Jinfeng CHEN, Zhongyi LEI, Chaofeng LIU, Hong FAN, Peng LEI, Xueping WU, Xiaoyong YU, Yanfen ZHOU, Jiejun HOU

1. Chinese Medical Science Master Research Institute, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 710003, China; 2. Shaanxi Provincial People’s Hospital, Xi’an 710068, China; 3. Shaanxi University of Chinese Medicine, Xianyang 712046, China

Abstract With the wide spread of COVID-19, some studies have confirmed that novel coronavirus enters the cell through the binding of spike protein and ACE2 protein, which has the risk of causing the virus to enter the cell to accelerate its transmission. ACEI and ARB are the key drugs for the treatment of hypertension and are widely used in clinic. They are good for ventricular and vascular remodeling in patients with hypertension, coronary heart disease and heart failure. ACEI and ARB drugs may increase the expression of ACE2 in lung tissue and increase the risk of aggravation of the disease. According to the advice of hypertension experts: for mild ordinary COVID-19 patients with hypertension, we can consider discontinuing ACEI and ARB drugs, while for severe COVID-19 patients with hypertension, ACEI and ARB drugs should be stopped immediately. During the discontinuation period, temporary replacement therapy with diuretics, dipine and vasodilatation hypotensive drugs can be considered.

Key words COVID-19, Hypertension, ACE2, ACEI, ARB

1 Introduction

At the end of 2019, pneumonia caused by novel coronavirus (COVID-19) appeared in Wuhan City, Hubei Province, and rapidly spread across China. Through the decision-making and deployment of the CPC Central Committee with General Secretary Xi Jinping as the core, and through the joint efforts of the personnel of national health and local health care system, the epidemic situation in China has been well controlled. As of 24:00 on March 5, according to reports from 31 provinces (autonomous regions, municipalities directly under the Central Government) and the Xinjiang Production and Construction Corps, there were 23 784 confirmed cases (including 5 737 severe cases), 53 726 cured cases, and 3 042 deaths. A total of 80 552 confirmed cases and 482 suspected cases were reported. A total of 670 854 close contacts were tracked and 29 896 were still under medical observation[1].

However, at present, the COVID-19 continues to spread around the world, and there are confirmed cases on all six continents except Antarctica. According to the latest news from the Dutch media BNO and the New York Times on March 6, the number of confirmed cases of COVID-19 in the world has reached 100 000. The latest figures for countries with severe outbreaks outside China are as follows: the cumulative number of confirmed cases in South Korea reached 6 593; the cumulative number of cases of COVID-19 in Iran rose to 4 747; the cumulative number of confirmed cases of COVID-19 in Italy increased to 3 858; the cumulative number of confirmed cases of COVID-19 in Japan increased to 1 098, with a total of 12 deaths; a total of 565 cases of COVID-19 have been diagnosed in Germany; the public health departments of various states in the United States reported a total of 232 cases of COVID-19 infection and 14 deaths[2].

TheNoticeonPrintingandDistributingtheDiagnosisandTreatmentProtocolforNovelCoronavirusPneumonia(TrialVersion7) jointly promulgated by the National Health Commission and the State Administration of Traditional Chinese Medicine has made some revisions[3], and added the content that COVID-19 treatment should strengthen circulatory support and it is necessary to closely monitor the changes of blood pressure, heart rate and urine volume. It is believed that people are generally susceptible to COVID-19, especially the elderly are more likely to be infected. Many of these confirmed cases suffer from basic diseases of hypertension. After the continuous study of the structure and infection mechanism of novel coronavirus (SARS-CoV-2) by experts, it was found that angiotensin converting enzyme 2 (ACE2) may be the binding site of the virus on the cell. It has the same infection pathway as severe acute respiratory syndrome virus (SARS-CoV)[4]. At the same time, ACE2 is an important part of renin-angiotensin system (RAS). People think about whether to continue to use angiotensin converting enzyme inhibitor (ACEI) or angiotensin 2 receptor antagonist (ARB) in patients with COVID-19 and hypertension[5].

