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Barreto Fernandes TF, Pilotto JH, Cezar PA, Côrtes FH, Morgado MG, Giacoia-Gripp CBW, De Sá NBR, Da Silva Cazote A, Neves AF, Quintana MDSB, Diniz Ribeiro MP, Cardoso SW, Veloso VG, Grinsztejn B, De Almeida DV. Modulation of RAAS receptors and miRNAs in COVID-19: implications for disease severity, immune response, and potential therapeutic targets. BMC Infect Dis 2025; 25:399. [PMID: 40128651 PMCID: PMC11934810 DOI: 10.1186/s12879-025-10803-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/14/2025] [Indexed: 03/26/2025] Open
Abstract
The SARS-CoV-2 spike protein interacts with ACE2, a key receptor within the renin-angiotensin-aldosterone system (RAAS), which plays a critical role in maintaining vascular homeostasis, regulating blood pressure, and modulating inflammation. An observational study analyzed the gene expression profiles of RAAS receptors and associated miRNAs in 88 hospitalized COVID-19 patients and 20 healthy controls, comparing the acute and post-acute phases to assess their impact on disease severity and recovery. Our findings revealed an association between reduced MAS1 expression in both advanced age (P = 0.03) and the need for oxygen supplementation (P = 0.04). Additionally, reduced ACE expression was associated with worse mortality outcomes (P = 0.01). Notably, ACE2 and TMPRSS2 expression was significantly decreased (P < 0.0001) in individuals requiring oxygen supplementation and in those with diabetes mellitus during both the acute and post-COVID-19 phases, further highlighting the impact of these conditions on RAAS. The miRNA analysis revealed significant downregulation of miR-200c (P = 0.005), miR-let-7 (P = 0.01), and miR-122 (P = 0.03) in acute-phase COVID-19 patients. This dysregulation contributes to the inflammatory response and highlights the interaction between viral entry and immune regulation. These results underscore the significance of the ACE2/Ang-(1-7)/MAS1 axis in inflammation regulation and suggest that targeting this pathway may have therapeutic potential. Our study provides valuable insights into the molecular mechanisms of COVID-19 pathogenesis and identifies the modulation of RAAS receptors and miRNAs as promising biomarkers for disease severity and potential therapeutic interventions. CLINICAL TRIAL: Not applicable.
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Affiliation(s)
| | - Jose Henrique Pilotto
- Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brasil
| | - Priscila Alves Cezar
- Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brasil
| | - Fernanda Heloise Côrtes
- Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brasil
| | - Mariza G Morgado
- Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brasil
| | | | | | - Andressa Da Silva Cazote
- Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brasil
| | - Agatha Freixinho Neves
- Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brasil
| | | | | | | | - Valdiléa G Veloso
- Instituto Nacional de Infectologia Evandro Chagas, FIOCRUZ, Rio de Janeiro, Brasil
| | - Beatriz Grinsztejn
- Instituto Nacional de Infectologia Evandro Chagas, FIOCRUZ, Rio de Janeiro, Brasil
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Vinod P, Krishnappa V, Rathell W, Dogbey G, Patel H, Herzog W. Effect of Renin-Angiotensin-Aldosterone System Blockers on Adverse Outcomes in COVID-19 Patients. Cardiology 2024; 149:551-560. [PMID: 39038438 DOI: 10.1159/000540499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Angiotensin-converting enzyme 2 (ACE2) of the renin-angiotensin-aldosterone system (RAAS) serves as a functional receptor to gain entry into the cells for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and ACE2 is a potential virulent factor in infectivity. Our study aimed to ascertain the association of RAAS inhibitors with adverse cardiovascular and other outcomes in hospitalized COVID-19 patients. METHODS This is a retrospective study of medical records of ≥18-year-old patients hospitalized for COVID-19 from March 2020 to October 2020. Primary outcomes were acute cardiovascular events (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction type 1, acute congestive heart failure, acute stroke) and mortality. Secondary outcomes were respiratory failure, need for and duration of mechanical ventilation, acute deep vein thrombosis or pulmonary embolism (DVT/PE), and readmission rate. RESULTS Among 376 hospitalized COVID-19 patients, 149 were on RAAS inhibitors. No statistically significant differences were found between RAAS inhibitor and non-RAAS inhibitor groups with respect to acute cardiovascular events (6% vs. 6.2%, p = 0.94), acute DVT/PE (4.7% vs. 4.8%, p = 0.97), hypoxia (62.4% vs. 58.6%, p = 0.46), need for mechanical ventilation (18.1% vs. 16.7%, p = 0.72), mortality (19.5% vs. 22%, p = 0.56), and readmission rate (11.4% vs. 14.1%, p = 0.45). Some nuances discovered were a higher rate of hospitalizations among Native Americans receiving RAAS inhibitors (30.2% vs. 19.8%) and significantly lower levels of procalcitonin in patients on RAAS inhibitors. CONCLUSIONS Among hospitalized patients with COVID-19, those on RAAS inhibitors showed no significant differences in acute cardiovascular events, acute DVT/PE, hypoxia, need for mechanical ventilation, readmission, or mortality rate compared to those not on them. However, further large-scale studies are needed to validate these findings.
