Surpoint algorithm for improved guidance of ablation for ventricular tachycardia (SURFIRE-VT): A pilot study.

INTRODUCTION: The utility of ablation index (AI) to guide ventricular tachycardia (VT) ablation in patients with structural heart disease is unknown. The aim of this study was to assess procedural characteristics and clinical outcomes achieved using AI-guided strategy (target value 550) or conventional non-AI-guided parameters in patients undergoing scar-related VT ablation. METHODS: Consecutive patients (n = 103) undergoing initial VT ablation at a single center from 2017 to 2022 were evaluated. Patient groups were 1:1 propensity-matched for baseline characteristics. Single lesion characteristics for all 4707 lesions in the matched cohort (n = 74) were analyzed. The impact of ablation characteristics was assessed by linear regression and clinical outcomes were evaluated by Cox proportional hazard model. RESULTS: After propensity-matching, baseline characteristics were well-balanced between AI (n = 37) and non-AI (n = 37) groups. Lesion sets were similar (scar homogenization [41% vs. 27%; p = .34], scar dechanneling [19% vs. 8%; p = .18], core isolation [5% vs. 11%; p = .4], linear and elimination late potentials/local abnormal ventricular activities [35% vs. 44%; p = .48], epicardial mapping/ablation [11% vs. 14%; p = .73]). AI-guided strategy had 21% lower procedure duration (-47.27 min, 95% confidence interval [CI] [-81.613, -12.928]; p = .008), 49% lower radiofrequency time per lesion (-13.707 s, 95% CI [-17.86, -9.555]; p < .001), 21% lower volume of fluid administered (1664 cc [1127, 2209] vs. 2126 cc [1750, 2593]; p = .005). Total radiofrequency duration (-339 s [-24%], 95%CI [-776, 62]; p = .09) and steam pops (-155.6%, 95% CI [19.8%, -330.9%]; p = .08) were nonsignificantly lower in the AI group. Acute procedural success (95% vs. 89%; p = .7) and VT recurrence (0.97, 95% CI [0.42-2.2]; p = .93) were similar for both groups. Lesion analysis (n = 4707) demonstrated a plateau in the magnitude of impedance drops once reaching an AI of 550-600. CONCLUSION: In this pilot study, an AI-guided ablation strategy for scar-related VT resulted in shorter procedure time and average radiofrequency time per lesion with similar acute procedural and intermediate-term clinical outcomes to a non-AI-guided approach utilizing traditional ablation parameters.

Mechanical Tensions Regulate Gene Expression in the Xenopus laevis Axial Tissues.

During gastrulation and neurulation, the chordamesoderm and overlying neuroectoderm of vertebrate embryos converge under the control of a specific genetic programme to the dorsal midline, simultaneously extending along it. However, whether mechanical tensions resulting from these morphogenetic movements play a role in long-range feedback signaling that in turn regulates gene expression in the chordamesoderm and neuroectoderm is unclear. In the present work, by using a model of artificially stretched explants of Xenopus midgastrula embryos and full-transcriptome sequencing, we identified genes with altered expression in response to external mechanical stretching. Importantly, mechanically activated genes appeared to be expressed during normal development in the trunk, i.e., in the stretched region only. By contrast, genes inhibited by mechanical stretching were normally expressed in the anterior neuroectoderm, where mechanical stress is low. These results indicate that mechanical tensions may play the role of a long-range signaling factor that regulates patterning of the embryo, serving as a link coupling morphogenesis and cell differentiation.

