ACE2 enhance viral infection or viral infection aggravate the underlying diseases.

ACE2 plays a critical role in SARS-CoV-2 infection to cause COVID-19 and SARS-CoV-2 spike protein binds to ACE2 and probably functionally inhibits ACE2 to aggravate the underlying diseases of COVID-19. The important factors that affect the severity and fatality of COVID-19 include patients' underlying diseases and ages. Therefore, particular care to the patients with underlying diseases is needed during the treatment of COVID-19 patients.

Renin-Angiotensin-Aldosterone Axis Inhibition Improves Outcome of Diabetic Patients with Chronic Hypertension and COVID-19: An Iranian Perspective.

Background: Safe use of drugs such as angiotensin-converting enzyme 2 (ACE2) inhibitors and angiotensin receptor blockers (ARBs) in COVID diabetic patients needs comprehensive studies. This study addressed this issue from the Iranian perspective. Materials and Methods: Admitted COVID-19 patients were divided into four groups in this historical cohort study. Group 1 included 740 non-diabetic, non-hypertensive patients. Group 2 included 132 non-hypertensive diabetic patients. Group 3 included 154 non-diabetic hypertensive patients. Group 4 included 183 diabetic patients who were under ACE inhibitors or ARBs. Death, intensive care unit (ICU) admission, and length of hospitalization were compared between the groups. Results: After considering associated factors such as age, gender, dyslipidemia, cardiovascular diseases, rheumatoid arthritis (RA), chronic kidney disease (CKD), history of surgery, and corticosteroid use, diabetic patients (group 2) were associated with increased mortality (CI 95%, OR 1.93 [1.11-3.33]). Presence of diabetes (group 2) and hypertension were associated with an increased need for ICU admission (CI 95%, OR 1.69 [1.04-2.76]; CI 95%, OR 1.71 [1.08-2.71], respectively). Group 4 patients although having a similar rate of ICU admission with group 2 and 3 patients, had significantly better ICU survival. Conclusions: The current study suggests that ACE inhibitors and ARBs are associated with decreased mortality, ICU admission, and better ICU survival in the diabetic subgroup of hypertensive patients.

Assessment Of Manifestations And Functional Status Of Post-COVID-19 Patients

Introduction: The subjects who recovered from COVID-19 should undergo long-term monitoring for evaluation and treatment of symptoms and conditions that might be precipitated with the new coronavirus infection. About 90% of the recovered participants had post-COVID-19 manifestations, which included various symptoms and illnesses ranging from mild to severe. Aim(s): This study analyses post COVID-19 manifestations severity and impact on recovered patients based on hospitalization. Material(s) and Method(s): The sample size was calculated using RAO software to be 514 samples. COVID-19 survivors (RT-PCR positive result) were included in the study. COVID-19 survivors include the patient under phase 1 category (2-5 weeks), 1st section: socio demographic factors like name, age, gender. 2nd section: to observe the clinical manifestations, questions were developed based on previous studies validated. To study the functional status post covid-19 functional status scale has be used. Result(s): In the study, most people shows that the post-COVID-19 symptoms persists after COVID-19 were found to be higher. Even though hospitalized patients shows more recurrance of the symptoms than the non hospitalized patients. Gastrointestinal symptoms shows more recurrance than other symptoms in hospitalized patients. Conclusion(s): The study result provided an insight to the complications of COVID-19 recovery when left unchecked and unattended. In this study higher count of hospitalized patients reporting post COVID-19 manifestations with more severity than non-hospitalized patients. Copyright © 2022, Anka Publishers. All rights reserved.

Covid-19 and adolescent acute kidney injury: Renal recovery with combined enalapril and estrogen therapy.

