Increased A-to-I RNA editing in atherosclerosis and cardiomyopathies.

Adenosine-to-inosine RNA editing is essential to prevent undesired immune activation. This diverse process alters the genetic content of the RNA and may recode proteins, change splice sites and miRNA targets, and mimic genomic mutations. Recent studies have associated or implicated aberrant editing with pathological conditions, including cancer, autoimmune diseases, and neurological and psychiatric conditions. RNA editing patterns in cardiovascular tissues have not been investigated systematically so far, and little is known about its potential role in cardiac diseases. Some hints suggest robust editing in this system, including the fact that ADARB1 (ADAR2), the main coding-sequence editor, is most highly expressed in these tissues. Here we characterized RNA editing in the heart and arteries and examined a contributory role to the development of atherosclerosis and two structural heart diseases -Ischemic and Dilated Cardiomyopathies. Analyzing hundreds of RNA-seq samples taken from the heart and arteries of cardiac patients and controls, we find that global editing, alongside inflammatory gene expression, is increased in patients with atherosclerosis, cardiomyopathies, and heart failure. We describe a single recoding editing site and suggest it as a target for focused research. This recoding editing site in the IGFBP7 gene is one of the only evolutionary conserved sites between mammals, and we found it exhibits consistently increased levels of editing in these patients. Our findings reveal that RNA editing is abundant in arteries and is elevated in several key cardiovascular conditions. They thus provide a roadmap for basic and translational research of RNA as a mediator of atherosclerosis and non-genetic cardiomyopathies.

Landscape of adenosine-to-inosine RNA recoding across human tissues.

RNA editing by adenosine deaminases changes the information encoded in the mRNA from its genomic blueprint. Editing of protein-coding sequences can introduce novel, functionally distinct, protein isoforms and diversify the proteome. The functional importance of a few recoding sites has been appreciated for decades. However, systematic methods to uncover these sites perform poorly, and the full repertoire of recoding in human and other mammals is unknown. Here we present a new detection approach, and analyze 9125 GTEx RNA-seq samples, to produce a highly-accurate atlas of 1517 editing sites within the coding region and their editing levels across human tissues. Single-cell RNA-seq data shows protein recoding contributes to the variability across cell subpopulations. Most highly edited sites are evolutionary conserved in non-primate mammals, attesting for adaptation. This comprehensive set can facilitate understanding of the role of recoding in human physiology and diseases.

Reconstruction of the left atrium for atrial fibrillation ablation using the machine learning CARTO 3 m-FAM software.

PURPOSE: Atrial fibrillation (AF) ablation requires a precise reconstruction of the left atrium (LA) and pulmonary veins (PV). Model-based FAM (m-FAM) is a novel module recently developed for the CARTO system which applies machine learning techniques to LA reconstruction. We aimed to evaluate the feasibility and safety of a m-FAM-guided AF ablation as well as the accuracy of LA reconstruction using the cardiac computed tomography angiography (CTA) of the same patient LA as the gold standard, in 32 patients referred for AF ablation. METHODS: Consecutive patients undergoing AF ablation. The m-FAM reconstruction was performed with the ablation catheter (group 1) or a Pentaray and ablation catheters (group 2). The reconstruction accuracy was confirmed prior to the ablation by verification of pre-specified landmarks of the LA and PVs by an intracardiac echocardiogram (ICE) visualization and fluoroscopy. A cardiac CTA performed before the ablation was used as the gold standard of LA anatomy. For each patient, the m-FAM reconstruction was compared to his/her cardiac CTA. RESULTS: The m-FAM reconstruction was accurate in all patients regardless of the catheter used for mapping. Twelve percent re-acquisition of the LA landmarks was necessary to improve the accuracy. m-FAM time was shorter in group 2 while the M-Fam fluoroscopy time was similar. Pulmonary vein isolation was achieved in 100% of patients without major complications. The m-FAM reconstructions accurately resemble the cardiac CTA of the same patients. CONCLUSIONS: The m-FAM module allows for rapid and precise reconstruction of the LA and PV anatomy, which can be safely used to guide AF ablation.

