Efficacy of Balloon Expandable Extreme-Low Temperature Ventricular Epicardial Cryoablation: A Preclinical Proof of Concept Evaluation.

BACKGROUND: Current epicardial ablation technologies are limited by the inability to create adequate depth lesions and risk of collateral injury to extracardiac structures. OBJECTIVE: To evaluate the feasibility and efficacy of ventricular epicardial ablation with a novel balloon-expandable extreme-low temperature (XLT) cryoablation catheter with an embedded insulation pontoon for protection of extracardiac structures which has been specifically designed for epicardial ablation. METHODS: 10 healthy swine underwent surgical (6) and subxiphoid percutaneous (4) epicardial access respectively. A total of 3-6 sites were targeted in the right and left ventricular wall for different exposure durations. Ablation was performed with a large footprint (surgical) and smaller footprint (percutaneous) version of the HeartPad® (Corfigo Inc., Montclair, NJ) XLT system. The system consists of the balloon-expandable cryoablation catheter and a console. The console vaporizes liquid helium (-269˚C) and controls continuous delivery of extremely cold helium gas at high flow rates through a high-efficiency ablation element mounted on an expandable insulation pontoon to protect extracardiac structures. Ablation lesions were assessed by gross pathology and histological examination. RESULTS: A total of 42 epicardial lesions were created. The mean lesion depth increased progressively with the ablation time (surgical catheter: 11±2 mm at ≤30 seconds, 13±4 mm at 60 seconds, 15±3 mm at ≥120 seconds, P =0.001; percutaneous catheter: 10±2 mm at 30 seconds, 14±2 mm at 60 seconds, 16±2 mm at 120 seconds], P =0.001). Lesion geometry appeared unaffected by presence and thickness of epicardial fat. One episode of ventricular fibrillation occurred following ablation over the atrioventricular groove and 2 adjacent obtuse marginal arteries. CONCLUSION: Surgical or percutaneous epicardial ablation using the HeartPad® XLT cryoablation system is feasible and can efficiently produce deep ventricular lesions in different epicardial locations.

Vascular Access Complications Following Catheter Ablation of Ventricular Arrhythmias: Impact of Vascular Closure Devices.

BACKGROUND: Vascular access-site complications are the most frequent complications of percutaneous catheter ablation (CA) of ventricular arrhythmias (VAs). Whether arterial/venous vascular closure devices (VCDs) prevent vascular complications is unknown. OBJECTIVE: We investigated the benefit of VCDs in patients undergoing CA of VAs. METHODS: Consecutive CA of VAs were included (2018-2022). Vascular accesses were obtained with ultrasound guidance. At the discretion of the operator, arterial and/or venous VCDs were used. Cases were divided into 3 groups: no use of VCDs for any of the arterial/venous accesses (manual compression - MC), use of VCDs for some but not the all of the accesses (Partial-VCDs), use of VCDs for all of the accesses (Complete-VCDs). Vascular complications were defined minor if they didn't require intervention or major if they required intervention. RESULTS: A total of 1,016 procedures were performed in 872 patients (62±13 years, BMI 30±6 kg/m2, 27% female) during the study period. Femoral arterial access was obtained in 887 procedures (875 single access - 7.4±1.5 Fr size, 12 two accesses - 7.3±3 Fr and 6.9±1.8 Fr). Femoral venous access was obtained in 1,014 procedures (unilateral in 17%, bilateral in 83%, mean N. 2.6±0.7, 8.4±1.3 Fr). Hemostasis was achieved with MC in 192 (19%) procedures, Partial-VCD in 275 (27%), and Complete-VCD in 549 (54%). A vascular complication occurred in 52 (5.1%) procedures, including a minor hematoma in 3.9% and/or a major complication in 1.7%. The rate of vascular complications was 6.8% (5.2% minor and 1.6% major) in the MC group, 7.6% (5.1% minor and 3.3% major) in the Partial-VCD group, and 3.3% (2.9% minor and 0.9% major, P=0.014 for comparison) in the Complete-VCD group. At multivariable analysis, Complete-VCD remained independently associated with lower risk of vascular complications (odds ratio 0.69, 95% confidence interval 0.48 to 0.96, P=0.036). CONCLUSIONS: In patients undergoing CA of VAs, Complete-VCD is associated with lower rates of vascular-related complications compared to MC or Partial-VCD.