Covid-19 in adolescence with multisystem inflammatory injury (MIS-C) is a newly described condition sharing key features with Kawasaki disease and toxic shock syndrome. A May 2020 United Nations WHO brief covering findings from North America and Europe drew notice to this acute post-viral illness characterized by severe, diffuse hyperinflammation leading to multiorgan failure. While females diagnosed with Covid-19 generally have more favorable outcomes than males, this protection is negated by a low estrogen state. This case reports on acute kidney injury/MIS-C with amenorrhea from ovarian insufficiency in childhood, itself an uncommon presentation of idiopathic hypogonadism. Three exon variants were previously identified in a healthy, phenotypically normal 46,XX adolescent who subsequently underwent whole genome sequencing (WGS). She had only two spontaneous menses with a provisional diagnosis of premature ovarian insufficiency made by age 15. Against this background, Covid-19 infection necessitated hospital admission where progressively reduced renal function was a prime component of MIS-C. Combined angiotensin-converting enzyme inhibitor plus transdermal estrogen replacement therapy resulted in normalized estimated glomerular filtration rate (eGFR) from baseline 43 to 68 ml/min/1.73 m2, post-treatment. Serum cystatin-C also improved during this interval from 1.69 to 1.19 mg/L. Among 7 Covid-19 high risk intron variants identified was rs3131294 (6p21), near NOTCH4. Another finding at rs8068318 (17q23) was associated with creatine level and eGFR. This is the first work to explore Covid-19 and associated kidney injury as a component of MIS-C at the intersection of rare multigene variants and functional ovarian loss. The context of transition from adolescence to adulthood is also considered, where successful recovery of renal function was achieved with combined enalapril and supplemental estrogen.

High Angiotensin-Converting Enzyme and Low Carboxypeptidase N Serum Activity Correlate with Disease Severity in COVID-19 Patients.

(1) Background: Angiotensin-converting enzyme 2 (ACE2) is a functional receptor of SARS-CoV-2 and counter-balances ACE in the renin-angiotensin system (RAS). An imbalance of the RAS could be associated with severe COVID-19 progression. (2) Methods: Activities of serum proteases angiotensin-converting enzyme (ACE) and carboxypeptidase N (CPN) for 45 hospitalized and 26 convalescent COVID-19 patients were investigated vs. healthy controls using labeled bradykinin (DBK) degradation with and without inhibition by captopril as a read-out. Data were correlated to clinical parameters. (3) Results: DBK degradation and CPN activity were significantly reduced gender-independently in COVID-19 and returned to normal during convalescence. ACE activity was over-active in severe disease progression; product DBK1-5 was significantly increased in critically ill patients and strongly correlated with clinical heart and liver parameters. ACE inhibitors seemed to be protective, as DBK1-5 levels were normal in moderately ill patients in contrast to critically ill patients. (4) Conclusions: CPN and ACE serum activity correlated with disease severity. The RAS is affected in COVID-19, and ACE could be a therapeutic target. Further proof from dedicated studies is needed.

COVID-19: A New Horizon in Congenital Heart Diseases.

Objective: Previous studies have demonstrated that both children and adult patients with a history of congenital heart disease (CHD) are at high risk for coronavirus disease 2019 (COVID-19) infection. This study investigates the status of COVID-19 infection among children undergoing surgical repair within the past 2 years. Methods: All alive patients operated on in a tertiary referral center between March 2018 and March 2020 were recruited in the present study. Detailed demographics, past medical and surgical history, and physical examination were reviewed for each patient. During the COVID-19 pandemic, data regarding the patient's status were collected by telephone survey from April 15 to April 30, 2020. Results: A total number of 210 patients are analyzed in this study. Participants' median age was 21.59 months [interquartile range (IQR) = 12-54.67], and 125 (59.5%) were female. The median interval between surgery and COVID-19 assessment was 305 days (IQR = 215-400). In addition, 67 (32%) patients used angiotensin receptor blocker (ARB)/angiotensin-converting enzyme (ACE) inhibitor (spironolactone and/or captopril). Sixteen patients (7.6%) were symptomatic and had positive chest CT results and/or RT-PCR compared to the previously reported prevalence of COVID-19 among the pediatric population (2.4% of children with <18 years of age); the prevalence of COVID-19 among the patients operated on due to CHD in the present study was significantly higher (p = 0.00012). Two patients were admitted to the intensive care unit (ICU); one patient was discharged 2 weeks later with acceptable status, and one patient died 2 days after ICU admission due to cardiac and respiratory arrest and myocarditis. The complexity of the underlying cardiac disorders was not different between patients with low risk (p = 0.522), suspicious patients (p = 0.920), and patients positive for COVID-19 (p = 0.234). The ARB/ACE inhibitor consumption was not associated with the COVID-19 infection [p = 0.527, crude odds ratio (OR) = 1.407, 95% CI = 0.489-4.052]. Conclusion: Children with a history of previous CHD surgery are more susceptible to infections, especially those infections with pulmonary involvements, as the lung involvement could cause worsening of the patient's condition by aggravating pulmonary hypertension. The results of the current study indicate that these patients are more prone to COVID-19 infection compared to the healthy children population.

