Orientation of conduction velocity vectors on cardiac mapping surfaces.

AIMS: Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using two-dimensional (2D) mapping tools. We studied the accuracy of mapping surface 2D CV, compared to the three-dimensional (3D) vectors, and the influence of mapping resolution in non-scarred animal and human heart models. METHODS AND RESULTS: Two models were used: a healthy porcine Langendorff model with transmural needle electrodes and a computer stimulation model of the ventricles built from an MRI-segmented, excised human heart. Local activation times (LATs) within the 3D volume of the mesh were used to calculate true 3D CVs (direction and velocity) for different pixel resolutions ranging between 500 µm and 4 mm (3D CVs). CV was also calculated for endocardial surface-only LATs (2D CV). In the experimental model, surface (2D) CV was faster on the epicardium (0.509 m/s) compared to the endocardium (0.262 m/s). In stimulation models, 2D CV significantly exceeded 3D CVs across all mapping resolutions and increased as resolution decreased. Three-dimensional and 2D left ventricle CV at 500 µm resolution increased from 429.2 ± 189.3 to 527.7 ± 253.8 mm/s (P < 0.01), respectively, with modest correlation (R = 0.64). Decreasing the resolution to 4 mm significantly increased 2D CV and weakened the correlation (R = 0.46). The majority of CV vectors were not parallel (<30°) to the mapping surface providing a potential mechanistic explanation for erroneous LAT-based CV over-estimation. CONCLUSION: Ventricular CV is overestimated when using 2D LAT-based CV calculation of the mapping surface and significantly compounded by mapping resolution. Three-dimensional electric field-based approaches are needed in mapping true CV on mapping surfaces.

Effects of azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation.

BACKGROUND: Proarrhythmic risk of conventional anti-arrhythmic agents is linked to unintended modulation of membrane voltage dynamics. We have demonstrated that the anti-fibrillatory effect of azumolene is mediated via stabilization of the hyperphosphorylated ryanodine receptor (RyR2), leading to attenuation of diastolic calcium leak. However, the concomitant effects on membrane voltage dynamics have not been evaluated yet. METHODS: After baseline optical mapping, Langendorff-perfused rabbit hearts treated with azumolene, or vehicle, were subjected to global ischemia-reperfusion (I/R) followed by two episodes of long-duration ventricular fibrillation (LDVF). Simultaneous dual epicardial calcium transient (CaT) and voltage dynamics were studied optically. RESULTS: Pre-treatment with azumolene was associated with higher CaT amplitude alternans ratios (0.94 ± 0.02 vs. 0.78 ± 0.03 in control hearts, at 6 Hz; p = 0.005; and action potential amplitude alternans ratio (0.95 ± 0.02 vs. 0.78 ± 0.04 at 6.0 Hz; p = 0.02), and reduction of action potential duration (APD80) dispersion (9.0 ± 4.8 msec vs. 19.3 ± 6.6 msec at 6.0 Hz p = 0.02) and optical action potential upstroke rise time (26.3 ± 2.6 msec in control vs. 13.8 ± 0.6 msec at 6.0 Hz, p = 0.02) after LDVF. No change in action potential duration (APD) was noted with azumolene treatment. CONCLUSION: In a model of ischemic recurrent LDVF, treatment with azumolene led to reduction of cardiac alternans, i.e., calcium and voltage alternans. Unlike conventional anti-arrhythmic agents, reduction of action potential upstroke rise time and preservation of action potential duration following azumolene treatment may reduce the proarrhythmia risk.

High density intramural mapping of post-infarct premature ventricular contractions and ventricular tachycardia.

