The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation.

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.

Association of Lipoprotein(a) with arterial stiffness: A Mendelian randomization study.

BACKGROUND: In this study we used Mendelian randomization (MR) to investigate the potential causal association of lipoprotein (a) [Lp(a)] levels with pulse wave velocity (PWV). METHODS: Genetic variants associated with Lp(a) were retrieved from the UK Biobank GWAS (N = 290,497). A non- overlapping GWAS based on a European cohort (N = 7,000) was used to obtain genetic associations with PWV (outcome) and utilized two different measures for the same trait, brachial-ankle (baPWV) and carotid-femoral (cfPWV) PWV. We applied a two-sample MR using the inverse variance weighting method (IVW) and a series of sensitivity analyses for 170 SNPs that were selected as instrumental variables (IVs). RESULTS: Our analyses do not support a causal association between Lp(a) and PWV for neither measurement [ßiwv(baPWV) = -.0005, p = .8 and ßiwv(cfPWV) = -.006, p = .16]. The above findings were consistent across sensitivity analyses including weighted median, mode-based estimation, MR-Egger regression and MR-PRESSO. CONCLUSION: We did not find evidence indicating that Lp(a) is causally associated with PWV, the gold standard marker of arterial stiffness.

Sexual function scores are associated with arterial stiffness in postmenopausal women.

BACKGROUND: Female sexual dysfunction (FSD) has been suggested to be correlated with the burden of cardiovascular risk factors. AIM: We aimed to evaluate the possible association between functional indices of vascular function and FSD scores in apparently healthy postmenopausal women. METHODS: This cross-sectional study included 116 postmenopausal women who underwent assessment of endothelial function with measurement of flow-mediated dilation (FMD) of the branchial artery and arterial stiffness estimation with measurement of the carotid-femoral pulse wave velocity (PWV). We used the Greene Climacteric Scale to evaluate vasomotor symptomatology, the Female Sexual Function Index (FSFI) to evaluate FSD and the Beck Depression Inventory to evaluate mood disorder. Low sexual function was defined as an FSFI score <26.55. OUTCOMES: These included FSFI and low sexual function scores as well as measures of PWV and FMD. RESULTS: Sexual function scores were associated with measures of blood pressure (normal vs low sexual function; systolic blood pressure: 120.2 ± 15.0 mm Hg vs 113.4 ± 14.6 mm Hg; analysis of covariance P = .026; diastolic blood pressure: 75.9 ± 10.5 mm Hg vs 70.3 ± 9.9 mm Hg; analysis of covariance P = .012; both adjusted for age, body mass index, current smoking, and PWV). Systolic blood pressure, but not diastolic blood pressure, was associated with FSFI (B = 0.249, P = .041) and PWV (B = 0.392, P < .001). PWV measures were associated with FSFI (B = -0.291, P = .047) and pulse pressure (B = 0.355, P = .017). FMD measures were also associated with FSFI (B = 0.427, P = .033). All models were adjusted for age, body mass index, current smoking, insulin resistance, vasomotor symptomatology, and Beck Depression Inventory. CLINICAL IMPLICATIONS: Our findings demonstrate that lower scores of sexual function are associated with deteriorated vascular function mainly manifested as arterial stiffening, further contributing to systolic blood pressure changes. STRENGTHS AND LIMITATIONS: The strength of this study is the carefully selected healthy sample of postmenopausal women, with simultaneous assessment of climacteric symptomatology and mood disorders. The limitations include the small sample size, the cross-sectional design, and the recruitment of consecutive outpatients of a university menopause clinic. CONCLUSION: Longitudinal studies and interventions to improve FSD should further assess the clinical relevance of these findings.

Outcomes for patients with systemic light chain amyloidosis and Mayo stage 3B disease.