Renin Angiotensin Aldosterone System Antagonism in 2019 Novel Coronavirus Acute Lung Injury.

It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019-associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.

Therapeutic targets of natural products for the management of cardiovascular symptoms of coronavirus disease 2019.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first occurred in China in December 2019 and subsequently spread all over the world with cardiovascular, renal, and pulmonary symptoms. Therefore, recognizing and treating the cardiovascular sign and symptoms that caused by coronavirus disease 2019 (COVID-19) can be effective in reducing patient mortality. To control the COVID-19-related cardiovascular symptoms, natural products are considered one of the promising choices as complementary medicine. Scientists are struggling to discover new antiviral agents specific to this virus. In this review, the natural products for management of cardiovascular symptoms of COVID-19 are categorized into three groups: (a) natural products with an impact on angiotensin II type 1 receptor; (b) natural products that inhibit angiotensin-converting enzyme activity; and (c) natural products that mimic adenosine activity. All these natural products should undergo clinical investigations to test their efficacy, safety, and toxicity in the treatment of cardiovascular symptoms of COVID-19. This article summarizes agents with potential efficacy against COVID-19-related cardiovascular symptoms.

Rooibos, a supportive role to play during the COVID-19 pandemic?

This article presents the potential health benefits of Rooibos to be considered a support during the COVID-19 pandemic. The recent pandemic of COVID-19 has led to severe morbidity and mortality. The highly infectious SARS-CoV-2 is known to prime a cytokine storm in patients and progression to acute lung injury/acute respiratory distress syndrome. Based on clinical features, the pathology of acute respiratory disorder induced by SARS-CoV-2 suggests that excessive inflammation, oxidative stress, and dysregulation of the renin angiotensin system are likely contributors to the COVID-19 disease. Rooibos, a well-known herbal tea, consumed for centuries, has displayed potent anti-inflammatory, antioxidant, redox modulating, anti-diabetic, anti-cancer, cardiometabolic support and organoprotective potential. This article describes how Rooibos can potentially play a supportive role by modulating the risk of some of the comorbidities associated with COVID-19 in order to promote general health during infections.

Characterization of ACE Inhibitors and AT1R Antagonists with Regard to Their Effect on ACE2 Expression and Infection with SARS-CoV-2 Using a Caco-2 Cell Model.

Blood-pressure-lowering drugs are proposed to foster SARS-CoV-2 infection by pharmacological upregulation of angiotensin-converting enzyme 2 (ACE2), the binding partner of the virus spike (S) protein, located on the surface of the host cells. Conversely, it is postulated that angiotensin-renin system antagonists may prevent lung damage caused by SARS-CoV-2 infection, by reducing angiotensin II levels, which can induce permeability of lung endothelial barrier via its interaction with the AT1 receptor (AT1R). METHODS: We have investigated the influence of the ACE inhibitors (lisinopril, captopril) and the AT1 antagonists (telmisartan, olmesartan) on the level of ACE2 mRNA and protein expression as well as their influence on the cytopathic effect of SARS-CoV-2 and on the cell barrier integrity in a Caco-2 cell model. RESULTS: The drugs revealed no effect on ACE2 mRNA and protein expression. ACE inhibitors and AT1R antagonist olmesartan did not influence the infection rate of SARS-CoV-2 and were unable to prevent the SARS-CoV-2-induced cell barrier disturbance. A concentration of 25 µg/mL telmisartan significantly reduced the virus replication rate. CONCLUSION: ACE inhibitors and AT1R antagonist showed neither beneficial nor detrimental effects on SARS-CoV-2-infection and cell barrier integrity in vitro at pharmacologically relevant concentrations.