BACKGROUND: Spontaneous ventricular premature contractions (PVCs) and ventricular tachycardia (VT) in the acute post infarct milieu is assumed to be due to automaticity. However, the mechanism has not been studied with intramural mapping. OBJECTIVE: To study the mechanism of spontaneous PVCs with high density intramural mapping in a canine model, and to test the hypothesis that post-infarct PVCs and VT are due to re-entry rather than automaticity. METHODS: In 15 anesthetized dogs, using 768 intramural unipolar electrograms, simultaneous recordings were made. After 20 min of stabilization, recordings were made during the first 10 min of ischemia, and activation maps of individual beats were constructed. Acute ischemia was produced by clamping the left anterior descending coronary artery proximal to the first diagonal branch. RESULTS: In all experiments ST-T alternans was present. Spontaneous ventricular beats occurred in five of 15 dogs where the earliest ectopic activity was manifested in the endocardium, well within the ischemic zone. From there, activity spread rapidly along the subendocardium, with endo-to epicardial spread along the non-ischemic myocardium. Epicardial breakthrough always occurred at the border of the ischemic myocardium. In three dogs, delayed potentials were observed, which were earliest at the ischemic epicardium and extended transmurally with increasing delay towards the endocardium, where they culminated in a premature beat. A similar sequence was observed in VT that followed. CONCLUSION: Graded responses that occur with each sinus beat intramurally, when able to propagate from epicardium to endocardium are the mechanism of PVCs and VT in post-infarct myocardium.

Automated Identification of Ventricular Tachycardia Ablation Targets: Multicenter Validation and Workflow Characterization.

Decrement evoked potentials (EPs) (DeEPs) constitute an accepted method to identify physiological ventricular tachycardia (VT) ablation targets without inducing VT. The feasibility of automated software (SW) in the detection of arrhythmogenic VT substrate has been documented. However, multicenter validation of automated SW and workflow has yet to be characterized. The objective of this study was to describe the functionality of a novel DeEP SW (Biosense Webster, Diamond Bar, CA, USA) and evaluate the independent performance of the automated algorithm using multicenter data. VT ablation cases were performed in the catheterization laboratory and retrospectively analyzed using the DeEP SW. The algorithm indicated and mapped DeEPs by first identifying capture in surface electrocardiograms (ECGs). Once capture was confirmed, the EPs of S1 paces were detected. The algorithm checked for the stability of S1 EPs by comparing the last 3 of the 8 morphologies and attributing standard deviation values. The extra-stimulus EP was then detected by comparing it to the S1 EP. Once detected, the DeEP value was computed from the extra-stimulus and displayed as a sphere on a voltage map. A total of 5,885 DeEP signals were extracted from 21 substrate mapping cases conducted at 3 different centers (in Spain, Canada, and Australia). A gold standard was established from ECGs manually marked by subject experts. Once the algorithm was deployed, 91.6% of S2 algorithm markings coincided with the gold standard, 1.9% were false-positives, and 0.1% were false-negatives. Also, 6.4% were non-specific DeEP detections. In conclusion, the automated DeEP algorithm identifies and displays DeEP points, revealing VT substrates in a multicenter validation study. The automation of identification and mapping display is expected to improve efficiency.

On the Electrophysiology and Mapping of Intramural Arrhythmic Focus.

BACKGROUND: Conventional mapping of focal ventricular arrhythmias relies on unipolar electrogram characteristics and early local activation times. Deep intramural foci are common and associated with high recurrence rates following catheter-based radiofrequency ablation. We assessed the accuracy of unipolar morphological patterns and mapping surface indices to predict the site and depth of ventricular arrhythmogenic focal sources. METHODS: An experimental beating-heart model used Langendorff-perfused, healthy swine hearts. A custom 56-pole electrode array catheter was positioned on the left ventricle. A plunge needle was placed perpendicular in the center of the grid to simulate arrhythmic foci at variable depths. Unipolar electrograms and local activation times were generated. Simulation models from 2 human hearts were also included with grids positioned simultaneously on the endocardium-epicardium from multiple left ventricular, septal, and outflow tract sites. RESULTS: A unipolar Q or QS complex lacks specificity for superficial arrhythmic foci, as this morphology pattern occupies a large surface area and is the predominant pattern as intramural depth increases without developing a R component. There is progressive displacement from the arrhythmic focus to the surface exit as intramural focus depth increases. A shorter total activation time over the overlying electrode array, larger surface area within initial 20 ms activation, and a dual surface breakout pattern all indicate a deep focus. CONCLUSIONS: Displacement from the focal intramural origin to the exit site on the mapping surface could lead to erroneous lesion delivery strategies. Traditional unipolar electrogram features lack specificity to predict the intramural arrhythmic source; however, novel endocardial-epicardial mapping surface indices can be used to determine the depth of arrhythmic foci.

