Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Signaling Pathways and Potential Therapeutic Strategies in Cardiac Fibrosis

Cardiac fibrosis constitutes irreversible necrosis of the heart muscle as a consequence of different acute (myocardial infarction) or chronic (diabetes, hypertension, …) diseases but also due to genetic alterations or aging. Currently, there is no curative treatment that is able to prevent or attenuate this phenomenon that leads to progressive cardiac dysfunction and life-threatening outcomes. This review summarizes the different targets identified and the new strategies proposed to fight cardiac fibrosis. Future directions, including the use of exosomes or nanoparticles, will also be discussed

Cellular Origins and Thrombogenic Activity of Microparticles Isolated From Human Atherosclerotic Plaques

ObjectivesIn this study, we evaluated the cellular origins and thrombogenic potential of microparticles.BackgroundHuman atherosclerotic plaques contain submicron vesicles (microparticles) released during cell activation or apoptosis.MethodsMicroparticles were purified from plaques and platelet-free plasma from 26 patients undergoing carotid endarterectomy. Flow cytometry analysis revealed the presence of large amounts of microparticles in plaques but not in healthy vessels.ResultsMost plaque microparticles originated from leukocytes, of which 29 ± 5% were macrophages, 15 ± 3% lymphocytes, and 8 ± 1% granulocytes. Plaques microparticles also derived from erythrocytes (27 ± 4%), smooth muscle (13 ± 4%) and endothelial cells (8 ± 2%), but not from platelets. Plaques from asymptomatic and symptomatic patients showed no differences in microparticle origins. Microparticles were at least 200-fold more concentrated in plaque than in plasma. Plasma microparticles were primarily platelet-derived in contrast with those of plaque and showed no smooth muscle cell origin. Both plaque and plasma microparticles exposed tissue factor and generated thrombin, but this activity was twice as high in microparticles isolated from plaques, reflecting the thrombogenic contribution of the individual classes of microparticles.ConclusionsThese results demonstrate that microparticles are more abundant and more thrombogenic in human atherosclerotic plaques than in plasma. The different cellular origins of plaque and plasma microparticles might explain the increased thrombogenic activity of plaque microparticles

Endothelial-derived microparticles: Biological conveyors at the crossroad of inflammation, thrombosis and angiogenesis

peer reviewedEndothelial microparticles (EMP) are complex vesicular structures that can be shed by activated or apoptotic endothelial cells. EMP are composed of a phospholipid bilayer that exposes transmembrane proteins and receptors and encloses cytosolic components such as enzymes, transcription factors and mRNA derived from their parent cells. Thus, EMP behave as biological conveyors playing a key role in the tuning of vascular homeostasis. This review focuses on the multifaceted roles of EMP, notably in coagulation, inflammation and angiogenesis and also on the mechanisms that trigger their formation. In this context, EMP could compromise vascular homeostasis and then represent key players in the pathogenesis of several inflammatory and thrombotic diseases. Consequently, elucidating their role and their mechanisms of formation will bring new insights into the understanding of endothelial-associated diseases. Moreover, in the future, it can open novel therapeutic perspectives based on the inhibition of EMP release

Circulating microvesicles correlate with radiation proctitis complication after radiotherapy

Abstract In a large retrospective study, we assessed the putative use of circulating microvesicles (MVs), as innovative biomarkers of radiation toxicity in a cohort of 208 patients with prostate adenocarcinoma overexposed to radiation. The level of platelet (P)-, monocyte (M)- and endothelial (E)-derived MVs were assessed by flow cytometry. Rectal bleeding toxicity scores were collected at the time of blood sampling and during the routine follow-up and were tested for association with MVs using a multivariate logistic regression. MVs dosimetric correlation was investigated using dose volume histograms information available for a subset of 36 patients. The number of PMVs was significantly increased in patients with highest toxicity grades compared to lower grades. Risk prediction analysis revealed that increased numbers of PMVs, and an increased amount of MMVs relative to EMVs, were associated with worst rectal bleeding grade compared to the time of blood sampling. Moreover, a significant correlation was found between PMV and MMV numbers, with the range of doses up to the median exposure (40 Gy) of bladder/rectum and anterior rectal wall, respectively. MVs could be considered as new biomarkers to improve the identification of patients with high toxicity grade and may be instrumental for the prognosis of radiation therapy complications