Impact of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on the Inflammatory Response and Viral Clearance in COVID-19 Patients.

Objectives: To evaluate the impact of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on the inflammatory response and viral clearance in coronavirus disease 2019 (COVID-19) patients. Methods: We included 229 patients with confirmed COVID-19 in a multicenter, retrospective cohort study. Propensity score matching at a ratio of 1:3 was introduced to eliminate potential confounders. Patients were assigned to the ACEI/ARB group (n = 38) or control group (n = 114) according to whether they were current users of medication. Results: Compared to the control group, patients in the ACEI/ARB group had lower levels of plasma IL-1ß [(6.20 ± 0.38) vs. (9.30 ± 0.31) pg/ml, P = 0.020], IL-6 [(31.86 ± 4.07) vs. (48.47 ± 3.11) pg/ml, P = 0.041], IL-8 [(34.66 ± 1.90) vs. (47.93 ± 1.21) pg/ml, P = 0.027], and TNF-α [(6.11 ± 0.88) vs. (12.73 ± 0.26) pg/ml, P < 0.01]. Current users of ACEIs/ARBs seemed to have a higher rate of vasoconstrictive agents (20 vs. 6%, P < 0.01) than the control group. Decreased lymphocyte counts [(0.76 ± 0.31) vs. (1.01 ± 0.45)*109/L, P = 0.027] and elevated plasma levels of IL-10 [(9.91 ± 0.42) vs. (5.26 ± 0.21) pg/ml, P = 0.012] were also important discoveries in the ACEI/ARB group. Patients in the ACEI/ARB group had a prolonged duration of viral shedding [(24 ± 5) vs. (18 ± 5) days, P = 0.034] and increased length of hospitalization [(24 ± 11) vs. (15 ± 7) days, P < 0.01]. These trends were similar in patients with hypertension. Conclusions: Our findings did not provide evidence for a significant association between ACEI/ARB treatment and COVID-19 mortality. ACEIs/ARBs might decrease proinflammatory cytokines, but antiviral treatment should be enforced, and hemodynamics should be monitored closely. Since the limited influence on the ACEI/ARB treatment, they should not be withdrawn if there was no formal contraindication.

Cardiovascular ACE2 receptor expression in patients undergoing heart transplantation.

AIMS: Membrane-bound angiotensin-converting enzyme (ACE)2 is the main cellular access point for SARS-CoV-2, but its expression and the effect of ACE inhibition have not been assessed quantitatively in patients with heart failure. The aim of this study was to characterize membrane-bound ACE2 expression in the myocardium and myocardial vasculature in patients undergoing heart transplantation and to assess the effect of pharmacological ACE inhibition. METHODS AND RESULTS: Left ventricular (LV) tissue was obtained from 36 explanted human hearts from patients undergoing heart transplantation. Immunohistochemical staining with antibodies directed against ACE2 co-registered with cardiac troponin T (cTnT) and α-smooth muscle cell actin (SMA) was performed across the entire cohort. ACE2 receptor expression was quantitatively assessed throughout the myocardium and vasculature. ACE2 was consistently expressed throughout the LV myocardium (28.3% ± 22.2% of cardiomyocytes). ACE2 expression was also detected in small calibre blood vessels (range, 2-9 µm), albeit at quantitatively much lower levels (5% ± 9% of blood vessels). There was no significant difference in ACE2 expression between patients receiving ACE inhibitors prior to transplantation and ACE inhibitor-negative controls (P > 0.05). ACE2 expression did not differ significantly between the different diagnostic groups as the underlying reason for heart transplantation (ANOVA > 0.05). N-terminal pro-brain natriuretic peptide (NT-proBNP) (R2  = 0.37, P = 0.0006) and pulmonary capillary wedge pressure (PCWP) (R2  = 0.13, P = 0.043) assessed by right heart catheterization were significantly correlated with greater ACE2 expression in cardiomyocytes. CONCLUSIONS: These data provide a comprehensive characterization of membrane-bound cardiac ACE2 expression in patients with heart failure with no demonstrable effect exerted by ACE inhibitors.

ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV.

Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin-angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer's dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure-function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect-host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.

High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation.

PURPOSE: We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients. METHODS: The literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions. RESULTS/CONCLUSION: Severe broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.

Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardiovascular disease.

AIMS: Coronavirus disease 2019 (COVID-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic. METHODS AND RESULTS: We have measured ACE2 mRNA expression using real-time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression. CONCLUSION: Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression.

Management of Renin-Angiotensin-Aldosterone System blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials. TRIAL DESIGN: This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy. PARTICIPANTS: Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis. INTERVENTION AND COMPARATOR: All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7. MAIN OUTCOMES: PRIMARY ENDPOINT: In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay > 4 days, development of acute kidney injury ( > 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to > 30% in 48 hours and lymphocyte count drop> 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts. RANDOMIZATION: Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm. BLINDING: This is an open label study with no blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations. TRIAL STATUS: Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1st 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1st 2021. TRIAL REGISTRATION: Trial registration: ClincalTrials.gov : NCT04508985 , date of registration: August 11th , 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Renin-angiotensin system inhibition and risk of infection and mortality in COVID-19: a systematic review and meta-analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, enters human cells by binding of its viral protein to the aminopeptidase angiotensin-converting enzyme 2 (ACE2). This has led to speculation whether treatment with renin-angiotensin system (RAS) inhibitors was associated with an increased likelihood of a positive test for COVID-19 and risk of mortality. AIMS: We performed a systematic review and meta-analysis to investigate whether RAS inhibitors increased the likelihood of a positive test or death/severe illness in patients with COVID-19. METHODS: A systematic search of MEDLINE, PubMed and EMBASE was conducted for studies stratified by the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Pooled analysis was performed using a random-effects model. RESULTS: Seven trials of 73 122 patients were included. Overall, 16 624 (22.7%) patients had a positive COVID-19 test and 7892 (10.8%) were on a RAS inhibitor. RAS inhibitors were not associated with higher likelihood of a positive COVID-19 test result (odds ratio (OR) 0.97 (95% CI 0.97-1.05, P = 0.48) with low heterogeneity. This was comparable when stratifying by use of each medication class. The use of RAS inhibitors was also not associated with mortality or severe illness (OR 0.89, 95% CI 0.73-1.07, P = 0.21) with moderate heterogeneity. CONCLUSION: Use of ACEI or ARB was not associated with a heightened susceptibility for a positive diagnosis of COVID-19. Furthermore, they were not associated with increased illness severity or mortality due to COVID-19. Randomised controlled trials are needed to address definitively the potential benefits or harms of RAS inhibitors in patients with COVID-19.

Targeting the renin-angiotensin signaling pathway in COVID-19: Unanswered questions, opportunities, and challenges.

