. In the patient with a septal focus, bipolar ablation resulted in termination of VT with no inducible VTs.nnnCONCLUSIONnBy using a bipolar ablation technique, we have demonstrated the creation of significantly deeper lesions without increasing the lesion width, compared with standard ablation. Further clinical trials are warranted to detail the risks of this technique.

Regional ion channel gene expression heterogeneity and ventricular fibrillation dynamics in human hearts

Rationale Structural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role. Objectives To define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics. Methods and Results High throughput real-time RT-PCR was used to quantify the expression patterns of 84 ion-channel, calcium cycling, connexin and related gene transcripts from sites in the LV, septum, and RV in 8 patients undergoing transplantation. An additional eight non-diseased donor human hearts served as controls. To relate local ion channel expression change to VF dynamics localized VF mapping was performed on the explanted myopathic hearts right adjacent to sampled regions. Compared to non-diseased ventricles, significant differences (p<0.05) were identified in the expression of 23 genes in the myopathic LV and 32 genes in the myopathic RV. Within the myopathic hearts significant regional (LV vs septum vs RV) expression differences were observed for 13 subunits: Nav1.1, Cx43, Ca3.1, Cavα2δ2, Cavβ2, HCN2, Na/K ATPase-1, CASQ1, CASQ2, RYR2, Kir2.3, Kir3.4, SUR2 (p<0.05). In a subset of genes we demonstrated differences in protein expression between control and myopathic hearts, which were concordant with the mRNA expression profiles for these genes. Variability in the expression of Cx43, hERG, Na+/K+ ATPase ß1 and Kir2.1 correlated to variability in local VF dynamics (p<0.001). To better understand the contribution of multiple ion channel changes on VF frequency, simulations of a human myocyte model were conducted. These simulations demonstrated the complex nature by which VF dynamics are regulated when multi-channel changes are occurring simultaneously, compared to known linear relationships. Conclusions Ion channel expression profile in myopathic human hearts is significantly altered compared to normal hearts. Multi-channel ion changes influence VF dynamic in a complex manner not predicted by known single channel linear relationships.

Decrement Evoked Potential Mapping Basis of a Mechanistic Strategy for Ventricular Tachycardia Ablation

Background—Substrate-based mapping for ventricular tachycardia (VT) ablation is hampered by its inability to determine critical sites of the VT circuit. We hypothesized that those potentials, which delay with a decremental extrastimulus (decrement evoked potentials or DEEPs), are more likely to colocalize with the diastolic pathways of VT circuits. Methods and Results—DEEPs were identified in intraoperative left ventricular maps from 6 patients with ischemic cardiomyopathy (total 9 VTs) and were compared with late potential (LP) and activation maps of the diastolic pathway for each VT. Mathematical modeling was also used to further validate and elucidate the mechanisms of DEEP mapping. All patients demonstrated regions of DEEPs and LPs. The mean endocardial surface area of these potentials was 18±4% and 21±6%, respectively (P=0.13). The mean sensitivity for identifying the diastolic pathway in VT was 50±23% for DEEPs and 36±32% for LPs (P=0.31). The mean specificity was 43±23% versus 20±8% for DEEP and LP mapping, respectively (P=0.031). The electrograms that displayed the greatest decrement in each case had a sensitivity and specificity for the VT isthmus of 29±10% and 95±1%, respectively. Mathematical modeling studies recapitulated DEEPs at the VT isthmus and demonstrated their role in VT initiation with a critical degree of decrement. Conclusions—In this preliminary study, DEEP mapping was more specific than LP mapping for identifying the critical targets of VT ablation. The mechanism of DEEPs relates to conduction velocity restitution magnified by zigzag conduction within scar channels.

Wavelet-based features for characterizing ventricular arrhythmias in optimizing treatment options

Ventricular arrhythmias arise from abnormal electrical activity of the lower chambers (ventricles) of the heart. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are the two major subclasses of ventricular arrhythmias. While VT has treatment options that can be performed in catheterization labs, VF is a lethal cardiac arrhythmia, often when detected the patient receives an implantable defibrillator which restores the normal heart rhythm by the application of electric shocks whenever VF is detected. The classification of these two subclasses are important in making a decision on the therapy performed. As in the case of all real world process the boundary between VT and VF is ill defined which might lead to many of the patients experiencing arrhythmias in the overlap zone (that might be predominately VT) to receive shocks by the an implantable defibrillator. There may also be a small population of patients who could be treated with anti-arrhythmic drugs or catheterization procedure if they can be diagnosed to suffer from predominately VT after objectively analyzing their intracardiac electrogram data obtained from implantable defibrillator. The proposed work attempts to arrive at a quantifiable way to scale the ventricular arrhythmias into VT, VF, and the overlap zone arrhythmias as VT-VF candidates using features extracted from the wavelet analysis of surface electrograms. This might eventually lead to an objective way of analyzing arrhythmias in the overlap zone and computing their degree of affinity towards VT or VF. A database of 24 human ventricular arrhythmia tracings obtained from the MIT-BIH arrhythmia database was analyzed and wavelet-based features that demonstrated discrimination between the VT, VF, and VT-VF groups were extracted. An overall accuracy of 75% in classifying the ventricular arrhythmias into 3 groups was achieved.