Maximizing detection and optimal characterization of local abnormal ventricular activity in nonischemic cardiomyopathy: LAVAMAX & LAVAFLOW.

BACKGROUND: Sites of local abnormal ventricular activation (LAVA) are ventricular tachycardia (VT) ablation targets. In nonischemic cardiomyopathy (NICM), minute and sparse LAVA potentials are mapped with difficulty with direction-sensitive bipolar electrograms (EGM). A method for its optimal characterization independent of electrode orientation has not been explored. OBJECTIVE: Maximize voltages and calculate overall activation direction at LAVA sites, independent of catheter and wave direction, using omnipolar technology (OT) in NICM. METHODS: Four diseased isolated human hearts from NICM patients were mapped epicardially using a high-density grid. Bipolar EGMs with at least 2 activation segments separated by at least 25 ms were identified. We used OT to maximize voltages (LAVAMAX) and measured overall wave direction (LAVAFLOW) for both segments. Clinically relevant voltage proportion (CRVP) was used to estimate the proportion of directionally corrected bipoles. Concordance and changes in direction vectors were measured via mean vector length and angular change. RESULTS: OT provides maximal LAVA voltages (OT: 0.83 ± 0.09 mV vs Bi: 0.61 ± 0.06 mV, P < .05) compared to bipolar EGMs. OT optimizes LAVA voltages, with 32% (CRVP) of LAVA bipoles directionally corrected by OT. OT direction vectors at LAVA sites demonstrate general concordance, with an average of 62% ± 5%. A total of 72% of direction vectors change by more than 35° at LAVA sites. CONCLUSION: The omnipolar mapping approach allows maximizing voltage and determining the overall direction of wavefront activity at LAVA sites in NICM.

Stimulation and propagation of activation in conduction tissue: Implications for left bundle branch area pacing.

BACKGROUND: Characterizing wavefront generation and impulse conduction in left bundle (LB) has implications for left bundle branch area pacing (LBBAP). OBJECTIVES: The purpose of this study was to describe the pacing characteristics of LB and to study the role of pacing pulse width (PW) in overcoming left bundle branch block. METHODS: Twenty fresh ovine heart slabs containing well-developed and easily identifiable tissues of the conduction system were used for the study. LB stimulation, activation, and propagation were studied under baseline conditions, simulated conduction slowing, conduction block, and fascicular block. RESULTS: The maximum radius of the LB early activation increased up to 13.4 ± 2.4 mm from the pacing stimulus, and the time from stimulus to evoked potential shortened when pacing PW was increased from 0.13 to 2 ms at baseline. Conduction slowing and block induced by cooling could be resolved by increasing pacing PW from 0.25 to 1.5 ms over a distance of 10 ± 1.5 mm from the pacing stimulus. The LB strength-duration (SD) curve was shifted to the left of the myocardial SD curve. CONCLUSION: Increasing PW resolved conduction slowing and block and bypassed the experimental model of fascicular block in LB. Precise positioning of the LB lead in left ventricular subendocardium is not mandatory in LBBAP, as the SD curve of LB was shifted to the left of the myocardium SD curve and could be captured from a distance by optimizing PW.

Multi-Axes Lead With Tetrahedral Electrode Tip for Cardiac-Implantable Devices: Creative Concept for Pacing and Sensing Technology.