Subcutaneous implantable cardioverter-defibrillator implantation position predicts successful defibrillation in obese and non-obese patients.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillators (S-ICD) are an alternative to transvenous ICDs for patients without a need for cardiac pacing. Obese patients have been proposed to be at higher risk for conversion failure with S-ICDs due to subcutaneous fat underneath the device. Optimal device positioning may promote equivalent outcomes between obese and non-obese patients by minimizing the effects of excess adipose tissue. METHODS: A retrospective analysis of patients undergoing defibrillation testing at the time of S-ICD implantation was performed. The primary endpoint was the rate of successful conversion of ventricular fibrillation (VF) at the time of implant. The secondary endpoint was shock impedance. RESULTS: A total of 184 patients were included in the study. The rate of successful conversion of VF was 90.3% for obese patients (n = 72) and 96.4% for non-obese patients (n = 112) (p = 0.086). Compared to non-obese patients, obese patients had a higher mean PRAETORIAN score (78.5 ± 58.1 vs. 48.8 ± 35.5, p < 0.001) and higher measured mean impedance (82.0 ohms ± 26.5 vs. 69.8 ohms ± 19.3, p < 0.001). Patients with a PRAETORIAN score < 90 all had successful defibrillation testing regardless of BMI. CONCLUSIONS: In this study, a PRAETORIAN score < 90 was associated with a 100% success rate of defibrillation testing following S-ICD implantation regardless of patient body mass index (BMI). Thus, the impact of obesity on impedance and the risk of failed shocks may be minimized with close attention to implantation technique to achieve a low PRAETORIAN score.

Utility of high resolution mapping to guide ablation of ventricular arrhythmias from the aortic sinuses of Valsalva.

PURPOSE: Left ventricular outflow tract (LVOT) arrhythmias are commonly targeted from the aortic sinuses of Valsalva (SOV). Both presystolic potentials during ventricular arrhythmia (VA) and late diastolic potentials during sinus rhythm have been recognized as markers of successful ablation sites. The study aimed to evaluate the utility of high resolution mapping (HRM) with small and closely spaced electrodes for guiding ablation of VA from the SOV. METHODS: Seventeen patients with LVOT VA underwent HRM in the SOV with either PentaRay (13) or Orion (4) catheters. Ablation was guided by low amplitude high frequency potentials that were identified with HRM and tagged on the electroanatomic map. RESULTS: High frequency low amplitude potentials during sinus rhythm (late) or VA (early) were demonstrated with HRM in all 17 consecutive patients; while these potentials were either absent or usually had a far-field appearance in the recordings obtained at the same sites with a 3.5-mm standard ablation catheter. On intracardiac echocardiogram, sites with these potentials corresponded to the bases of the sinuses adjacent to the LV ostium. Ablation was acutely successful in 16 out of 17 patients. Significant reduction in VA burden (≥ 90%) was noted in 15 patients. CONCLUSIONS: High frequency low amplitude potentials during sinus rhythm (late) and VA (early) are consistently recorded using HRM in the SOV in patients with VA arising from the aortic sinuses of Valsalva. Standard ablation catheters have limited resolution for detecting these potentials. HRM may potentially improve outcomes of ablation of VA originating from the aortic SOV.

Reduction in Ventricular Tachyarrhythmia Burden in Patients Enrolled in the RAID Trial.

BACKGROUND: The RAID (Ranolazine Implantable Cardioverter-Defibrillator) randomized placebo-controlled trial showed that ranolazine treatment was associated with reduction in recurrent ventricular tachycardia (VT) requiring appropriate implantable cardioverter-defibrillator (ICD) therapy. OBJECTIVES: This study aimed to identify groups of patients in whom ranolazine treatment would result in the highest reduction of ventricular tachyarrhythmia (VTA) burden. METHODS: Andersen-Gill analyses were performed to identify variables associated with risk for VTA burden among 1,012 patients enrolled in RAID. The primary endpoint was VTA burden defined as VTA episodes requiring appropriate treatment. RESULTS: Multivariate analysis identified 7 factors associated with increased VTA burden: history of VTA, age ≥65 years, New York Heart Association functional class ≥III, QRS complex (≥130 ms), low ejection fraction (<30%), atrial fibrillation (AF), and concomitant antiarrhythmic drug (AAD) therapy. The effect of ranolazine on VTA burden was seen among patients without concomitant AAD therapy (HR [HR]: 0.68; 95% CI: 0.55-0.84; P < 0.001), whereas no effect was seen among those who are concomitantly treated with other AADs (HR: 1.33; 95% CI: 0.90-1.96; P = 0.16); P = 0.003 for interaction. In patients with cardiac resynchronization therapy (CRT) ICDs, ranolazine treatment was associated with a 36% risk reduction for VTA recurrence (HR: 0.64; 95% CI: 0.47-0.86; P < 0.001), whereas among patients with ICDs without CRT no significant effect was noted (HR: 0.94; 95% CI: 0.74-1.18; P = 0.57); P = 0.047 for interaction. CONCLUSIONS: In patients with high risk for VTA, ranolazine is effective in reducing VTA burden, with significantly greater effect in CRT-treated patients, those without AF, and those not treated with concomitant AADs. In patients already on AADs or those with AF, the addition of ranolazine did not affect VTA burden. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).

