key: cord-0894025-ok62havd
authors: Groß, Sonja; Jahn, Christopher; Cushman, Sarah; Bär, Christian; Thum, Thomas
title: SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: From basic science to clinical implications
date: 2020-04-30
journal: J Mol Cell Cardiol
DOI: 10.1016/j.yjmcc.2020.04.031
sha: c4a830d87a06bbb09c0ba54fea40db2ca7420e7b
doc_id: 894025
cord_uid: ok62havd

Abstract The current COVID-19 pandemic started several months ago and is still exponentially growing in most parts of the world – this is the most recent and alarming update. COVID-19 requires the collaboration of nearly 200 countries to curb the spread of SARS-CoV-2 while gaining time to explore and improve treatment options especially for cardiovascular disease (CVD) and immunocompromised patients, who appear to be at high-risk to die from cardiopulmonary failure. Currently unanswered questions are why elderly people, particularly those with pre-existing comorbidities seem to exhibit higher mortality rates after SARS-CoV-2 infection and whether intensive care becomes indispensable for these patients to prevent multi-organ failure and sudden death. To face these challenges, we here summarize the molecular insights into viral infection mechanisms and implications for cardiovascular disease. Since the infection starts in the upper respiratory system, first flu-like symptoms develop that spread throughout the body. The wide range of affected organs is presumably based on the common expression of the major SARS-CoV-2 entry-receptor angiotensin-converting enzyme 2 (ACE2). Physiologically, ACE2 degrades angiotensin II, the master regulator of the renin-angiotensin-aldosterone system (RAAS), thereby converting it into vasodilatory molecules, which have well-documented cardio-protective effects. Thus, RAAS inhibitors, which may increase the expression levels of ACE2, are commonly used for the treatment of hypertension and CVD. This, and the fact that SARS-CoV-2 hijacks ACE2 for cell-entry, have spurred controversial discussions on the role of ACE2 in COVID-19 patients. In this review, we highlight the state-of-the-art knowledge on SARS-CoV-2-dependent mechanisms and the potential interaction with ACE2 expression and cell surface localization. We aim to provide a list of potential treatment options and a better understanding of why CVD is a high risk factor for COVID-19 susceptibility and further discuss the acute as well as long-term cardiac consequences.

Since the coronavirus disease (COVID- 19) is still an emerging pandemic with more than 2.1 million confirmed cases worldwide [1] , special focus is currently directed towards the understanding of why people are hospitalized, receive intensive care, and frequently die as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Mortality rates seem particularly high when patients suffer from distinct comorbidities. First studies were initiated mainly on Chinese cohorts, as China is the suspected point of origin of These studies indicate that patients subjected to intensive care units (ICU) frequently show hypertension, diabetes and/or cardiovascular diseases (CVD) [2, 3] . These patients demonstrate much higher mortality rates compared with patients that are free of these comorbidities [4] [5] [6] [7] . While higher mortality rates among CVD patients are also associated with other respiratory diseases (especially influenza virus-induced flu or previous SARS epidemics), the question was put forward, whether people treated for heart-related illness are more prone to SARS-CoV-2 viral infection, based on first epidemiological evidence, but particularly based on the presumed upregulation of the SARS-CoV-2 entry receptor. While this association is currently heavily discussed, and will be also be a subject of this review, latest epidemiological studies coming from Europe at least underpin the greater risk for a critical disease progression in this group of patients [8, 9] . Therefore, we here aim to outline the mechanisms influencing the cardiac system because of its central implications in the COVID-19 course. We further highlight currently investigated and upcoming therapy options for COVID-19 patients with cardiac disease conditions.

launched to determine the presence of anti-SARS-CoV-2 antibodies. Preliminary results from the Heinsberg-Study (named after a town that was the first COVID-19 hotspot in Germany) suggest that around 15% of 500 people chosen at random showed an antibody response [14] .

