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Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Post intensive care syndrome (PICS) affects an increasing number of critical illness survivors and their families, with serious physical and psychological sequelae. Since little is known about the burden of critical illness on ICU survivor families, we conducted a prospective observational study aiming to assess this, and investigate correlations of the patients’ psychometric and health-related quality of life (HRQOL) scores with family burden.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49–1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93–1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52–1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78–1.34)] compared to the survivors [0.57 (0.48–0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in mean pulmonary arterial pressure. Mutations in the BMPR2 and AQP1 genes have been described in familial PAH. The bone morphogenetic proteins BMP9 and BMP10 bind with high affinity to BMPR2. Administration of BMP9 has been proposed as a potential therapeutic strategy against PAH, although recent conflicting evidence dispute the effect of such a practice. Considering the involvement of the above molecules in PAH onset, progression, and therapeutic value, we examined the effects of modulation of BMP9, BMPR2, and AQP1 on BMP9, BMP10, BMPR2, AQP1, and TGFB1 expression in human pulmonary microvascular endothelial cells in vitro. Our results demonstrated that silencing the BMPR2 gene resulted in increased expression of its two main ligands, namely BMP9 and BMP10. Exogenous administration of BMP9 caused the return of BMP10 to basal levels, while it restored the decreased AQP1 protein levels and the decreased TGFB1 mRNA and protein expression levels caused by BMPR2 silencing. Moreover, AQP1 gene silencing also resulted in increased expression of BMP9 and BMP10. Our results might possibly imply that the effect of exogenously administered BMP9 on molecules participating in the BMP signaling pathway could depend on the expression levels of BMPR2. Taken together, these results may provide insight into the highly complex interactions of the BMP signaling pathway. [ABSTRACT FROM AUTHOR]

A potential complication in critically ill patients is the formation of bone in soft tissues, termed heterotopic ossification. The exact pathogenetic mechanisms are still undetermined. Bone morphogenetic proteins induce bone formation, while signalling through the receptor activator of nuclear factor kappa-Β (RANK) and its ligand (RANKL), regulates osteoclast formation, activation, and survival in normal bone modelling and remodelling. Osteoprotegerin protects bone from excessive bone loss by blocking RANKL from binding to RANK.

Healthcare professionals who are directly involved in the diagnosis, treatment, and general care of patients with SARS-CoV-2 are at risk of developing adverse psychological reactions. A cross-sectional study of healthcare professionals aimed to determine the impact of the SARS-CoV-2 pandemic on the mental health of healthcare professionals in two of the largest referral hospitals in Athens, Greece.

Bone morphogenetic proteins (BMPs) were once considered only to have a role in bone formation. It is now known that they have pivotal roles in other organ diseases, including heritable pulmonary arterial hypertension (PAH), where genetic mutations in the type II BMP receptor (BMPR2) are the commonest cause of receptor dysfunction. However, it has also recently been demonstrated that aquaporin 1 (Aqp1) dysfunction may contribute to PAH, highlighting that PAH development may involve more than one pathogenic pathway. Whether reduction in BMPR2 affects Aqp1 is unknown. We therefore studied Aqp1 in BMPR2-silenced human pulmonary microvascular endothelial cells (HPMECs). We demonstrated reduced Aqp1 mRNA protein, and function in the BMPR2-silenced cells. Additionally, BMPR2-silenced cells exhibited lower expression of BMP-signaling molecules. In conclusion, decreased BMPR2 appears to affect Aqp1 at the mRNA, protein, and functional levels. This observation may identify a contributory mechanism for PAH. Key words: Aqp1, BMPR2, PAH, HPMEC. On a deja considere que les proteines morphogeniques osseuses (BMP pour << bone morphogenetic proteins >>) jouent uniquement un role dans la formation d'os. On sait maintenant qu'elles jouent un role central dans d'autres maladies, y compris l'hypertension arterielle pulmonaire hereditaire (HAP), ou des mutations genetiques dans les recepteurs aux BMP de type 2 (BMPR2) sont la cause la plus frequente de dysfonctionnement des recepteurs. Toutefois, on a aussi montre recemment qu'un dysfonctionnement de l'aquaporine 1 (Aqp1) pourrait contribuer a l'HAP, ce qui met en relief que l'apparition de l'HAP pourrait mettre enjeu plus d'une voie de signalisation de pathogenie. On ne sait pas si l'abaissement des BMPR2 affecte l'Aqp1. Nous avons donc etudie l'Aqp1 dans des cellules endotheliales de microvaisseaux pulmonaires humains (CEMPH) dont les BMPR2 etaient reprimes. Nous avons montre un abaissement de l'Aqp1 en ARNm, en proteines et quant au fonctionnement dans des cellules dont les BMPR2 etaient reprimes. De plus, les cellules dont les BMPR2 etaient reprimes presentaient une plus faible expression de molecules de signalisation des BMP. En conclusion, l'abaissement des BMPR2 semble affecter l'Aqp1 au niveau de l'ARNm, des proteines et du fonctionnement. Cette observation pourrait permettre de distinguer un mode d'action qui contribuerait a l'HAP. [Traduit par la Redaction] Mots-cles: Aqp1, BMPR2, hypertension arterielle pulmonaire hereditaire, cellules endotheliales de microvaisseaux pulmonaires humains., Introduction Bone morphogenetic proteins (BMPs) are a group of signaling molecules that belong to the transforming growth factor-p (TGF-[beta]) superfamily of proteins. BMPs have multiple roles in the development and [...]