BACKGROUND: We developed a multi-axes lead (MaxLead) incorporating 4 electrodes arranged at the lead-tip, organized in an equidistant tetrahedron. Here, we studied MaxLead performance in sensing, pacing, and activation wavefront-direction analysis. METHODS: Sixteen explanted animal hearts (from 7 pigs, 7 sheep, and 2 rabbits) were used. Pacing threshold was tested from all axes of MaxLead from right-ventricular (RV) apex before and after simulated dislodgement. In addition, conduction-system pacing was performed in sheep heart preparations from all axes of MaxLead. Sensing via MaxLead positioned at RV apex was tested during sinus rhythm (SR), pacing from RV and left-ventricular (LV) free-wall, and ventricular fibrillation (VF). MaxLead-enabled voltage (MaxV), defined as the largest span of the sensed electric field loop, was compared with traditional lead-tip voltage detection. RESULTS: Pacing: MaxLead minimized change in pacing threshold owing to lead dislodgement (average voltage change 0.2 mV; 95% confidence interval [CI], -0.5 to 0.9), using multiple bipoles available for pacing. In animals with high conduction system-pacing thresholds (> 2 mV) in 1 or more bipoles (3 of 7), acceptable thresholds (< 1 mV) were demonstrated in an average of 2.5 remaining bipoles. Sensing: MaxV of SR and VF was consistently higher than the highest bipolar voltage (voltage difference averaged -0.18 mV, 95% CI, -0.28 to -0.07), P = 0.001). Electric field-loop geometry consistently differentiated ventricular activation in SR from that during pacing from RV and LV free walls. CONCLUSIONS: The multi-axes MaxLead electrode showed advantages in pacing, sensing, and mapping and has the potential to allow for improvements in lead-electrode technology for cardiac-implanted electronic devices.

Safety, efficacy, and monitoring of bipolar radiofrequency ablation in beating myopathic human and healthy swine hearts.

BACKGROUND: The safety and efficacy parameters for bipolar radiofrequency (RF) ablation are not well defined. OBJECTIVE: The purpose of this study was to investigate the safe range of power, utility of transmyocardial bipolar electrogram (EGM) amplitude, and circuit impedance in ablation monitoring. METHODS: Sixteen beating ex vivo human and swine hearts were studied in a Langendorff setup. Ninety-two bipolar ablations using two 4-mm irrigated catheters were performed at settings of 20-50 W, 60 seconds, and 30 mL/min irrigation in the left ventricle. RESULTS: For low-power ablations (20 and 30 W), transmurality was observed in 29 of 38 (76%) and 10 of 28 (36%) ablations for tissue thickness ≤17 mm and >17 mm, respectively. For high-power ablations (40 and 50 W), transmurality was observed in 5 of 7 (71%) and 7 of 19 (37%) ablations for tissue thickness ≤17 mm and >17 mm, respectively. Steam pop occurrence for low- and high-power ablations was 11 of 66 (16%) and 16 of 26 (62%), respectively (P = .0001), respectively. Lesion depth (limited by transmurality) was 12.0 ± 5.7 mm and 12.3 ± 5.8 mm, respectively (P = 1). Transmyocardial EGM amplitude decrement >60% strongly predicted transmurality (area under the curve [AUC] 0.8), and circuit impedance decrement >26% predicted steam pops (AUC 0.75). Half-normal saline did not affect transmurality or incidence of steam pops compared to normal saline irrigation. CONCLUSION: Bipolar RF ablation at power of 20-30 W provided an ideal balance of safety and efficacy, whereas power ≥40 W should be used with caution due to the high incidence of steam pops. Lesion transmurality monitoring and steam pop avoidance were best achieved using transmyocardial bipolar EGM voltage and circuit impedance, respectively.

Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice.

BACKGROUND: Doxorubicin (Dox) is a potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. Intracellular calcium dysregulation has been reported to be involved in doxorubicin-induced cardiomyopathy (DICM). The cardioprotective role of RyR stabilizer dantrolene (Dan) on the calcium dynamics of DICM has not yet been explored. OBJECTIVE: To evaluate the effects of dantrolene on intracellular calcium dysregulation and cardiac contractile function in a DICM model. METHODS: Adult male C57BL/6 mice were randomized into 4 groups: (1) Control, (2) Dox Only, (3) Dan Only, and (4) Dan + Dox. Fractional shortening (FS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography. In addition, mice were sacrificed 2 weeks after doxorubicin injection for optical mapping of the heart in a Langendorff setup. RESULTS: Treatment with Dox was associated with a reduction in both FS and LVEF at 2 weeks (P < .0001) and 4 weeks (P < .006). Dox treatment was also associated with prolongation of calcium transient durations CaTD50 (P = .0005) and CaTD80 (P < .0001) and reduction of calcium amplitude alternans ratio (P < .0001). Concomitant treatment with Dan prevented the Dox-induced decline in FS and LVEF (P < .002 at both 2 and 4 weeks). Dan also prevented Dox-induced prolongation of CaTD50 and CaTD80 and improved the CaT alternans ratio (P < .0001). Finally, calcium transient rise time was increased in the doxorubicin-treated group, indicating RyR2 dyssynchrony, and dantrolene prevented this prolongation (P = .02). CONCLUSION: Dantrolene prevents cardiac contractile dysfunction following doxorubicin treatment by mitigating dysregulation of calcium dynamics.

