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1.
Sci Rep ; 11(1): 24397, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1585779

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is an important factor in coronavirus disease (COVID-19) interactions. Losartan (LOS) belongs to the angiotensin receptor blocker (ARB) family. Additionally, the protective role of ACE2 restored by LOS has been suggested and clinically examined in the treatment of COVID-19 patients. Furthermore, clinical trials with LOS have been conducted. However, the mechanism through which LOS enhances ACE2 expression remains unclear. In addition, the response of ACE2 to LOS differs among patients. Our LOS-treated patient data revealed a correlated mechanism of ACE2 with components of the renin-angiotensinogen system. We observed a significant positive regulation of MAS1 and ACE2 expression. In the context of LOS treatment of COVID-19, ACE2 expression could depend on LOS regulated MAS1. Thus, MAS1 expression could predict the COVID-19 treatment response of LOS.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Losartan/pharmacology , Renin-Angiotensin System/drug effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Databases, Factual , Humans , Losartan/therapeutic use , /metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , SARS-CoV-2/isolation & purification , Up-Regulation/drug effects
3.
Cardiovasc Hematol Disord Drug Targets ; 20(3): 181-184, 2020.
Article in English | MEDLINE | ID: covidwho-1435708

ABSTRACT

Nowadays Coronavirus Disease 2019 (Covid-19) is increasing mortality all over the world mercilessly. We are learning almost every day about its new symptoms and that it mutates quickly. This disease has tied us up and made us desperate. The death rate from this disease has increased in patients who had pre-existing medical conditions, especially cardiovascular ones, by eliminating the angiotensin-converting enzyme (ACE)-2 receptor in the lungs. Also, ACE1 and angiotensin receptor blockers (ARB) may stimulate ACE2 expression and worse the prognosis. Intravenous infusions of ACEIs and ARBs in experimental animals increase the number of ACE2 receptors. Therefore, it may be one of the reasons that COVID-19 infects the cells of patients treating hypertension. However, most of the congress of cardiology do not recommend to discontinue these anti-hypertensive drugs. Therefore, this brief report evaluates Covid-19 in the view of cardiovascular diseases taking into account current reports and suggests some possible solutions to keep the virus under control.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Age Factors , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antihypertensive Agents/therapeutic use , COVID-19/complications , COVID-19/mortality , Cardiovascular Diseases/metabolism , Humans , Hypertension/drug therapy , Pandemics , SARS-CoV-2 , Severity of Illness Index , Thromboembolism/etiology , Thromboembolism/physiopathology
5.
Front Cell Infect Microbiol ; 11: 639177, 2021.
Article in English | MEDLINE | ID: covidwho-1389152

ABSTRACT

Several comorbidities, including hypertension, have been associated with an increased risk of developing severe disease during SARS-CoV-2 infection. Angiotensin II receptor blockers (ARBs) are currently some of the most widely-used drugs to control blood pressure by acting on the angiotensin II type 1 receptor (AT1R). ARBs have been reported to trigger the modulation of the angiotensin I converting enzyme 2 (ACE2), the receptor used by the virus to penetrate susceptible cells, raising concern that such treatments may promote virus capture and increase their viral load in patients receiving ARBs therapy. In this in vitro study, we reviewed the effect of ARBs on ACE2 and AT1R expression and investigated whether treatment of permissive ACE2+/AT1R+ Vero E6 cells with ARBs alters SARS-CoV-2 replication in vitro in an angiotensin II-free system. After treating the cells with the ARBs, we observed an approximate 50% relative increase in SARS-CoV-2 production in infected Vero E6 cells that correlates with the ARBs-induced up-regulation of ACE2 expression. From this data, we believe that the use of ARBs in hypertensive patients infected by SARS-CoV-2 should be carefully evaluated.


