Idiopathic Ventricular Arrhythmias Originating From the Pulmonary Sinus Cusp Prevalence, Electrocardiographic/Electrophysiological Characteristics, and Catheter Ablation

AbstractBackgroundIdiopathic ventricular arrhythmias (VAs) originating from the pulmonary sinus cusp (PSC) have not been sufficiently clarified.ObjectivesThe goal of this study was to investigate the prevalence, electrocardiographic characteristics, mapping, and ablation of idiopathic VAs arising from the PSC.MethodsData were analyzed from 218 patients undergoing successful endocardial ablation of idiopathic VAs with a left bundle branch block morphology and inferior axis deviation.ResultsTwenty-four patients had VAs originating from the PSC. In the first 7 patients, initial ablation performed in the right ventricular outflow tract failed to abolish the clinical VAs but produced a small change in the QRS morphology in 3 patients. In all 24 patients, the earliest activation was eventually identified in the PSC, at which a sharp potential was observed preceding the QRS complex onset by 28.2 ± 2.9 ms. The successful ablation site was in the right cusp (RC) in 10 patients (42%), the left cusp (LC) in 8 (33%), and the anterior cusp (AC) in 6 (25%). Electrocardiographic analysis showed that RC-VAs had significantly larger R-wave amplitude in lead I and a smaller aVL/aVR ratio of Q-wave amplitude compared with AC-VAs and LC-VAs, respectively. The R-wave amplitude in inferior leads was smaller in VAs localized in the RC than in the LC but did not differ between VAs from the AC and LC.ConclusionsVAs arising from the PSC are not uncommon, and RC-VAs have unique electrocardiographic characteristics. These VAs can be successfully ablated within the PSC

Multiple biomarkers and arrhythmia outcome following catheter ablation of atrial fibrillation: The Guangzhou Atrial Fibrillation Project.

BackgroundBiomarkers have been related to the arrhythmia recurrence following catheter ablation (CA) of atrial fibrillation (AF). We hypothesized that concurrent measurement of several biomarkers would additively improve their predictive value.MethodsOne thousand four hundred and ten consecutive AF patients (68% male; 57.2 ± 11.6 years) undergoing CA were enrolled. Baseline characteristics, serum B type brain natriuretic peptide (BNP) and high sensitivity C reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), ablation parameters, arrhythmia data at discharge, 1, 3, 6, and then every 6 months post CA were collected. Follow-up ended when arrhythmia recurred or until 31st December 2016.ResultsThree hundred and sixty-five (25.9%) patients had arrhythmia recurrence post-CA during a mean follow-up of 20.7 ± 8.8 months. BNP, hsCRP, and eGFR levels and their cut-off values of 237.45 pg/mL, 1.6 mg/dL, and 82.5 mL/min/1.73 m2 were good predictors for AF recurrence (all P P P ConclusionMeasurement of BNP, CRP, and eGFR were incrementally additive to clinical risk factors in a cumulative manner to improve prediction of arrhythmia recurrence post-CA of AF. The implications of poor arrhythmia outcome in AF patients with multiple abnormal biomarkers pre-CA procedure may help with patient selection and inform the likelihood of success or the need of more complicated CA procedure(s)

Loss‐of‐Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia

Background and aims: Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of HCC. Approach and results: From a genome-wide CRISPR/CRISPR-associated 9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion and consequently inhibits tumor growth. Supplementation with lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by hypoxia-inducible factor-1α and fat mass and obesity-associated protein-mediated N6 -methyladenosine modification through transcriptional and posttranscriptional regulation, respectively. Analysis of The Cancer Genome Atlas shows that elevated levels of ALDOA are significantly correlated with poor prognosis of patients with HCC. In a screen of Food and Drug Administration-approved drugs based on structured hierarchical virtual platforms, we identified the sulfamonomethoxine derivative compound 5 (cpd-5) as a potential inhibitor to target ALDOA, evidenced by the antitumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC. Conclusions: Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in the hypoxic TME is a promising therapeutic strategy for treating HCC

RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer

Objective: Dysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood. Design: We analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models. Results: We identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m6A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models. Conclusions: Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC

A U-shaped relationship of body mass index on atrial fibrillation recurrence post ablation: A report from the Guangzhou atrial fibrillation ablation registry

Background: Obesity or overweight is related to worse outcomes in patients with atrial fibrillation (AF) following catheter ablation (CA). The role of being underweight in relation to recurrent arrhythmias post AF ablation is less certain. We conducted a retrospective study to investigate the association of body mass index (BMI) with arrhythmia outcomes in AF patients undergoing CA. Methods: In a cohort of 1410 AF patients (mean age 57.2 ± 11.6 years; 68% male) undergoing single CA, the association between BMI and AF ablation outcome was analyzed using BMI as a continuous variable and by four BMI categories (<18.5 kg/m2, 18.5-24 kg/m2, 25-29 kg/m2, and ≥ 30 kg/m2). Result: We observed a positive association between a cut off value of BMI and risk of AF recurrence post AF ablation. BMI ≥26.36 kg/m2 was related to more AF recurrence (c-statistic 0.55, 95%CI 0.51–0.58; P < 0.01) with 50% increased risk of AF recurrence (HR 1.50, 95% CI 1.22–1.86; P < 0.01). Recurrence rates in the four BMI categories were 33.3%, 23.2%, 27.2 and 41.8%, respectively (P < 0.01).Kaplan-Meier analysis showed that BMI categories of <18.5 kg/m2 and ≥ 30 kg/m2 were all associated with more AF recurrence (P = 0.01). Both underweight (HR 1.85, 95%CI 1.12–3.08; P = 0.02) and obesity (HR 1.78, 95%CI 1.17–2.72; P = 0.01) significantly increased the risk of AF recurrence in a Cox proportional hazard model. Conclusion: BMI had good predictive value for AF ablation outcomes with a cut off value of ≥26.36 kg/m2. Apart from being obese/overweight, being underweight might also be a risk factor for AF recurrence post ablation. Keywords: Atrial fibrillation, Body mass index, Obesity, Underweight, Catheter ablatio

High-Power, Short-Duration Ablation under the Guidance of Relatively Low Ablation Index Values for Paroxysmal Atrial Fibrillation: Long-Term Outcomes and Characteristics of Recurrent Atrial Arrhythmias

Objective: The purpose of this study was to evaluate the difference in effectiveness and safety of high-power, short-duration (HPSD) radiofrequency catheter ablation (RFA) guided by relatively low ablation index (AI) values and conventional RFA in paroxysmal atrial fibrillation (PAF) patients. Methods: The HPSD RFA strategy (40&ndash;50 W, AI 350&ndash;400 for anterior, 320&ndash;350 for posterior wall; n = 547) was compared with the conventional RFA strategy (25&ndash;40 W, without AI; n = 396) in PAF patients who underwent their first ablation. Propensity-score matching analyses were used to compare the outcomes of the two groups while controlling for confounders. Results: After using propensity-score matching analysis, the HPSD group showed a higher early recurrence rate (22.727% vs. 13.636%, p = 0.003), similar late recurrence rate, and comparable safety (p = 0.604) compared with the conventional group. For late recurrent atrial arrhythmia types, the rate of regular atrial tachycardia was significantly higher in the HPSD group (p = 0.013). Additionally, the rate of chronic pulmonary vein reconnection and non-pulmonary vein triggers during repeat procedures was similar in both groups. Conclusions: For PAF patients, compared with the conventional RFA strategy, the HPSD RFA strategy at relatively low AI settings had a higher early recurrence rate, similar long-term success rate, and comparable safety