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Affiliation(s)
- Poornima Vinod
- Department of Internal Medicine, University of North Carolina Health Southeastern, Lumberton, North Carolina, USA
| | - Vinod Krishnappa
- Department of Internal Medicine, University of North Carolina Health Southeastern, Lumberton, North Carolina, USA
| | - William Rathell
- Department of Internal Medicine, University of North Carolina Health Southeastern, Lumberton, North Carolina, USA
| | - Godwin Dogbey
- Department of Research and Medical Education, Campbell University, Buies Creek, North Carolina, USA
| | - Hiten Patel
- Department of Cardiology, University of North Carolina Health Southeastern, Lumberton, North Carolina, USA
| | - William Herzog
- Department of Cardiology, University of North Carolina Health Southeastern, Lumberton, North Carolina, USA
- Department of Cardiology, Duke University, Durham, North Carolina, USA
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You J, Huang R, Zhong R, Shen J, Huang S, Chen J, Chen F, Kang Y, Chen L. Serum AXL is a potential molecular marker for predicting COVID-19 progression. Front Immunol 2024; 15:1394429. [PMID: 38799467 PMCID: PMC11116689 DOI: 10.3389/fimmu.2024.1394429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Background The severity, symptoms, and outcome of COVID-19 is thought to be closely linked to how the virus enters host cells. This process involves the key roles of angiotensin-converting enzyme 2 (ACE2) and the Tyrosine protein kinase receptor UFO (AXL) receptors. However, there is limited research on the circulating levels of ACE2 and AXL and their implications in COVID-19. Methods A control group of 71 uninfected individuals was also included in the study. According to the Guidance for Corona Virus Disease 2019 (10th edition), a cohort of 358 COVID-19 patients were categorized into non-severe and severe cases. Serum ACE2/AXL levels in COVID-19 patients were detected by enzyme-linked immunosorbent assay (ELISA) at different time points post-COVID-19 infection, including days 0-7, 8-15, 31-179 and >180 days. Serum SARS-CoV-2 IgG/IgM antibodies in COVID-19 patients at the same intervals were assessed by using an iFlash 3000 Chemiluminescence Immunoassay Analyzer. The receiver operating characteristic (ROC) curves were used to assess the diagnostic value of the biological markers, and the association between laboratory parameters and illness progression were explored. Results Compared with the uninfected group, the levels of ACE2 and AXL in the COVID-19 group were decreased, and the SARS-COV-2 IgG level was increased. AXL (AUC = 0.774) demonstrated a stronger predictive ability for COVID-19 than ACE2. In the first week after infection, only the level of AXL was statistically different between severe group and non-severe group. After first week, the levels of ACE2 and AXL were different in two groups. Moreover, in severe COVID-19 cases, the serum ACE2, AXL, and SARS-COV-2 IgM levels reached a peak during days 8-15 before declining, whereas serum SARS-COV-2 IgG levels continued to rise, reaching a peak at day 31-180 days before decreasing. In addition, the AXL level continued to decrease and the SARS-COV-2 IgG level continued to increase in the infected group after 180 days compared to the uninfected group. Conclusions The levels of serum ACE2 and AXL correlate with COVID-19 severity. However, AXL can also provide early warning of clinical deterioration in the first week after infection. AXL appears to be a superior potential molecular marker for predicting COVID-19 progression.
