Bwh là gì

List of authors.Muthiah Vaduganathan, M.D., M.P.H., Orly Vardeny, Pharm.D., Thomas Michel, M.D., Ph.D., John J.V. McMurray, M.D., Marc A. Pfeffer, M.D., Ph.D., & Scott D. Solotháng, al.

The renin–angiotensin–aldosterone system (RAAS) is an elegant cascade of vasoactive peptides that orchestrate key processes in human physiology. Severe adễ thương respiratory syndrome coronavi khuẩn 1 (SARS-CoV-1) và SARS-CoV-2, which have sầu been responsible for the SARS epidemic in 2002 khổng lồ 2004 và for the more recent coronavirus disease 2019 (Covid-19) pandemic, respectively, interface with the RAAS through angiotensin-converting enzyme 2 (ACE2), an enzyme that physiologically counters RAAS activation but also functions as a receptor for both SARS viruses.1,2 The interaction between the SARS viruses và ACE2 has been proposed as a potential factor in their infectivity,3,4 & there are concerns about the use of RAAS inhibitors that may alter ACE2 và whether variation in ACE2 expression may be in part responsible for disease virulence in the ongoing Covid-19 pandemic.5-8 Indeed, some media sources & health systems have sầu recently called for the discontinuation of ACE inhibitors & angiotensin-receptor blockers (ARBs), both prophylactically and in the context of suspected Covid-19.

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Given the common use of ACE inhibitors & ARBs worldwide, guidance on the use of these drugs in patients with Covid-19 is urgently needed. Here, we highlight that the data in humans are too limited to lớn support or refute these hypotheses and concerns. Specifically, we discuss the uncertain effects of RAAS blockers on ACE2 levels và activity in humans, & we propose an alternative sầu hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. We also explicitly raise the concern that withdrawal of RAAS inhibitors may be harmful in certain high-risk patients with known or suspected Covid-19.

Covid-19 and Older Adults with Coexisting Conditions

Initial reports5-8 have called attention to lớn the potential overrepresentation of hypertension aước ao patients with Covid-19. In the largest of several case series from Đài Loan Trung Quốc that have sầu been released during the Covid-19 pandemic (Table S1 in the Supplementary Appendix, available with the full text of this article at, hypertension was the most frequent coexisting condition in 1099 patients, with an estimated prevalence of 15%9; however, this estimate appears khổng lồ be lower than the estimated prevalence of hypertension seen with other viral infections10 và in the general population in China.11,12

Coexisting conditions, including hypertension, have consistently been reported lớn be more comtháng among mỏi patients with Covid-19 who have had severe illness, been admitted to lớn the intensive sầu care unit, received mechanical ventilation, or died than among mỏi patients who have had mild illness. There are concerns that medical management of these coexisting conditions, including the use of RAAS inhibitors, may have sầu contributed to lớn the adverse health outcomes observed. However, these conditions appear lớn traông chồng closely with advancing age,13 which is emerging as the strongest predictor of Covid-19–related death.14 Unfortunately, reports khổng lồ date have sầu not rigorously accounted for age or other key factors that contribute to health as potential confounders in risk prediction. With other infective sầu illnesses, coexisting conditions such as hypertension have been key prognostic determinants,10 and this also appears lớn be the case with Covid-19.15

It is important lớn note that, despite inferences about the use of background RAAS inhibitors, specific details have been lacking in studies (Table S1). Population-based studies have sầu estimated that only 30 to 40% of patients in China who have hypertension are treated with any antihypertensive therapy; RAAS inhibitors are used alone or in combination in 25 to lớn 30% of these treated patients.11,12 Given such estimates, only a fraction of patients with Covid-19, at least in Trung Quốc, are anticipated to have been previously treated with RAAS inhibitors. Data showing patterns of use of RAAS inhibitors và associated health outcomes that rigorously tài khoản for treatment indication and illness severity aao ước patients with Covid-19 are needed.

Figure 1.
Figure 1. Interaction between SARS-CoV-2 và the Renin–Angiotensin–Aldosterone System.

Shown is the initial entry of severe ađáng yêu respiratory syndrome coronavi khuẩn 2 (SARS-CoV-2) inlớn cells, primarily type II pneumocytes, after binding to its functional receptor, angiotensin-converting enzyme 2 (ACE2). After endocytosis of the viral complex, surface ACE2 is further down-regulated, resulting in unopposed angiotensin II accumulation. Local activation of the renin–angiotensin–aldosterone system may mediate lung injury responses lớn viral insults. ACE denotes angiotensin-converting enzyme, và ARB angiotensin-receptor blocker.

