Ventricular Tachycardia Ablation Endpoints: Moving Beyond Noninducibility.

In patients with structural heart disease and ventricular tachycardia (VT) undergoing catheter ablation, the response to programmed electrical stimulation (PES) at the end of the procedure has been traditionally used to evaluate the acute success and predict long-term outcomes. Although noninducibility at PES has been extensively investigated and validated in clinical trials and large multicenter registries, its performance in predicting long-term freedom from VT is suboptimal. In addition, PES has inherent limitations related to the influence of background antiarrhythmic drug therapy, periprocedural use of anesthesia, and the heterogeneity in PES protocols. The increased utilization of substrate-based ablation approaches that focus on ablation of abnormal electrograms identified with mapping in sinus or paced rhythm has been paralleled by a need for additional procedural endpoints beyond VT noninducibility at PES. This article critically appraises the relative merits and limitations of different procedural endpoints according to different ablation techniques for catheter ablation of scar-related VT.

Polylysine-Containing Hydrogel Formulation of Fuzapladib, Inhibitor of Leukocyte-Function Associated Antigen-1 (LFA-1) Activation, for Sustained Release.

The aim of the present study was to develop an injectable hydrogel (HG) formulation of fuzapladib sodium (FZP), an animal drug for acute pancreatitis (AP), with the use of polyethyleneoxide (PEO) and polylysine (pLys), a cationic polymer. A mixture of pLys and FZP was added to PEO to prepare an HG formulation, and the formulation was optimized by release test and viscosity measurements. Circular dichroism (CD) and infrared absorption (IR) spectral analyses were applied to clarify the intermolecular interactions between FZP and pLys. The pharmacokinetic behavior of FZP was evaluated after a subcutaneous administration of FZP samples (2.0 mg-FZP/kg) to rats. Although the immediate release of FZP was observed for the HG formulation, the addition of pLys at a 20-fold amount of FZP or higher led to the sustained release of FZP. Considering release behavior, the concentration of pLys was optimized as 100-fold that of FZP in the HG formulation. CD and IR spectroscopic analyses of FZP and/or pLys demonstrated an intermolecular interaction between FZP and pLys, as evidenced by the slight spectral transition. After a subcutaneous administration of HG formulation containing pLys to rats, compared with FZP alone, significant differences were observed in the pharmacokinetic behavior with a decrease of Cmax from 2.3 to 0.9 mg/mL and slower elimination kinetics. HG formulation using pLys might be a viable dosage option for FZP for the treatment of AP in animals.

Utility and Limitations of Ablation Index for Guiding Therapy in Ventricular Myocardium.

BACKGROUND: Ablation index (AI) is used for guiding therapy during pulmonary vein isolation. However, its potential utility in ventricular myocardium is unknown. OBJECTIVES: This study sought to examine the correlation between AI and lesion dimensions in healthy and infarcted ventricles. METHODS: In ex vivo experiments using healthy swine ventricles, the correlation between AI (400-1,200) and lesion dimensions was examined at fixed power (30 W) and contact force (CF) (15 g). To examine the accuracy of AI in predicting lesion dimensions created by different combinations of ablation parameters, applications with a similar prespecified AI value created using different power (30 vs 40 W), CF (15 vs 25 g) or impedance (130-170 Ω) were created. In in vivo experiments, the correlation between AI and lesion dimensions was examined in healthy and infarcted myocardium. RESULTS: Ex vivo experiments (247 lesions, 36 hearts) showed good correlation between AI and lesion depth (R = 0.93; P < 0.001). However, in vivo experiments (9 healthy swine and 10 infarcted swine) showed moderate correlation in healthy myocardium (R = 0.64; P < 0.01) and poor correlation in infarcted myocardium (R = 0.23; P = 0.61). AI values achieved using different combinations of power, CF, and baseline impedance resulted in different lesion depths: Ablation at 30 W produced deeper lesions compared with 40 W, ablation with CF of 15 g produced deeper lesions compared with CF of 25 g, and ablation at lower impedance produced larger lesions at similar prespecified AI values (P < 0.01 for all). CONCLUSIONS: AI has limited value for guiding ablation in ventricular myocardium, particularly scar. This may be related to small proportional significance of application duration and complex tissue architecture.