Outcomes of Atrial Fibrillation Ablation in Heart Failure Subtypes.

BACKGROUND: Catheter ablation (CA) improves clinical outcomes in patients with atrial fibrillation (AF) and heart failure (HF) with reduced ejection fraction (HFrEF). We aimed to evaluate the impact of CA on clinical and quality-of-life outcomes across HF subtypes. METHODS: All patients undergoing AF ablation at a tertiary center were enrolled in a prospective registry and included in this study (2013-2021). The primary end point was AF recurrence. Secondary end points included AF-related hospitalizations and quality-of-life outcomes. Patients were categorized according to their HF status: no HF, HFrEF, HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). RESULTS: A total of 7020 patients were included (80% no HF, 8% HFrEF, 7% HFmrEF, and 5% HFpEF). Over 3 years, the cumulative incidence of AF recurrence after ablation was as follows: HFpEF (53%), HFmrEF (41%), HFrEF (41%), and no HF (34%); P<0.01. Multivariable Cox analyses confirmed these findings using no HF group as reference (HFpEF: hazard ratio, 1.47 [95% CI, 1.21-1.78]; HFmrEF: hazard ratio, 1.23 [95% CI, 1.04-1.45]; and HFrEF: hazard ratio, 1.17 [95% CI, 1.01-1.37]; P<0.05 for all). In all groups, CA resulted in a significant reduction of AF-related hospitalization (mean rate per 1 patient-years [before and after CA]; HFpEF [1.8 versus 0.3], HFmrEF [1.1 versus 0.2], HFrEF [1.1 versus 0.2], and no HF [1 versus 0.1]; P<0.01 for each comparison) and significant improvement in quality of life as measured by both the AF symptom severity score and the AF burden score (P<0.01 for the comparison between baseline and follow-up for each score when tested separately). CONCLUSIONS: AF recurrence rates after CA were higher in patients with HF compared with those without HF, with patients with HFpEF being at the highest risk of recurrence. Nonetheless, CA was associated with a significant reduction in AF symptoms, AF-related hospitalization, and HF symptoms in most patients irrespective of HF subtypes.

Left ventricular mass as a modulator of ventricular arrhythmia risk and sex differences after CRT for nonischemic cardiomyopathy and LBBB.

BACKGROUND: The risk of ventricular arrhythmias (VAs) after cardiac resynchronization therapy (CRT) has been associated with ischemic disease/scar, sex, and possibly left ventricular mass (LVM). OBJECTIVE: The purpose of this study was to evaluate sex differences and baseline/postimplant change in LVM on VA risk after CRT implantation in patients with nonischemic cardiomyopathy and left bundle branch block. METHODS: In patients meeting the criteria, baseline and follow-up echocardiographic images were obtained for LVM assessment. VA events were reported from device diagnostics and therapies. VA risk was stratified by receiver operating characteristic (Youden index cutoff point) for baseline LVM and baseline/postimplant change in LVM. Multivariate Cox regression model was also used for VA risk stratification. RESULTS: One hundred eighteen patients (71 female patients [60.2%]; mean age 60.5 ± 11.3 years; left ventricular ejection fraction 19.2% ± 7.0%; QRS duration 165.6 ± 20 ms; LVM 313.9 ± 108.8 g) were enrolled and followed up for a median of 90 months (interquartile range 44-158 months). Thirty-five patients (29.6%) received appropriate shocks or antitachycardia pacing at a median of 73.5 months (interquartile range 25-130 months) postimplantation. Males had a higher VA incidence (male patients 18 of 47 [38.3%] vs female patients 17 of 71 [23.9%]; P = .02). Baseline LVM > 308.9 g separated patients with higher VA risk (P = .001). Less than a 20% decrease in LVM increased VA risk (P < .001). Baseline LVM was the only baseline characteristic predicting VA events in the Cox regression model (hazard ratio 1.01; 95% confidence interval 1.001-1.009; log-rank, P = .003). Sex differences in VA risk were eliminated by the baseline LVM parameters. CONCLUSION: VA risk after CRT implantation in nonischemic cardiomyopathy was associated with baseline LV > 308.9 g and a decrease in LVM ≤ 20%, without sex differences.

