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Thromb Haemost 2020; 120(12): 1629-1641
DOI: 10.1055/s-0040-1718735
Theme Issue Article

Immunoinflammatory, Thrombohaemostatic, and Cardiovascular Mechanisms in COVID-19

Selin Gencer‡   *
1   Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany
,
Michael Lacy   *
1   Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany
2   DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
,
Dorothee Atzler
1   Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany
2   DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
3   Walther Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-Universität, Munich, Germany
,
Emiel P. C. van der Vorst
1   Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany
2   DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
4   Interdisciplinary Center for Clinical Research (IZKF), Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
5   Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
,
Yvonne Döring
1   Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany
2   DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
6   Divison of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Switzerland
,
Christian Weber   **
1   Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany
2   DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
7   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands
8   Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
› Author Affiliations Funding This study was supported by Deutsche Forschungsgemeinschaft (SFB1123).
› Further Information
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Abstract

The global coronavirus disease 2019 (COVID-19) pandemic has deranged the recent history of humankind, afflicting more than 27 million individuals to date. While the majority of COVID-19 patients recuperate, a considerable number of patients develop severe complications. Bilateral pneumonia constitutes the hallmark of severe COVID-19 disease but an involvement of other organ systems, namely the cardiovascular system, kidneys, liver, and central nervous system, occurs in at least half of the fatal COVID-19 cases. Besides respiratory failure requiring ventilation, patients with severe COVID-19 often display manifestations of systemic inflammation and thrombosis as well as diffuse microvascular injury observed postmortem. In this review, we survey the mechanisms that may explain how viral entry and activation of endothelial cells by severe acute respiratory syndrome coronavirus 2 can give rise to a series of events including systemic inflammation, thrombosis, and microvascular dysfunction. This pathophysiological scenario may be particularly harmful in patients with overt cardiovascular disease and may drive the fatal aspects of COVID-19. We further shed light on the role of the renin–angiotensin aldosterone system and its inhibitors in the context of COVID-19 and discuss the potential impact of antiviral and anti-inflammatory treatment options. Acknowledging the comorbidities and potential organ injuries throughout the course of severe COVID-19 is crucial in the clinical management of patients affecting treatment approaches and recovery rate.

Keywords

COVID-19 - SARS-CoV-2 - cardiovascular disease - inflammation - thrombosis - RAAS - ACE2

* These authors contributed equally to this manuscript and share first authorship.