The Kagoshima-DVT Score Is a Useful Predictive Model for Cancer-Associated Thrombosis in Patients With Gastrointestinal Cancer.

Background: Cancer-associated thrombosis (CAT) is a common complication of cancer and has received increasing attention; the Khorana Risk Score (KRS) is a recommended but insufficient risk assessment model for CAT. We propose a novel Kagoshima-DVT score (KDS) to predict preoperative deep vein thrombosis (DVT). This scoring method scores D-dimer ≥1.5 µg/mL, age ≥60 years, female sex, ongoing glucocorticoids, cancer with high risk of DVT, and prolonged immobility. The purpose of this study was to compare the performance of the KDS and KRS in predicting CAT in patients with gastrointestinal cancer. Methods and Results: In all, 250 patients without a history of thrombosis who received their first chemotherapy for gastrointestinal cancer were divided into low- (48.0%), intermediate- (38.8%), and high-risk (13.2%) groups for CAT development by the KDS. The patients' median age was 67 years and 63.2% were men. In all, 61 (27.1%) patients developed CAT (17.6%, 35.3%, and 36.4% of patients in the low-, intermediate, and high-risk groups, respectively; log-rank P=0.006). The area under the time-dependent receiver operating characteristic curve for CAT occurrence within 1 year was larger for the KDS than KRS (0.653 vs. 0.494). Conclusions: A high KDS at the start of first chemotherapy is a risk indicator for CAT development during chemotherapy. Moreover, the KDS is more useful than the KRS in predicting CAT risk.

Atrial Endocardial Unipolar Voltage Mapping for Detection of Viable Intramural Myocardium: A Proof-of-Concept Study.

BACKGROUND: Endocardial bipolar voltage amplitude is largely derived from endocardial and subendocardial wall layers. This may result in situations of low bipolar voltage amplitude despite the presence of mid-myocardial including epicardial (ie, intramural-epicardial) viable myocardium. This study examined the utility of endocardial unipolar voltage mapping for detection of viable intramural-epicardial atrial myocardium. METHODS: In 15 swine, an atrial intercaval ablation line with an intentional gap was created. Animals survived for 6 to 8 weeks before electroanatomical mapping followed by sacrifice. Gaps were determined by the presence of electrical conduction and classified based on the histopathologiclly layer(s) of viable myocardium into the following: (1) transmural, (2) endocardial, and (3) intramural-epicardial. Voltage data from healthy, scar, and gap points were exported into excel. The sensitivity and specificity of bipolar and unipolar voltage amplitude to detect intramural-epicardial gaps were compared using receiver operating characteristic analysis. RESULTS: In 9 of 15 (60%) swine, a focal ablation gap was detected in the intercaval line, while in the remainder 6 of 15 (40%), the line was complete without gaps. Gaps were classified into transmural (n=3), endocardial (n=3), or intramural-epicardial (n=3). Intramural-epicardial gaps were characterized by very low bipolar voltage amplitude that was similar to areas with transmural scar (P=0.91). In comparison, unipolar voltage amplitude in intramural-epicardial gaps was significantly higher compared to transmural scar (P<0.001). Unipolar voltage amplitude had higher sensitivity (93% versus 14%, respectively) and similar specificity (95% versus 98%, respectively) to bipolar voltage for detection of intramural-epicardial gaps. CONCLUSIONS: Atrial unipolar voltage mapping may be a useful technique for identifying viable intramural-epicardial myocardium in patients with endocardial scar.

The utility of combining continuous wavelet transform analysis and high-density voltage map in predicting the long-term outcomes after ablation of persistent atrial fibrillation.