Sepsis is an inflammatory disorder caused by the host's dysfunctional response to infection. Septic patients present diverse clinical characteristics, and in the recent years, it has been the main cause of death in intensive care units (ICU). Aquaporins, membrane proteins with a role in water transportation, have been reported to participate in numerous biological processes. Their role in sepsis progression has been studied extensively. This review aims to examine recent literature on aquaporin expression and regulation in clinical sepsis, as well as established experimental models of sepsis. We will present how sepsis affects aquaporin expression at the molecular and protein level. Moreover, we will delve into the importance of aquaporin regulation at transcriptional, post-transcriptional, translational, and post-translational levels in sepsis by presenting data on aquaporin regulation by non-coding RNAs and selected chemical molecules. Finally, we will focus on the importance of aquaporin single-nucleotide polymorphisms in the setting of sepsis. [ABSTRACT FROM AUTHOR]

Severe COVID-19 is related to hyperinflammation and multiple organ injury, including respiratory failure, thus requiring intensive care unit (ICU) admission. Galectin-3, a carbohydrate-binding protein exhibiting pleiotropic effects, has been previously recognized to participate in inflammation, the immune response to infections and fibrosis. The aim of this study was to evaluate the relationship between galectin-3 and the clinical severity of COVID-19, as well as assess the prognostic accuracy of galectin-3 for the probability of ICU mortality. The study included 235 COVID-19 patients with active disease, treated in two different Greek hospitals in total. Our results showed that median galectin-3 serum levels on admission were significantly increased in critical COVID-19 patients (7.2 ng/mL), as compared to the median levels of patients with less severe disease (2.9 ng/mL, p = 0.003). Galectin-3 levels of the non-survivors hospitalized in the ICU were significantly higher than those of the survivors (median 9.1 ng/mL versus 5.8 ng/mL, p = 0.001). The prognostic accuracy of galectin-3 for the probability of ICU mortality was studied with a receiver operating characteristic (ROC) curve and a multivariate analysis further demonstrated that galectin-3 concentration at hospital admission could be assumed as an independent risk factor associated with ICU mortality. Our results were validated with galectin-3 measurements in a second patient cohort from a different Greek university hospital. Our results, apart from strongly confirming and advancing previous knowledge with two patient cohorts, explore the possibility of predicting ICU mortality, which could provide useful information to clinicians. Therefore, galectin-3 seems to establish its involvement in the prognosis of hospitalized COVID-19 patients, suggesting that it could serve as a promising biomarker in critical COVID-19. [ABSTRACT FROM AUTHOR]

Aging negatively affects the endothelium. Endocan (ESM-1), an endothelium-derived soluble proteoglycan, participates in fundamental biological processes of endothelial cells. We aimed to examine the role of endothelial dysfunction and age in poor outcomes in critical illness. ESM-1 levels were measured in the sera of mechanically ventilated critically ill patients, including COVID-19, non-septic, and septic patients. The 3 patient cohorts were divided based on age (≥65 and <65). Critically ill COVID-19 patients had statistically higher ESM-1 levels compared to critically ill septic and non-septic patients. Only in critically ill septic patients were ESM-1 levels higher in older compared to younger patients. Finally, the age-subgrouped patients were further subdivided based on intensive care unit (ICU) outcome. ESM-1 levels were similar in COVID-19 survivors and non-survivors, irrespective of age. Interestingly, only for the younger critically ill septic patients, non-survivors had higher ESM-1 levels compared to survivors. In the non-septic survivors and non-survivors, ESM-1 levels remained unaltered in the younger patients and tended to be higher in the elderly. Even though endocan has been recognized as an important prognostic biomarker in critically ill patients with sepsis, in our patient cohort, increased age, as well as the extent of endothelial dysfunction, seemed to affect its prognostic ability. [ABSTRACT FROM AUTHOR]

Hypoxia is characterized as one of the main consequences of sepsis, which is recognized as the leading cause of death in intensive care unit (ICU) patients. In this study, we aimed to examine whether the expression levels of genes regulated under hypoxia could be utilized as novel biomarkers for sepsis prognosis in ICU patients. Whole blood expression levels of hypoxia-inducible factor-1α (HIF1A), interferon-stimulated gene 15 (ISG15), hexokinase 2 (HK2), lactate dehydrogenase (LDHA), heme oxygenase-1 (HMOX1), erythropoietin (EPO), and the vascular endothelial growth factor A (VEGFA) were measured on ICU admission in 46 critically ill, initially non-septic patients. The patients were subsequently divided into two groups, based on the development of sepsis and septic shock (n = 25) or lack thereof (n = 21). HMOX1 mRNA expression was increased in patients who developed sepsis/septic shock compared to the non-septic group (p < 0.0001). The ROC curve, multivariate logistic regression, and Kaplan–Meier analysis demonstrated that HMOX1 expression could be utilized for sepsis and septic shock development probability. Overall, our results indicate that HMOX1 mRNA levels have the potential to be a valuable predictive factor for the prognosis of sepsis and septic shock in ICU patients. [ABSTRACT FROM AUTHOR]

Author(s): Christian Patry [sup.1], Stylianos E. Orfanos [sup.2], Neysan Rafat [sup.1] Author Affiliations: (1) grid.7700.0, 0000000121904373, Department of Pediatrics I, University Children's Hospital, University of Heidelberg, , Im Neuenheimer Feld [...]