Subject(s)
Angiotensin Receptor Antagonists , COVID-19 , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antihypertensive Agents/pharmacology , Humans , Renin-Angiotensin System , SARS-CoV-2
6.
Hipertens Riesgo Vasc ; 37(4): 169-175, 2020.
Article in Spanish | MEDLINE | ID: covidwho-1322115

ABSTRACT

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Pandemics , Pneumonia, Viral/physiopathology , Renin-Angiotensin System/physiology , ADAM17 Protein/physiology , Angiotensin II/physiology , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Humans , Hypertension/complications , Hypertension/physiopathology , Lung/physiopathology , Models, Biological , Pandemics/prevention & control , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Receptors, Virus/drug effects , Renin-Angiotensin System/drug effects , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Serine Endopeptidases/physiology , Viral Vaccines , Virus Internalization/drug effects
7.
J Reprod Immunol ; 146: 103344, 2021 08.
Article in English | MEDLINE | ID: covidwho-1315509

ABSTRACT

The pandemic COVID-19 presents a major challenge to identify effective drugs for treatment. Clinicians need evidence based on randomized trials regarding effective medical treatments for this infection. Currently no effective therapies exist for the progression of the mild forms to severe disease. Knowledge however is rapidly expanding. Remdesivir, an anti- retroviral agent has in vitro activity against this virus and has shown to decrease the duration of ICU care in patients with severe disease, while low dose dexamethasone also showed a decrease in the duration of stay in cases of severe disease requiring assisted ventilation. At the time of writing this article, two mRNA-based vaccines have shown an approximate 95 % efficacy in preventing infection in large clinical trials. At least one of these drugs has regulatory permission for vaccination in high-income countries. Low and middle-income countries may have difficulties in initiating vaccine programs on large scales because of availability, costs, refrigeration and dissemination. Adequately powered randomized trials are required for drugs with in vitro activity against the virus. Supportive care should be provided for stable, hypoxia and pneumonia free patients on imaging. Vaccines are of obvious benefit and given the preliminary evidence of the efficacy of over 95 %, Low and middle-income countries must develop links with the WHO COVAX program to ensure global distribution of vaccines.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/therapy , Evidence-Based Medicine/methods , Pandemics/prevention & control , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antimalarials/pharmacology , Antimalarials/therapeutic use , Antiviral Agents/pharmacology , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , COVID-19 Vaccines/immunology , Clinical Trials as Topic , Evidence-Based Medicine/trends , Global Health , Humans , International Cooperation , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Spike Glycoprotein, Coronavirus/metabolism , Treatment Outcome , Virus Internalization/drug effects
8.
Biomolecules ; 11(7)2021 07 03.
Article in English | MEDLINE | ID: covidwho-1295754

ABSTRACT

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy.


Subject(s)
Angiotensin II/metabolism , Angiotensin Receptor Antagonists/chemistry , Angiotensin Receptor Antagonists/pharmacology , COVID-19/drug therapy , Drug Discovery , Receptor, Angiotensin, Type 1/metabolism , Angiotensin II/analogs & derivatives , Animals , COVID-19/metabolism , Crystallography, X-Ray , Humans , Hypertension/drug therapy , Hypertension/metabolism , Male , Models, Molecular , Rabbits , Receptor, Angiotensin, Type 1/chemistry , Vasoconstriction/drug effects
9.
J Hypertens ; 39(4): 795-805, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1290201

ABSTRACT

Concerns over ACE inhibitor or ARB use to treat hypertension during COVID-19 remain unresolved. Although studies using more robust methodologies provided some clarity, sources of bias persist and it remains critical to quickly address this question. In this review, we discuss pernicious sources of bias using a causal model framework, including time-varying confounder, collider, information, and time-dependent bias, in the context of recently published studies. We discuss causal inference methodologies that can address these issues, including causal diagrams, time-to-event analyses, sensitivity analyses, and marginal structural modeling. We discuss effect modification and we propose a role for causal mediation analysis to estimate indirect effects via mediating factors, especially components of the renin--angiotensin system. Thorough knowledge of these sources of bias and the appropriate methodologies to address them is crucial when evaluating observational studies to inform patient management decisions regarding whether ACE inhibitors or ARBs are associated with greater risk from COVID-19.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Renin-Angiotensin System/drug effects , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Humans , Hypertension/drug therapy , Observational Studies as Topic , SARS-CoV-2
11.
Circ Res ; 128(7): 1062-1079, 2021 04 02.
Article in English | MEDLINE | ID: covidwho-1166630

