Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation.

Glucose is a universal bioenergy source; however, its role in controlling protein interactions is unappreciated, as are its actions during differentiation-associated intracellular glucose elevation. Azido-glucose click chemistry identified glucose binding to a variety of RNA binding proteins (RBPs), including the DDX21 RNA helicase, which was found to be essential for epidermal differentiation. Glucose bound the ATP-binding domain of DDX21, altering protein conformation, inhibiting helicase activity, and dissociating DDX21 dimers. Glucose elevation during differentiation was associated with DDX21 re-localization from the nucleolus to the nucleoplasm where DDX21 assembled into larger protein complexes containing RNA splicing factors. DDX21 localized to specific SCUGSDGC motif in mRNA introns in a glucose-dependent manner and promoted the splicing of key pro-differentiation genes, including GRHL3, KLF4, OVOL1, and RBPJ. These findings uncover a biochemical mechanism of action for glucose in modulating the dimerization and function of an RNA helicase essential for tissue differentiation.

Ambient circulation surrounding an ablation catheter tip affects ablation lesion characteristics.

INTRODUCTION: The association between ambient circulating environments (CEs) and ablation lesions has been largely underexplored. METHODS: Viable bovine myocardium was placed in a saline bath in an ex vivo endocardial model. Radiofrequency (RF) ablation was performed using three different ablation catheters: 3.5 mm open irrigated (OI), 4, and 8 mm. Variable flow rates of surrounding bath fluids were applied to simulate standard flow, high flow, and no flow. For in vivo epicardial ablation, 24 rats underwent a single OI ablation and performed with circulating saline (30 ml/min; n = 12), versus those immersed in saline without circulation (n = 12). RESULTS: High flow reduced ablation lesion volumes for all three catheters. In no-flow endocardial CE, both 4 mm and OI catheters produced smaller lesions compared with standard flow. However, the 8 mm catheter produced the largest lesions in a no-flow CE. Ablation performed in an in vivo model with CE resulted in smaller lesions compared with ablation performed in a no-flow environment. No statistically significant differences in steam pops were found among the groups. CONCLUSION: A higher endocardial CE flow can decrease RF effectiveness. Cardiac tissue subjected to no endocardial CE flow may also limit RF for 4 mm catheters, but not for OI catheters; these findings may have implications for RF ablation safety and efficacy, especially in the epicardial space without circulating fluid or in the endocardium under varying flow conditions.

Evaluating temperature gradients across the posterior left atrium with radiofrequency ablation.

INTRODUCTION: Esophageal injury is a well-known complication associated with catheter ablation. Though novel methods to mitigate esophageal injury have been developed, few studies have evaluated temperature gradients with catheter ablation across the posterior wall of the left atrium, interstitium, and esophagus. METHODS: To investigate temperature gradients across the tissue, we developed a porcine heart-esophageal model to perform ex vivo catheter ablation on the posterior wall of the left atrium (LA), with juxtaposed interstitial tissue and esophagus. Circulating saline (5 L/min) was used to mimic blood flow along the LA and alteration of ionic content to modulate impedance. Thermistors along the region of interest were used to analyze temperature gradients. Varying time and power, radiofrequency (RF) ablation lesions were applied with an externally irrigated ablation catheter. Ablation strategies were divided into standard approaches (SAs, 10-15 g, 25-35 W, 30 s) or high-power short duration (HPSD, 10-15 g, 40-50 W, 10 s). Temperature gradients, time to the maximum measured temperature, and the relationship between measured temperature as a function of distance from the site of ablation was analyzed. RESULTS: In total, five experiments were conducted each utilizing new porcine posterior LA wall-esophageal specimens for RF ablation (n = 60 lesions each for SA and HPSD). For both SA and HPSD, maximum temperature rise from baseline was markedly higher at the anterior wall (AW) of the esophagus compared to the esophageal lumen (SA: 4.29°C vs. 0.41°C, p < .0001 and HPSD: 3.13°C vs. 0.28°C, p < .0001). Across ablation strategies, the average temperature rise at the AW of the esophagus was significantly higher with SA relative to HPSD ablation (4.29°C vs. 3.13°C, p = .01). From the start of ablation, the average time to reach a maximum temperature as measured at the AW of the esophagus with SA was 36.49 ± 12.12 s, compared to 16.57 ± 4.54 s with HPSD ablation, p < .0001. Fit to a linear scale, a 0.37°C drop in temperature was seen for every 1 cm increase in distance from the site of ablation and thermistor location at the AW of the esophagus. CONCLUSION: Both SA and HPSD ablation strategies resulted in markedly higher temperatures measured at the AW of the esophagus compared to the esophageal lumen, raising concern about the value of clinical intraluminal temperature monitoring. The temperature rise at the AW was lower with HPSD. A significant time delay was seen to reach the maximum measured temperature and a modest increase in distance between the site of ablation and thermistor location impacted the accuracy of monitored temperatures.

