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SEE PDF] Dysregulated RAS signaling with enhanced aldosterone-mediated MR activation could represent an important link between SARS-CoV-2/ACE2 interaction and inflammatory lung injury, suggesting an interesting therapeutic potential of RAS inhibitors [1] and in particular MR antagonists. [...]effects may be particularly useful in the context of SARS-CoV-2 infection, by inhibiting the androgen-dependent expression of TMPRSS2, a transmembrane protease crucial for viral entry through its priming effect on the viral S protein [5]. [...]by its dual actions as an MR antagonist and an androgenic inhibitor, spironolactone might provide significant benefits in COVID-19 ARDS. [...]the primary action of spironolactone (reduction of pulmonary edema) would also be beneficial in COVID-19 ARDS. [...]we hypothesize that through its combined pharmacological actions, spironolactone may provide therapeutic benefit, when applied in the later stage of COVID-19 ARDS.

Pulmonary hypertension (PH) associated with left heart diseases (PH-LHD), also termed group 2 PH, represents the most common form of PH. It develops through the passive backward transmission of elevated left heart pressures in the setting of heart failure, either with preserved (HFpEF) or reduced (HFrEF) ejection fraction, which increases the pulsatile afterload of the right ventricle (RV) by reducing pulmonary artery (PA) compliance. In a subset of patients, progressive remodeling of the pulmonary circulation resulted in a pre-capillary phenotype of PH, with elevated pulmonary vascular resistance (PVR) further increasing the RV afterload, eventually leading to RV-PA uncoupling and RV failure. The primary therapeutic objective in PH-LHD is to reduce left-sided pressures through the appropriate use of diuretics and guideline-directed medical therapies for heart failure. When pulmonary vascular remodeling is established, targeted therapies aiming to reduce PVR are theoretically appealing. So far, such targeted therapies have mostly failed to show significant positive effects in patients with PH-LHD, in contrast to their proven efficacy in other forms of pre-capillary PH. Whether such therapies may benefit some specific subgroups of patients (HFrEF, HFpEF) with specific hemodynamic phenotypes (post- or pre-capillary PH) and various degrees of RV dysfunction still needs to be addressed.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .

The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression. The development of cardiovascular diseases in patients with chronic liver failure is associated with increased morbidity and mortality, and cardiovascular complications can in turn affect liver function and liver disease progression. Furthermore, numerous infectious, inflammatory, metabolic and genetic diseases, as well as alcohol abuse can also influence both hepatic and cardiovascular outcomes. In this Review, we highlight how chronic liver diseases and associated cardiovascular effects can influence different organ pathologies. Furthermore, we explore the potential roles of inflammation, oxidative stress, vasoactive mediator imbalance, dysregulated endocannabinoid and autonomic nervous systems and endothelial dysfunction in mediating the complex interplay between the liver and the systemic vasculature that results in the development of the extrahepatic complications of chronic liver disease. The roles of ageing, sex, the gut microbiome and organ transplantation in this complex interplay are also discussed.Chronic liver disease can promote the development of numerous cardiac disorders and circulatory complications. In this Review, Pacher and colleagues describe some of the extrahepatic complications of chronic liver disease and their shared pathophysiological mechanisms, including inflammation and oxidative stress.

Severe PJP requiring admission to the intensive care unit is associated with mortality rates > 50%, and several factors have been associated with reduced survival including age, a non-HIV status, invasive mechanical ventilation and the admission SOFA score [1, 2]. MetHb formed from Hb autooxidation is normally maintained at very low levels due to the activity of MetHb reductase, but may increase in critically ill patients with sepsis, or treated with inhaled NO or prooxidant drugs such as dapsone [4]. Since none of our patients received these therapies at the time of MetHb measurements, we propose that MetHb formation could reflect more severe lung inflammation, favoring a greater pro-oxidant environment fostering hemoglobin oxidation. Endogenous CO formation results from the activity of heme oxygenase (HO), and pulmonary HO induction has been reported in a variety of lung inflammatory diseases [5]. [...]we speculate that the early increase of HbCO in PJP non-survivors could reflect such an induction of HO due to more severe lung inflammation.