Real-time electrogram analysis for monitoring coronary blood flow during human ventricular fibrillation: Implications for CPR

BACKGROUNDnEffective chest compressions during prolonged ventricular fibrillation (VF) have been shown to increase the chances of successful defibrillation to a rhythm associated with a sustainable cardiac output. There is currently no effective method of recording the degree of antegrade coronary artery flow during chest compression in VF.nnnOBJECTIVEnThis study sought to quantify the relationship between the antegrade coronary flow and the characteristics of human VF using near real-time wavelet-based electrocardiographic markers.nnnMETHODSnVF experiments were conducted in 8 isolated human hearts. The Langendorff perfusion enabled different flow rates (perfusion) during VF, which allowed for the simulation of chest compression with different efficacies. After the initiation of VF, the hearts were maintained in ischemia (no flow) for 3 minutes, followed by a 2-minute reperfusion and defibrillation. The experiments were repeated at flows of 0%, 30%, and 100% of baseline perfusion, and volume-conducted surface electrograms were recorded and analyzed using continuous wavelet transform in 5-second frames.nnnRESULTSnNear real-time wavelet features were derived that demonstrated significant differences in the multicomponent nature of VF signals and predicted perfusion rate characteristics for different flow rates (i.e., 0%, 30%, and 100%; P < .0006). A pattern classifier was trained using the feature values from 5 hearts, and the flow rates for 3 additional hearts were predicted with an accuracy of 90%.nnnCONCLUSIONnVF electrogram characteristics as measured by wavelet analysis relate to antegrade coronary flow rate during VF. These findings suggest that chest compression efficacy of physiological importance could be monitored using near real-time wavelet analysis.

Relating spatial heterogeneities to rotor formation in studying human ventricular fibrillation

Ventricular fibrillation (VF) occurs due to disorganized electrical activity in the ventricles. This leads to rapid uncoordinated contractions of the ventricles and sudden cardiac death if not treated within minutes of its occurrence. The mechanism of VF initiation and maintenance is still elusive, however the mother rotor and multiple wavelet theories attempt to explain the mechanism behind this lethal arrhythmia. In mother rotor theory, VF is believed to be maintained by high frequency periodic sources called rotors that could be tracked using the phase progression along and through the myocardium using spatio-temporal electrical mapping of the heart. There are exiting works including our previous works that have related the formation of these rotors to anatomical and physiological heterogeneities observed in the myocardium. In this study we performed an correlation exercise of the locations of rotors with scar boundary maps and dominant frequency maps and elucidated this relation using human VF data acquired from isolated human hearts. The results suggest that in 14 rotors over 6 human hearts that we studied, all rotors co-localized to boundary zones of scar and low-high dominant frequency locations. The mean variance of the dominant frequency over the spatial location of the rotor was found to be 0.55 with average minimum of 4.15 Hz to a maximum of 5.71 Hz. This results in human VF data strongly suggest that boundary zones of healthy-non-healthy tissues and low-high frequency boundaries form a favorite substrate for rotor formation.

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.

Effect of spatial resolution and filtering on mapping cardiac fibrillation

BACKGROUNDnEndocardial mapping tools use variable interelectrode resolution, whereas body surface mapping tools use narrow bandpass filtering (BPF) to map fibrillatory mechanisms established by high-resolution optical imaging.nnnOBJECTIVEnThe purpose of this study was to study the effect of resolution and BPF on the underlying mechanism being mapped.nnnMETHODSnHearts from 14 healthy New Zealand white rabbits were Langendorff perfused. We studied the effect of spatial resolution and BPF on the location and characterization of rotors by comparing phase singularities detected by high-resolution unfiltered optical maps and of fibrillating myocardium with decimated and filtered maps with simulated electrode spacing of 2, 5, and 8 mm.nnnRESULTSnAs we decimated the maps with 2-mm, 5-mm, and 8-mm interelectrode spacing, the mean ( ± SD) number of rotors detected decreased from 10.2 ± 9.6, 1.6 ± 3.2, and 0.2 ± 0.5, respectively. Lowering the resolution led to synthesized pseudo-rotors that may be inappropriately identified. Applying a BPF led to fewer mean phase singularities detected (248 ± 207 vs 333 ± 130; P<.01), giving the appearance of pseudo-spatial stability measured as translation index (with BPF 3.6 ± 0.4 mm vs 4.0 ± 0.5 mm without BPF; P<.01) and pseudo-temporal stability with longer duration (70.0 ± 17.6 ms in BPF maps vs 44.1 ± 6.6 ms in unfiltered maps; P<.001) than true underlying fibrillating myocardium mapped.nnnCONCLUSIONnElectrode resolution and BPF of electrograms can result in distortion of the underlying electrophysiology of fibrillation. Newer mapping techniques need to demonstrate sensitivity analysis to quantify the degree of distortion before clinical use to avoid inaccurate electrophysiologic interpretation.