M. Kusha

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.

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.

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.

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.

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

Background— The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium. Methods and Results— Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio–renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (P=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus tachycardia rates were significantly reduced after RDN. Conclusions— RDN in the infarcted pig model leads to reduction of postinfarction VAs and myocardial sympathetic effectors. This may form the basis for a potential therapeutic role of RDN in postinfarct VAs.

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.

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.

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Background— After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na+ current to inactivate leads to intracellular Ca2+ dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na+ current, on ventricular refibrillation. Methods and Results— Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%; P=0.005) or GS-967–treated (45.83%, P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967–treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%; P=0.01). Ca2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca2+ alternans (P=0.03). Conclusions— Late Na+ current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models.

Studying semblances of a true killer: experimental model of human ventricular fibrillation

It is unknown whether ventricular fibrillation (VF) studied in experimental models represents in vivo human VF. First, we examined closed chest in vivo VF induced at defibrillation threshold testing (DFT) in four patients with ischemic cardiomyopathy pretransplantation. We examined VF in these same four hearts in an ex vivo human Langendorff posttransplantation. VF from DFT was compared with VF from the electrodes from a similar region in the right ventricular endocardium in the Langendorff using two parameters: the scale distribution width (extracted from continuous wavelet transform) and VF mean cycle length (CL). In a second substudy group where multielectrode phase mapping could be performed, we examined early VF intraoperatively (in vivo open chest condition) in three patients with left ventricular cardiomyopathy. We investigated early VF in the hearts of three patients in an ex vivo Langendorff and compared findings with intraoperative VF using two metrics: dominant frequency (DF) assessed by the Welch periodogram and the number of phase singularities (lasting >480 ms). Wavelet analysis (P = 0.9) and VF CL were similar between the Langendorff and the DFT groups (225 ± 13, 218 ± 24 ms; P = 0.9), indicating that wave characteristics and activation rate of VF was comparable between the two models. Intraoperative DF was slower but comparable with the Langendorff DF over the endocardium (4.6 ± 0.1, 5.0 ± 0.4 Hz; P = 0.9) and the epicardium (4.5 ± 0.2, 5.2 ± 0.4 Hz; P = 0.9). Endocardial phase singularity number (9.6 ± 5, 12.1 ± 1; P = 0.6) was lesser in number but comparable between in vivo and ex vivo VF. VF dynamics in the limited experimental human studies approximates human in vivo VF.