Patients with cardiac light chain amyloidosis and Mayo stage 3b disease define a high-risk population with very poor prognosis. Here, we report treatment outcomes of 80 consecutive patients with newly diagnosed AL and Mayo 3b who received novel regimens. Early mortality (<1 month) rate was 12.5%. On intention-to-treat, overall hematologic response rate was 40%, with complete response (CR)/very good partial response (VGPR) in 25% and partial response (PR) in 15%. At 1- and 3- month landmark analysis CR or VGPR/PR rates were 25%/23.5% and 34%/25.5%, respectively. Among patients that were treated with daratumumab-based therapies, 52.6% and 85.7% achieved at least VGPR within one 1 and 3 months, respectively. Three-month cardiac response rate was 11.3% and 6-month was 18.8%. At least hemVGPR at 3 months was associated with cardiac response at 6 months (p = 0.034). Median overall survival (OS) was 6.3 months. At 1-month landmark at least hemPR was associated with better median OS (24.1 vs. 4.9 months, p = 0.017) and at 3-month landmark, at least hemVGPR was associated with a median OS of 40.7 versus 17 months for hemPR and 7.4 months for those without hematologic response (p = 0.028). Cardiac response at 3 months was associated with longer median OS (59.7 vs. 10.9 months, p = 0.044). Factors associated with poorer survival were κ-light chain amyloidosis (median OS 2.9 vs. 7.4 months, p = 0.028), peripheral nerve involvement (3.4 vs. 10.45 months, p = 0.024), systolic blood pressure <90 mmHg (2 vs. 8 months, p = 0.002), baseline LVEF <55% (median OS 3.4 vs. 32 months, p = 0.29) and New York Heart Association (NYHA) class (2.7 months for NYHA 3B-4 vs. 8 months for NYHA 2-3A, p = 0.02). Twenty-one patients (26.3%) received salvage therapy and ORR was 57.1%. Median OS for patients who received second line therapy was 24 months. In conclusion, patients with Mayo 3b disease benefit from early hematologic response but cardiac response rates remain low.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes.

AIMS: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031). CONCLUSION: Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD. CLINICAL TRIAL REGISTRATION: NCT01000701.

Clinical implications of vascular dysfunction in acute and convalescent COVID-19: A systematic review.

BACKGROUND: Accumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID-19). In this context, vascular impairment in COVID-19 might be associated with clinical manifestations and could refine risk stratification in these patients. METHODS: This systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post-recovery COVID-19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1 December 2019 until 05 March 2022, we identified 24 eligible studies with laboratory confirmed COVID-19 and a thorough examination of vascular function. Flow-mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post-recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in three studies in the acute and four studies in the post-recovery phase. RESULTS: All studies except for one in the acute and in the post-recovery phase showed positive association between vascular dysfunction and COVID-19 infection. Endothelial dysfunction in two studies and increased arterial stiffness in three studies were related to inferior survival in COVID-19. DISCUSSION: Overall, a detrimental effect of COVID-19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.

Consumption of Fruits, Vegetables and Bladder Cancer Risk: A Systematic Review and Meta-Analysis of Prospective Cohort Studies.

We examined the association between fruit/vegetable consumption and bladder cancer (BC) risk in a systematic review and meta-analysis of prospective cohort studies stratifying results by gender, smoking status and geographical region. Eligible studies were sought in MEDLINE and EMBASE up to April 20, 2020. Random-effects (DerSimonian-Laird) models were implemented for the calculation of pooled relative risks (RRs) and 95% confidence intervals (CI). Fifteen eligible studies were identified (1,993,881 subjects, 11,097 BC cases). Vegetable consumption (pooled RR = 0.95, 95% CI: 0.87-1.04, n = 10) as well as combined fruit/vegetable consumption was not associated with BC risk. Regarding fruit intake, the overall protective trend did not reach significance (pooled RR = 0.91, 95%CI: 0.81-1.02, n = 11); we found however a significant association in East Asians. A trend toward a protective association with citrus fruit consumption was also noted (pooled RR = 0.83, 95%CI: 0.69-1.01, n = 6), once again with a significant effect in East Asians. Moreover, no association was found regarding the subgroups of leafy vegetables, dark green vegetables, and berries. Single studies pointed to a reduced BC risk in never smoking males consuming cruciferous vegetables and East Asians consuming yellow vegetables. In conclusion, our study reveals possible protective effects; larger studies are needed to investigate the emerging trends.

Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo- double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.

Adenosine-to-inosine RNA editing contributes to type I interferon responses in systemic sclerosis.