2 The binding of spike protein of novel coronavirus and ACE2 protein causes the virus to enter the cell

ACE2 protein is a kind of transmembrane glycoprotein, which is expressed in lung, heart, kidney, testis, pancreas islet, gastrointestinal tract and other tissues, and is the most active on the surface of lung tissue. Through biological analysis, Xuetal.[7]found that novel coronavirus was similar to SARS virus and had spike protein on its protein. The spike protein is the crown-like spike on the coronavirus envelope. These spikes help the virus bind to transmembrane receptor proteins on the host cell membrane, thus helping the virus enter the host cell. Novel coronavirus enters the cell through the binding of spike protein and ACE2 protein. Therefore, some studies have suggested that spike protein can cause acute lung injury. SARS-CoV-2 virus generally enters the cell through a certain receptor to replicate, which causes cell damage[8]. SARS-CoV-2 uses spike protein to attach to host cells[9]. Some studies have confirmed that SARS-CoV-2 is very similar to SARS-CoV, and it has a sequence recognition rate of 79.5% with SARS-CoV[10]. The main difference between them lies in the difference between the three short insertions of the N-terminal domain and the 4/5 key residues of the receptor binding sequence. Perhaps because of this difference, the interaction between SARS-CoV-2 and ACE2 is higher than that between SARS-CoV and ACE2[11]. Comparing the difference between SARS-CoV and SARS-CoV-2 by cryo-electron microscopy, it was confirmed that the change of SARS-CoV-2 residues did not reduce the affinity between SARS-CoV-2 and ACE2 receptors, but greatly increased the affinity between SARS-CoV-2 and ACE2 receptors[12]. Therefore, it is suggested that SARS-CoV-2 may enter the cell through ACE2 like SARS-CoV[13]. Wan used human HeLa cells to study the infectivity of the isolated virus. This study showed that SARS-CoV-2 must enter the cell using the ACE2 receptor (but cannot enter the cell using the mouse ACE2 receptor), suggesting that ACE2 might be the receptor of SARS-CoV-2[14]. The spread of SARS-CoV-2 is very fast, which may be closely related to the interaction between ACE2 and SARS-CoV-2. According to the above research, it is inferred that ACE2 may be the key for SARS-CoV-2 to enter the cell. Its infectious ability may be related to ACE2, and the combination ability of the two may be better than that of SARS-CoV.

3 Renin angiotensin system (RAS) is an important link in the mechanism of hypertension

The RAS system is the most widespread neuroendocrine regulatory system in the body[15]. Abnormal activation of the RAS system can lead to cardiovascular and renal diseases. RAS system is an important endocrine system in human body, including the classic angiotensin converting enzyme (ACE)-angiotensin ii (Ang II)-angiotensin ii receptor type 1 (AT1R) axis. ACE is an angiotensin converting enzyme, which can convert angiotensin I (Ang I) into angiotensin ii (Ang II). Ang II is a bioactive substance in RAS with vasoconstriction[16]. Angiotensin converting enzyme (ACE) homologue-angiotensin converting enzyme 2 (ACE2), angiotensin 1-7[Ang (1-7)]and its receptor Mas constitute the ACE2-Ang (1-7)-Mas axis. ACE2 can directly degrade Ang II to Ang (1-7), and Ang (1-7) plays a role in vasodilation, anti-proliferation and anti-oxidative stress by acting on Mas receptor[17]. ACE can increase hypertension by converting angiotensin I into active angiotensin ii. The role of ACE2 is to convert angiotensin I into the form of vasodilator, thus antagonizing the effect of angiotensin on blood pressure. In the RAS system, ACE increases blood pressure while ACE2 lowers blood pressure. The expression of ACE2 is decreased in patients with hypertension, so the ability of ACE2 to lower blood pressure decreases.

4 ACE enhances inflammatory response and promotes lung injury

ACE2 is abundant in lung, kidney, heart, pancreas islet and other tissues. ACE2 is distributed in alveolar epithelial cells in the lung[22]. In lung injury, ACE promotes the production of Ang II, and the increase of Ang II will strengthen the inflammatory response, which makes the lung injury more serious[23-24]. ACE2 hydrolyzes Ang II to produce Ang 1-7, which has the effects of vasodilation, anti-inflammation, anticoagulation and anti-fibrosis[15]. It can improve the lung injury induced by Ang II, and it is suggested that Ang 1-7 is helpful to regulating the balance between ACE and ACE2. In the SARS study, ACE2 is a key negative regulator of the severity of pulmonary edema and acute lung failure. The binding of spike protein of SARS-CoV to ACE2 results in a decrease in the number of ACE2 and aggravates the severity of lung disease[25]. According to the latest report released in 2020, the study of[26]Kuba showed that the content of Ang II in COVID-19 patients infected in Shenzhen was significantly higher than that in normal people, and the content of Ang II was positively correlated with the degree of lung injury. After novel coronavirus infects the lungs, it will further reduce the quantity and function of ACE2 proteins in the lungs, and lead to acute lung failure. Patients with high blood pressure will have a decreased expression of ACE2 protein, and if infected by novel coronavirus, it may lead to more serious lung failure.

5 Effect of COVID-19 ACE2 on cardiovascular system

NoticeonPrintingandDistributingtheDiagnosisandTreatmentProtocolforNovelCoronavirusPneumonia(TrialVersion7) released recently has made some revisions[3], and the new content shows that the increase of troponin and myocardial enzymes, especially the increase of myocardial kinase (CK) and myocardial kinase isoenzyme (CKMB), can be seen in critically illed patients. In animal experiments, the expression of ACE2 in myocardium decreases after coronavirus infection. SARS virus RNA, is found in about 33% of the infected myocardium and the expression of ACE2 in the damaged myocardium is also decreased. ACEI/ARB drugs can increase the level of ACE2 in the lungs. ACE2 is highly expressed in the heart, which also provides the necessary receptor for the virus to invade the heart. ACE2 plays an important role in mediating cardiac coronavirus infection. The expression of ACE2 protein decreases significantly, which will lead to the increase of Ang II. Ang II regulates and participates in the growth of cardiomyocytes and affects intercellular communication, immunity and lipid peroxidation, as well as intercellular and intracellular signal transduction mechanisms of insulin resistance. It plays an important role in the pathophysiological mechanism of cardiovascular disease[18]. According to Huangetal.[19], Ang II leads to aortic vascular remodeling, accompanied by increased medium thickness and enhanced fibrosis, and eventually leads to cardiac hypertrophy and activation of clots associated with cardiac fibrosis and inflammation. Novel coronavirus can cause myocardial inflammation and injury related to down-regulation of myocardial ACE2 system. From previous studies on SARS, it has been found that the heart damage caused by SARS is also diverse. It affects the conduction system, endocardium, myocardium and epicardium, causing arrhythmia (atrioventricular block), decreased exercise tolerance, changes after myocarditis, endocardial lesions, left ventricular segmental dyskinesia, decreased left ventricular ejection fraction, left atrial enlargement, pericardial effusion,etc.[20-21]. Once the heart is harmed, most of the patients show severe symptoms.

6 The role of ACEI or ARB in lowering blood pressure through RAS system

ACEI and ARB drugs are the most commonly used drugs for the treatment of hypertension[27-28]. A number of studies have shown that ACEI or ARB drugs have a wide range of pharmacological effects in cardiovascular system, endocrine system, cerebrovascular system and blood system. ACEI drugs inhibit the activity of ACE, block the conversion of Ang I to Ang II, and reduce the level of Ang II in plasma, thus affecting the activity of RAS system[30]. ARB drugs can selectively block AT1 receptors, reduce the effect of Ang II on vasoconstriction, and then block the abnormally activated RAS system[31].