** The review process for this paper was fully handled by Gregory Y. H. Lip, Editor-in-Chief.




Publication History

Received: 03 July 2020

Accepted: 14 September 2020

Article published online:
29 October 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 2020; 20 (05) 533-534
    CrossrefPubMedGoogle Scholar
  • 2 Wu Z, McGoogan JM. Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323 (13) 1239-1242
    CrossrefPubMedGoogle Scholar
  • 3 Cheng VCC, Lau SKP, Woo PCY, Yuen KY. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev 2007; 20 (04) 660-694
    CrossrefPubMedGoogle Scholar
  • 4 Guan WJ, Ni ZY, Hu Y. et al. China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18) 1708-1720
    CrossrefPubMedGoogle Scholar
  • 5 Lovato A, de Filippis C. Clinical presentation of COVID-19: a systematic review focusing on upper airway symptoms. Ear Nose Throat J 2020; DOI: 10.1177/0145561320920762.
    CrossrefPubMedGoogle Scholar
  • 6 Inciardi RM, Lupi L, Zaccone G. et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; 5 (07) 819-824
    CrossrefPubMedGoogle Scholar
  • 7 Sala S, Peretto G, Gramegna M. et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J 2020; 41 (19) 1861-1862
    CrossrefPubMedGoogle Scholar
  • 8 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
    Google Scholar
  • 9 Lippi G, Favaloro EJ. D-dimer is associated with severity of coronavirus disease 2019: a pooled analysis. Thromb Haemost 2020; 120 (05) 876-878
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association?. Eur Heart J 2020; 41 (19) 1858
    CrossrefPubMedGoogle Scholar
  • 11 Shi S, Qin M, Shen B. et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020; 5 (07) 802-810
    CrossrefPubMedGoogle Scholar
  • 12 Cowan LT, Lutsey PL, Pankow JS, Matsushita K, Ishigami J, Lakshminarayan K. Inpatient and outpatient infection as a trigger of cardiovascular disease: the ARIC study. J Am Heart Assoc 2018; 7 (22) e009683
    CrossrefPubMedGoogle Scholar
  • 13 Madjid M, Miller CC, Zarubaev VV. et al. Influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: results from 8 years of autopsies in 34,892 subjects. Eur Heart J 2007; 28 (10) 1205-1210
    CrossrefPubMedGoogle Scholar
  • 14 Peiris JSM, Chu CM, Cheng VCC. et al. HKU/UCH SARS Study Group. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 2003; 361 (9371): 1767-1772
    CrossrefPubMedGoogle Scholar
  • 15 Chong PY, Chui P, Ling AE. et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 2004; 128 (02) 195-204
    CrossrefPubMedGoogle Scholar
  • 16 Merkler AE, Parikh NS, Mir S. et al. Risk of ischemic stroke in patients with Covid-19 versus patients with influenza. medRxiv 2020; DOI: 10.1101/2020.05.18.20105494.
    CrossrefPubMedGoogle Scholar
  • 17 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
    CrossrefPubMedGoogle Scholar
  • 18 Wang D, Hu B, Hu C. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323 (11) 1061-1069
    CrossrefPubMedGoogle Scholar
  • 19 Zhu L, She ZG, Cheng X. et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab 2020; 31 (06) 1068.e3-1077.e3
    PubMedGoogle Scholar
  • 20 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271.e8-280.e8
    CrossrefPubMedGoogle Scholar
  • 21 Lu R, Zhao X, Li J. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395 (10224): 565-574
    CrossrefPubMedGoogle Scholar
  • 22 Renhong Y, Yuanyuan Z, Yaning L, Lu X, Yingyang G, QIang Z. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020; 367 (6485): 1444-1448
    CrossrefPubMedGoogle Scholar
  • 23 Li MY, Li L, Zhang Y, Wang XS. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty 2020; 9 (01) 45
    CrossrefPubMedGoogle Scholar
  • 24 Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 2020; 116 (06) 1097-1100
    CrossrefPubMedGoogle Scholar
  • 25 Nicin L, Abplanalp WT, Mellentin H. et al. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur Heart J 2020; 41 (19) 1804-1806
    CrossrefPubMedGoogle Scholar
  • 26 Fountain J, Lappin S. Physiology, Renin Angiotensin System. [Updated July 27, 2020]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing;
    Google Scholar
  • 27 Ma TKW, Kam KKH, Yan BP, Lam YY. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 2010; 160 (06) 1273-1292
    CrossrefPubMedGoogle Scholar
  • 28 Wu CH, Mohammadmoradi S, Chen JZ, Sawada H, Daugherty A, Lu HS. Renin-angiotensin system and cardiovascular functions. Arterioscler Thromb Vasc Biol 2018; 38 (07) e108-e116
    PubMedGoogle Scholar
  • 29 Rüster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 2006; 17 (11) 2985-2991
    CrossrefPubMedGoogle Scholar
  • 30 Cohn JN. Role of the renin-angiotensin system in cardiovascular disease. Cardiovasc Drugs Ther 2010; 24 (04) 341-344
    CrossrefPubMedGoogle Scholar
  • 31 Ruiz-Ortega M, Lorenzo O, Rupérez M. et al. Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension 2001; 38 (06) 1382-1387
    CrossrefPubMedGoogle Scholar
  • 32 Underwood PC, Adler GK. The renin angiotensin aldosterone system and insulin resistance in humans. Curr Hypertens Rep 2013; 15 (01) 59-70
    CrossrefPubMedGoogle Scholar
  • 33 Favre GA, Esnault VLM, Van Obberghen E. Modulation of glucose metabolism by the renin-angiotensin-aldosterone system. Am J Physiol Endocrinol Metab 2015; 308 (06) E435-E449
    CrossrefPubMedGoogle Scholar
  • 34 Umemura S, Nyui N, Tamura K. et al. Plasma angiotensinogen concentrations in obese patients. Am J Hypertens 1997; 10 (06) 629-633
    CrossrefPubMedGoogle Scholar
