Adrenomedullin (ADM) is a peptide hormone with vasodilatory effects and involved in the regulation of the endothelial barrier function. Previous research found increased ADM plasma levels in patients with sepsis and ADM levels correlated with disease severity and mortality in sepsis [1]. Although severe coronavirus disease (COVID-19) shares some clinical features of sepsis (e.g., endothelial barrier dysfunction [2]), it is not known whether pathophysiological pathways of COVID-19 resemble those of sepsis [2, 3]. To our knowledge, this is the first study to evaluate ADM in context of COVID-19 [4]. We present here data regarding ADM in patients with COVID-19. Starting from March 2020, we included 45 adult patients presenting with signs of respiratory infection (cough and/or fever) to the Emergency Department in this ongoing study. The study was approved by the ethics committee of the University of Regensburg. Each individual provided written informed consent prior to inclusion. SARS-CoV-2 infection status was evaluated by PCR analysis mainly using throat rinse water (or less frequently nasopharyngeal swabs). Patients were classified as COVID-19 positive (PCR positive for SARS-CoV-2 and signs of respiratory infection) or control (other viral or bacterial respiratory infection). Whole blood was drawn by venipuncture and lysed in Trifast (Ambion) buffer solution. Further, RNA expression analysis of ADM in whole blood was performed using qPCR and normalized to GAPDH as housekeeper

Background Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. Methods This randomised, multinational study enrolled hospitalised patients (18–80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. Findings Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC ( n = 71) or SoC alone ( n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. Interpretation DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. Trial registration ClinicalTrials.gov, NCT04382053. Supplementary Information The online version contains supplementary material available at 10.1007/s15010-022-01904-w.

AimsLeft and right atria show compelling differences regarding organogenesis and specific clinical diseases. In congestive heart failure (CHF), remodelling of the atria occurs leading to increased arrhythmogenic susceptibility and deterioration of clinical symptoms. We aimed to assess the basal left and right atrial molecular set-up and different chamber-specific atrial changes in heart failure. Methods and resultsWe combined an animal model of rapid ventricular pacing induced heart failure in the rabbit and a gel-based proteomic screening of left and right atrial specimen. A gene ontology over-representation analysis was performed for biological function. Ultrastructural adaptations were evaluated using transmission electron microscopy. Comparing left and right atria of healthy control animals (CTRL), 39 proteins displayed significant expression differences involving various biological functions. Upon further statistical analyses, four pathways of energy metabolism were confirmed to be significantly over-represented beneath the other biological processes. Rapid ventricular pacing induced severe left ventricular systolic dysfunction, symptomatic heart failure and a macroscopic atrial remodelling. In CHF versus CTRL, metabolic and antioxidative enzymes were differentially expressed and showed chamber-specific bidirectional alterations. Transmission electron microscopy visualized a remarkable and again chamber-specific ultrastructural disturbance of mitochondrial morphology.

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BackgroundInhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF).Methods and ResultsBy progressive right ventricular pacing, distinct HF stages were induced in 15 rabbits, and 6 animals served as controls (CTRL). Six animals with manifest HF (CHF) were treated with the RAS-/NEP-inhibitor omapatrilat. Echocardiographic studies and invasive blood pressure measurements were undertaken during HF progression. Mitochondria were isolated from LV tissue, respectively, and further worked up for proteomic analysis using the SWATH technique. Enzymatic activities of citrate synthase and the electron transfer chain (ETC) complexes I, II, and IV were assessed. Ultrastructural analyses were performed by transmission electron microscopy. During progression to overt HF, intricate expression changes were mainly detected for proteins belonging to the tricarboxylic acid cycle, glucose and fat metabolism, and the ETC complexes, even though ETC complex I, II, or IV enzymatic activities were not significantly influenced. Treatment with a RAS-/NEP-inhibitor then reversed some maladaptive metabolic adaptations, positively influenced the decline of citrate synthase activity, and altered the composition of each respiratory chain complex, even though this was again not accompanied by altered ETC complex enzymatic activities. Finally, ultrastructural evidence pointed to a reduction of autophagolytic and degenerative processes with omapatrilat-treatment.ConclusionsThis study describes complex adaptations of the mitochondrial proteome in experimental tachycardia-induced heart failure and shows that a combined RAS-/NEP-inhibition can beneficially influence mitochondrial key pathways.