BACKGROUND: Continuous wavelet transform (CWT) analysis is a frequency analysis to detect areas of stable high-frequent activity (stable pseudo frequency [sPF]) during atrial fibrillation (AF). As previously reported, patients with the highest sPF area in pulmonary veins (PV) showed better short-term outcomes after PV isolation (PVI). This study sought to evaluate the efficacy of CWT analysis in predicting the long-term (2 years) outcomes after PVI. We also combined the left atrial (LA) voltage map with CWT analysis to further predict the outcome. METHODS: Persistent AF patients (n = 109, age 65 ± 10) underwent a CWT analysis at PVs and 8 LA sites during AF for pre-PVI analysis. After PVI during AF, CWT analysis was performed again in the LA as post-PVI analysis and was compared with pre-PVI analysis. A sinus voltage map of LA was created after cardioversion. RESULTS: Seventy patients had the highest sPF within PVs (PV-dominant group), while 39 patients had the highest sPF outside PVs (LA-dominant group). The global frequency in the LA showed a significant decrease after PVI only in PV-dominant group (6.55 ± 0.27 to 6.43 ± 0.37, P < 0.01). AF-free survival was better in PV-dominant group than LA-dominant group at 2-year follow-up (87.1% vs. 64.3%, P < 0.002). This trend was recognized throughout all degrees of low voltage area in the LA (LA-LVA), and AF-free survival was well predicted by combining CWT analysis and LA-LVA. CONCLUSIONS: By combining CWT analysis and sinus LA-LVA, the long-term AF-free survival after PVI was well stratified and predicted.

Lattice-tip catheter for single-shot pulmonary vein isolation with pulsed field ablation.

BACKGROUND: A compressible lattice-tip catheter designed for focal ablation using radiofrequency or pulsed-field energies has been recently described. The objective of this study is to describe a new lattice catheter designed for single-shot pulmonary vein isolation (PVI). METHODS: This 8F catheter consists of a compressible lattice tip that is delivered over the wire and is expandable up to 34 mm (SpherePVI™, Affera Inc.). Pulsed field ablation (PFA) was applied from 6 elements using a biphasic waveform of microsecond scale (± 1.3-2.0 kV, 5 s per application). In 12 swine, the superior vena cava (SVC) and right superior pulmonary vein (RSPV) were targeted for isolation. Animals were survived for 12-24 h (n = 6) or 3 weeks (n = 6) for evaluation of short and long-term safety and efficacy parameters. PVI was evaluated immediately after ablation and at the terminal procedure. Ablation-related microbubbles were examined using intracardiac echocardiography and phrenic nerve function by pacing. The tissue was examined by histopathology. RESULTS: In all 12 animals, PFA resulted in successful acute isolation of the SVC and RSPV using 2.8 ± 1.1 and 3.2 ± 1.2 applications per vein, respectively. After a survival period of 23 ± 5.9 days, all targeted veins remained isolated, and the level of isolation persisted without significant regression or expansion. In one animal, SVC isolation at the level of the right atrial appendage resulted in sinus node arrest. PFA did not affect phrenic nerve function, and it was associated with a few isolated bubbles formation. CONCLUSIONS: In this pre-clinical study, a new expandable lattice catheter designed for single-shot PVI was able to achieve rapid and durable isolation.

Effect of Pulsed-Field and Radiofrequency Ablation on Heterogeneous Ventricular Scar in a Swine Model of Healed Myocardial Infarction.

BACKGROUND: Pulsed-field ablation (PFA) is a nonthermal energy with higher selectivity to myocardial tissue in comparison to radiofrequency ablation (RFA). We compared the effects of PFA and RFA on heterogeneous ventricular scar in a swine model of healed infarction. METHODS: In 9 swine, myocardial infarction was created by balloon occlusion of the left anterior descending artery. After a survival period of 8 to 10 weeks, ablation with PFA or RFA was performed at infarct border zones identified by abnormal electrograms. In the PFA group (4 swine), ablation was performed with a lattice catheter (Sphere-9, Affera, Inc). In the RFA group (5 swine), ablation was performed using a 3.5-mm tip catheter (Thermocool ST-SF; Biosense Webster). To further investigate the effect of RFA on temperature development in scar tissue, intramyocardial temperature was measured in healthy and infarcted myocardium using an ex vivo bath model. RESULTS: A total of 11 PFA and 15 RFA lesions were created at infarct border zones with heterogeneous scar. PFA produced uniform and well-demarcated lesions exhibiting irreversible injury characterized by cardiomyocyte death, contraction bands, and lymphocytic infiltration. This effect of PFA extended from the subendocardium through collagen and fat to the epicardial layers. In contrast, the effect of RFA is less uniform and largely limited to the subendocardium with minimal effect on viable myocardium deeper to separating layers of collagen and fat. PFA produced deeper and more transmural lesions (6.4 [interquartile range, 5.5-7.5) versus 5.4 [interquartile range, 4.8-5.9]), 72% versus 30%, respectively; P≤0.02 for each comparison). The limited effect of RFA on viable myocardium at deeper infarct layers was related to a lower intramyocardial maximal temperature compared with healthy myocardium (P=0.01). CONCLUSIONS: PFA may be advantageous for ablation in ventricular scar, producing lesions that unlike RFA are not limited to the subendocardium, but also eliminate viable myocardium separated from the catheter by collagen and fat.

