SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy

Chung, Mina K.; Karnik, Sadashiva S.; Saef, Joshua; Bergmann, Cornelia C.; Barnard, John; Lederman, Michael M.; Tilton, John C.; Cheng, Feixiong; Harding, Clifford V.; Young, James B.; Mehta, Neil; Cameron, Scott J.; McCrae, Keith R.; Schmaier, Alvin H.; Smith, Jonathan; Kalra, Ankur; Gebreselassie, Surafel; Thomas, George; Hawkins, E.; Svensson, Lars G.

doi:10.1016/j.ebiom.2020.102907

Cited by 127 publications

(154 citation statements)

References 76 publications

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“…The exact role renin-angiotensin-aldosterone system agents have on both infection rates and mortality remains controversial, and the consequences of their subsequent discontinuation in the hospital setting in COVID-19 remain unclear. [24][25][26], this has not been seen consistently in other cohorts and likely requires further study [27,28]. Notably, despite lower severity of illness, prior ICU cohorts reported mortality rates of 75-89% for patients with COVID-19 requiring RRT with shorter follow up [12,17,19].…”

Section: Plos Onementioning

confidence: 99%

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy

et al. 2020

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Introduction A large proportion of patients with COVID-19 develop acute kidney injury (AKI). While the most severe of these cases require renal replacement therapy (RRT), little is known about their clinical course. Methods We describe the clinical characteristics of COVID-19 patients in the ICU with AKI requiring RRT at an academic medical center in New York City and followed patients for outcomes of death and renal recovery using time-to-event analyses. Results Our cohort of 115 patients represented 23% of all ICU admissions at our center, with a peak prevalence of 29%. Patients were followed for a median of 29 days (2542 total patient-RRT-days; median 54 days for survivors). Mechanical ventilation and vasopressor use were common (99% and 84%, respectively), and the median Sequential Organ Function Assessment (SOFA) score was 14. By the end of follow-up 51% died, 41% recovered kidney function (84% of survivors), and 8% still needed RRT (survival probability at 60 days: 0.46 [95% CI: 0.36–0.56])). In an adjusted Cox model, coronary artery disease and chronic obstructive pulmonary disease were associated with increased mortality (HRs: 3.99 [95% CI 1.46–10.90] and 3.10 [95% CI 1.25–7.66]) as were angiotensin-converting-enzyme inhibitors (HR 2.33 [95% CI 1.21–4.47]) and a SOFA score >15 (HR 3.46 [95% CI 1.65–7.25). Conclusions and relevance Our analysis demonstrates the high prevalence of AKI requiring RRT among critically ill patients with COVID-19 and is associated with a high mortality, however, the rate of renal recovery is high among survivors and should inform shared-decision making.

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Section: Plos Onementioning

confidence: 99%

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy

et al. 2020

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“…It has also been suggested that the interaction between ACE2 and viral glycoproteins leads to the creation of an ACE2 receptor-glycoprotein complex that results in ACE2 downregulation, although this proposal has yet to be fully explored ( Glowacka et al, 2010 ). The downregulation of ACE2 is thought to increase levels of Ang II that are able to bind to the angiotensin II type 1 receptor (AT 1 R), since there are fewer ACE2 binding sites on the cell to degrade Ang II into the anti-inflammatory Ang 1-7 ( Kuba et al, 2005 ; Escobales et al, 2019 ; Chung et al, 2020 ; Vaduganathan et al, 2020 ). Supporting this theory, a clinical study of 12 patients found that those infected with SARS-CoV-2 demonstrated higher plasma levels of Ang II compared to healthy controls.…”

Section: Sars-cov-2 and The Endothelial Cellsmentioning

confidence: 99%

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

et al. 2021

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Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial cells can promote chronic inflammation and disease processes like thrombosis, atherosclerosis, and lung injury. In endothelial cells, mitochondria regulate these inflammatory pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that can initiate and exacerbate senescence, a state that promotes inflammation and chronic endothelial dysfunction. Oxidative stress can also activate feedback loops that perpetuate mitochondrial dysfunction, mtROS overproduction, and inflammation. In this review, we provide an overview of phenotypes mediated by mtROS in endothelial cells – such as mitochondrial dysfunction, inflammation, and senescence – as well as how these chronic states may be initiated by SARS-CoV-2 infection of endothelial cells. We also propose that SARS-CoV-2 activates mtROS-mediated feedback loops that cause long-term changes in host redox status and endothelial function, promoting cardiovascular disease and lung injury after recovery from COVID-19. Finally, we discuss the implications of these proposed pathways on long-term vascular health and potential treatments to address these chronic conditions.

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“…Nevertheless, it has been hypothesized that they could increase Ang II plasma levels, increasing ACE2 expression, and inducing more target molecules to be available for the SARS-CoV-2 virus [105][106][107]. At present, no evidence has shown that continued use of ACE inhibitors and ARBs increases the risk of SARS-CoV-2 severe infection or the risk of death [108][109][110][111]. At skeletal muscle levels, a minor activity of the RAS classical pathway could decrease the atrophic stimulus.…”

Section: Possible Therapeutic Interventionsmentioning

confidence: 99%

SARS-CoV-2/Renin–Angiotensin System: Deciphering the Clues for a Couple with Potentially Harmful Effects on Skeletal Muscle

González

Orozco-Aguilar

Achiardi

et al. 2020

IJMS

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Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has produced significant health emergencies worldwide, resulting in the declaration by the World Health Organization of the coronavirus disease 2019 (COVID-19) pandemic. Acute respiratory syndrome seems to be the most common manifestation of COVID-19. A high proportion of patients require intensive care unit admission and mechanical ventilation (MV) to survive. It has been well established that angiotensin-converting enzyme type 2 (ACE2) is the primary cellular receptor for SARS-CoV-2. ACE2 belongs to the renin–angiotensin system (RAS), composed of several peptides, such as angiotensin II (Ang II) and angiotensin (1-7) (Ang-(1-7)). Both peptides regulate muscle mass and function. It has been described that SARS-CoV-2 infection, by direct and indirect mechanisms, affects a broad range of organ systems. In the skeletal muscle, through unbalanced RAS activity, SARS-CoV-2 could induce severe consequences such as loss of muscle mass, strength, and physical function, which will delay and interfere with the recovery process of patients with COVID-19. This article discusses the relationship between RAS, SARS-CoV-2, skeletal muscle, and the potentially harmful consequences for skeletal muscle in patients currently infected with and recovering from COVID-19.

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SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy

Cited by 127 publications

References 76 publications

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

SARS-CoV-2/Renin–Angiotensin System: Deciphering the Clues for a Couple with Potentially Harmful Effects on Skeletal Muscle

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