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Affiliation(s)
- Jianbin You
- Department of Clinical Laboratory, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Rong Huang
- Department of Clinical Laboratory, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Ruifang Zhong
- Department of Clinical Laboratory, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Jing Shen
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Shuhang Huang
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China
| | - Jinhua Chen
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Falin Chen
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Yanli Kang
- Department of Clinical Laboratory, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Liangyuan Chen
- Department of Clinical Laboratory, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, Fujian, China
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Tóth E, Fagyas M, Nagy B, Siket IM, Szőke B, Mártha L, Mahdi M, Erdősi G, Pólik Z, Kappelmayer J, Papp Z, Borbély A, Szabó T, Balla J, Balla G, Bácsi A, Szekanecz Z, Bai P, Tóth A. Distinct subsets of anti-pulmonary autoantibodies correlate with disease severity and survival in severe COVID-19 patients. GeroScience 2024; 46:1561-1574. [PMID: 37656328 PMCID: PMC10828368 DOI: 10.1007/s11357-023-00887-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/24/2023] [Indexed: 09/02/2023] Open
Abstract
Autoantibodies targeting the lung tissue were identified in severe COVID-19 patients in this retrospective study. Fifty-three percent of 104 patients developed anti-pulmonary antibodies, the majority of which were IgM class, suggesting that they developed upon infection with SARS-CoV-2. Anti-pulmonary antibodies correlated with worse pulmonary function and a higher risk of multiorgan failure that was further aggravated if 3 or more autoantibody clones were simultaneously present (multi-producers). Multi-producer patients were older than the patients with less or no autoantibodies. One of the identified autoantibodies (targeting a pulmonary protein of ~ 50 kDa) associated with worse clinical outcomes, including mortality. In summary, severe COVID-19 is associated with the development of lung-specific autoantibodies, which may worsen the clinical outcome. Tissue proteome-wide tests, such as the ones applied here, can be used to detect autoimmunity in the post-COVID state to identify the cause of symptoms and to reveal a new target for treatment.
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Affiliation(s)
- Emese Tóth
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
- Center of Excellence, The Hungarian Academy of Sciences, Budapest, Hungary
| | - Miklós Fagyas
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Béla Nagy
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ivetta Mányiné Siket
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Blanka Szőke
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Lilla Mártha
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Mohamed Mahdi
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gábor Erdősi
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsófia Pólik
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - János Kappelmayer
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Papp
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
| | - Attila Borbély
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamás Szabó
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - József Balla
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - György Balla
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Bácsi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Bai
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
- Center of Excellence, The Hungarian Academy of Sciences, Budapest, Hungary.
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
- MTA-DE Cell Biology and Signaling Research Group ELKH, Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, 4032, Debrecen, Hungary.
| | - Attila Tóth
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