QT interval dynamics in patients with ST-elevation MI.

Background: An association between excessively prolonged QT and ventricular arrhythmia in patients with ST-elevation myocardial infarction has been described; however, the QT dynamics, characterization, and long-term predictive value are not well known. Objective: To characterize QT interval dynamics in patients undergoing ST elevation myocardial infarction (STEMI) and determine its association with mortality. Methods: A retrospective analysis of 4,936 consecutive patients, hospitalized for STEMI between 01/2013-12/2021. Patients with less than three electrocardiograms (ECGs) during index hospitalization were excluded. Baseline demographics, cardiovascular history, clinical risk factors, treatment measures, laboratory results, and mortality data were retrieved from the hospital's electronic medical records. Results: We included 1,054 patients and 5,021 ECGs in our cohort with a median follow-up of 6 years [interquartile range (IQR) 4.3-7.4 years]. The QT was longer in women in comparison to men (428.6 ms ± 33.4 versus 419.8 ms ± 32.52, P-value = 0.001). QT prolongation was greater in females, elderly patients, and patients with STEMI caused by occlusion of the left anterior descending (LAD) coronary artery. We determined QT cutoff to be 445 ms. This value of QT divided our cohort upon arrival into a long QT group (217 patients, 26% of the cohort) and a "normal" QT group (835 patients, 74% of the cohort). The long QT group experienced an increase in combined short and long terms all-cause mortality. The QT upon arrival, on day 2 of hospitalization, and before discharge from the hospital, correlated with long-term mortality. Conclusion: QT duration is often prolonged during STEMI; this prolongation is associated with increased mortality and adverse events. Gender is an important mediator of QT dynamics.

Natural History of Moderate Aortic Stenosis with Preserved and Low Ejection Fraction.

BACKGROUND: There is a shortage of data concerning the natural history of patients with moderate aortic stenosis (AS). The aim of this study was to assess the effect of moderate AS on mortality in the general population and in the subgroups of patients with moderate AS and reduced ejection fractions (EF) and patients with moderate AS and low aortic valve gradients. The study was not designed to address the applicability of treatment in this population. METHODS: Outcomes were compared between patients with moderate AS and a propensity-matched cohort (1:3 ratio) without AS. The primary outcome was survival until end of follow-up. RESULTS: Among approximately 40,000 patients who underwent echocardiographic evaluations between 2011 and 2016, 952 had moderate AS. Median follow-up duration was 181 weeks (interquartile range, 179-182 weeks) for the entire cohort and 174 weeks (interquartile range, 169-179 weeks) for the propensity-matched groups. Propensity matching successfully balanced most preexisting clinical differences. Increased mortality was observed in the group of patients with moderate AS before propensity matching and persisted following propensity matching (median survival 4.1 vs 5.2 years, P = .008). Survival rates and corresponding standard errors at 1, 2, 3, and 5 years were 80 ± 1% versus 82 ± 0.7%, 70 ± 1.5% versus 74 ± 0.8%, 62 ± 1.7% versus 66 ± 0.9%, and 47 ± 2.4% versus 52 ± 1.3%, respectively. A survival difference was similarly observed for the subgroup analyses of moderate AS and reduced ejection fraction (P = .028) and moderate AS and low aortic valve gradients (P = .039). CONCLUSIONS: Moderate AS is associated with increased mortality. The increased mortality was also observed in the subgroups of patients with either reduced ejection fraction or low aortic valve gradients.

Correction to: Lung ultrasound predicts clinical course and outcomes in COVID-19 patients.

The original article can be found online.

Lung ultrasound predicts clinical course and outcomes in COVID-19 patients.