In symptomatic cases, flu-like symptoms range from fatigue, coughing and shortness of breath, to fever as well as gastrointestinal disorders. Less common symptoms are upper respiratory-related signs such as sneezing and a sore throat [7, 15, 16] . When the symptoms first appear, a relatively rapid spread of the virus towards the lungs might cause severe pneumonia, which then frequently requires an oxygen supply or mechanical ventilation [17] .

The progression of a COVID-19 infection towards this critical phase should be urgently avoided if possible, because at this stage there is not only serious damage to the lungs but to the heart due to pre-existing CVDs making COVID-19 a life-threatening infection. In the past two months, unjustified attempts were made to place the number of cases and estimated mortality rates of COVID-19 into perspective by comparing it to influenza [18, 19] . The major differences revoking such comparison are: firstly, a suspected high prevalence for asymptomatic disease spreaders; secondly, a prolonged incubation period compared to common seasonal influenza viruses; and thirdly, an extended disease progression, reflected by an average ICU stay of 15 days with a minimum of 10 days in Italy [13, 20] . Altogether, this establishes the basis for the COVID-19 outbreak and the fast spread of this pandemic.

A critical disease progression of SARS-CoV-2 infected patients is supposed to be initiated by the inability of the immune system to prevent the spreading of viruses to the lungs. This can rapidly lead to pneumonia evidenced by typical visible features in computed tomographic analyses [21, 22] . Delayed clinical treatment of those critical patients causes not only an undersupply of oxygen in the lungs, but additionally causes cardiac ischemia [23, 24] . Lung and heart damage is further promoted by an over-reaction of the immune system associated with a pronounced cytokine storm [5, 25] . Clinical features include extremely elevated levels of interleukin 6 (IL-6) and ferritin [3, 25, 26] , which are also well-known markers for sepsis.

The latest guidelines therefore recommend first measuring basic blood parameters in order to assess the state of infection and adjust medication accordingly, even if SARS-CoV-2 infection mode of action is related to a direct infection of cardiomyocytes (CMCs) by SARS-CoV-2 during the critical phase that leads to the development of myocarditis [29, 30] . To date, there is no indisputable evidence for myocarditis in deceased COVID-19 patients, which requires confirmation through a biopsy or an autopsy. Therefore, to address whether inflammation of the cardiac muscle contributes to the observed heart failure (HF), additional investigations are still necessary. A second assumption that is currently pursued, is that an over-activated immune system is predominantly contributing to SARS-CoV-2-induced heart damage. Subsequent to cardiac ischemia as a consequence of pneumonia and the associated acute respiratory distress syndrome (ARDS) [7, 31, 32] , CMC damage and death induces a variety of pro-inflammatory mechanisms, which in turn spiral out of control and further promote loss of CMCs [33] . Hence, a secondary induced cardiac injury seems to be quite likely, although specific evidence is still lacking owing to the currently tense clinical situation. However, these ideas are strongly endorsed by previous studies investigating the SARS-CoV outbreak in 2002 or later on the MERS-CoV-associated epidemic in 2012 [34, 35] , where acute myocarditis and heart failure have also been reported [36] . Similar long-term implications on the cardiovascular system as observed in a study for SARS-CoV can only be suggested [37] .

Considering the multiple effects on the heart, it can already be assumed that previous CVDs would lead to an unfavorable progression of COVID-19. Interestingly, the drastically increased mortality rate in patients with pre-existing or new cardiac injuries is associated with elevated serum levels of troponin T (TnT), a biomarker for cardiac damage. Indeed, the study of Guo et al. points out that CVD patients without significantly raised TnT serum levels only represent a slightly increased mortality compared to patients without CVD [23, 38] . Therefore, in the case of expected cardiac damage due to distinct comorbidities or severe disease progression, TnT levels should always be strictly monitored, but also critically interpreted since some medications and interventions themselves can cause an upregulation of TnT [39] [40] [41] . Together with other biomarkers such as the inflammatory cytokines IL-6 and Ferritin as well as D-dimers [26, 33, 42, 43] , TnT may be used to predict the outcome of the SARS-CoV-2 infection and aid in clinical decision making for the best possible treatment options, which ultimately help to reduce COVID-19 mortality [44, 45] .

