Renin–angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study

Matsuzawa, Yasushi; Ogawa, Hisao; Kimura, Kazuo; Konishi, Masaaki; Kirigaya, Jin; Fukui, Kazuki; Tsukahara, Kengo; Shimizu, Hiroyuki; Iwabuchi, Kazuya; Yamada, Yuichi; Saka, Kenichiro; Takeuchi, Ichiro; Hirano, Toshio; Tamura, Kouichi

doi:10.1038/s41440-020-00535-8

Cited by 46 publications

(34 citation statements)

References 22 publications

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“…26 Table 2 summarizes the points of evaluation and management of CVDs related to COVID-19, which are described in this section. [26][27][28][29][30][31][32][33][34][35][36][37] Besides, the COVID-19 pandemic has brought great changes in people's lifestyles. The number of outpatients who directly visit a medical institution decreases due to restrictions on going outdoors.…”

Section: F I G U R Ementioning

confidence: 99%

“…In severe cases, evaluation of biomarkers related to myocardial injury and of lung lesions is necessary to stratify the risk of CVD complications and organ damage 26 . Table 2 summarizes the points of evaluation and management of CVDs related to COVID‐19, which are described in this section 26–37 . Besides, the COVID‐19 pandemic has brought great changes in people’s lifestyles.…”

Section: Covid‐19 Pandemic and Cvdmentioning

confidence: 99%

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Disaster hypertension and cardiovascular events in disaster and COVID‐19 pandemic

Narita

Hoshide

Tsoi

et al. 2021

J of Clinical Hypertension

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The incidence of large disasters has been increasing worldwide. This has led to a growing interest in disaster medicine. In this review, we report current evidence related to disasters and coronavirus disease-2019 (COVID-19) pandemic, such as cardiovascular diseases during disasters, management of disaster hypertension, and cardiovascular diseases associated with COVID-19. This review summarizes the time course and mechanisms of disaster-related diseases. It also discusses the use of information and communication technology (ICT) as a cardiovascular risk management strategy This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Section: F I G U R Ementioning

confidence: 99%

Section: Covid‐19 Pandemic and Cvdmentioning

confidence: 99%

Disaster hypertension and cardiovascular events in disaster and COVID‐19 pandemic

Narita

Hoshide

Tsoi

et al. 2021

J of Clinical Hypertension

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“…Moreover, the efficiency of SARS-CoV-2 infection depends on not only the amount of cell-surface ACE2 as the entrance receptor but also many other important factors including viral exposure load, binding affinity of ACE2 for the spike protein of SARS-CoV-2, internalization kinetics of the virus-ACE2 complex, and expression and activity of host cell proteases, such as transmembrane protease serine 2, that mediate spike-protein priming and facilitate cell entry following ACE2 binding [4,107]. Indeed, an increasing number of large-scale cohort studies from China, Europe, the United States, and Japan have provided evidence that the administration of ARBs and ACEIs does not increase either susceptibility to SARS-CoV-2 infection or the risk of aggravation or mortality from COVID-19 among patients with hypertension or CVD [108][109][110][111][112]. Recently, a multicenter, randomized clinical trial showed that among patients who were hospitalized with mild-to-moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no difference in the mean number of days alive and out of hospital for those assigned to discontinuing vs. continuing these medications [113].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies

Kai

Niiyama

et al. 2021

Hypertens Res

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Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.

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“…However, recent observational studies indicate that the use of RASi is not associated with an increased risk of COVID-19 in patients with hypertension. [28][29][30][31] Therefore, it is desirable to find a theoretical basis to explain why the use of RASi might not increase the risk of COVID-19 despite its potential influence on ACE2. In our review, we raised several issues that need to be addressed in order to understand the actual impact of RASi on ACE2 in relation to SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

“…Theoretically, increased tissue ACE2 could increase the chances of virus invasion, resulting in the initiation of infection or local inflammation of each organ. However, recent observational studies indicate that the use of RASi is not associated with an increased risk of COVID‐19 in patients with hypertension 28‐31 . Therefore, it is desirable to find a theoretical basis to explain why the use of RASi might not increase the risk of COVID‐19 despite its potential influence on ACE2.…”

Section: Introductionmentioning

confidence: 99%

A pressor dose of angiotensin II has no influence on the angiotensin‐converting enzyme 2 and other molecules associated with SARS‐CoV‐2 infection in mice

et al. 2021

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In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cellsurface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.

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Renin–angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study

Cited by 46 publications

References 22 publications

Disaster hypertension and cardiovascular events in disaster and COVID‐19 pandemic

Disaster hypertension and cardiovascular events in disaster and COVID‐19 pandemic

Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies

A pressor dose of angiotensin II has no influence on the angiotensin‐converting enzyme 2 and other molecules associated with SARS‐CoV‐2 infection in mice

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