OBJECTIVE: Adenosine deaminase acting on RNA-1 (ADAR1) enzyme is a type I interferon (IFN)-stimulated gene (ISG) catalyzing the deamination of adenosine-to-inosine, a process called A-to-I RNA editing. A-to-I RNA editing takes place mainly in Alu elements comprising a primate-specific level of post-transcriptional gene regulation. Whether RNA editing is involved in type I IFN responses in systemic sclerosis (SSc) patients remains unknown. METHODS: ISG expression was quantified in skin biopsies and peripheral blood mononuclear cells derived from SSc patients and healthy subjects. A-to-I RNA editing was examined in the ADAR1-target cathepsin S (CTSS) by an RNA editing assay. The effect of ADAR1 on interferon-α/ß-induced CTSS expression was assessed in human endothelial cells in vitro. RESULTS: Increased expression levels of the RNA editor ADAR1, and specifically the long ADAR1p150 isoform, and its target CTSS are strongly associated with type I IFN signature in skin biopsies and peripheral blood derived from SSc patients. Notably, IFN-α/ß-treated human endothelial cells show 8-10-fold increased ADAR1p150 and 23-35-fold increased CTSS expression, while silencing of ADAR1 reduces CTSS expression by 60-70%. In SSc patients, increased RNA editing rate of individual adenosines located in CTSS 3' UTR Alu elements is associated with higher CTSS expression (r = 0.36-0.6, P < 0.05 for all). Similar findings were obtained in subjects with activated type I IFN responses including SLE patients or healthy subjects after influenza vaccination. CONCLUSION: ADAR1p150-mediated A-to-I RNA editing is critically involved in type I IFN responses highlighting the importance of post-transcriptional regulation of proinflammatory gene expression in systemic autoimmunity, including SSc.

Clinical value of amyloid-beta1-40 as a marker of thrombo-inflammation in antiphospholipid syndrome.

OBJECTIVE: Amyloid-beta1-40 (Aß40) is a pro-inflammatory peptide under investigation as a novel biomarker of vascular inflammation, endothelial dysfunction and atherothrombosis in the general population. Herein we tested the hypothesis that Aß40 is deregulated in APS, a systemic autoimmune disease characterized by a thrombo-inflammatory state. METHODS: Between January 2016 and July 2017, we consecutively recruited 80 regularly followed thrombotic APS patients (44 primary, 36 SLE/APS) and 80 age- and sex-matched controls. Plasma Aß40 levels were measured using ELISA and APS-related clinical and laboratory characteristics were recorded. The adjusted Global Anti-Phospholipid Syndrome Score (aGAPSS), a validated risk score in APS, was calculated as a comparator to Aß40 performance to detect arterial thrombotic APS-related events. RESULTS: Higher Aß40 levels were significantly associated with the presence of APS [odds ratio (OR) 1.024 per 1 pg/ml (95% CI 1.007, 1.041)] after adjustment for cardiovascular risk factors (CVRFs), including smoking, arterial hypertension, dyslipidaemia and BMI, and for estimated glomerular filtration rate (eGFR). Among APS patients, increased high-sensitivity CRP (hs-CRP) serum levels was the only independent determinant of Aß40 levels. Importantly, Aß40 levels above the optimal receiver operating characteristics (ROC)-derived cut-off value were independently associated with recurrent arterial events [OR 4.93 (95% CI 1.31, 18.51)] after adjustment for age, sex, CVRFs, hs-CRP and high anti-ß2 glycoprotein I IgG titres. Finally, by ROC curve analysis, Aß40 provided incremental additive value over the aGAPSS by significantly improving its discrimination ability for recurrent arterial thromboses. CONCLUSION: In APS, Aß40 plasma levels are elevated and associated with an adverse thrombo-inflammatory profile. The pathophysiological and prognostic role of Aß40 in APS merits further investigation.

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications.