cohorts, different prevalence of these diseases and inadequate testing of potentially SARS-CoV-2 infected patients. In general, various organ systems are believed to participate in COVID-19 due to the widespread expression of the primary SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2) [47] . ACE2 is an important regulator of the reninangiotensin-aldosterone system (RAAS), which systemically influences the vasculature and blood pressure via distinct hormones. This endocrine system additionally regulates the fluid and electrolyte balance in the kidneys. Briefly, the peptide prorenin is cleaved in the kidneys and activated renin is then released into the blood stream where it in turn activates angiotensinogen, which is converted into angiotensin I and finally into angiotensin II (AngII).

Specific angiotensin-converting enzymes (ACEs), mainly expressed on renal and pulmonary epithelium, facilitate this activation cascade. The vasoconstrictive angiotensin II is the major driver of the blood pressure-increasing response, when the juxtaglomerular apparatus in the kidneys detects critically low blood pressure [48] . Thus, dysregulation of this fine-tuned system results in hypertension and heart failure as well as chronic kidney disease [49, 50] .

Specific ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) are the first choice as an antihypertensive drug [49, 51] . However, ACE2 is a well-characterized negative regulator of the RAAS system as it converts AngII into the vasodilatory fragment Ang 1-7, which simultaneously decreases the AngII concentration to further facilitate the antihypertensive effect [52, 53] . ACE2 is located on the cell surface e.g. in the renal, cardiac, pulmonary and gastrointestinal systems [54] , providing an explanation for the observed symptoms of COVID-19. In the following part of this review, we will highlight potentially connective mechanisms of SARS-CoV-2 and the dysregulated presentation of ACE2 with the described clinical features in the context of cardiac injury.

The central role of ACE2 in cardiac physiology and pathology, as well as the fact that it acts as the major entry receptor for both SARS-CoV and SARS-CoV-2 suggests that it is a promising therapeutic target [47, 55] . Receptor binding is facilitated through the viral spike protein that is processed by the protease TMPRSS2 [47] . Then, the spike protein interacts with the extracellular domain of ACE2, which triggers clathrin-dependent endocytosis of the complex [47, 55, 56] . Interestingly, this interaction is remarkably enhanced in patients suffering from hypertension or coronary heart disease as well as in diabetic or other comorbid conditions [57] [58] [59] . While elevated plasmin or plasminogen levels have already been associated with patients suffering from these medical conditions, the impact of these increased J o u r n a l P r e -p r o o f Journal Pre-proof levels on viral infections was only very recently highlighted by Ji et al. [60] . The viral spike protein is cleaved at a furin site, which is not present in SARS-CoV, by the furin protease plasmin, thereby increasing the cellular uptake of viral particles and enhancing its pathogenicity [56, 60] . Furthermore, there is an association of elevated plasmin levels with the strong induction of D-dimer as a product of hyper-fibrinolysis, which is an additional critical parameter of severe COVID-19 progression [42, 43, 61] .

Once the virus enters the cell, the viral RNA is released and the host-cell's cellular programs are utilized for viral replication. In addition to producing infectious progeny, several mechanisms of the SARS-CoV-2 infection and replication influence ACE2 expression and presentation. Firstly, internalization of the receptor is accompanied by a reduced availability on the cell surface. Secondly, so far unknown viral mediators inhibit ACE2 and concurrently induce ADAM metallopeptidase domain 17 (ADAM-17) gene expression [53, 62] . The membrane-bound metalloprotease is involved in processing the tumor necrosis factor α (TNFα), but is also functioning as a "sheddase" by releasing anchored receptors and cytokines [63] . As a physiological regulator of the RAAS system, ADAM-17 mediates cleavage of ACE2, pointing towards its direct involvement in COVID-19 [53] . Thirdly, not only the release of TNFα [63] , but also processing of different important pro-inflammatory cytokines such as interleukin 4 (IL-4) and interferon γ (IFNγ) is accomplished [62, 64, 65] . The latter two act directly on ACE2 expression via autocrine pathways [65] , further promoting the downregulation of ACE2 on the cellular surface of infected cells, and might secondary imply an imbalance of T cell responses and over-reaction of the immune system by provoking a cytokine storm (Figure 1 ).