Perpendicular catheter orientation during papillary muscle ablation results in larger, deeper lesions.

INTRODUCTION: Ablation of papillary muscles (PMs) for refractory ventricular arrhythmias can often be challenging. The catheter approach and orientation during ablation may affect optimal radiofrequency (RF) delivery. Yet, no previous study investigated the association between catheter orientation and PM lesion size. We evaluated ablation lesion characteristics with various catheter orientations relative to the PM tissue during open irrigated ablation, using a standardized, experimental setting. METHODS: Viable bovine PM was positioned on a load cell in a circulating saline bath. RF ablation was performed over PM tissue at 50 W, with the open irrigated catheter positioned either perpendicular or parallel to the PM surface. Applied force was 10 g. Ablation lesions were sectioned and underwent quantitative morphometric analysis. RESULTS: A catheter position oriented directly perpendicular to the PM tissue resulted in the largest ablation lesion volumes and depths compared with ablation with the catheter parallel to PM tissue (75.26 ± 8.40 mm3 vs. 34.04 ± 2.91 mm3 , p < .001) and (3.33 ± 0.18 mm vs. 2.24 ± 0.10 mm, p < .001), respectively. There were no significant differences in initial impedance, peak voltage, peak current, or overall decrease in impedance among groups. Parallel catheter orientation resulted in higher peak temperature (41.33 ± 0.28°C vs. 40.28 ± 0.24°C, p = .003), yet, there were no steam pops in either group. CONCLUSION: For PM ablation, catheter orientation perpendicular to the PM tissue achieves more effective and larger ablation lesions, with greater lesion depth. This may have implications for the chosen ventricular access approach, the type of catheter used, consideration for remote navigation, and steerable sheaths.

Uncovering a unique path: Antidromic AVRT utilizing a left anteroseptal Mahaim-like accessory pathway.

A 40-year-old man presented to our emergency department 2 hours after onset of shortness of breath, palpitations, and presyncope secondary to an adenosine-responsive wide complex tachycardia. Electrophysiology study was diagnostic for antidromic atrioventricular (AV) reentrant tachycardia utilizing a muscular connection from the anterior interventricular vein to the left ventricle with Mahaim-like properties, successfully treated with ablation in the distal coronary sinus (CS) system. This case highlights accessory pathways (a) with unique features (i.e., Mahaim-like characteristics) and (b) involving musculature from the distal CS system, thereby limiting the value of endocardial ablation for durable treatment. Importantly, the coronary venous system is an accessible vascular network for evaluation and catheter ablation of such arrhythmias.

Forging ahead: Update on radiofrequency ablation technology and techniques.

Innovations in radiofrequency (RF) ablation and nonablative techniques have led to significant advances in addressing complex arrhythmogenic substrates for a variety of cardiac arrhythmias. Anatomical challenges, deep substrate, and mid-myocardial locations may pose difficulties and decrease success rates using routine methods. In this review, we provide an update on novel RF technology and techniques including (a) high-power, low-duration ablation, (b) ablation facilitated by low-ionic irrigant, and (c) bipolar ablation. In addition, we review emerging technologies including electroporation, needle catheter ablation, and ablation with the lattice catheter.

Continuous ablation improves lesion maturation compared with intermittent ablation strategies.