Non-invasive localization of premature ventricular focus: A prospective multicenter study.

BACKGROUND: Accurate localization of premature ventricular contractions (PVC) focus is a prerequisite to successful catheter ablation. OBJECTIVE: The objective was to evaluate the software View Into Ventricular Onset (VIVO) accuracy at locating the anatomical origins for premature ventricular contractions. The VIVO device noninvasively creates a model of the patient's heart and torso, with exact locations of 12­lead ECG electrodes, and applies a mathematical algorithm from surface signals to determine the origin of the arrhythmia. We sought to compare the agreement between VIVO-predicted locations to invasive electroanatomical mapping results. METHODS: 51 consecutive patients who presented for PVC ablations at the study centers were recruited. VIVO images were collected at baseline preprocedure and all patients underwent invasive electroanatomical activation mapping of the clinical arrhythmia. Pacing was performed in pre-specified locations in the right and/or left ventricle. The successful sites of ablation and the pacing locations were compared to VIVO predicted locations. The results were adjudicated by physician experts in a blinded fashion. RESULTS: Seven patients were excluded from analyses. VIVO accurately identified the origin of the clinical premature ventricular contractions in 44/44 patients (100.00%). The accuracy in identifying the paced location for all patients (right and left sides of the heart) was 99.5% using the VIVO system. No adverse events were reported. CONCLUSIONS: VIVO is a novel noninvasive system that could be used to help guide ablation procedures with a high degree of accuracy. The VIVO algorithm is easy to use and may be useful in the workflow for ventricular arrhythmia ablation.

Junctional AV ablation in patients with atrial fibrillation undergoing cardiac resynchronization therapy (JAVA-CRT): results of a multicenter randomized clinical trial pilot program.

INTRODUCTION: Cardiac resynchronization therapy (CRT) improves outcomes in sinus rhythm, but the data in atrial fibrillation (AF) is limited. Atrio-ventricular junctional ablation (AVJA) has been proposed as a remedy. The objective was to test if AVJA results in LV end-systolic volume (ESV) reduction ≥ 15% from baseline to 6 months. METHODS: The trial was a prospective multicenter randomized trial in 26 patients with permanent AF who were randomized 1:1 to CRT-D with or without AVJA. RESULTS: LVESV improved similarly by at least 15% in 5/10 (50%) in the CRT-D-only arm and in 6/12 (50%) in the AVJA + CRT-D arm (OR = 1.00 [0.14, 7.21], p = 1.00). In the CRT-D-only arm, the median 6-month improvement in LVEF was 9.2%, not different from the AVJA + CRT-D arm, 8.2%. When both groups were combined, a significant increase in LVEF was observed (25.4% at baseline vs 36.2% at 6 months, p = 0.002). NYHA class from baseline to 6 months for all patients combined improved 1 class in 15 of 24 (62.5%), whereas 9 remained in the same class and 0 degraded to a worse class. CONCLUSION: In patients with permanent AF, reduced LVEF, and broad QRS who were eligible for CRT, there was insufficient evidence that AVJA improved echocardiographic or clinical outcomes; the results should be interpreted in light of a smaller than planned sample size. CRT, however, seemed to be effective in the combined study cohort overall, suggesting that CRT can be reasonably deployed in patients with AF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02946853.

An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer.

Hypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the transcriptional program associated with HIF1A transcription factor. Inactivation of Von Hippel-Lindau Tumour Suppressor gene (VHL) by genetic or epigenetic events, which also induces aberrant activation of HIF1A, is the most common driver event for renal cancer. With whole-genome bisulphite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We showed that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate - a metabolite that inhibits DNA demethylation by TET enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in the cells with the wild-type isocitrate dehydrogenases.

Comparative Analysis of Genome Editors Efficiency on a Model of Mice Zygotes Microinjection.

Genome editing is an indispensable tool for functional genomics. The caveat of the genome-editing pipeline is a prevalence of error-prone non-homologous end joining over homologous recombination, while only the latter is suitable to introduce particularly desired genetic variants. To overcome this problem, a toolbox of genome engineering was appended by a variety of improved instruments. In this work, we compared the efficiency of a number of recently suggested improved systems for genome editing applied to the same genome regions on a murine zygote model via microinjection. As a result, we observed that homologous recombination utilizing an ssDNA template following sgRNA directed Cas9 cleavage is still the method of choice for the creation of animals with precise genome alterations.

Kaiso Regulates DNA Methylation Homeostasis.

Gain and loss of DNA methylation in cells is a dynamic process that tends to achieve an equilibrium. Many factors are involved in maintaining the balance between DNA methylation and demethylation. Previously, it was shown that methyl-DNA protein Kaiso may attract NCoR, SMRT repressive complexes affecting histone modifications. On the other hand, the deficiency of Kaiso resulted in reduced methylation of ICR in H19/Igf2 locus and Oct4 promoter in mouse embryonic fibroblasts. However, nothing is known about how Kaiso influences DNA methylation at the genome level. Here we show that deficiency of Kaiso led to whole-genome hypermethylation, using Kaiso deficient human renal cancer cell line obtained via CRISPR/CAS9 genome editing. However, Kaiso serves to protect genic regions, enhancers, and regions with a low level of histone modifications from demethylation. We detected hypomethylation of binding sites for Oct4 and Nanog in Kaiso deficient cells. Kaiso immunoprecipitated with de novo DNA methyltransferases DNMT3a/3b, but not with maintenance methyltransferase DNMT1. Thus, Kaiso may attract methyltransferases to surrounding regions and modulate genome methylation in renal cancer cells apart from being methyl DNA binding protein.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Obese Patients with Atrial Fibrillation.

BACKGROUND: Unlike warfarin direct oral anticoagulants (DOACs) are administered in fixed doses, which raises concerns of its effectiveness on larger patients. Data from randomized trials are limited on the safety and efficacy of DOACs in morbidly obese individuals with atrial fibrillation (AF). METHODS: We analyzed a cohort of obese (≥ 120 kg) and morbidly obese (BMI > 40 kg/m2) patients from the Veterans Health Administration system with AF who initiated apixaban, rivaroxaban, dabigatran, or warfarin between years 2012 and 2018. We used inverse probability of treatment weighting (IPTW) and Cox proportional hazards regression models to evaluate the relative hazard of death, myocardial infarction (MI), ischemic stroke, heart failure (HF), and bleeding events between oral anticoagulant (OAC) groups while censoring for medication cessation. RESULTS: We identified 6052 obese patients on apixaban, 4233 on dabigatran, 4309 on rivaroxaban, and 13,417 on warfarin (mean age 66.7 years, 91% males, 80.4% whites). At baseline patients on apixaban had the lowest glomerular filtration rate and highest rates of previous stroke and MI compared to other OACs. Among patients with weight ≥ 120 kg and those with BMI > 40 kg/m2, all DOACs were associated with lower risk of any hemorrhage, hemorrhagic stroke, and gastrointestinal (GI) bleeding. Patients with BMI > 40 kg/m2 treated with DOACs had similar ischemic stroke risk with those on warfarin. CONCLUSIONS: In this large cohort of obese Veterans Health Administration system patients, the use of DOACs resulted in lower hemorrhagic complications than warfarin while maintaining efficacy on ischemic stroke prevention.

Syncope After Transcatheter Aortic Valve Replacement: Two Faces of Abnormal Intraventricular Conduction.