The consequences of SARS-CoV-2 infection alone are already an enormous stress for the body. Considering that many patients suffer from pre-existing illness and elderly people present a compromised immune system [2, 3, 66] , the severity and the potential life-threat of a SARS-CoV-2 infection becomes very clear. The treatment plan of CVD patients regularly includes inhibitors of the RAAS, namely ACE-I and ARBs. Recently, upregulation of ACE2 has been associated with RAAS inhibitor medication [67] [68] [69] . The point was recently raised that the susceptibility in those patients is even increased based on high viral loads that were detected in patients with poor outcomes [30, 70] . A broad spectrum of institutions and scientist have discussed this topic extensively as treatment guidelines were and are still required very urgently because of the rapidly growing number of cases. Summarizing the most important J o u r n a l P r e -p r o o f Journal Pre-proof aspects of this ongoing discussion, antihypertensive drugs should not be discontinued if there is no medical necessity, as uncontrolled blood pressure or clinical instability is a superior high-risk factor for severe complications [71] . So far, there is no evidence of increased susceptibility of hypertensive patients; on the contrary, studies in Chinese cohorts suggest an even lower estimated prevalence of COVID-19 in blood-pressure controlled subjects compared to the distribution of high blood pressure in the population in general [31, 46] . Indeed, a retrospective study of hospitalized COVID-19 patients with hypertension identified a lower risk of all-cause mortality in patients under ACE-I and ARB treatment [72] .

Moreover, a cardio-protective activity of ACE2 has been previously described in different animal models and clinical studies of heart diseases [73] [74] [75] , concluding that an even desirable effect might be achieved through this medication. Therefore, a clinical trial was initiated at the end of February aiming to re-raise ACE2 levels without risking increased infection rates. Here, soluble human recombinant ACE2 (rhACE2) infusions were planned in a COVID-19 patient cohort consisting of 24 participants [76] . The conceptual idea is that the non-membrane-bound receptor functions as a trap for viral particles by intercepting SARS-CoV-2, thereby preventing binding to cell surface-located ACE2 and the subsequent infection.

an open question to date. It is generally conceivable that every drug or clinical intervention leading to a decreased viral load might result in an improved outcome combined with reduced long-term complications. However, for non-declared reasons, the promising pilot study has been recently withdrawn as indicated at www.clinicaltrials.gov (NCT number: NCT04287686) [76] . Nevertheless, the pharmaceutical company APEIRON Biologics AG announced a large phase II clinical study a few days ago. They plan to treat 200 COVID-19 patients in Austria, Germany and Denmark with APN01, synonymous for rhACE2 [77] .

Importantly, preclinical models reinforce the potential benefit of this treatment. Monteil et al.

demonstrated that SARS-CoV-2 infection of engineered human organoids, more precisely blood vessel and kidney organoids, is significantly limited when soluble hrACE2 is applied.

In this approach, the group of Penninger specifically investigated the infection-limiting effects at early stages of COVID-19, thus substantiating the previous hypothesis [78] . Altogether, despite the current lack of evidence of efficacy in humans, first studies support the use of rhACE2 to decrease viral load [53, 78] . Additional cardio-protective effects of the treatment are also conceivable, although it is questionable whether non-membrane anchored plasma ACE2 can completely fulfil the protease function [63] . To sum up, rhACE2 appears to offer great potential to improve the outcome of COVID-19 patients and minimize adverse chronic J o u r n a l P r e -p r o o f Journal Pre-proof damages to the lung, heart and additional organ systems and therefore, the results of the first clinical trials are eagerly anticipated.