Development of stabilized fuzapladib solution for injection: forced degradation study and pharmacokinetic evaluation.

The aim of the present study was to develop and evaluate stabilized injection solutions of fuzapladib sodium hydrate using antioxidants as the stabilizers. To estimate the possible degradation factors and pathways of fuzapladib, forced degradation studies were conducted under thermal, acid, base, oxidative, and light conditions. To select an optimal excipient to stabilize fuzapladib under a solution state, a screening study of antioxidants was carried out to evaluate their effects to inhibit the degradation. The influence of the selected stabilizers on its pharmacokinetic behavior was evaluated in rats after intravenous administration. On the basis of data from the forced degradation study, thermal and oxidative stresses were significant factors accelerating the degradation of fuzapladib. Among eight tested antioxidants, vitamin C (VC) was the most effective stabilizer to suppress the accelerated degradation by heating, as evidenced by 45% inhibition of the degradation. The stabilization effect was enhanced depending on the concentration of VC. After the intravenous administration of fuzapladib (0.5 mg/kg) with or without VC (2.1 mg/kg), there were no significant differences between the pharmacokinetic behaviors of each group. From these findings, VC might be a promising excipient to stabilize the injection solution of fuzapladib without significant influence on its pharmacokinetic behavior.

Increasing Lesion Dimensions of Bipolar Ablation by Modulating the Surface Area of the Return Electrode.

OBJECTIVES: This study sought to examine the effect of the return electrode's surface area on bipolar RFA lesion size. BACKGROUND: Bipolar radiofrequency ablation (RFA) is typically performed between 2 3.5-mm tip catheters serving as active and return electrodes. We hypothesized that increasing the surface area of the return electrode would increase lesion dimensions by reducing the circuit impedance, thus increasing the current into a larger tissue volume enclosed between the electrodes. METHODS: In step 1, ex vivo bipolar RFA was performed between 3.5-mm and custom-made return electrodes with increasing surface areas (20, 80, 180 mm2). In step 2, ex vivo bipolar RFA was performed between 3.5-mm and 3.5-mm or 8-mm electrode catheters positioned perpendicular or parallel to the tissue. In step 3, in vivo bipolar RFA was performed between 3.5-mm and either 3.5-mm or 8-mm parallel electrode at the: 1) left ventricular summit; 2) interventricular septum; and 3) healed anterior infarction. RESULTS: In step 1, increasing the surface area of the return electrode resulted in lower circuit impedance (R = -0.65; P < 0.001), higher current (R = +0.80; P < 0.001), and larger lesion volume (R = +0.88; P < 0.001). In step 2, an 8-mm return electrode parallel to tissue produced larger and deeper lesions compared with a 3.5-mm return electrode (P = 0.014 and P = 0.02). Similarly, in step 3, compared with a 3.5-mm, bipolar RFA with an 8-mm return electrode produced larger (volume: 1,525 ± 871 mm3 vs 306 ± 310 mm3, respectively; P < 0.001) and more transmural lesions (88% vs 0%; P < 0.001). CONCLUSIONS: Bipolar RFA using an 8-mm return electrode positioned parallel to the tissue produces larger lesions in comparison with a 3.5-mm return electrode.

Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability.