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Tissue-specific & circulating components of the RAAS Cosplay a complex intersecting network of regulatory & counterregulatory peptides (Figure 1). ACE2 is a key counterregulatory enzyme that degrades angiotensin II lớn angiotensin-(1–7), thereby attenuating its effects on vasoconstriction, sodium retention, and fibrosis. Although angiotensin II is the primary substrate of ACE2, that enzyme also cleaves angiotensin I khổng lồ angiotensin-(1–9) and participates in the hydrolysis of other peptides.16 In studies in humans, tissue samples from 15 organs have sầu shown that ACE2 is expressed broadly, including in the heart and kidneys, as well as on the principal target cells for SARS-CoV-2 (and the site of dominant injury), the lung alveolar epithelial cells.17 Of interest, the circulating levels of soluble ACE2 are low and the functional role of ACE2 in the lungs appears lớn be relatively minimal under normal conditions18 but may be up-regulated in certain clinical states.

Because ACE inhibitors and ARBs have sầu different effects on angiotensin II, the primary substrate of ACE2, the effects of these agents on ACE2 levels and activity may be anticipated khổng lồ differ. Despite substantial structural homology between ACE and ACE2, their enzyme active sites are distinct. As a result, ACE inhibitors in clinical use vì chưng not directly affect ACE2 activity.19 Experimental animal models have shown mixed findings with respect khổng lồ the effects of ACE inhibitors on ACE2 levels or activity in tissue.20-25 Similarly, animal models have had inconsistent findings with respect khổng lồ the effects of ARBs on ACE2, with some showing that ARBs may increase messenger RNA expression or protein levels of ACE2 in tissue21,26-34 and others showing no effect.23

In contrast to lớn available animal models, there are few studies in humans regarding the effects of RAAS inhibition on ACE2 expression. In one study, the intravenous administration of ACE inhibitors in patients with coronary artery disease did not influence angiotensin-(1–7) production, a finding that calls inkhổng lồ question whether ACE inhibitors have any direct effects on ACE2-directed angiotensin II metabolism.35 Similarly, in another study, among mỏi patients with hypertension, angiotensin-(1–7) levels appeared lớn be unaffected after initial treatment with the ACE inhibitor captopril; however, with exposure khổng lồ captopril monotherapy over a period of 6 months, angiotensin-(1–7) levels increased.36 Furthermore, few studies have examined plasma ACE2 activity or urinary ACE2 levels in patients who have received long-term treatment with RAAS inhibitors. In cross-sectional studies involving patients with heart failure,37 atrial fibrillation,38 aortic stenosis,39 & coronary artery disease,40 plasma ACE2 activity was not higher aý muốn patients who were taking ACE inhibitors or ARBs than aý muốn untreated patients. In a longitudinal cohort study involving Japanese patients with hypertension, urinary ACE2 levels were higher among muốn patients who received long-term treatment with the ARB olmesartung than among muốn untreated control patients, but that association was not observed with the ACE inhibitor enalapril or with other ARBs (losarchảy, candesarrã, valsartan, & telmisartan).41 Previous treatment with ACE inhibitors was associated with increased intestinal messenger RNA levels of ACE2 in one study, but that association was not observed with ARBs25; data are lacking regarding the effects of RAAS inhibitors on lung-specific expression of ACE2.

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These seemingly conflicting data indicate the complexity underlying RAAS responses to lớn pathway modulators and reinforce the concept that findings from preclinical models may not readily translate lớn human physiology. Such data vì chưng suggest that effects on ACE2 should not be assumed lớn be uniform across RAAS inhibitors or even in response to therapies within a given drug class.41 It is important to lớn note that the plasma ACE2 cấp độ may not be a reliable indicator of the activity of the full-length membrane-bound khung, in part because ACE2 is shed from the membrane, a process that appears khổng lồ be separately regulated by an endogenous inhibitor.42 In addition khổng lồ the degree of expression, the bioxúc tích relevance of ACE2 may vary according lớn tissue and clinical state. Unfortunately, data showing the effects of ACE inhibitors, ARBs, and other RAAS inhibitors on lung-specific expression of ACE2 in experimental animal models and in humans are lacking. Furthermore, even if RAAS inhibitors modify ACE2 levels or activity (or both) in target tissue beds, clinical data are lacking to indicate whether this would in turn facilitate greater engagement và entry of SARS-CoV-2 spike protein. Further mechanistic studies in humans are needed to better define the unique interplay between SARS-CoV-2 & the RAAS network.

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