BACKGROUND: Interrupted ablation is increasingly proposed as part of high-power short-duration radiofrequency ablation (RFA) strategies and may also result from loss of contact from respiratory patterns or cardiac motion. To study the extent that ablation interruption affects lesions. METHODS: In ex vivo and in vivo experiments, lesion characteristics and tissue temperatures were compared between continuous (group 1) and interrupted (groups 2 and 3) RFA with equal total ablation duration and contact force. Extended duration ablation lesions were also characterized from 1 to 5 minutes. RESULTS: In the ex vivo study, continuous RFA (group 1) produced larger total lesion volumes compared with each interrupted ablation lesion group (273.8 ± 36.5 vs 205.1 ± 34.2 vs 174.3 ± 32.3 mm3 , all P < .001). Peak temperatures for group 1 were higher at 3 and 5 mm than groups 2 and 3. In vivo, continuous ablation resulted in larger lesions, greater lesion depths, and higher tissue temperatures. Longer ablation durations created larger lesion volumes and increased lesion depths. However, after 3 minutes of ablation, the rate of lesion volume, and depth formation decreased. CONCLUSIONS: Continuous RFA delivery resulted in larger and deeper lesions with higher tissue temperatures compared with interrupted ablation. This study may have implications for high-power short duration ablation strategies, motivates strategies to reduce variations in ablation delivery, and provides an upper limit for ablation duration beyond which power delivery has diminishing returns.

Impact of epicardial adipose tissue and catheter ablation strategy on biophysical parameters and ablation lesion characteristics.

BACKGROUND: Epicardial adipose (EA) tissue may limit effective radiofrequency ablation (RFA). OBJECTIVES: We sought to evaluate the lesion formation of different ablation strategies on ventricular myocardium with overlying EA. METHODS: Bovine myocardium with EA was placed in a circulating saline bath in an ex vivo model. Open-irrigated (OI) RFA was performed, parallel to the myocardium, over fat at 50 W for variable RF durations, variable contact force, catheter configurations (unipolar RF vs bipolar RF), and catheter irrigants (normal saline vs half-normal saline). Ablation was also performed with a needle-tipped ablation catheter (NTAC), perpendicular to the myocardium. RESULTS: Increasingly thick EA attenuated lesion size regardless of ablation strategy. RF applied with longer durations and increasing CF produced larger lesion volumes and deeper lesions with ablation over EA more than 3 mm but was unable to produce measurable lesions when EA less than 3 mm. Similarly, ablation with half normal saline irrigant created slightly deeper lesions than bipolar RF and unipolar RF with normal saline as EA thickness increased, but was unable to produce measurable lesions when EA more than 3 mm. Of all ablation strategies, only NTAC produced effective lesion volumes when ablating over thick (>3 mm) EA. CONCLUSIONS: While EA attenuates lesion depth and size, relatively larger, and deeper lesions can be achieved with longer RFA duration, higher CF, half normal saline irrigant, and, to a greater extent, by utilizing bipolar RF or NTAC, but only over thin adipose (<3 mm). Of those catheters/strategies tested, only NTAC was able to effectively deliver RF over thick (>3 mm) EA with this model.

Lymphatic Valves Separate Lymph Flow Into a Central Stream and a Slow-Moving Peri-Valvular Milieu.

The lymphatic system plays a pivotal role in the transport of fats, waste, and immune cells, while also serving as a metastatic route for select cancers. Using live imaging and particle tracking, we experimentally characterized the lymph flow field distal from the inguinal lymph node in the vicinity of normal bileaflet and malformed unileaflet intraluminal valves. Particle tracking experiments demonstrated that intraluminal lymphatic valves concentrate higher velocity lymph flow in the center of the vessel, while generating adjacent perivalvular recirculation zones. The recirculation zones are characterized by extended particle residence times and low wall shear stress (WSS) magnitudes in comparison to the rest of the lymphangion. A malformed unileaflet valve skewed lymph flow toward the endothelium on the vessel wall, generating a stagnation point and a much larger recirculation zone on the opposite wall. These studies define physical consequences of bileaflet and unileaflet intraluminal lymphatic valves that affect lymph transport and the generation of a heterogeneous flow field that affects the lymphatic endothelium nonuniformly. The characterized flow fields were recreated in vitro connecting different flow environments present in the lymphangion to a lymphatic endothelial cell (LEC) pro-inflammatory phenotype. Unique and detailed insight into lymphatic flow is provided, with potential applications to a variety of diseases that affect lymph transport and drug delivery.

Bipolar radiofrequency ablation creates different lesion characteristics compared to simultaneous unipolar ablation.