This study aimed to develop an oral nanocrystal solid dispersion (nCSD) of fuzapladib (FZP) with enhanced absorbability for the treatment of acute pancreatitis (AP). The hydration properties of crystalline FZP free acid (crystalline FZP) and FZP sodium salt (FZP/Na) were assessed to select a stable crystal form. The nCSD of FZP free acid (nCSD/FZP) was prepared using a multi-inlet vortex mixer and evaluated in terms of physicochemical and pharmacokinetic properties. The results of X-ray powder diffraction analysis indicated that crystalline FZP was stable as an anhydrate, while FZP/Na was converted to its monohydrate at water activity of above 0.2. The nanocrystals in nCSD/FZP were dispersed in hydroxy propyl cellulose-SSL, and their mean particle size were 160 nm with uniform spherical shape. In dissolution testing, nCSD/FZP exhibited rapid dissolution compared with crystalline FZP and reached a saturated concentration of FZP within initial 30 min. After oral administration (2 mg-FZP/kg) to rats, the maximum plasma concentration and bioavailability were 7.3- and 5.2-fold higher for nCSD/FZP than crystalline FZP, respectively, due to improved dissolution by nanosization. In conclusion, nCSD/FZP may be a novel oral dosage form with enhanced absorbability facilitating potent therapeutic effects of FZP for the treatment of AP in animals.

A case series of very slow atrioventricular nodal reentrant tachycardia resembling junctional tachycardia.

INTRODUCTION: The surface electrocardiography of typical atrioventricular nodal reentrant tachycardia (AVNRT) shows simultaneous ventricular-atrial (RP) activation with pseudo R' in V1 and typical heart rates ranging from 150 to 220/min. Slower rates are suspicious for junctional tachycardia (JT). However, occasionally we encounter typical AVNRT with slow ventricular rates. We describe a series of typical AVNRT cases with heart rates under 110/min. METHODS: A total of 1972 patients with AVNRT who underwent slow pathway ablation were analyzed. Typical AVNRT was diagnosed when; (1) evidence of dual atrioventricular nodal conduction, (2) tachycardia initiation by atrial drive train with atrial-His-atrial response, (3) short septal ventriculoatrial time, and (4) ventricular-atrial-ventricular (V-A-V) response to ventricular overdrive (VOD) pacing with corrected post pacing interval-tachycardia cycle length (cPPI-TCL) > 110 ms. JT was excluded by either termination or advancement of tachycardia by atrial extrastimuli (AES) or atrial overdrive (AOD) pacing. RESULTS: We found 11 patients (age 20-78 years old, six female) who met the above-mentioned criteria. The TCL ranged from 560 to 782 ms. Except for one patient showing tachycardia termination, all patients demonstrated a V-A-V response and cPPI-TCL over 110 ms with VOD. AES or AOD pacing successfully excluded JT by either advancing the tachycardia in 10 patients or by tachycardia termination in one patient. Slow pathway was successfully ablated, and tachycardia was not inducible in all patients. CONCLUSIONS: This case series describes patients with typical AVNRT with slow ventricular rate (less than 110/min) who may mimic JT. We emphasize the importance of using pacing maneuvers to exclude JT.

How to use bipolar and unipolar electrograms for selecting successful ablation sites of ventricular premature contractions.

BACKGROUND: Local activation time is often determined by the maximal negative of the extracellular unipolar potential (-dV/dTmax). While this is accurate in 2-dimensional uniform tissue, propagation through nonuniform or 3-dimensional structures have shown discordance between -dV/dTmax and local activation time. OBJECTIVE: The purpose of this study was to examine the relationship between bipolar and unipolar electrograms for selecting successful ablation sites of endocardial (superficial) vs intramural (deep) ventricular premature contractions (VPCs). METHODS: This cohort consisted of 66 patients with VPCs presenting for ablation in a bigeminy, trigeminy, or quadrigeminy pattern. VPCs were classified as endocardial if ablation at the earliest endocardial site resulted in immediate suppression (<10 seconds) or as intramural if ablation resulted in delayed suppression (≥10 seconds), required multiple applications, or was not achieved. Unipolar and bipolar electrograms were analyzed. RESULTS: In endocardial VPCs, the first rapid bipolar deflection corresponded with unipolar -dV/dTmax, occurring 20.5 ms (17.8-26.0 ms) and 16.0 ms (6.8-22.0 ms), respectively, before the QRS onset. In successfully ablated intramural VPCs, the first rapid bipolar deflection preceded the QRS onset by 14.0 ms (11.2-22.6 ms) and coincided with the first rapid unipolar deflection, although -dV/dTmax occurred 10.5 ms (0.0-20.8 ms) after the QRS onset and often coincided with far-field activity. In unsuccessfully ablated intramural VPCs, the first rapid bipolar deflection to QRS onset interval was shorter in comparison to successfully ablated intramural VPCs (1.5 ms vs 14.0 ms; P < .001) while the unipolar -dV/dTmax to QRS onset interval was similar (P = .095). CONCLUSION: Mapping of VPCs should be guided by the first rapid bipolar deflection that corresponds to a similarly early unipolar deflection but not with -dV/dTmax.

