5.3 Rebalancing the RAAS axes by ACEI/ARB
In addition to the treatment with rhACE2, ACEI and ARB can inhibit the ACE/Ang Ⅱ/AT1R axis, leading to alleviation of inflammation, fibrosis, hypertension and so on. Since ACEI/ARB treatment up-regulates ACE2 expression, there are some controversy about the treatment of ACEI/ARBs in the infected patients coexist with cardiovascular disease. Fang(Fanget al. , 2020) and Diaz(Diaz, 2020) both hypothesized patients treated with ACEI/ARBs are at higher risk for SARS-CoV-2 infection due to up-regulation of ACE2 induced by ACEI/ARB, which would enhance viral binding and uptake, while there is no scientific evidence to demonstrate their prediction. On the contrary, someone insisted that ACEI/ARB may be beneficial in COVID-19 therapy, because up-regulation of the ACE2/Ang (1-7)/Mas axis contributes to relieve excessive inflammation(Baiet al. , 2016; Igase et al. , 2005; Ishiyama et al. , 2004). A retrospective study found that continuous administration of ACEI in hospital can reduce the mortality and intubation rate of patients with common viral pneumonia(Henry et al. , 2018). However, ACEI was divided into water soluble (captopril and lisinopril) and liposoluble (fosinopril). Some studies found that only lipophilic ACEI can reduce mortality of pneumonia patients. Long term use of lipophilic perindopril can significantly reduce the risk of pneumonia in patients with stroke and hypertension, but also significantly reduce the risk of pneumonia in elderly patients with hypertension(Mortensenet al. , 2008). It may be related to the drug characteristics that lipophilic ACEI can inhibit the RAAS activity more effectively, theoretically help to rebuild the balance of RAAS. Meanwhile, use of ARBs can delay the progression of ARDS(Raiden et al. , 2002), which may play a role in inhibiting ACE/Ang Ⅱ/AT1R axis activity and neutrophil activation. Recent findings also demonstrate that patients treated with ARB (Olmesartan) had increased secretion of urinary ACE2, likely from an upregulation mechanism, although unclear(Furuhashiet al. , 2015). A new study assessed the impact of ACEI and ARBs treatment on the severity and prognosis in 1128 COVID-19 patients with hypertension. In this multi-center study, they compared the mortality rate between ACEI/ARB group and non-ACEI/ARB group and subsequently found that patients treatment with ACEI/ARBs were associated with lower risk of all-cause mortality compared with ACE/ARB non-users among hospitalized COVID-19 patients(Zhang et al. , 2020). Meanwhile, the other smaller retrospective study noted that hypertensive COVID-19 patients receiving ACEI or ARB treatment had a lower rate of severe COVID-19 diseases, a trend toward reduced blood levels of Interleukin-6 plus reduced viral load and increased counts of cytotoxic T cells(Menget al. , 2020). Furthermore, one preliminary study examined 28 patients with severe COVID-19 and 18 patients with mild disease, all of whom also had hypertension, ARB use could reduce the higher risk of severe COVID-19 disease, morbidity and mortality, the result that contradicts the hypothesis that ACEI/ARB use is not benefit(Liu et al. , 2020).
Although there is no evidence to support the treatment with ACEI/ARBs could enhance the susceptibility of SARS-CoV-2, withdrawal of ACEI/ARB is not benefit for the patients with cardiovascular diseases. COVID-19 is particularly severe in patients with underlying cardiovascular diseases(Guan et al. , 2020), and in many of these patients, active myocardial injury(Arentz et al. , 2020) and cardiomyopathy develop during the course of illness. Among patients with chronic symptomatic heart failure, withdrawal of quinapril resulted in a progressive decline in clinical status(Wang et al. , 2020). Meanwhile, among asymptomatic patients with heart failure with recovered left ventricular ejection fraction, withdrawal of RAAS inhibitors resulted in rapid relapse of dilated cardiomyopathy(Halliday et al. , 2019). These evidences show among COVID-19 patients with cardiovascular diseases may higher risks after withdrawal of ACEI/ARB. Several cardiology associations released an official statement regarding the treatment of ACEI/ARB for COVID-19 patients. Actually, for those high-risk patients, individualized treatment decisions regarding the maintenance of RAAS inhibitors that should be guided by the hemondynamic status, and clinical stability.