INTRODUCTION: Both bipolar and simultaneous radiofrequency ablation (bRFA, simRFA) have been used to treat thick midmyocardial substrate as well as during circular, multipolar ablation between shorter distances. OBJECTIVES: We sought to evaluate the biophysical parameters of simRFA, sequential unipolar RFA (seqRFA), and bRFA. METHODS: Bovine myocardium was placed in a circulating saline bath. To simulate thick substrate conditions, two open irrigated ablation catheters were oriented across from each other, with myocardium in between. Thermocouples were placed in the center, ±2 mm, of the myocardium. Unipolar ablations were performed sequentially or simultaneously at 50 W for 60 seconds and compared to bRFA using the same settings. In addition, to simulate multipolar ablation, two open irrigated ablation catheters were oriented on the same side and perpendicular to myocardium at 1, 2, and 4 mm spacing. SimRFA were performed at 15 and 25 W for 60 seconds and compared to bRFA. RESULTS: For thicker tissue, simRFA produced similar lesion volume and depth compared to bRFA but with a lesion geometry similar to seqRFA. Unlike seqRFA and simRFA, bRFA had a necrotic core spanning the myocardium. Core depths, volumes, and temperatures were significantly greater for bRFA lesions compared to simRFA or seqRFA (Figure, P < .001). Similar results were consistent for bRFA and simRFA at shorter spacings. CONCLUSIONS: BRFA has greater core lesion temperatures, corresponding to a denser and larger necrotic core, than either simRFA or seqRFA. This may have implications for considering the optimal strategy for deep midmyocardial substrates or during multipolar ablation.

Long term follow-up after ventricular tachycardia ablation in patients with congenital heart disease.

BACKGROUND: Ventricular tachycardia (VT) is frequently encountered in patients with repaired and unrepaired congenital heart disease (CHD), causing significant morbidity and sudden cardiac death. Data regarding underlying VT mechanisms and optimal ablation strategies in these patients remain limited. OBJECTIVE: To describe the electrophysiologic mechanisms, ablation strategies, and long-term outcomes in patients with CHD undergoing VT ablation. METHODS: Forty-eight patients (mean age 41.3 ± 13.3 years, 77.1% male) with CHD underwent a total of 57 VT ablation procedures at two centers from 2000 to 2017. Electrophysiologic and follow-up data were analyzed. RESULTS: Of the 77 different VTs induced at initial or repeat ablation, the underlying mechanism in 62 (81.0%) was due to scar-related re-entry; the remaining included four His-Purkinje system-related macrore-entry VTs and focal VTs mainly originating from the outflow tract region (8 of 11, 72.7%). VT-free survival after a single procedure was 72.9% (35 of 48) at a median follow-up of 53 months. VT-free survival after multiple procedures was 85.4% (41 of 48) at a median follow-up of 52 months. There were no major complications. Three patients died during the follow-up period from nonarrhythmic causes, including heart failure and cardiac surgery complication. CONCLUSION: While scar-related re-entry is the most common VT mechanism in patients with CHD, importantly, nonscar-related VT may also be present. In experienced tertiary care centers, ablation of both scar-related and nonscar-related VT in patients with CHD is safe, feasible, and effective over long-term follow-up.

Electrophysiologic testing for diagnostic evaluation and risk stratification in patients with suspected cardiac sarcoidosis with preserved left and right ventricular systolic function.