Direction-aware mapping algorithms have minimal impact on bipolar voltage maps created using high-resolution multielectrode catheters.

INTRODUCTION: Direction-aware mapping algorithms improve the accuracy of voltage mapping by measuring the maximal voltage amplitude recorded in the direction of wavefront propagation. While beneficial for stationary catheters, its utility for roving catheters collecting electrograms (EGMs) at multiple angles is unknown. OBJECTIVE: To compare the directional dependence of bipolar voltage amplitude between stationary and roving catheters. METHODS: In 10 swine, a transcaval ablation line with a gap was created. The gap was mapped using an array catheter (Optrell™; Biosense Webster). In Step 1, the array was kept stationary over the gap, and four voltage maps were created during activation of the gap from superior, inferior, septal, and lateral directions. In Step 2, four additional maps were created; however, the catheter was allowed to move with points acquired at multiple angles. In Step 3, the gap was remapped; however, bipoles were computed using a direction-aware mapping algorithm. RESULTS: In a stationary catheter position, bipolar voltage distribution was influenced by the direction of activation with maximal differences obtained between orthogonal directions 32% (13%-53%). However, roving the catheter produced similar bipolar voltage maps irrespective of the direction of activation 11% (5%-18%). A direction-aware mapping algorithm was beneficial for reducing the directional dependence of voltage maps created by stationary catheters but not by roving catheters. CONCLUSION: The directional dependency of bipolar voltage amplitude is greatest when the catheter is stationary. However, when the catheter is allowed to rove and collect EGMs at multiple angles as occurs clinically, the directional dependence of bipolar voltage is minimal.

Impact of High-Power Short-Duration Radiofrequency Ablation on Esophageal Temperature Dynamic.

BACKGROUND: High-power short-duration (HP-SD) radiofrequency ablation (RFA) has been proposed as a method for producing rapid and effective lesions for pulmonary vein isolation. The underlying hypothesis assumes an increased resistive heating phase and decreased conductive heating phase, potentially reducing the risk for esophageal thermal injury. The objective of this study was to compare the esophageal temperature dynamic profile between HP-SD and moderate-power moderate-duration (MP-MD) RFA ablation strategies. METHODS: In patients undergoing pulmonary vein isolation, RFA juxtaposed to the esophagus was delivered in an alternate sequence of HP-SD (50 W, 8-10 s) and MP-MD (25 W, 15-20 s) between adjacent applications (distance, ≤4 mm). Esophageal temperature was recorded using a multisensor probe (CIRCA S-CATH). Temperature data included magnitude of temperature rise, maximal temperature, time to maximal temperature, and time return to baseline. In swine, a similar experimental design compared the effect of HP-SD and MP-MD on patterns of esophageal injury. RESULTS: In 20 patients (68.9±5.8 years old; 60% persistent atrial fibrillation), 55 paired HP-SD and MP-MD applications were analyzed. The esophageal temperature dynamic profile was similar between HP-SD and MP-MD ablation strategies. Specifically, the magnitude of temperature rise (2.1 °C [1.4-3] versus 2.0 °C [1.5-3]; P=0.22), maximal temperature (38.4 °C [37.8-39.3] versus 38.5 °C [37.9-39.4]; P=0.17), time to maximal temperature (24.9±7.5 versus 26.3±6.8 s; P=0.1), and time of temperature to return to baseline (110±23.2 versus 111±25.1 s; P=0.86) were similar between HP-SD and MP-MD ablation strategies. In 6 swine, esophageal injury was qualitatively similar between HP-SD and MP-MD strategies. CONCLUSIONS: Esophageal temperature dynamics are similar between HP-SD and MP-MD RFA strategies and result in comparable esophageal tissue injury. Therefore, when using a HP-SD RFA strategy, the shorter application duration should not prompt shorter intervals between applications.

Pulsed-Field Ablation in Ventricular Myocardium Using a Focal Catheter: The Impact of Application Repetition on Lesion Dimensions.

[Figure: see text].