Overactivation of the sympatho-adrenergic system is an essential mechanism providing short-term adaptation to the stressful conditions of critical illnesses. In the same way, the administration of exogenous catecholamines is mandatory to support the failing circulation in acutely ill patients. In contrast to these short-term benefits, prolonged adrenergic stress is detrimental to the cardiovascular system by initiating a series of adverse effects triggering significant cardiotoxicity, whose pathophysiological mechanisms are complex and only partially elucidated. In addition to the development of myocardial oxygen supply/demand imbalance induced by the sustained activation of adrenergic receptors, catecholamines can damage cardiomyocytes by fostering mitochondrial dysfunction, via two main mechanisms. The first one is calcium overload, consecutive to β-adrenergic receptor-mediated activation of protein kinase A and subsequent phosphorylation of multiple Ca 2+ -cycling proteins. The second one is oxidative stress, primarily related to the transformation of catecholamines into “aminochromes,” which undergo redox cycling in mitochondria to generate copious amounts of oxygen-derived free radicals. In turn, calcium overload and oxidative stress promote mitochondrial permeability transition and cardiomyocyte cell death, both via the apoptotic and necrotic pathways. Comparable mechanisms of myocardial toxicity, including marked oxidative stress and mitochondrial dysfunction, have been reported with the use of cocaine, a common recreational drug with potent sympathomimetic activity. The aim of the current review is to present in detail the pathophysiological processes underlying the development of catecholamine and cocaine-induced cardiomyopathy, as such conditions may be frequently encountered in the clinical practice of cardiologists and ICU specialists.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-saving technology that provides transient respiratory and circulatory support for patients with profound cardiogenic shock or refractory cardiac arrest. Among its potential complications, VA-ECMO may adversely affect lung function through various pathophysiological mechanisms. The interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response which may increase pulmonary vascular permeability and promote the sequestration of polymorphonuclear neutrophils within the lung parenchyma. Also, VA-ECMO increases the afterload of the left ventricle (LV) through reverse flow within the thoracic aorta, resulting in increased LV filling pressure and pulmonary congestion. Furthermore, VA-ECMO may result in long-standing pulmonary hypoxia, due to partial shunting of the pulmonary circulation and to reduced pulsatile blood flow within the bronchial circulation. Ultimately, these different abnormalities may result in a state of persisting lung inflammation and fibrotic changes with concomitant functional impairment, which may compromise weaning from VA-ECMO and could possibly result in long-term lung dysfunction. This review presents the mechanisms of lung damage and dysfunction under VA-ECMO and discusses potential strategies to prevent and treat such alterations.

Patients with cardiogenic shock (CS) display systemic inflammation and a high rate of infections, suggesting important immune disturbances. To explore the immune response to CS, we prospectively measured, in 24 consecutive CS patients, differential white blood cell (WBC) counts and the cytokines IL-1β, IL-5, IL-6, IL-10, TNFα, IFNγ, MCP-1 and eotaxin (CCL11), at Day 1 (T1), day 3 (T2) and day 6-8 (T3). Secondary infections and their influence on cytokines and WBCs were determined. CS induced early (T1) neutrophilia and elevated levels of IL-6, IL-10 and MCP-1, correlating with shock severity. The eosinophil chemoattractant eotaxin was elevated at T1 and decreased thereafter, and a progressive rise of blood eosinophils was noted over time. Patients with the most severe shock had reduced lymphocytes and monocytes at T2 and T3. Sixty-two percent of patients developed an infection, which did not alter the profile of immune response, except from higher IL-6 levels at T2. Therefore, CS elicits an acute pro-inflammatory response, followed by a delayed increase in blood eosinophils, consistent with the development of a tissue repair response, as well as depletion of immune cells in the most severely affected patients, which might predispose to secondary infections.

Infection with the novel severe acute respiratory coronavirus-2 (SARS-CoV2) results in COVID-19, a disease primarily affecting the respiratory system to provoke a spectrum of clinical manifestations, the most severe being acute respiratory distress syndrome (ARDS). A significant proportion of COVID-19 patients also develop various cardiac complications, among which dysfunction of the right ventricle (RV) appears particularly common, especially in severe forms of the disease, and which is associated with a dismal prognosis. Echocardiographic studies indeed reveal right ventricular dysfunction in up to 40% of patients, a proportion even greater when the RV is explored with strain imaging echocardiography. The pathophysiological mechanisms of RV dysfunction in COVID-19 include processes increasing the pulmonary vascular hydraulic load and others reducing RV contractility, which precipitate the acute uncoupling of the RV with the pulmonary circulation. Understanding these mechanisms provides the fundamental basis for the adequate therapeutic management of RV dysfunction, which incorporates protective mechanical ventilation, the prevention and treatment of pulmonary vasoconstriction and thrombotic complications, as well as the appropriate management of RV preload and contractility. This comprehensive review provides a detailed update of the evidence of RV dysfunction in COVID-19, its pathophysiological mechanisms, and its therapy.

Background Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery. Methods We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care ( n  = 15) or CytoSorb® HA ( n  = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors’ activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII). Results Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors’ adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes. Conclusions CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts. Trial registration ClinicalTrials.gov NCT02775123 . Registered 17 May 2016.