Acute post-procedural inducibility is a poor predictor of clinical outcomes in high-risk patients (PAINESD > 17) undergoing scar-related ventricular tachycardia ablation.

AIMS: Ventricular tachycardia (VT) non-inducibility in response to programmed ventricular stimulation (PVS) is a widely used procedural endpoint for VT ablation despite inconclusive evidence with respect to clinical outcomes in high-risk patients. The aim is to determine the utility of acute post-ablation VT inducibility as a predictor of VT recurrence, mortality, or mortality equivalent in high-risk patients. METHODS AND RESULTS: We conducted a retrospective analysis of high-risk patients (defined as PAINESD > 17) who underwent scar-related VT ablation at our institution between July 2010 and July 2022. Patients' response to PVS (post-procedure) was categorized into three groups: Group A, no clinical VT or VT with cycle length > 240 ms inducible; Group B, only non-clinical VT with cycle length > 240 ms induced; and Group C, all other outcomes (including cases where no PVS was performed). The combined primary endpoint included death, durable left ventricular assist device placement, and cardiac transplant (Cox analysis). Ventricular tachycardia recurrence was considered a secondary endpoint (competing risk analysis). Of the 1677 VT ablation cases, 123 cases met the inclusion criteria for analysis. During a 19-month median follow-up time (interquartile range 4-43 months), 82 (66.7%) patients experienced the composite primary endpoint. There was no difference between Groups A and C with respect to the primary [hazard ratio (HR) = 1.21 (0.94-1.57), P = 0.145] or secondary [HR = 1.18 (0.91-1.54), P = 0.210] outcomes. These findings persisted after multivariate adjustments. The size of Group B (n = 13) did not permit meaningful statistical analysis. CONCLUSION: The results of post-ablation PVS do not significantly correlate with long-term outcomes in high-risk (PAINESD > 17) VT ablation patients.

Characteristics of rumen microbiota and Prevotella isolates found in high propionate and low methane-producing dairy cows.

Ruminal methane production is the main sink for metabolic hydrogen generated during rumen fermentation, and is a major contributor to greenhouse gas (GHG) emission. Individual ruminants exhibit varying methane production efficiency; therefore, understanding the microbial characteristics of low-methane-emitting animals could offer opportunities for mitigating enteric methane. Here, we investigated the association between rumen fermentation and rumen microbiota, focusing on methane production, and elucidated the physiological characteristics of bacteria found in low methane-producing cows. Thirteen Holstein cows in the late lactation stage were fed a corn silage-based total mixed ration (TMR), and feed digestion, milk production, rumen fermentation products, methane production, and rumen microbial composition were examined. Cows were classified into two ruminal fermentation groups using Principal component analysis: low and high methane-producing cows (36.9 vs. 43.2 L/DMI digested) with different ruminal short chain fatty acid ratio [(C2+C4)/C3] (3.54 vs. 5.03) and dry matter (DM) digestibility (67.7% vs. 65.3%). However, there were no significant differences in dry matter intake (DMI) and milk production between both groups. Additionally, there were differences in the abundance of OTUs assigned to uncultured Prevotella sp., Succinivibrio, and other 12 bacterial phylotypes between both groups. Specifically, a previously uncultured novel Prevotella sp. with lactate-producing phenotype was detected, with higher abundance in low methane-producing cows. These findings provide evidence that Prevotella may be associated with low methane and high propionate production. However, further research is required to improve the understanding of microbial relationships and metabolic processes involved in the mitigation of enteric methane.

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.

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.

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.

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.