BACKGROUND: Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology of COVID-19 will support the design of rational treatments targeting the life cycle of the virus and/or the adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) and/or other pathologies. MAIN BODY: COVID-19 is a two-phase disease being marked by (phase 1) increased virus transmission and infection rates due to the wide expression of the main infection-related ACE2, TMPRSS2 and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by (phase 2) host- and probably sex- and/or age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure likely because of imbalanced ACE/ANGII/AT1R and ACE2/ANG(1-7)/MASR axes signaling. CONCLUSION: Here we discuss SARS-CoV-2 life cycle and a number of approaches aiming to suppress viral infection rates or propagation; increase virus antigen presentation in order to activate a robust and durable adaptive immune response from the host, and/or mitigate the ARDS-related "cytokine storm" and collateral tissue damage that triggers the severe life-threatening complications of COVID-19.

Reactive Vasodilation Predicts Mortality in Primary Systemic Light-Chain Amyloidosis.

Rationale: Cardiac involvement and hypotension dominate the prognosis of light-chain amyloidosis (AL). Evidence suggests that there is also peripheral vascular involvement in AL but its prognostic significance is unknown. Objective: To evaluate vascular dysfunction in patients with AL as a potential future area of intervention, we assessed the prognostic utility of flow-mediated dilatation (FMD), a marker of vascular reactivity, which is augmented under conditions of hypotension and autonomic dysfunction. Methods and Results: We prospectively evaluated 115 newly diagnosed untreated AL patients in whom FMD was measured. FMD in AL patients was significantly higher than age-, sex- and risk factors-matched controls (4.0% versus 2.32%; P=0.006) and comparable with control groups at lower cardiovascular risk (P>0.1). Amyloidosis patients presented increased plasma and exhaled markers of the NO pathway while their FMD significantly correlated with augmented sustained vasodilatation after sympathetic stimulation. Increased FMD (≥4.5%) was associated with early mortality (hazard ratio, 4.36; 95% CI, 1.41-13.5; P=0.010) and worse survival (hazard ratio, 2.11; 95% CI, 1.17-3.82; P=0.013), even after adjustment for Mayo stage, nerve involvement and low systolic blood pressure. This finding was confirmed in a temporal validation AL cohort (n=55; hazard ratio, 4.2; 95% CI, 1.45-12.3; P=0.008). FMD provided significant reclassification value over the best prognostic model (continuous Net Reclassification Index, 0.61; P=0.001). Finally, better hematologic response was associated with lower posttreatment FMD. Conclusions: FMD is relatively increased in AL and independently associated with inferior survival with substantial reclassification value. Reactive vasodilation merits further investigation as a novel risk biomarker in AL.Visual Overview: An online visual overview is available for this article.

Experimental Devices Versus Hand-Sewn Anastomosis of the Aorta: A Systematic Review and Meta-Analysis.

BACKGROUND: To minimize complications associated with the construction of the hand-sewn aortic anastomosis, alternative experimental methods have been pursued. This study aimed to evaluate the efficacy of experimental anastomotic devices in relation to time and point of rupture of the anastomosis in comparison to the conventional technique. MATERIALS AND METHODS: An electronic search was performed using MEDLINE, Scopus, Science Direct, and Cochrane Library databases by two independent authors. Our exclusion criteria referred to studies reporting results solely from end-to-side anastomosis, results on vessels other than the aorta, studies that did not involve animal experiments, and non-English publications. The last search date was January 1, 2020. RESULTS: The meta-analysis included 22 studies with 34 anastomosis samples and a total of 316 animals. The pooled mean automated anastomosis time was 10.38 min, and the mean point of rupture was 32.7 N. In the subgroup analysis of automated anastomosis time by device category, the anastomotic stenting technique reported significantly lower anastomosis time but also showed significantly lower point of rupture. Comparing the efficacy of experimental devices and the hand-sewn technique, our pooled analysis showed that automated devices significantly decrease the time needed to perform the anastomosis (weighted mean difference -7.24 min). On the other hand, the automated anastomosis is also associated with decreased tensile strength (weighted mean difference -20.68 N). CONCLUSIONS: Although experimental devices seem to offer a faster anastomosis, they lack endurance when compared with the hand-sewn technique. Further research is needed for the development of an "ideal" anastomotic technique.

Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis.

BACKGROUND: Sacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF). METHODS: We compared the treatment arms (sacubitril/valsartan, vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on vericiguat and the HFrEF subgroup of DECLARE-TIMI 58. RESULTS: There was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat. CONCLUSIONS: Based on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to vericiguat. REGISTRATION NUMBER: PROSPERO ID 186351.