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Leowattana W, Leowattana T, Leowattana P. Circulating angiotensin converting enzyme 2 and COVID-19. World J Clin Cases 2022; 10:12470-12483. [PMID: 36579082 PMCID: PMC9791519 DOI: 10.12998/wjcc.v10.i34.12470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/20/2022] [Accepted: 11/08/2022] [Indexed: 12/02/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a widespread outbreak since December 2019. The SARS-CoV-2 infection-related illness has been dubbed the coronavirus disease 2019 (COVID-19) by the World Health Organization. Asymptomatic and subclinical infections, a severe hyper-inflammatory state, and mortality are all examples of clinical signs. After attaching to the angiotensin converting enzyme 2 (ACE2) receptor, the SARS-CoV-2 virus can enter cells through membrane fusion and endocytosis. In addition to enabling viruses to cling to target cells, the connection between the spike protein (S-protein) of SARS-CoV-2 and ACE2 may potentially impair the functionality of ACE2. Blood pressure is controlled by ACE2, which catalyzes the hydrolysis of the active vasoconstrictor octapeptide angiotensin (Ang) II to the heptapeptide Ang-(1-7) and free L-Phe. Additionally, Ang I can be broken down by ACE2 into Ang-(1-9) and metabolized into Ang-(1-7). Numerous studies have demonstrated that circulating ACE2 (cACE2) and Ang-(1-7) have the ability to restore myocardial damage in a variety of cardiovascular diseases and have anti-inflammatory, antioxidant, anti-apoptotic, and anti-cardiomyocyte fibrosis actions. There have been some suggestions for raising ACE2 expression in COVID-19 patients, which might be used as a target for the creation of novel treatment therapies. With regard to this, SARS-CoV-2 is neutralized by soluble recombinant human ACE2 (hrsACE2), which binds the viral S-protein and reduces damage to a variety of organs, including the heart, kidneys, and lungs, by lowering Ang II concentrations and enhancing conversion to Ang-(1-7). This review aims to investigate how the presence of SARS-CoV-2 and cACE2 are related. Additionally, there will be discussion of a number of potential therapeutic approaches to tip the ACE/ACE-2 balance in favor of the ACE-2/Ang-(1-7) axis.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Bangkok, Thailand
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Fagyas M, Nagy B, Ráduly AP, Mányiné IS, Mártha L, Erdősi G, Sipka S, Enyedi E, Szabó AÁ, Pólik Z, Kappelmayer J, Papp Z, Borbély A, Szabó T, Balla J, Balla G, Bai P, Bácsi A, Tóth A. The majority of severe COVID-19 patients develop anti-cardiac autoantibodies. GeroScience 2022; 44:2347-2360. [PMID: 36112333 PMCID: PMC9483490 DOI: 10.1007/s11357-022-00649-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/21/2022] [Indexed: 01/06/2023] Open
Abstract
Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for COVID-19. Inflammatory mediators facilitate the immune system to combat viral infection by producing antibodies against viral antigens. Several studies reported that the pro-inflammatory state and tissue damage in COVID-19 also promotes autoimmunity by autoantibody generation. We hypothesized that a subset of these autoantibodies targets cardiac antigens. Here we aimed to detect anti-cardiac autoantibodies in severe COVID-19 patients during hospitalization. For this purpose, 104 COVID-19 patients were recruited, while 40 heart failure patients with dilated cardiomyopathy and 20 patients with severe aortic stenosis served as controls. Patients were tested for anti-cardiac autoantibodies, using human heart homogenate as a bait. Follow-up samples were available in 29 COVID-19 patients. Anti-cardiac autoantibodies were detected in 68% (71 out of 104) of severe COVID-19 patients. Overall, 39% of COVID-19 patients had anti-cardiac IgG autoantibodies, while 51% had anti-cardiac autoantibodies of IgM isotype. Both IgG and IgM anti-cardiac autoantibodies were observed in 22% of cases, and multiple cardiac antigens were targeted in 38% of COVID-19 patients. These anti-cardiac autoantibodies targeted a diverse set of myocardial proteins, without apparent selectivity. As controls, heart failure patients (with dilated cardiomyopathy) had similar occurrence of IgG (45%, p = 0.57) autoantibodies, while significantly lower occurrence of IgM autoantibodies (30%, p = 0.03). Patients with advanced aortic stenosis had significantly lower number of both IgG (11%, p = 0.03) and IgM (10%, p < 0.01) type anti-cardiac autoantibodies than that in COVID-19 patients. Furthermore, we detected changes in the anti-cardiac autoantibody profile in 7 COVID-19 patients during hospital treatment. Surprisingly, the presence of these anti-cardiac autoantibodies did not affect the clinical outcome and the prevalence of the autoantibodies did not differ between the elderly (over 65 years) and the patients younger than 65 years of age. Our results demonstrate that the majority of hospitalized COVID-19 patients produce novel anti-cardiac IgM autoantibodies. COVID-19 also reactivates resident IgG autoantibodies. These autoantibodies may promote autoimmune reactions, which can complicate post-COVID recuperation, contributing to post-acute sequelae of COVID-19 (long COVID).