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19-related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Hypertension/drug therapy , Hypertension/epidemiology , Angiotensin Receptor Antagonists/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , COVID-19/metabolism , Humans , Hypertension/metabolism , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Factors
12.
JAMA Netw Open ; 4(3): e213594, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1159048

ABSTRACT

Importance: The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes. Objective: To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19. Data Sources: PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020. Study Selection: The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs. Data Extraction and Synthesis: Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs. Main Outcomes and Measures: Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19. Results: A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101 949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P < .001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P = .01; aOR, 0.51 [95% CI, 0.32-0.84]; P = .008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P = .007; aOR, 0.55 [95% CI, 0.36-0.85]; P = .007). Conclusions and Relevance: In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to establish causality.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antihypertensive Agents/pharmacology , COVID-19/mortality , Hypertension/drug therapy , Renin-Angiotensin System , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/therapeutic use , COVID-19/epidemiology , Comorbidity , Female , Humans , Hypertension/epidemiology , Male , Middle Aged , SARS-CoV-2
13.
Cerebrovasc Dis ; 50(3): 245-261, 2021.
Article in English | MEDLINE | ID: covidwho-1147303

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , COVID-19/complications , Heparin, Low-Molecular-Weight/pharmacology , SARS-CoV-2/pathogenicity , Stroke/etiology , COVID-19/virology , Humans , Spike Glycoprotein, Coronavirus/metabolism , Stroke/diagnosis
14.
Kidney Blood Press Res ; 46(2): 245-249, 2021.
Article in English | MEDLINE | ID: covidwho-1146805

ABSTRACT

BACKGROUND: Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression. METHODS: In this study, we evaluated the effect of ACEi or ARB treatment on expression of ACE2, ACE, and AGTR1 in 3-month protocol kidney allograft biopsies of stable patients using RT-qPCR (n = 48). Protein ACE2 expression was assessed using immunohistochemistry from paraffin sections. RESULTS: The therapy with RAAS blockers was not associated with increased ACE2, ACE, or ATGR1 expression in kidney allografts and also ACE2 protein immunohistochemistry did not reveal differences among groups. CONCLUSIONS: ACEis or ARBs in kidney transplant recipients do not affect local ACE2 expression. This observation supports long-term RAAS treatment in kidney transplant recipients, despite acute complications such as COVID-19 where ACE2 serves as the entry protein for infection.


Subject(s)
Allografts/drug effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , Antihypertensive Agents/therapeutic use , Gene Expression/drug effects , Kidney/drug effects , Adult , Aged , Allografts/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antihypertensive Agents/pharmacology , COVID-19/complications , COVID-19/genetics , Female , Humans , Kidney/metabolism , Kidney Transplantation , Male , Middle Aged , RNA, Messenger/analysis , RNA, Messenger/genetics , Renin-Angiotensin System/drug effects
15.
Cells ; 10(3)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1136461

ABSTRACT

Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1-7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Receptors, Angiotensin/metabolism , Renin-Angiotensin System/drug effects , Aging/metabolism , Aging/pathology , Animals , Autoimmunity/drug effects , Autoimmunity/genetics , COVID-19/drug therapy , COVID-19/genetics , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Humans , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Receptors, Angiotensin/genetics , Regeneration/drug effects , Regeneration/genetics , Regeneration/physiology , Renin-Angiotensin System/genetics , Renin-Angiotensin System/physiology , Vulvodynia/immunology , Vulvodynia/physiopathology
16.
Nat Commun ; 12(1): 1660, 2021 03 12.
Article in English | MEDLINE | ID: covidwho-1132065

ABSTRACT

In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin-angiotensin-aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies.