Wenckebach cycle length: A novel predictor for AV block in AVNRT patients treated with ablation.

BACKGROUND: Radiofrequency catheter ablation remains the most effective management option for atrioventricular nodal reentry tachycardia (AVNRT). The risk of atrioventricular (AV) block requiring permanent pacemaker is substantial, but, currently, a reliable method to predict this complication is lacking. METHODS: The electrophysiologic studies (EPS) and baseline characteristics of patients who underwent catheter ablation for the treatment of AVNRT were retrospectively analyzed to investigate predisposing factors for AV block after treatment. Patients were followed for AV block at one month and one year after hospital discharge. RESULTS: Among 784 patients treated with catheter ablation for AVNRT between 1999 to 2019, 15 developed AV block. Patients with AV block were older (p = .001). Among the recorded EPS parameters, patients with AV block had significantly higher Atrial His interval (120 vs. 110 ms, p = .049), Wenckebach cycle length (WCL) (400 vs. 353 ms, p < .001) and tachycardia CL (400 vs. 387 ms, P = .01) during the ablation compared to their peers without AV block. Additionally, only WCL (OR = 1.1, 95% CI 1.02-1.19, p = .017) remained significant after adjustment for age, gender, ERP, AH interval, and HR. This association was confirmed by comparing patients with (n = 15) and without (n = 15) AV block using propensity score-matching. A WCL≥400ms was associated with a 4-fold higher incidence of AV block (4.79% vs. 1.25%). CONCLUSION: Increased pre-procedural WCL was associated with a high risk for AV block after catheter ablation treatment for AVNRT. These findings suggest that this readily available EPS-derived parameter may be a novel marker of risk for severe complications in these patients.

Right drug, wrong dosage: insights from the PAVE-AF antithrombotic study in older patients with atrial fibrillation.

Optimal antithrombotic treatment of older patients is usually impeded by several prevailing misconceptions. The aim of our study was to assess the type, dosage and predictors of antithrombotic therapy in older patients with non-valvular atrial fibrillation (NVAF). PAVE-AF was a prospective, cross-sectional study, including NVAF patients ≥ 80 years from 30 participating centers. Demographic data, comorbidities and treatment patterns were documented in a single visit. Patients treated with non-vitamin K oral anticoagulants (NOACs) were further classified into three dosing categories (recommended, underdosing and overdosing). Among 1018 patients (85.4±4.0 years), 88.4% received anticoagulants (AC), 8% antiplatelets (AP) and 3.6% no treatment. The primary reason for AP administration was physician concern of bleeding followed by patient denial. Patients ≥90 years had two times greater probability to receive AP therapy compared to patients < 90 years. Among patients treated with AC, one third received vitamin K antagonists, while two thirds received NOACs [34.6% apixaban, 9.5% dabigatran and 22.6% rivaroxaban]. Independent predictors of AC prescription over AP or no treatment were low HAS-BLED score, hypertension, labile INR, permanent AF, absence of uncontrolled hypertension, prior stroke/systemic embolism, age and male gender. In total, 37% of NOAC recipients received inappropriate dosage, while the number of patients receiving recommended dosing differed significantly among NOAC subgroups (p < 0.001). In our study, a minority of older NVAF patients received AP or no therapy for stroke prevention. Among patients treated with anticoagulants, two thirds were on NOAC treatment, though with a considerable proportion of inappropriate dosing.

Hypertension: An immune related disorder?

Hypertension is a multifactorial disorder with serious complications and unknown etiology. Among potential contributors, immune dysregulation has been also proposed. The study population included 61 consecutive hypertensive patients and 55 healthy individuals of similar age and sex distribution. All study participants underwent a thorough evaluation for subclinical atherosclerosis. A full immunological profile including quantification of immunoglobulins (IgG, IgM, IgA) and lymphocyte subpopulations was also obtained. Immunoglobulin levels IgG, IgA and IgM and complement factor C3 were found to be significantly increased in the hypertensive compared to the HC group while a statistically significant decrease in peripheral blood CD3+, CD4+ and CD8+ in hypertensive patients versus controls was detected. These findings might support a putative involvement of altered cellular and humoral immune responses in the pathogenesis of hypertension, implying a promising role for immunomodulatory strategies, already implemented in the treatment of autoimmune diseases, in the future management of hypertension.