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Affiliation(s)
- Miklós Fagyas
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Béla Nagy
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Arnold Péter Ráduly
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
| | - Ivetta Siket Mányiné
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Lilla Mártha
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gábor Erdősi
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Sándor Sipka
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Enikő Enyedi
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
| | - Attila Ádám Szabó
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
| | - Zsófia Pólik
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - János Kappelmayer
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Papp
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Borbély
- Division of Cardiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamás Szabó
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - József Balla
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - György Balla
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Bai
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group ELKH, Debrecen, Hungary
| | - Attila Bácsi
- ELKH-DE Allergology Research Group, Debrecen, Hungary
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Tóth
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Bani Hani A, Abu Tarboush N, Bani Ali M, Alabhoul F, Alansari F, Abuhani A, Al-Kawak M, Shamoun B, Albdour S, Abu Abeeleh M, Ahram M. Serum ACE2 Level is Associated With Severe SARS-CoV-2 Infection: A Cross-Sectional Observational Study. Biomark Insights 2022; 17:11772719221125123. [PMID: 36156891 PMCID: PMC9500304 DOI: 10.1177/11772719221125123] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/24/2022] [Indexed: 01/08/2023] Open
Abstract
Objectives: Angiotensin-converting enzyme 2 (ACE2) represents the primary receptor for SARS-CoV-2 to enter endothelial cells, causing coronavirus disease of 2019 (COVID-19). In this study, we investigate the association between circulating ACE2 levels with the severity of COVID-19. Methods: Serum ACE2 levels were measured in 144 COVID-19-positive subjects at hospital admission, and 123 COVID-19-negative control subjects. The association between ACE2 and clinical outcomes was analyzed. Results: About 144 COVID-19 patients and 123 healthy controls data were analyzed, the mean age of patients was 62 years and 50% of them were males. The mean age of the control group was 55 years and 63% were males. ACE-II level was measured and compared between COVID-19 patients and controls and revealed no significant differences (P > .05). ACE-II level was measured in COVID-19 patients and compared between different patient’s subgroups, ACE II level was not dependent on gender, smoking, ACE intake, or comorbidities (P > .05), and was significantly correlated with cardiovascular diseases (CVS) (P-value = .046) ICU admission (P-value = .0007) and Death (P-value = .0082). Conclusion: There was no significant difference between the COVID-19 and Control group, however, ACE2 serum level was significantly higher in patients with COVID-19 who were critically ill or non-survivors, its increased level is also associated with length of stay. Elevated ACE2 level is associated with the severity of COVID-19 disease, and it has the potential to be a predictor of the severity of the disease.
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Affiliation(s)
- Amjad Bani Hani
- Department of General Surgery, School of Medicine, The University of Jordan, Amman, Jordan
| | - Nafez Abu Tarboush
- Department of Biochemistry and Physiology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Mo'ath Bani Ali
- Department of Medicine, School of Medicine, The University of Jordan, Amman, Jordan
| | - Fahad Alabhoul
- Department of Biochemistry and Physiology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Fahad Alansari
- Department of Biochemistry and Physiology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Ahmad Abuhani
- Department of Biochemistry and Physiology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Mustafa Al-Kawak
- Department of Biochemistry and Physiology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Badea'a Shamoun
- Department of Anesthesia and Critical Care, Prince Hamza Hospital, Amman, Jordan
| | - Suzan Albdour
- Department of Biochemistry and Physiology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Mahmoud Abu Abeeleh
- Department of General Surgery, School of Medicine, The University of Jordan, Amman, Jordan
| | - Mamoun Ahram
- Department of General Surgery, School of Medicine, The University of Jordan, Amman, Jordan
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Hernandez-Hernandez ME, Zee RYL, Pulido-Perez P, Torres-Rasgado E, Romero JR. The Effects of Biological Sex and Cardiovascular Disease on COVID-19 Mortality. Am J Physiol Heart Circ Physiol 2022; 323:H397-H402. [PMID: 35867708 PMCID: PMC9359635 DOI: 10.1152/ajpheart.00295.2022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cardiovascular disease (CVD) is a common comorbidity observed in patients with COVID-19 that is associated with increased severity and mortality. However, the effects of biological sex on CVD associated mortality in COVID-19 patients is poorly established particularly among Hispanic/Latin Americans. We examined the association of preexisting CVD with COVID-19 mortality in hospitalized Latin American men and women. This multicenter study included hospitalized Mexican patients with a positive diagnosis of COVID-19. The main outcome was in-hospital mortality. Multivariable regression analyses were used to calculate the adjusted odd ratios with 95% confidence interval for mortality in women and men. Of 81,400 patients with a positive diagnosis for SARS-CoV-2 infection, 28,929 (35.54%) hospitalized patients were evaluated. Of these, the 35.41% (10,243) were women. In-hospital death was higher in men than in women. In relation to CVD between the sexes, women had a higher incidence of CVD than men (4.69% vs 3.93%. P=0.0023). The adjusted logistic regression analyses showed that CVD was significantly associated with COVID-19 mortality in women but not men. We then stratified by sex according to age <52 and ≥52 years old. Similar significant association was also found in pre-specified analysis in women ≥52 years old but not in men of similar age. We conclude that CVD's effect on mortality among COVID-19 hospitalized patients is dependent on biological sex and age in this Latin American cohort. These results suggest that therapeutic strategies for Latin American women with CVD and COVID-19 should include particular attention to their cardiovascular health.
