Plasma ACE2 Activity Predicts Mortality in Aortic Stenosis and Is Associated With Severe Myocardial Fibrosis

Ramchand, Jay; Patel, Sheila K.; Kearney, L.; Matalanis, George; Farouque, Omar; Srivastava, Piyush; Burrell, Louise M.

doi:10.1016/j.jcmg.2019.09.005

Cited by 89 publications

(97 citation statements)

References 33 publications

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“…We measured plasma ACE2 catalytic activity using a validated, sensitive quenched fluorescent substrate-based assay as previously described [3][4][5] in a cohort of Australians aged ³18 years (n=66) who had recovered from mild, moderate or severe SARS-CoV-2 infection (positive result by PCR testing) and age and gender matched uninfected controls (n=70). Serial samples were available in 23 recovered SARS-CoV-2 patients.…”

Section: Methodsmentioning

confidence: 99%

Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences

Patel

Juno

Lee

et al. 2020

Preprint

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COVID-19 causes persistent endothelial inflammation, lung and cardiovascular complications. SARS-CoV-2 utilises the catalytic site of full-length membrane-bound angiotensin converting enzyme 2 (ACE2) for cell entry causing downregulation of tissue ACE2. We reported downregulation of cardiac ACE2 is associated with increased plasma ACE2 activity. In this prospective observational study in recovered COVID-19 patients, we hypothesised that SARS-CoV-2 infection would be associated with shedding of ACE2 from cell membranes and increased plasma ACE2 activity. Methods We measured plasma ACE2 catalytic activity using a validated, sensitive quenched fluorescent substrate-based assay in a cohort of Australians aged 18 years and over who had recovered from mild, moderate or severe SARS-CoV-2 infection (positive result by PCR testing) (n=66) and age and gender matched uninfected controls (n=70). Serial samples were available in 23 recovered SARS-CoV-2 patients. Results Plasma ACE2 activity at a median of 35 days post-infection [interquartile range 30-38 days] was 97-fold higher in recovered SARS-CoV-2 patients compared to controls (5.8 [2-11.3] vs. 0.06 [0.02-2.2] pmol/min/ml, p<0.0001). There was a significant difference in plasma ACE2 activity according to disease severity (p=0.033), with severe COVID-19 associated with higher ACE2 activity compared to mild disease (p=0.027). Men (n=39) who were SARS-CoV-2 positive had higher median plasma ACE2 levels compared to women (n=27) (p<0.0001). We next analysed whether an elevated plasma ACE2 activity level persisted following SARS-CoV-2 infection in subjects with blood samples at 63 [56-65] and 114 [111-125] days post infection. Plasma ACE2 activity remained persistently elevated in almost all subjects, with no significant differences between timepoints in post-hoc comparisons (p>0.05). Discussion This is the first description that plasma ACE2 activity is elevated after COVID-19 infection, and the first with longitudinal data indicating plasma ACE2 activity remains elevated out to a median of 114 days post- infection. Larger studies are now needed to determine if persistent elevated plasma ACE2 activity identifies people at risk of prolonged illness following COVID-19.

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Section: Methodsmentioning

confidence: 99%

Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences

Patel

Juno

Lee

et al. 2020

Preprint

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“…In several animal models and human studies, the expression of ACE2 is increased with the chronic administration of RAS inhibitors, which suggests a possibility for the increased susceptibility to SARS-CoV-2 infection and a more severe course of illness with the use of RAS inhibitors [10][11][12][13][14][15][16][17]. Conversely, there are studies [18][19][20][21][22][23] that reported no association between increased expression of ACE2 receptor and the use of RAS inhibitors. Interestingly, a protective role of ACE2 has been suggested in the mitigation of coronavirus-induced lung injury [24,25].…”

Section: Introductionmentioning

confidence: 99%

Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis

Hasan

Kow

Hadi

et al. 2020

Am J Cardiovasc Drugs

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Introduction The use of renin-angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), was alleged to cause a more severe course of novel coronavirus disease 2019 (COVID-19). Methods We systematically reviewed the published studies to assess the association of RAS inhibitors with mortality as well as disease severity in COVID-19 patients. A systematic literature search was performed to retrieve relevant original studies investigating mortality and severity (severe/critical disease) in COVID-19 patients with and without exposure to RAS inhibitors. Results A total of 59 original studies were included for qualitative synthesis. Twenty-four studies that reported adjusted effect sizes (24 studies reported mortality outcomes and 16 studies reported disease severity outcomes), conducted in RAS inhibitor-exposed and unexposed groups, were pooled in random-effects models to estimate overall risk. Quality assessment of studies revealed that most of the studies included were of fair quality. The use of an ACEI/ARB in COVID-19 patients was significantly associated with lower odds (odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.56-0.95; n = 18,749) or hazard (hazard ratio [HR] = 0.75, 95% CI 0.60-0.95; n = 26,598) of mortality compared with non-use of ACEI/ARB. However, the use of an ACEI/ARB was non-significantly associated with lower odds (OR = 0.91, 95% CI 0.75-1.10; n = 7446) or hazard (HR = 0.73, 95% CI 0.33-1.66; n = 6325) of developing severe/critical disease compared with non-use of an ACEI/ARB. Discussion Since there was no increased risk of harm, the use of RAS inhibitors for hypertension and other established clinical indications can be maintained in COVID-19 patients.

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“…In contrast, ACEIs had no effect on ACE2 protein levels in renal biopsies from patients with renal pathologies, including recipients of kidney transplant [86]. Other human studies have focussed on investigating plasma ACE2 activity or urinary ACE2 levels in patients who have received chronic treatment with ACEIs or ARBs but most have failed to show any significant changes [87][88][89][90]. In a study of Japanese patients with hypertension, urinary ACE2 levels were reported to be higher among patients who received long-term treatment with olmesartan but not with other ARBs (losartan, candesartan, valsartan, and telmisartan) or with enalapril, an ACEI, compared to untreated control patients [55].…”

Section: Ace2 Raising Drugs-what Is the Experimental Evidence For CLImentioning

confidence: 99%

Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety

Akhtar

Benter

Danjuma

et al. 2020

Journal of Drug Targeting

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The COVID-19 pandemic is caused by the severe acute-respiratory-syndrome-coronavirus-2 that uses ACE2 as its receptor. Drugs that raise serum/tissue ACE2 levels include ACE inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) that are commonly used in patients with hypertension, cardiovascular disease and/or diabetes. These comorbidities have adverse outcomes in COVID-19 patients that might result from pharmacotherapy. Increasing ACE2 could potentially increase the risk of infection, severity or mortality in COVID-19 or it might be protective as it forms angiotensin-(1-7) which exhibits anti-inflammatory/anti-oxidative effects and prevents diabetes-and/or hypertension-induced end-organ damage. Thus, there existed clinical uncertainty. Here, we review studies implicating 15 classes of drugs in increasing ACE2 levels in vivo and the available literature on the clinical safety of these drugs in COVID-19 patients. Further, in a re-analysis of clinical data from a meta-analysis of 9 studies, we show that ACEIs/ARBs usage was not associated with an increased risk of all-cause mortality. Literature suggests that ACEIs/ARBs usage generally appears to be clinically safe though their use in severe COVID-19 patients might increase the risk of acute renal injury. For definitive clarity, further clinical and mechanistic studies are needed in assessing the safety of all classes of ACE2 raising medications.

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Plasma ACE2 Activity Predicts Mortality in Aortic Stenosis and Is Associated With Severe Myocardial Fibrosis

Cited by 89 publications

References 33 publications

Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences

Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences

Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis

Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety

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