7 The relationship between ACEI or ARB drugs and ACE2[5]

At present, there are many studies on the regulation of ACE2 by ACEI and ARB drugs in the kidney and heart, but there are few studies on the lung. Whether the regulatory effect of ACEI or ARB drugs in kidney and heart is the same as that in lung remains to be further studied[5]. With regard to the study of ACEI or ARB drugs in lung ACE2, Lietal.[32]studied the relationship between captopril and endotoxin-induced lung injury in 2008. In this experiment, rats were pretreated with captopril for 30 min, and then treated with endotoxin to induce lung injury. The results showed that the level of ACE decreased and the level of ACE2 increased in the lungs. The other part of the experiment was the study of pulmonary endothelial cells in vitro, which showed that captopril could not only inhibit the secretion of inflammatory cytokines induced by endotoxin, but also regulate the expression of ACE and ACE2. It is inferred that ACEI drugs may increase the expression of ACE2 in lung tissue. The experiment of Lietal.[33]on the use of ARB drugs (olmesartan) in rats with chronic heart failure showed that olmesartan could reduce the level of serum Ang II and improve lung structural remodeling and pulmonary inflammation. Based on the above experiments, the experimenter inferred that the possible mechanism of the decrease of Ang II was that olmesartan degraded Ang II into Ang 1-7 by activating ACE2. As a result, the introduction of ARB drugs may increase the expression of ACE2.

8 Strategies or recommendations for the use of ACEI/ARB drugs in hypertensive patients infected with COVID-19

8.1NowthereisadebateaboutwhetherCOVID-19patientsshouldstopusingACEIorARBdrugsThe reasons for recommending discontinuation of ACEI or ARB drugs are as follows[5]: (i) ACEI or ARB drugs have an effect on ACE2, while ACE2 has a close relationship with lung injury and SARS-CoV-2 infection. Drugs such as ACEI or ARB can cause the increase of ACE2 and accelerate the invasion and rapid spread of SARS-CoV-2. (ii) According to the recommendations of hypertension medication guidelines, there are 6 types of antihypertensive drugs, and other antihypertensive drugs can be used instead of ACEI or ARB antihypertensive drugs. (iii) Liu Lishengetal.[34]gave medication advice to COVID-19 patients with hypertension on February 5, 2020. For mild ordinary COVID-19 patients with hypertension, we can consider discontinuing ACEI and ARB drugs, while for severe COVID-19 patients with hypertension, ACEI and ARB drugs should be stopped immediately. The reasons for recommending the continued use of ACEI or ARB drugs are as follows[5]: (i) ACEI or ARB drugs can promote the production of ACE2 and inhibit the production of Ang II. The increase of ACE2 and the decrease of Ang II help to reduce inflammatory factors and effectively protect lung tissue. (ii) In 2020, there are two latest reports, which take ACEI or ARB drugs as possible recommended drugs[35].

The above two views are reasonable, both believe that ACEI or ARB drugs will have a certain impact on COVID-19. The first view is that ACEI or ARB drugs induce and accelerate the entry of SARS-CoV-2 into cells, while the second view is to reduce inflammatory factors and avoid lung injury. The mechanism of the latter is complex, and there may be other ways of regulation. For example, in another animal study, Dengetal.[36]found that losartan could reduce the oxidized LDL receptor-1, and then reduce the inflammatory response of acute lung injury; although the mechanism was different, it did reduce lung injury. ACEI or ARB drugs may have a regulatory function on ACE2, and clinical studies are needed to verify the effectiveness and safety of the evidence that can be provided at present. According to current research, the risk of worsening the disease caused by the use of ACEI or ARB drugs coexists with the opportunity to improve the disease[5].

8.2PossiblemedicationstrategiesforhypertensioninCOVID-19patients[5]ACEI and ARB drugs are the key drugs for the treatment of hypertension, which are widely used in clinic, and are beneficial to the cardiac and vascular remodeling in patients with hypertension, coronary heart disease and heart failure. At present, there is a real risk of causing the virus to enter cells to accelerate its spread. In view of the co-existence of protecting lung tissue damage and promoting the aggravation of the disease by using ACEI or ARB drugs, we can follow the antihypertensive strategy recommended by hypertension expert Liu Lisheng: for mild ordinary COVID-19 patients with hypertension, we can consider discontinuing ACEI and ARB drugs, while for severe COVID-19 patients with hypertension, ACEI and ARB drugs should be stopped immediately; during the discontinuation period, temporary replacement therapy with diuretics, dipine and vasodilatation hypotensive drugs can be considered.