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Affiliation(s)
- Maria Elena Hernandez-Hernandez
- Doctorate in Biological Science, Autonomous University of Tlaxcala, Puebla, Mexico.,Faculty of Medicine, Autonomous University of Puebla, Puebla, Puebla, Mexico
| | - Robert Y L Zee
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.,Department of Pediatric Dentistry, Tufts University School of Dental Medicine, Boston, MA, United States
| | | | | | - Jose R Romero
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, United States
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Péterfi A, Mészáros Á, Szarvas Z, Pénzes M, Fekete M, Fehér Á, Lehoczki A, Csípő T, Fazekas-Pongor V. Comorbidities and increased mortality of COVID-19 among the elderly: A systematic review. Physiol Int 2022; 109:163-176. [PMID: 35575986 DOI: 10.1556/2060.2022.00206] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/14/2022] [Accepted: 03/01/2022] [Indexed: 02/18/2024]
Abstract
Purpose The purpose of current review is to conduct a systematic overview of articles published between 2019 and 2021 on the relationship of comorbidities and mortality due to Coronavirus Disease 2019 (COVID-19) among the elderly population. Methods We conducted a systematic search on PubMed for articles published between 2019 and 2021 to identify any cohort and case-control studies that investigated the relationship of comorbidities and COVID-19 mortality among the elderly, defined as 60 years of age and above. Databases were searched independently by two authors. Disagreements were resolved by the inclusion of a third investigator. Reviews, systematic reviews, and meta-analyses were excluded from our systematic review. Results A total of 15 studies were selected for our systematic review. Of the included studies, 3 were case-control, 3 were prospective cohort studies and 9 were retrospective cohort studies. As for size, 10 studies were conducted on populations of <1000 participants, 3 ranging from 1001 to 10,000, and 2 on populations of >10,000 individuals. The included studies found that the presence of certain conditions, such as cardiovascular, respiratory, renal diseases, malignancies, diseases of the nervous system and diabetes are associated to increased mortality in populations that consisted of elderly patients. Conclusion Results of our systematic review suggest that comorbidities contribute to increased COVID-19 mortality among the elderly. The detrimental effect of comorbidities and advanced age on the immune response could lead to a more frequent occurrence of symptomatic and severe infections with COVID-19.
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Affiliation(s)
- Anna Péterfi
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Ágota Mészáros
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Zsófia Szarvas
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Melinda Pénzes
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Mónika Fekete
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Ágnes Fehér
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Andrea Lehoczki
- 2 National Institute for Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, South Pest Central Hospital, Budapest, Hungary
| | - Tamás Csípő
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Vince Fazekas-Pongor
- 1 Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
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10
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Quarleri J, Delpino MV. SARS-CoV-2 interacts with renin-angiotensin system: impact on the central nervous system in elderly patients. GeroScience 2022; 44:547-565. [PMID: 35157210 PMCID: PMC8853071 DOI: 10.1007/s11357-022-00528-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/08/2022] [Indexed: 01/18/2023] Open
Abstract
SARS-CoV-2 is a recently identified coronavirus that causes the current pandemic disease known as COVID-19. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, suggesting that the initial steps of SARS-CoV-2 infection may have an impact on the renin-angiotensin system (RAS). Several processes are influenced by RAS in the brain. The neurological symptoms observed in COVID-19 patients, including reduced olfaction, meningitis, ischemic stroke, cerebral thrombosis, and delirium, could be associated with RAS imbalance. In this review, we focus on the potential role of disturbances in the RAS as a cause for central nervous system sequelae of SARS-CoV-2 infection in elderly patients.