PURPOSE: Information regarding the use of lung ultrasound (LUS) in patients with Coronavirus disease 2019 (COVID-19) is quickly accumulating, but its use for risk stratification and outcome prediction has yet to be described. We performed the first systematic and comprehensive LUS evaluation of consecutive patients hospitalized with COVID-19 infection, in order to describe LUS findings and their association with clinical course and outcome. METHODS: Between 21/03/2020 and 04/05/2020, 120 consecutive patients admitted to the Tel Aviv Medical Center due to COVID-19, underwent complete LUS within 24 h of admission. A second exam was performed in case of clinical deterioration. LUS score of 0 (best)-36 (worst) was assigned to each patient. LUS findings were compared with clinical data. RESULTS: The median baseline total LUS score was 15, IQR [7-20]. Baseline LUS score was 0-18 in 80 (67%) patients, and 19-36 in 40 (33%) patients. The majority had patchy pleural thickening (n = 100; 83%), or patchy subpleural consolidations (n = 93; 78%) in at least one zone. The prevalence of pleural thickening, subpleural consolidations and the total LUS score were all correlated with severity of illness on admission. Clinical deterioration was associated with increased follow-up LUS scores (p = 0.0009), mostly due to loss of aeration in anterior lung segments. The optimal cutoff point for LUS score was 18 (sensitivity = 62%, specificity = 74%). Both mortality and need for invasive mechanical ventilation were increased with baseline LUS score > 18 compared to baseline LUS score 0-18. Unadjusted hazard ratio of death for LUS score was 1.08 per point [1.02-1.16], p = 0.008; Unadjusted hazard ratio of the composite endpoint (death or need for invasive mechanical ventilation) for LUS score was 1.12 per point [1.05-1.2], p = 0.0008. CONCLUSION: Hospitalized patients with COVID-19, at all clinical grades, present with pathological LUS findings. Baseline LUS score strongly correlates with the eventual need for invasive mechanical ventilation and is a strong predictor of mortality. Routine use of LUS may guide patients' management strategies, as well as resource allocation in case of surge capacity.

RNA editing of Filamin A pre-mRNA regulates vascular contraction and diastolic blood pressure.

Epitranscriptomic events such as adenosine-to-inosine (A-to-I) RNA editing by ADAR can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin crosslinking protein Filamin A (FLNA) mediates a Q-to-R transition in the interactive C-terminal region. While FLNA editing is conserved among vertebrates, its physiological function remains unclear. Here, we show that cardiovascular tissues in humans and mice show massive editing and that FLNA RNA is the most prominent substrate. Patient-derived RNA-Seq data demonstrate a significant drop in FLNA editing associated with cardiovascular diseases. Using mice with only impaired FLNA editing, we observed increased vascular contraction and diastolic hypertension accompanied by increased myosin light chain phosphorylation, arterial remodeling, and left ventricular wall thickening, which eventually causes cardiac remodeling and reduced systolic output. These results demonstrate a causal relationship between RNA editing and the development of cardiovascular disease indicating that a single epitranscriptomic RNA modification can maintain cardiovascular health.

The use of virtual reality simulation to determine potential for endoscopic surgery skill acquisition.

BACKGROUND: Efficient acquisition of endoscopic technique is essential for high-level care in surgical practice. In contrast to similar substantial risk industries, there is no standard instrument capable of detecting the potential of surgical residency candidates to develop such skills. MATERIAL AND METHODS: We used the Simbionix "Lapmentor" Virtual reality simulator basic skills tasks 1, 5 and 6 to establish baseline performance of 17 subjects lacking surgical experience, then divided them into two groups. One group trained on the Lapmentor, a validated trainer. The second group trained on a video box trainer using 3 FLS tasks, which correlate with real OR performance. After completing the training program, each group was tested on its training modality and correlations were sought between performance in the screening tasks and final scores in both groups. RESULTS: Time in Lapmentor task 1 showed significant correlations with total FLS scores (R 0.807 P 0.015), in addition to other benchmark parameters. With the Lapmentor group, time on task 5 demonstrated correlation with itself on the final scores (R 0.794 P 0.011). CONCLUSIONS: Time in the Lapmentor task 1 demonstrates correlations with FLS scores, which translate to better OR performance. The Lapmentor thus shows potential to be used as a screening test for surgical talent.