Recently, diverse therapeutic approaches have been considered and several clinical trials have already begun. There is an intriguing variety of proposed pharmacological interventions, which arose from intensive research, the collaboration of many working groups and scientific journals around the globe. There are many possible targets in addition to ACE2, thus combined therapies may be possible and probably even more potent. Here, we highlight some of these therapeutic strategies, which have a special focus on adjuvant therapies to prevent cardiac injury. As mentioned above, high plasmin/plasminogen levels are often abundant in distinct comorbidities, and can therefore serve as a predictive biomarker for risk assessment [60] . It has already been demonstrated in vitro that specific protease inhibitors impair viral entry and based on these results [42] , first protease inhibitors are administered in COVID-19 patients in China [79, 80] . In this context, the study of Hoffmann et al. revealed that the protease TMPRSS2 is critically involved in SARS-CoV-2 cell entry, so that specific inhibitors or antibodies might have a beneficial effect [47] . Antiviral activity has also been shown for Remdesivir, an inhibitor of the viral RNA polymerase, currently used in the clinics.

While compassionate use of this nucleotide analogue improved the outcome in 36 out of 53 COVID-19 patients, placebo-controlled and randomized trials are required to assess the therapeutic efficacy [81] . Indeed, such studies further testing Remdesivir but also several other therapeutic candidates are currently ongoing. Table 1 provides a comprehensive overview of potential COVID-19 therapeutics including their mode of action and their implication for the cardiovascular system.

When the world health organization (WHO) announced COVID-19 as an international emergency at the end of January and declared it a pandemic in March 2020 [82] , several efforts were already made to understand the diagnosis and prognosis of this respiratory syndrome. Noteworthy, there are regional differences in COVID-19 severity, which seem to reflect on socio-economic parameters and the readiness of the healthcare systems to cope with such a challenge. Whether COVID-19 has direct or indirect effects to the young or aged cardiovascular system is poorly understood so far because we are only at the beginning of monitoring the COVID-19. This includes specific biomarker discovery to predict patients at J o u r n a l P r e -p r o o f Journal Pre-proof very high risk as well as superior imaging tools to monitor cardiac remodeling and inflammation (e.g. MRI). Especially ACE2 abundancy is of high interest in context of SARS-CoV-2 and a potential impact on cardiac tissue; however, insufficient number of cases has been reported so far to draw reliable conclusion and rhACE2 is rather considered a therapeutic strategy to limit viral infection, which will be now investigated in phase-II clinical trials. In addition, clinical association studies in the early, mid and late phase of COVID-19 are urgently needed to discuss standard care, in particular for HF patients who seem to be at highest risk for a severe course of COVID-19. 

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The authors declare no conflict of interest in relation to this manuscript.

Mechanism Initial usage Cardiac implementationCamostat mesylate 1. Inhibitor of serine proteases, especially transmembrane protease serine subtype 2 (TMPRSS2), 2. Protease important for SARS-CoV2 S-protein cleavage for viral membrane fusion.Therapeutic against pancreatitis Inhibition of pancreatic fibrosis  Additional function: Inhibition of monocyte activation and reduced TNFα-production,  Reduction of detrimental proinflammatory mechanisms in the heart. Antiproteases (antiplasmin)1. Inhibition of endogenous proteases responsible for SARS-CoV2 S-protein cleavage into S1-and S2-subunit (TMPRSS2, Cathepsin B/L, plasmin) 2. Increased plasmin during SARS-CoV2 leads to increased fibrin degradation products (FDPs), hyperfibrinolysis and reduced platelet conc. Disturbed blood coagulation may lead to hemophilia or thrombosis,  anti-proteases directed against plasmin could reverse those effects  Plasmin additionally induces hypertension by activation of Na + -retention Inhibition of ACE-1 leads to: 1. less angiotensin II 2. increased levels of ACE-2 (controversial). 3. ACE-2 product angiotensin 1-7 has a vasodilatory effect  Increased ACE-2 level initially might result in a higher viral uptake  Withdrawal of ACE-inhibitors might be detrimental, since Ang II might be responsible for acute lung injury  ACEII possesses cardioprotective effect monoclonal neutralizing AB 1. SARS-CoV2 specific Abs isolated from convalescent patients 2. Cross-reactivity of mABs from SARS and MERS