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Background Real‐world data regarding clinical outcomes according to aortic stenosis (AS) management are scarce. Therefore, we aimed to investigate long‐term management across the spectrum of outpatients with AS. Methods and Results Between May 2016 and December 2017, consecutive outpatients with mild (peak aortic velocity, 2.5–2.9 m/s), moderate (3–3.9 m/s), and severe AS (≥4 m/s) were included by 117 cardiologists in the VALVENOR (Follow‐Up of a Cohort of Patients With Valvular Aortic Stenosis in the Nord‐pas‐de‐Calais Region) study and followed‐up for aortic valve replacement (AVR) and modes of death. Among 2704 patients included, 1156 (42.7%) had mild, 1121 (41.5%) moderate, and 427 (15.8%) severe AS. After a median follow‐up of 5 years, 993 AVRs (488 surgical and 505 transcatheter) and 1098 deaths occurred. The 5‐year cumulative incidence of AVR or of the composite of death or AVR was 13.3% and 45.2% in mild AS, 45.5% and 75.3% in moderate AS, and 62.8% and 90.6% in severe AS, respectively. Of the 292 patients who met the criteria for AVR but were not treated, AVR was considered futile in 137 patients and 155 patients refused AVR. Mortality rates after 3 years were high: 86% for anticipated futility and 72.3% for refusal. While patients at anticipated futility showed a well‐balanced proportion of cardiovascular and noncardiovascular deaths, cardiovascular deaths predominated among those who refused AVR. Conclusions At 5‐year follow‐up, only two thirds of patients with severe AS underwent AVR. Patients with untreated severe AS experienced high mortality rates, mostly cardiovascular for patients who declined AVR. This advocates for better patient education based on shared decision making and for optimizing AS quality of care, from diagnosis to treatment.

Abstract Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.

Background Cardiac surgery triggers sterile innate immune responses leading to postoperative complications. Clonal hematopoiesis (CH) is associated with short‐term inflammation‐mediated outcomes after cardiac surgery. The impact of CH on long‐term postoperative outcomes remains unknown. Methods and Results In this cohort study, patients undergoing elective cardiac surgery were included from January 2017 to September 2019. Patients were screened for CH using a predefined gene panel of 19 genes. Recorded clinical events were all‐cause death, major adverse cardiac and cerebral events including cardiovascular death, myocardial infarction or nonscheduled coronary revascularization, stroke, and hospitalization for acute heart failure. The primary study outcome was time to a composite criterion including all‐cause mortality and major adverse cardiac and cerebral events. Among 314 genotyped patients (median age: 67 years; interquartile range 59–74 years), 139 (44%) presented with CH, based on a variant allelic frequency ≥1%. Carriers of CH had a higher proportion of patients with a history of atrial fibrillation (26% for CH versus 17% for non‐CH carriers, P=0.022). The most frequently mutated genes were DNMT3A, TET2, and ASXL1. After a median follow‐up of 1203 [813–1435] days, the primary outcome occurred in 50 patients. After multivariable adjustment, CH was independently associated with a higher risk for the primary outcome (hazard ratio, 1.88 [95% CI, 1.05–3.41], P=0.035). Most adverse events occurred in patients carrying TET2 variants. Conclusions In patients undergoing cardiac surgery, CH is frequent and associated with a 2‐fold increased long‐term risk for major adverse clinical outcomes. CH is a novel risk factor for long‐term postcardiac surgery complications and might be useful to personalize management decisions. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03376165.

Interventricular septum pellet retention after air-gunshot injury in a persistently asymptomatic patient is a rare, clinically significant occurrence. Management involved monitoring, echocardiography, and computed tomography scans. After risk-benefit analysis, we favored a nonsurgical management without prophylactic antibiotics or colchicine. No post-traumatic pericarditis was observed. Patient remained asymptomatic and in excellent condition at 1-month follow-up.