Subject(s)
COVID-19/genetics , COVID-19/virology , SARS-CoV-2/genetics , Adult , Aged , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19 Nucleic Acid Testing , Drug Interactions , Female , Gene Expression Profiling , Genome, Viral , HLA Antigens/genetics , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Humans , Male , Middle Aged , Molecular Diagnostic Techniques , New York City/epidemiology , Nucleic Acid Amplification Techniques , Pandemics , RNA-Seq , SARS-CoV-2/classification , SARS-CoV-2/drug effects
17.
J Clin Pharmacol ; 61(8): 987-1000, 2021 08.
Article in English | MEDLINE | ID: covidwho-1103313

ABSTRACT

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), numerous research has been undertaken to delineate the various effects of the virus which manifests in many ways all over the body. The association between the SARS-CoV-2 invasion mechanism and the renin-angiotensin-aldosterone system (RAAS) receptors, created many debates about the possible consequences of using RAAS-modulating drugs including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) during the pandemic. Many clinical studies were conducted to assess the outcomes of coronavirus disease 2019 (COVID-19) in patients who use ACEi/ARBs following the arguments claiming to discontinue these drugs as a precautionary measure. Although several studies mainly analyzed the outcomes of the disease, this review aimed to compare specific blood markers in both groups of COVID-19 patients to gain better insight into the interaction of ACEi/ARBs with different body functions during the infection. Several databases were searched using a combination of keywords followed by screening and data extraction. Only 28 studies met our inclusion criteria, the majority of which showed no significant difference between the inflammation markers of COVID-19 patients who used or did not use ACEi/ARBs. Interestingly, 6 studies reported lower inflammatory markers in COVID-19 patients who used ACEi/ARBs, and 6 studies reported better outcomes among the same group. We therefore concluded that the use of ACEi/ARBs may not lead to worse prognosis of COVID-19 and may even play a protective role against the hyperinflammatory response associated with COVID-19.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19 , Immunity , Renin-Angiotensin System/immunology , SARS-CoV-2/physiology , COVID-19/diagnosis , COVID-19/immunology , COVID-19/metabolism , Humans , Immunity/drug effects , Immunity/physiology , Prognosis , Protective Factors
19.
Epidemiol Prev ; 44(5-6 Suppl 2): 226-234, 2020.
Article in English | MEDLINE | ID: covidwho-1068143

