Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3' untranslated region (3' UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx regions, which form a long stem-loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3' UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-γ and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases.

Introduction SARS-CoV-2 infection has been associated with thrombotic complications such as deep vein thrombosis or stroke. Recently, numerous cases of acute limb ischemia (ALI) have been reported although pooled data are lacking. Methods We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for studies published online up to January 2021 that reported cases with SARS-CoV-2 infection and ALI. Eligible studies should have reported early outcomes including mortality. Primary endpoints included also pooled amputation, clinical improvement and reoperation rates. Results In total, 34 studies (19 case reports and 15 case series/cohort studies) including a total of 540 patients (199 patients were eligible for analysis) were evaluated. All studies were published in 2020. Mean age of patients was 61.6 years (range 39-84 years; data from 32 studies) and 78.4% of patients were of male gender (data from 32 studies). There was a low incidence of comorbidities: arterial hypertension: 49% (29 studies); diabetes mellitus: 29.6% (29 studies); dyslipidemia: 20.5% (27 studies); chronic obstructive pulmonary disease: 8.5% (26 studies); coronary disease: 8.3% (26 studies); and chronic renal disease: 7.6% (28 studies). Medical treatment was selected as first-line treatment for 41.8% of cases. Pooled mortality rate among 34 studies reached 31.4% (95% CI = 25.4% to 37.7%). Pooled amputation rate among 34 studies reached 23.2% (95% CI = 17.3% to 29.7%). Pooled clinical improvement rate among 28 studies reached 66.6% (95% CI = 55.4% to 76.9%). Pooled reoperation rate among 29 studies reached 10.5% (95% CI = 5.7% to 16.7%). Medical treatment was associated with a higher death risk compared to any intervention (OR = 4.04; 95% CI [1.075 – 15.197]; P = .045) although amputation risk was not different between the two strategies (OR = .977; 95% CI [.070 – 13.600]; P = .986) (data from 31 studies). Conclusions SARS-CoV-2 infection is associated with a high risk for thrombotic complications including ALI. Covid-associated ALI presents in patients with a low incidence of comorbidities, and it is associated with a high mortality and amputation risk. Conservative treatment seems to have a higher mortality risk compared to any intervention although amputation risk is similar.

Surgical repair of descending and thoracoabdominal aortic aneurysms provides excellent short- and mid-term results in patients with Marfan syndrome. In this series, a surgical protocol with cerebrospinal fluid drainage, distal aortic and selective organ perfusion and monitoring motor evoked potentials resulted in low morbidity and absent mortality. These outcomes of open surgery should be considered when discussing endovascular aneurysm repair in Marfan patients.