The role of the renin-angiotensin signaling (RAS) pathway in COVID-19 has received much attention. A central mechanism for COVID-19 pathophysiology has been proposed: imbalance of angiotensin converting enzymes (ACE)1 and ACE2 (ACE2 being the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] virus "receptor") that results in tissue injury from angiotensin II (Ang II)-mediated signaling. This mechanism provides a rationale for multiple therapeutic approaches. In parallel, clinical data from retrospective analysis of COVID-19 cohorts has revealed that ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be beneficial in COVID-19. These findings have led to the initiation of clinical trials using approved drugs that target the generation (ACEIs) and actions (ARBs) of Ang II. However, treatment of COVID-19 with ACEIs/ARBs poses several challenges. These include choosing appropriate inclusion and exclusion criteria, dose optimization, risk of adverse effects and drug interactions, and verification of target engagement. Other approaches related to the RAS pathway might be considered, for example, inhalational administration of ACEIs/ARBs (to deliver drugs directly to the lungs) and use of compounds with other actions (e.g., activation of ACE2, agonism of MAS1 receptors, ß-arrestin-based Angiotensin receptor agonists, and administration of soluble ACE2 or ACE2 peptides). Studies with animal models could test such approaches and assess therapeutic benefit. This Perspective highlights questions whose answers could advance RAS-targeting agents as mechanism-driven ways to blunt tissue injury, morbidity, and mortality of COVID-19.

Using genetics to understand the role of antihypertensive drugs modulating angiotensin-converting enzyme in immune function and inflammation.

AIM: Angiotensin-converting enzyme 2 (ACE 2) is the binding domain for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARSCoV-2. Some antihypertensive drugs affect ACE2 expression or activity (ACE inhibitors and angiotensin II receptor blockers [ARBs]), suggesting use of other hypertensives might be preferable, such as calcium channel blockers (CCBs). Given the limited evidence, the International Society of Hypertension does not support such a policy. METHODS: We used a Mendelian randomization study to obtain unconfounded associations of antihypertensives, instrumented by published genetic variants in genes regulating target proteins of these drugs, with immune (lymphocyte and neutrophil percentage) and inflammatory (tumour necrosis factor alpha [TNF-α]) markers in the largest available genome-wide association studies. RESULTS: Genetically predicted effects of ACE inhibitors increased lymphocyte percentage (0.78, 95% confidence interval [CI] 0.35, 1.22), decreased neutrophil percentage (-0.64, 95% CI -1.09, -0.20) and possibly lowered TNF-α (-4.92, 95% CI -8.50, -1.33). CCBs showed a similar pattern for immune function (lymphocyte percentage 0.21, 95% CI 0.05 to 0.36; neutrophil percentage -0.23, 95% CI -0.39 to -0.08) but had no effect on TNF-α, as did potassium-sparing diuretics and aldosterone antagonists, and vasodilator antihypertensives. ARBs and other classes of hypertensives had no effect on immune function or TNF-α. CONCLUSION: Varying effects of different classes of antihypertensives on immune and inflammatory markers do not suggest antihypertensive use based on their role in ACE2 expression, but instead suggest investigation of the role of antihypertensives in immune function and inflammation might reveal important information that could optimize their use in SARSCoV-2.

Angiotensin converting enzyme inhibitors do not increase the risk of poor outcomes in COVID-19 disease. A multi-centre observational study.

BACKGROUND AND AIMS: Hypertension is associated with an increased risk of severe outcomes with COVID-19 disease. Angiotensin Converting Enzyme (ACE) inhibitors are widely used as a first line medication for the treatment of hypertension in the UK, although their use was suggested in early reports to increase the risk associated with SARS-CoV-2 infection. METHODS: A prospective cohort study of hospitalised patients with laboratory confirmed COVID-19 was conducted across three hospital sites with patients identified on the 9th April 2020. Demographic and other baseline data were extracted from electronic case records, and patients grouped depending on ACE inhibitor usage or not. The 60-day all-cause mortality and need for intubation compared. RESULTS: Of the 173 patients identified, 88 (50.8%) had hypertension. Of these 27 (30.7%) used ACE inhibitors. We did not find significant differences in 60-day all-cause mortality, the requirement for invasive ventilation or length of stay between our patient cohorts after adjusting for covariates. CONCLUSION: This study contributes to the growing evidence supporting the continued use of ACE inhibitors in COVID-19 disease, although adequately powered randomised controlled trials will be needed to confirm effects.