ABSTRACT

OBJECTIVES: to describe the clinical and demographical characteristics of COVID-19 infected people in the Friuli Venezia Giulia Region (FVG, Northern Italy). DESIGN: retrospective cohort study with an individual level record linkage procedure of different administrative databases. SETTING AND PARTICIPANTS: the cohort included 3,010 patients residing in FVG who tested positive for COVID-19 between 1 March and 15 May 2020, 2020. Regional hospital admissions and deaths without hospital admissions up to June 1st, 2020 were analysed. Determinants of the probability of a highly severe illness were investigated in terms of hospitalisations or death without hospital admission. MAIN OUTCOME MEASURES: COVID-19 patients were identified from regional epidemiological data warehouse. Demographical and clinical variables such as gender, age, patient's comorbidities, vaccinations, ARBs/sartans prescriptions, and geographical residence variables were collected by linking different databases. Descriptive analyses were performed. Logistic multivariate regressions were used to estimate the probability of hospitalisation or death, whichever came first. Model coefficients and odds ratios (OR) were reported. RESULTS: COVID-19 population in FVG had a mean age of 60 years and 59% were females. The study found that 37% had hypertension while patients with cardiologic diseases, diabetes, and cancer were around 15%; 22% of the cases were residing in retirement homes. Approximately 30% received flu or pneumococcal vaccination and a similar proportion of patients had at least one prescription of ARBs /sartans in the previous 6 months. Statistical models showed a higher probability of a worst course of disease for males, elderly, highly complicated (in terms of resource use) subjects, in the presence of cardiologic diseases, diabetes, and pneumococcal vaccination. People living in retirement homes had a lower probability of hospitalisation/death without hospital admission. The cohort was divided into two groups: COVID-19 patients infected in the territory and infected in retirement homes. Among COVID-19 patients infected in the territory, the probability of hospitalisation/death was higher for males, for older individuals, and for those with comorbidities. Diabetes resulted to be a risk factor (OR 1.79; 95%CI 1.23-2.62), as well as pneumococcal vaccination (OR 1.64; 95%CI: 1.18-2.29), which is a likely proxy of fragile patients with pulmonary disease. The flu vaccination showed a potential protective effect with a 40% lower probability of hospitalisation or death (OR 0.62; 95%CI 0.44-0.85). Among the retirement homes cohort group, a higher probability of a bad course of disease emerged for males and for more complex patients. CONCLUSIONS: the greatest risk of hospitalisation/death as a measure of more severe illness was confirmed for males, elderly, and for individuals with comorbidities. Flu vaccination seemed to have had a protective effect while pneumococcal vaccination likely identified a group of high-risk patients to be actively monitored. For patients infected in the territory, different hospitalisation strategies were implemented by the regional health districts.


Subject(s)
COVID-19/epidemiology , Pandemics , Age Distribution , Aged , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin Receptor Antagonists/pharmacology , Catchment Area, Health , Comorbidity , Databases, Factual , Female , Homes for the Aged/statistics & numerical data , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Italy/epidemiology , Male , Medical Record Linkage , Middle Aged , Multivariate Analysis , Pneumococcal Vaccines , Residence Characteristics , Retrospective Studies , Sex Distribution , Vaccination/statistics & numerical data
20.
Open Heart ; 7(2)2020 12.
Article in English | MEDLINE | ID: covidwho-1066930

ABSTRACT

SARS-CoV-2 is the virus responsible for the ongoing COVID-19 outbreak. The virus uses ACE2 receptor for viral entry. ACE2 is part of the counter-regulatory renin-angiotensin-aldosterone system and is also expressed in the lower respiratory tract along the alveolar epithelium. There is, however, significant controversy regarding the role of ACE2 expression in COVID-19 pathogenesis. Some have argued that decreasing ACE2 expression would result in decreased susceptibility to the virus by decreasing available binding sites for SARS-CoV-2 and restricting viral entry into the cells. Others have argued that, like the pathogenesis of other viral pneumonias, including those stemming from previous severe acute respiratory syndrome (SARS) viruses, once SARS-CoV-2 binds to ACE2, it downregulates ACE2 expression. Lack of the favourable effects of ACE2 might exaggerate lung injury by a variety of mechanisms. In order to help address this controversy, we conducted a literature search and review of relevant preclinical and clinical publications pertaining to SARS-CoV-2, COVID-19, ACE2, viral pneumonia, SARS, acute respiratory distress syndrome and lung injury. Our review suggests, although controversial, that patients at increased susceptibility to COVID-19 complications may have reduced baseline ACE2, and by modulating ACE2 expression one can possibly improve COVID-19 outcomes. Herein, we elucidate why and how this potential mechanism might work.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , Renin-Angiotensin System/drug effects , SARS-CoV-2/genetics , Adult , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , COVID-19/drug therapy , COVID-19/virology , Down-Regulation , Female , Humans , Immunity/immunology , Lung Injury/drug therapy , Lung Injury/physiopathology , Male , Mice , Middle Aged , Models, Animal , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/drug therapy , Risk Factors , SARS-CoV-2/drug effects , Virus Internalization/drug effects
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