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Affiliation(s)
- Jorge Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus Y Sida (INBIRS), Universidad de Buenos Aires-CONICET, Paraguay 2155-Piso 11 (1121), Buenos Aires, Argentina.
| | - M Victoria Delpino
- Instituto de Investigaciones Biomédicas en Retrovirus Y Sida (INBIRS), Universidad de Buenos Aires-CONICET, Paraguay 2155-Piso 11 (1121), Buenos Aires, Argentina.
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11
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Calcific aortic valve stenosis and COVID-19: clinical management, valvular damage, and pathophysiological mechanisms. CARDIOLOGY PLUS 2022. [DOI: 10.1097/cp9.0000000000000001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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12
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Fekete M, Szarvas Z, Fazekas-Pongor V, Feher A, Dosa N, Lehoczki A, Tarantini S, Varga JT. COVID-19 infection in patients with chronic obstructive pulmonary disease: From pathophysiology to therapy. Mini-review. Physiol Int 2022; 109:9-19. [PMID: 35230261 DOI: 10.1556/2060.2022.00172] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 02/06/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Patients with chronic obstructive pulmonary disease (COPD) are a vulnerable group in terms of the outcome of coronavirus infection in relation to their disease or its treatment, with a higher risk of developing serious complications compared to the healthy population. AIM The aim of our summary study is to review the background and health outcomes of chronic obstructive pulmonary disease and COVID-19 infection in the presence of both diseases. METHODS Review of national and international medical databases (PubMed, MEDLINE, and MOB) with keywords COPD, COVID-19, disease risk, cause, prevention, complications, and prognosis. RESULTS Meta-analyses show that COPD is one of the most common underlying conditions in patients hospitalized for COVID-19. Such patients are five times more likely to develop a serious complication due to oxygen supply problems therefore they are more likely to be admitted to intensive care units, where they may require mechanical ventilation. In the case of underlying COPD, the usual care plan for COVID-19 infection should be followed, as well as all public health recommendations to minimize the risk of developing and transmitting COVID-19. CONCLUSION Coronavirus infection is especially dangerous for COPD patients, who are much more likely to become seriously ill, so increased surveillance, prevention, early detection, adequate treatment and rehabilitation of the disease group are of paramount importance.
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Affiliation(s)
- Monika Fekete
- 1 Department of Public Health, Semmelweis University, Faculty of Medicine, Budapest, Hungary
| | - Zsofia Szarvas
- 1 Department of Public Health, Semmelweis University, Faculty of Medicine, Budapest, Hungary
| | - Vince Fazekas-Pongor
- 1 Department of Public Health, Semmelweis University, Faculty of Medicine, Budapest, Hungary
| | - Agnes Feher
- 1 Department of Public Health, Semmelweis University, Faculty of Medicine, Budapest, Hungary
| | - Norbert Dosa
- 1 Department of Public Health, Semmelweis University, Faculty of Medicine, Budapest, Hungary
| | - Andrea Lehoczki
- 2 Department of Hematology and Stem Cell Transplantation, National Institute for Hematology and Infectious Diseases, South Pest Central Hospital, Budapest, Hungary
| | - Stefano Tarantini
- 1 Department of Public Health, Semmelweis University, Faculty of Medicine, Budapest, Hungary
- 3 Department of Biochemistry and Molecular Biology at University of Oklahoma Health Sciences Center, Oklahoma City, OK,USA
| | - Janos Tamas Varga
- 4 Department of Pulmonology, Semmelweis University, Budapest, Hungary
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Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning. Int J Mol Sci 2021; 22:ijms222011064. [PMID: 34681724 PMCID: PMC8537248 DOI: 10.3390/ijms222011064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 11/23/2022] Open
Abstract
Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague–Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 ± 2.1% to 50 ± 1.6%, mean ± SEM, p < 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 ± 4.8% to 55.2 ± 4.1%, p < 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca2+-sensitivities of force production (pCa50) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa50, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI.
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