Increased adenosine-to-inosine RNA editing in rheumatoid arthritis.

OBJECTIVE: Adenosine-to-inosine (A-to-I) RNA editing of Alu retroelements is a primate-specific mechanism mediated by adenosine deaminases acting on RNA (ADARs) that diversifies transcriptome by changing selected nucleotides in RNA molecules. We tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA). METHODS: Synovium expression analysis of ADAR1 was investigated in 152 RA patients and 50 controls. Peripheral blood mononuclear cells derived from 14 healthy subjects and 19 patients with active RA at baseline and after 12-week treatment were examined for ADAR1p150 and ADAR1p110 isoform expression by RT-qPCR. RNA editing activity was analysed by AluSx+ Sanger-sequencing of cathepsin S, an extracellular matrix degradation enzyme involved in antigen presentation. RESULTS: ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the blood of active RA patients. Individual nucleotide analysis revealed that A-to-I RNA editing rate was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rate of cathepsin S AluSx+ decreased after treatment only in those patients with good clinical response. Upregulation of the expression and/or activity of the RNA editing machinery were associated with a higher expression of edited Alu-enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5. CONCLUSION: A previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control in RA underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.

Predictors of adverse prognosis in COVID-19: A systematic review and meta-analysis.

BACKGROUND: Identification of reliable outcome predictors in coronavirus disease 2019 (COVID-19) is of paramount importance for improving patient's management. METHODS: A systematic review of literature was conducted until 24 April 2020. From 6843 articles, 49 studies were selected for a pooled assessment; cumulative statistics for age and sex were retrieved in 587 790 and 602 234 cases. Two endpoints were defined: (a) a composite outcome including death, severe presentation, hospitalization in the intensive care unit (ICU) and/or mechanical ventilation; and (b) in-hospital mortality. We extracted numeric data on patients' characteristics and cases with adverse outcomes and employed inverse variance random-effects models to derive pooled estimates. RESULTS: We identified 18 and 12 factors associated with the composite endpoint and death, respectively. Among those, a history of CVD (odds ratio (OR) = 3.15, 95% confidence intervals (CIs) 2.26-4.41), acute cardiac (OR = 10.58, 5.00-22.40) or kidney (OR = 5.13, 1.78-14.83) injury, increased procalcitonin (OR = 4.8, 2.034-11.31) or D-dimer (OR = 3.7, 1.74-7.89), and thrombocytopenia (OR = 6.23, 1.031-37.67) conveyed the highest odds for the adverse composite endpoint. Advanced age, male sex, cardiovascular comorbidities, acute cardiac or kidney injury, lymphocytopenia and D-dimer conferred an increased risk of in-hospital death. With respect to the treatment of the acute phase, therapy with steroids was associated with the adverse composite endpoint (OR = 3.61, 95% CI 1.934-6.73), but not with mortality. CONCLUSIONS: Advanced age, comorbidities, abnormal inflammatory and organ injury circulating biomarkers captured patients with an adverse clinical outcome. Clinical history and laboratory profile may then help identify patients with a higher risk of in-hospital mortality.

A novel optical biosensor for the early diagnosis of sepsis and severe Covid-19: the PROUD study.

BACKGROUND: The accuracy of a new optical biosensor (OB) point-of-care device for the detection of severe infections is studied. METHODS: The OB emits different wavelengths and outputs information associated with heart rate, pulse oximetry, levels of nitric oxide and kidney function. At the first phase, recordings were done every two hours for three consecutive days after hospital admission in 142 patients at high-risk for sepsis by placing the OB on the forefinger. At the second phase, single recordings were done in 54 patients with symptoms of viral infection; 38 were diagnosed with COVID-19. RESULTS: At the first phase, the cutoff value of positive likelihood of 18 provided 100% specificity and 100% positive predictive value for the diagnosis of sepsis. These were 87.5 and 91.7% respectively at the second phase. OB diagnosed severe COVID-19 with 83.3% sensitivity and 87.5% negative predictive value. CONCLUSIONS: The studied OB seems valuable for the discrimination of infection severity.