INTRODUCTION: While cardiac sarcoidosis (CS) carries a risk of ventricular arrhythmias (VAs) and sudden cardiac death (SCD), risk stratification of patients with CS and preserved left ventricular/right ventricular (LV/RV) systolic function remains challenging. We sought to evaluate the role of electrophysiologic testing and programmed electrical stimulation of the ventricle (EPS) in patients with suspected CS with preserved ventricular function. METHODS: One hundred twenty consecutive patients with biopsy-proven extracardiac sarcoidosis and preserved LV/RV systolic function underwent EPS. All patients had either probable CS defined by an abnormal cardiac positron emission tomography or cardiac magnetic resonance imaging, or possible CS with normal advanced imaging but abnormal echocardiogram (ECG), SAECG, Holter, or clinical factors. Patients were followed for 4.5 ± 2.6 years for SCD and VAs. RESULTS: Seven of 120 patients (6%) had inducible ventricular tachycardia (VT) with EPS and received an implantable cardioverter defibrillator (ICD). Three patients (43%) with positive EPS later had ICD therapies for VAs. Kaplan-Meier analysis stratified by EPS demonstrated a significant difference in freedom from VAs and SCD (P = 0.009), though this finding was driven entirely by patients within the cohort with probable CS (P = 0.018, n = 69). One patient with possible CS and negative EPS had unrecognized progression of the disease and unexplained death with evidence of CS at autopsy. CONCLUSIONS: EPS is useful in the risk stratification of patients with probable CS with preserved LV and RV function. A positive EPS was associated with VAs. While a negative EPS appeared to confer low risk, close follow-up is needed as EPS cannot predict fatal VAs related to new cardiac involvement or disease progression.

VT arising from sub-aortic muscular outflow tract structures: In two patients with ventricular septal defects.

BACKGROUND: Outflow tract ventricular tachycardias (OTVT) most commonly occur in the absence of structural abnormalities. We present two cases in which a structural variant in the outflow tract was critical to the OTVT. CASES: Subaortic muscular bands were identified using intracardiac echocardiography (ICE) in each of our cases with history of VSD and VT. Mapping demonstrating their critical involvement to the tachycardia and ablation along the muscular bands rendered the ventricular tachycardias non-inducible. CONCLUSION: In rare instances, a structural variant may be involved in OTVTs. The use of ICE along with electroanatomic mapping can assist in successful ablation of these ventricular tachycardias.

Use of half-normal saline irrigant with cooled radiofrequency ablation within the great cardiac vein to ablate premature ventricular contractions arising from the left ventricular summit.

A 62-year-old man was referred to our institution for high-density, symptomatic premature ventricular contractions (PVCs) with resultant decrease in left ventricular (LV) function having failed prior ablation attempts. Successful, durable ablation of the patient's mid-myocardial PVC arising from the LV summit region was achieved through the proximal great cardiac vein with ablation depth augmented by use of half-normal saline irrigant. Though standard ablation of ventricular arrhythmias using normal saline irrigation from the coronary venous system has been well-reported, this may be of limited value in addressing mid-myocardial sites of origin. This novel case describes the safe use of cooled radiofrequency ablation with use of half-normal saline irrigant from the distal coronary sinus as an option to address complex sites of PVC origin such as the LV summit.

Esophageal position, measured luminal temperatures, and risk of atrioesophageal fistula with atrial fibrillation ablation.

BACKGROUND: Despite improvement in catheter ablation for atrial fibrillation (AF), ability to recognize and prevent esophageal injury remains challenging. We hypothesized that esophageal course may impact esophageal heating, as measured through ablation, and thereby, risk of injury. METHODS: We evaluated all patients undergoing first-time AF ablation with preprocedural computed tomography (CT) imaging from 2014 to 2016 at our institution, focusing on esophageal position at the left atrial (LA)/pulmonary vein junction. Esophageal luminal temperatures (ELTs) were analyzed by esophageal course. In exploratory work by investigation of published reports of atrioesophageal fistula (AEF), we evaluated for a relationship between esophageal course and risk of AEF. RESULTS: Of 68 patients, 48.5% had midline, 36.8% leftward, and 14.7% rightward esophageal positions. Of 20 patients (29% of cohort) with esophageal confinement-defined as a midline or leftward position relative to the LA, vertebrae, and aorta, with luminal distortion-14 had leftward position. No significant differences in patient or procedure characteristics were noted between confinement and nonconfinement cohorts. The average peak ELT was significantly higher in those with confinement (36.9°C vs 36.2°C, P < 0.05) and confinement with a left-sided esophagus (37.1°C vs 36.2°C, P < 0.05). There was a significant correlation between esophageal confinement and risk of AEF (odds ratio [OR]: 2.7, 95% confidence interval [CI]: 1.2-6.2, P < 0.01). CONCLUSION: Approximately one-third of patients undergoing AF ablation display leftward esophageal course along the ablation zone on preprocedure CT imaging, with a significant portion exhibiting esophageal confinement. In those with confinement, higher peak ELTs are noted with ablation. Esophageal confinement may be a risk factor for development of AEF.