Acute Effects of Ibrutinib on Ventricular Arrhythmia in Spontaneously Hypertensive Rats.

BACKGROUND: The Bruton's Tyrosine Kinase Inhibitor ibrutinib is associated with ventricular arrhythmia (VA) and sudden death. However, the pro-arrhythmic electrophysiological dysregulation that results from ibrutinib with age and cardiovascular disease is unknown. OBJECTIVES: This study sought to investigate the acute effects of ibrutinib on left ventricular (LV) VA vulnerability, cytosolic calcium dynamics, and membrane electrophysiology in old and young spontaneous hypertensive rats (SHRs). METHODS: Langendorff-perfused hearts of young (10 to 14 weeks) and old (10 to 14 months) SHRs were treated with ibrutinib (0.1 µmol/l) or vehicle for 30 min. Simultaneously, LV epicardial action potential and cytosolic calcium transients were optically mapped following an incremental pacing protocol. Calcium and action potential dynamics parameters were analyzed. VA vulnerability was assessed by electrically inducing ventricular fibrillations (VFs) in each heart. Western blot analysis was performed on LV tissues. RESULTS: Ibrutinib treatment resulted in higher vulnerability to VF in old SHR hearts (27.5 ± 7.5% vs. 5.7 ± 3.7%; p = 0.026) but not in young SHR hearts (8.0 ± 4.9% vs. 0%; p = 0.193). In old SHR hearts, following ibrutinib treatment, action potential duration (APD) alternans (p = 0.008) and APD alternans spatial discordance (p = 0.027) were more prominent. Moreover, calcium transient duration 50 was longer (p = 0.032), calcium amplitude alternans ratio was significantly lower (p = 0.001), and time-to-peak of calcium amplitude was shorter (p = 0.037). In young SHR hearts, there were no differences in calcium and APD dynamics. CONCLUSIONS: Ibrutinib-induced VA is associated with old age in SHR. Acute dysregulation of calcium and repolarization dynamics play important roles in ibrutinib-induced VF.

Tracking rotors with minimal electrodes: modulation index-based strategy.

BACKGROUND: High-frequency periodic sources during cardiac fibrillation can be detected by phase mapping techniques. To enable practical therapeutic options for modulating periodic sources (existing techniques require high density multielectrode arrays and real time simultaneous mapping capability), a method to identify electrogram morphologies colocalizing to rotors that can be implemented on few electrograms needs to be devised. METHOD AND RESULTS: Multichannel ventricular fibrillation electrogram data from 7 isolated human hearts using Langendorff setup and intraoperative clinical data from 2 human hearts were included in the analysis. The spatial locations of rotors were identified using phase maps constructed from 112 electrograms. Electrograms were analyzed for repeating patterns and discriminating signal morphologies around the locations of rotors and nonrotors were identified and quantified. Features were extracted from the unipolar electrogram patterns, which corroborated well with the spatial location of rotors. The results suggest that using the proposed modulation index feature, and as low as 1 sample point in the vicinity of the rotors, an accuracy as high as 86% (P<0.001) was obtained in separating rotor locations versus nonrotor locations. The analysis of bipolar electrogram signatures in the vicinity of the rotor locations suggest that 62.5% of the rotors occur at locations where the bipolar electrogram demonstrates continuous activities during ventricular fibrillation. CONCLUSIONS: Unipolar electrogram extracted modulation index-based detection of rotors is feasible with few electrodes and has greater detection rate than bipolar approach. This strategy may be suitable for nonarray-based single mapping catheter enabled detection of rotors.