Conduction system damage is the most common complication of transcatheter aortic valve replacement (TAVR), which frequently requires placement of a permanent pacemaker. Bundle branch reentry (BBR) is a well-recognized mechanism of ventricular tachycardia (VT) in the setting of abnormal intraventricular conduction. We describe a case of a patient with post-TAVR intraventricular conduction abnormalities who presented with intermittent advanced atrioventricular block and BBR VT and discuss the potential risks, diagnosis, and management of BBR after TAVR.

A partial genome assembly of the miniature parasitoid wasp, Megaphragma amalphitanum.

Body size reduction, also known as miniaturization, is an important evolutionary process that affects a number of physiological and phenotypic traits and helps animals conquer new ecological niches. However, this process is poorly understood at the molecular level. Here, we report genomic and transcriptomic features of arguably the smallest known insect-the parasitoid wasp, Megaphragma amalphitanum (Hymenoptera: Trichogrammatidae). In contrast to expectations, we find that the genome and transcriptome sizes of this parasitoid wasp are comparable to other members of the Chalcidoidea superfamily. Moreover, compared to other chalcid wasps the gene content of M. amalphitanum is remarkably conserved. Intriguingly, we observed significant changes in M. amalphitanum transposable element dynamics over time, in which an initial burst was followed by suppression of activity, possibly due to a recent reinforcement of the genome defense machinery. Overall, while the M. amalphitanum genomic data reveal certain features that may be linked to the unusual biological properties of this organism, miniaturization is not associated with a large decrease in genome complexity.

Coronary Spasm and Polymorphic Ventricular Tachycardia One Year After Takotsubo.

Stress cardiomyopathy is typically considered to be a disease with a favorable long-term prognosis, with malignant arrhythmias accompanying only the acute phase. We describe a 51-year-old female who presented with palpitations one year after stress cardiomyopathy and complete recovery of apical left ventricular wall motion. Coronary spasm was strongly suspected based on transient ST-segment elevations followed by sustained polymorphic ventricular tachycardia captured on ambulatory Holter. Contrast injection during coronary angiography reproduced spasm and ventricular arrhythmia that resolved with intracoronary nitroglycerine. The patient was intolerant to nitrates therefore discharged on 2 calcium channel blockers. Shared decision was made to implant cardioverter defibrillator.

New insights from Opisthorchis felineus genome: update on genomics of the epidemiologically important liver flukes.

BACKGROUND: The three epidemiologically important Opisthorchiidae liver flukes Opisthorchis felineus, O. viverrini, and Clonorchis sinensis, are believed to harbour similar potencies to provoke hepatobiliary diseases in their definitive hosts, although their populations have substantially different ecogeographical aspects including habitat, preferred hosts, population structure. Lack of O. felineus genomic data is an obstacle to the development of comparative molecular biological approaches necessary to obtain new knowledge about the biology of Opisthorchiidae trematodes, to identify essential pathways linked to parasite-host interaction, to predict genes that contribute to liver fluke pathogenesis and for the effective prevention and control of the disease. RESULTS: Here we present the first draft genome assembly of O. felineus and its gene repertoire accompanied by a comparative analysis with that of O. viverrini and Clonorchis sinensis. We observed both noticeably high heterozygosity of the sequenced individual and substantial genetic diversity in a pooled sample. This indicates that potency of O. felineus population for rapid adaptive response to control and preventive measures of opisthorchiasis is higher than in O. viverrini and C. sinensis. We also have found that all three species are characterized by more intensive involvement of trans-splicing in RNA processing compared to other trematodes. CONCLUSION: All revealed peculiarities of structural organization of genomes are of extreme importance for a proper description of genes and their products in these parasitic species. This should be taken into account both in academic and applied research of epidemiologically important liver flukes. Further comparative genomics studies of liver flukes and non-carcinogenic flatworms allow for generation of well-grounded hypotheses on the mechanisms underlying development of cholangiocarcinoma associated with opisthorchiasis and clonorchiasis as well as species-specific mechanisms of these diseases.