Repeat ablation of refractory ventricular arrhythmias in patients with nonischemic cardiomyopathy: Impact of midmyocardial substrate and role of adjunctive ablation techniques.

INTRODUCTION: Multiple ablations are often necessary to manage ventricular arrhythmias (VAs) in nonischemic cardiomyopathy (NICM) patients. We assessed characteristics and outcomes and role of adjunctive, nonstandard ablation in repeat VA ablation (RAbl) in NICM. METHODS AND RESULTS: Consecutive NICM patients undergoing RAbl were analyzed, with characteristics of the last VA ablations compared between those undergoing 1 versus multiple-repeat ablations (1-RAbl vs. >1RAbl), and between those with or without midmyocardial substrate (MMS). VA-free survival was compared. Eighty-eight patients underwent 124 RAbl, 26 with > 1RAbl, and 26 with MMS. 1-RAbl and > 1-RAbl groups were similar in age (57 ± 16 vs. 57 ± 17 years; P = 0.92), males (76% vs. 69%; P = 0.60), LVEF (40 ± 17% vs. 40 ± 18%; P = 0.96), and amiodarone use (31% vs. 46%, P = 0.22). One-year VA freedom between 1-RAbl vs. > 1RAbl was similar (82% vs. 80%; P = 0.81); adjunctive ablation was utilized more in >1RAbl (31% vs. 11%, P = 0.02), and complication rates were higher (27% vs. 7%, P = 0.01), most due to septal substrate and anticipated heart block. >1-RAbl patients had more MMS (62% vs. 16%, P < 0.01). Although MMS was associated with worse VA-free survival after 1-RAbl (43% vs. 69%, P = 0.01), when >1RAbl was performed, more often with nonstandard ablation, VA-free survival was comparable to non-MMS patients (85% vs. 81%; P = 0.69). More RAbls were required in MMS versus non-MMS patients (2.00 ± 0.98 vs. 1.16 ± 0.37; P < 0.001). CONCLUSION: For NICM patients with recurrent, refractory VAs despite previous ablation, effective arrhythmia control can safely be achieved with subsequent ablation, although >1 repeat procedure with adjunctive ablation is often required, especially with MMS.

Effect of Irrigant Characteristics on Lesion Formation After Radiofrequency Energy Delivery Using Ablation Catheters with Actively Cooled Tips.

BACKGROUND: The delivery of radiofrequency (RF) energy through irrigated ablation catheters may be affected by irrigant osmolarity and by catheter position. We sought to characterize lesion formation characteristics using different irrigants in both open and closed irrigated catheter. METHODS: An ex vivo model consisting of viable bovine myocardium and a submersible load cell was assembled in a circulating saline bath at 37°C. An externally irrigated ablation catheter and a closed irrigated catheter were positioned with 10 g of force in both perpendicular and parallel positions. A series of ablation lesions using different irrigants were delivered using a constant rate of irrigation (30 cc/min) at 50 W. Potential clinical applicability was evaluated in vivo by targeting porcine epicardium with different irrigants during open irrigation ablation and assessing lesion sizes. RESULTS: Ablation in the perpendicular position produced significantly larger lesions for all irrigants, compared to their respective parallel position ablation. For both open and closed irrigated ablation, half normal saline (HNS) ablation created larger lesions than normal saline (NS), and dextrose water (D5W) lesions were significantly larger than both HNS and NS lesions. Steam pops were mostly observed in the perpendicular position, and the rate of steam pops was statistically higher only for open irrigated D5W, but not for HNS, when compared to NS. Both open and closed irrigated ablation with D5W and HNS in the parallel position created larger lesions than parallel NS ablation without causing more steam pops. In an in vivo porcine model, open irrigated ablation with D5W created larger lesions compared to standard NS irrigation. CONCLUSIONS: In ex vivo and in vivo models, decreased osmolarity and charge density increased RF energy delivery to tissue, resulting in larger lesions for both open and closed irrigated ablations. A perpendicular catheter position created larger lesions across all irrigants for both open and closed irrigation ablation. The incidence of steam pops was observed more frequently with high power open irrigated using D5W, especially if the catheter was in a perpendicular position. Further research is required to evaluate any clinical role for using different irrigants with an externally irrigated catheter.