key: cord-0820373-qqngyxrs authors: Ferreira, Jason; Mcmanus, Jessica; Jankowski, Christopher A.; Searcy, Randi title: Why the Use of Angiotensin II May Be a Fatal Mistake in Covid-19 date: 2020-05-21 journal: Shock DOI: 10.1097/shk.0000000000001577 sha: 07e6621a4bc08eefd448426b3c6e660c362ec4d2 doc_id: 820373 cord_uid: qqngyxrs nan therapies continues to outpace what is known. This has led many to draw clinical conclusions from inadequate data sets from publications with small sample sizes in a patient population with medical conditions that are also not currently well understood. Because SARS-CoV-2 relies heavily on the angiotensin converting enzyme (ACE) 2 pathway, many investigators have generated hypotheses that consider augmentation of this system as a potential treatment option. (1) (2) (3) (4) We read with interest the article recently published by Busse et al suggesting a potential benefit of the use of angiotensin II and more recently by Sanders et al., omitting this recommendation, within critically ill populations afflicted with SARS-CoV-2. (5, 6) Although the ACE2 receptor appears to play an integral role in cell entry, the downstream influence on this pathway may be responsible for a number of the complications seen within this illness. A balance of ACE and ACE2 is required among the multiple angiotensin pathways as inappropriate regulation has the potential to have catastrophic complications, some of which were noted within clinical trials of angiotensin II.(7-10) Dysregulated ratios of ACE to ACE2 concentrations have demonstrated potentially detrimental local effects on organ function, which is thought to be secondary to loss of counter regulatory effects within these localized tissues. (9, Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited. 10) These coronavirus species down regulate both the ACE2 receptor and pathway, thereby favoring diversion to the ACE pathway.(2, 3) Enhanced function of the ACE pathway has been associated with organ dysfunction, fibrosis, volume dysregulation, increased inflammation and hypercoagulation. (9, 11, 12) In contrast, researchers have shown a protective effect of the ACE2 pathway on lung injury thought to be largely due to shunting of the pathway to the production of the peptides angiotensin 1-7 and 1-9 in some alternative conditions. Previous studies have speculated that the lungs are the primary producers of Ang II due to a disproportionate activity ratio of ACE to ACE2 present. (9) This leads to the hypothesis that many of the complications seen within the COVID19 illness are that of angiotensin II toxicity, and considering the similarities of the current presentation of SARS-CoV-2 with unbridled angiotensin II activity, this hypothesis may not be far off. Predominance of Ang II via the ACE pathway rather than the protective pathway of Ang 1-7 and Ang 1-9, which is diminished by Lastly, when compared to placebo in the acute respiratory distress syndrome (ARDS) population, administration of ACE2 and subsequent decline in Ang II concentrations, have been shown to blunt the rise in IL-6, a cytokine that currently is correlated with the risk of multi-organ dysfunction and respiratory failure in the SARS-CoV-2 population. (12) (13) (14) (15) (16) 24) It is well known that Ang II is responsible for regulation of IL-6 leading, many to speculate that this illness and subsequent hyperinflammatory response to the SARS-CoV-2 virus may largely be driven by Ang II and an imbalance of ACE/ACE2. This imbalance and ACE/Ang II predominance has additionally shown a substantial worsening in ventilation perfusion mismatch and progression/incidence of ARDS.(1, 16) These findings may be related to the severe shunt, despite compliant lungs, being observed within the SARS-CoV-2 infected patients. While the evidence is largely anecdotal and extremely limited at this time, there is a strong concern that much of the pathology of this illness may be explained by Ang II/ACE hyperactivity and that further perpetuation of the Ang II pathway may be placing proverbial fuel on the fire and may explain a large amount of the downstream sequelae of this illness. At the end of the day as health care professionals we have all taken an oath to first do no harm. Given the availability of alternative hemodynamic support therapies and the theorized detrimental Classic and Nonclassic Renin-Angiotensin Systems in the Critically Ill SARScoronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS System Inhibitors in Patients with Covid-19 COVID-19, ACE2 and the Cardiovascular Consequences COVID-19 and the RAAS-a potential role for angiotensin II? Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Unauthorized reproduction of this article is prohibited Angiotensin II for the Treatment of Vasodilatory Shock ACE2: more of Ang-(1-7) or less Ang II? Angiotensin-converting enzyme 2 (ACE2) and ACE activities display tissuespecific sensitivity to undernutrition-programmed hypertension in the adult rat Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis Reduced circulating levels of angiotensin-(1--7) in systemic sclerosis: a new pathway in the dysregulation of endothelial-dependent vascular tone control Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome Unauthorized reproduction of this article is prohibited Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome Angiotensin-converting enzyme 2 protects from severe acute lung failure Angiotensin-converting enzyme insertion/deletion polymorphism is associated with severe hypoxemia in pediatric ARDS Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury Angiotensin II for the Treatment of COVID-19-Related Vasodilatory Shock Angiotensin and vascular fibrinolytic balance Unauthorized reproduction of this article is prohibited Gavins FNE: A critical role for both CD40 and VLA5 in angiotensin II-mediated thrombosis and inflammation A systematic review to investigate whether -7) is a promising therapeutic target in human heart failure Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2 Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited.