Talha Farid

Role of KATP Channels in the Maintenance of Ventricular Fibrillation in Cardiomyopathic Human Hearts

Rationale: Ventricular fibrillation (VF) leads to global ischemia. The modulation of ischemia-dependent pathways may alter the electrophysiological evolution of VF. Objective: We addressed the hypotheses that there is regional disease-related expression of KATP channels in human cardiomyopathic hearts and that KATP channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness. Methods and Results: In a human Langendorff model, electric mapping of 6 control and 9 treatment (10 &mgr;mol/L glibenclamide) isolated cardiomyopathic hearts was performed. Spontaneous defibrillation was studied and mean VF cycle length was compared regionally at VF onset and after 180 seconds between control and treatment groups. KATP subunit gene expression was compared between LV endocardium versus epicardium in myopathic hearts. Spontaneous VF termination occurred in 1 of 6 control hearts and 7 of 8 glibenclamide-treated hearts (P=0.026). After 180 seconds of ischemia, a transmural dispersion in VF cycle length was observed between epicardium and endocardium (P=0.001), which was attenuated by glibenclamide. There was greater gene expression of all KATP subunit on the endocardium compared with the epicardium (P<0.02). In an ischemic rat heart model, transmural dispersion of refractoriness (&Dgr;ERPTransmural=ERPEpicardium−ERPEndocardium) was verified with pacing protocols. &Dgr;ERPTransmural in control was 5±2 ms and increased to 36±5 ms with ischemia. This effect was greatly attenuated by glibenclamide (&Dgr;ERPTransmural for glibenclamide+ischemia=4.9±4 ms, P=0.019 versus control ischemia). Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation in cardiomyopathic human hearts by attenuating the ischemia-dependent spatiotemporal heterogeneity of refractoriness during early VF.

Electrogram fractionation in murine HL-1 atrial monolayer model

BACKGROUND Complex 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. OBJECTIVE This study sought to study the origin of electrogram fractionation under the conditions of rotor formation and wave fragmentation, using atrial monolayer preparations. METHODS We performed optical mapping of 45 atrial monolayer preparations using a complementary metal oxide semiconductor (CMOS) Brainvision Ultima camera system (SciMedia-Brainvision, Tokyo, Japan). RESULTS We 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. CONCLUSION Complex 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

OBJECTIVES We tested the hypothesis that exposure to concentrated ambient particles (CAP) and/or ozone (O(3)) would increase dispersion of ventricular repolarization. BACKGROUND Elevated levels of air pollution are associated with cardiac arrhythmias through mechanisms yet to be elucidated. METHODS Each 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. RESULTS Spatial 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). CONCLUSIONS CAP + 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.

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.

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

AIMS Current 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. METHODS AND RESULTS Ablation 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. CONCLUSION By 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.

Controlled Exposure Study of Air Pollution and T-Wave Alternans in Volunteers without Cardiovascular Disease

Background: Epidemiological studies have assessed T-wave alternans (TWA) as a possible mechanism of cardiac arrhythmias related to air pollution in high-risk subjects and have reported associations with increased TWA magnitude. Objective: In this controlled human exposure study, we assessed the impact of exposure to concentrated ambient particulate matter (CAP) and ozone (O3) on T-wave alternans in resting volunteers without preexisting cardiovascular disease. Methods: Seventeen participants without preexisting cardiovascular disease were randomized to filtered air (FA), CAP (150 μg/m3), O3 (120 ppb), or combined CAP + O3 exposures for 2 hr. Continuous electrocardiograms (ECGs) were recorded at rest and T-wave alternans (TWA) was computed by modified moving average analysis with QRS alignment for the artifact-free intervals of 20 beats along the V2 and V5 leads. Exposure-induced changes in the highest TWA magnitude (TWAMax) were estimated for the first and last 5 min of each exposure (TWAMax_Early and TWAMax_Late respectively). ΔTWAMax (Late–Early) were compared among exposure groups using analysis of variance. Results: Mean ± SD values for ΔTWAMax were –2.1 ± 0.4, –2.7 ± 1.1, –1.9 ± 1.5, and –1.2 ± 1.5 in FA, CAP, O3, and CAP + O3 exposure groups, respectively. No significant differences were observed between pollutant exposures and FA. Conclusion: In our study of 17 volunteers who had no preexisting cardiovascular disease, we did not observe significant changes in T-wave alternans after 2-hr exposures to CAP, O3, or combined CAP + O3. This finding, however, does not preclude the possibility of pollution-related effects on TWA at elevated heart rates, such as during exercise, or the possibility of delayed responses.

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.

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.

Short-term memory and restitution during ventricular fibrillation in human hearts: an in vivo study.

Background—Action potential duration (APD) variation is an important determinant of wave break and reentry. The determinants of APD variability during early ventricular fibrillation (VF) in myopathic human hearts have not been studied. The objective of this study was to study the role of APD restitution and short-term cardiac memory on variation in human VF. Methods and Results—The study consisted of 7 patients (67±9 years old) with ejection fraction <35%. Monophasic action potentials were recorded from the right and/or left ventricular septum during VF. APD60/90 was measured in sinus beat preceding induction of VF, and its amplitude was used to define 60%/90% repolarization in VF. The monophasic action potential upstroke (dV/dtmax) was used to characterize local excitability. Simple linear regression showed that variability in APDn60 was determined by APD/diastolic interval restitution (R2=0.48, P<0.0001) and short-term memory (APD60 n−1, n−2, n−3, n−4; R2=0.55, 0.40, 0.33, and 0.27 respectively; P<0.001). Using multiple stepwise regression, short-term memory and restitution accounted for 62% of variance in APD60 (P<0.001). Individually, memory effect had the greatest contribution to APD variability (R2=0.55, P<0.0001). Conclusions—In early human VF, short-term memory and APD/diastolic interval restitution explain most of the APD variability, with memory effects predominating. This suggests that in early human VF, short-term cardiac memory may provide a novel therapeutic target to modulate progression of VF in myopathic patients.