  • 35 Sharma AM, Engeli S. Obesity and the renin- angiotensin-aldosterone system. Expert Rev Endocrinol Metab 2006; 1 (02) 255-264
    CrossrefPubMedGoogle Scholar
  • 36 Schütten MTJ, Houben AJHM, de Leeuw PW, Stehouwer CDA. The link between adipose tissue renin-angiotensin-aldosterone system signaling and obesity-associated hypertension. Physiology (Bethesda) 2017; 32 (03) 197-209
    CrossrefPubMedGoogle Scholar
  • 37 Dorresteijn JAN, Visseren FLJ, Spiering W. Mechanisms linking obesity to hypertension. Obes Rev 2012; 13 (01) 17-26
    CrossrefPubMedGoogle Scholar
  • 38 Goodfriend TL, Egan BM, Kelley DE. Aldosterone in obesity. In: Endocrine Research. Vol 24. New York, NY: Marcel Dekker Inc.; 1998: 789-796
    Google Scholar
  • 39 Frigolet ME, Torres N, Tovar AR. The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J Nutr Biochem 2013; 24 (12) 2003-2015
    CrossrefPubMedGoogle Scholar
  • 40 Carroll WX, Kalupahana NS, Booker SL. et al. Angiotensinogen gene silencing reduces markers of lipid accumulation and inflammation in cultured adipocytes. Front Endocrinol (Lausanne) 2013; 4: 10
    CrossrefPubMedGoogle Scholar
  • 41 Gheblawi M, Wang K, Viveiros A. et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020; 126 (10) 1456-1474
    CrossrefPubMedGoogle Scholar
  • 42 Dalan R, Bornstein SR, El-Armouche A. et al. The ACE-2 in COVID-19: foe or friend?. Horm Metab Res 2020; 52 (05) 257-263
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Echeverría-Rodríguez O, Del Valle-Mondragón L, Hong E. Angiotensin 1-7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo. Peptides 2014; 51: 26-30
    CrossrefPubMedGoogle Scholar
  • 44 Passos-Silva DG, Verano-Braga T, Santos RAS. Angiotensin-(1-7): beyond the cardio-renal actions. Clin Sci (Lond) 2013; 124 (07) 443-456
    CrossrefPubMedGoogle Scholar
  • 45 Meng Y, Yu CH, Li W. et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway. Am J Respir Cell Mol Biol 2014; 50 (04) 723-736
    CrossrefPubMedGoogle Scholar
  • 46 Rodrigues Prestes TR, Rocha NP, Miranda AS, Teixeira AL, Simoes-E-Silva AC. The anti-inflammatory potential of ACE2/angiotensin-(1-7)/Mas receptor axis: evidence from basic and clinical research. Curr Drug Targets 2017; 18 (11) 1301-1313
    CrossrefPubMedGoogle Scholar
  • 47 Tseng YH, Yang RC, Lu TS. Two hits to the renin-angiotensin system may play a key role in severe COVID-19. Kaohsiung J Med Sci 2020; 36 (06) 389-392
    CrossrefPubMedGoogle Scholar
  • 48 Wang Q, Zhang Y, Wu L. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 2020; 181 (04) 894-904.e9
    CrossrefPubMedGoogle Scholar
  • 49 Ou X, Liu Y, Lei X. et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11 (01) 1620
    CrossrefPubMedGoogle Scholar
  • 50 Satarker S, Nampoothiri M. Structural proteins in severe acute respiratory syndrome coronavirus-2. Arch Med Res 2020; 51 (06) 482-491
    CrossrefPubMedGoogle Scholar
  • 51 Shang J, Wan Y, Luo C. et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A 2020; 117 (21) 11727-11734
    CrossrefPubMedGoogle Scholar
  • 52 Aimes RT, Zijlstra A, Hooper JD. et al. Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. Thromb Haemost 2003; 89 (03) 561-572
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol 2008; 93 (05) 543-548
    CrossrefPubMedGoogle Scholar
  • 54 Kuba K, Imai Y, Rao S. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11 (08) 875-879
    CrossrefPubMedGoogle Scholar
  • 55 Zhong J, Basu R, Guo D. et al. Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation 2010; 122 (07) 717-728
    CrossrefPubMedGoogle Scholar
  • 56 South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol 2020; 318 (05) H1084-H1090
    CrossrefPubMedGoogle Scholar
  • 57 Wang K, Gheblawi M, Oudit GY. Angiotensin converting enzyme 2: a double-edged sword. Circulation 2020; DOI: 10.1161/circulationaha.120.047049.
    CrossrefPubMedGoogle Scholar
  • 58 Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med 2020; 76: 14-20
    CrossrefPubMedGoogle Scholar
  • 59 Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med 2020; 382 (25) e102
    CrossrefPubMedGoogle Scholar
  • 60 Farah C, Michel LYM, Balligand JL. Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol 2018; 15 (05) 292-316
    CrossrefPubMedGoogle Scholar
  • 61 Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and endothelial function. Nutrients 2020; 12 (02) 1-17
    CrossrefPubMedGoogle Scholar
  • 62 Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS. Nitric oxide and endothelial dysfunction. Crit Care Clin 2020; 36 (02) 307-321
    CrossrefPubMedGoogle Scholar
  • 63 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
    CrossrefPubMedGoogle Scholar
  • 64 Asadi-Pooya AA, Simani L. Central nervous system manifestations of COVID-19: A systematic review. J Neurol Sci 2020; 413: 116832
    CrossrefPubMedGoogle Scholar
  • 65 Castro Dias M, Mapunda JA, Vladymyrov M, Engelhardt B. Structure and junctional complexes of endothelial, epithelial and glial brain barriers. Int J Mol Sci 2019; 20 (21) 5372
    CrossrefPubMedGoogle Scholar
  • 66 Wang K, Chen W, Zhou Y-S. et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv 2020; DOI: 10.1101/2020.03.14.988345.
    CrossrefPubMedGoogle Scholar
  • 67 Yetik-Anacak G, Catravas JD. Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascul Pharmacol 2006; 45 (05) 268-276
    CrossrefPubMedGoogle Scholar
  • 68 Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care 2002; 25 (08) 1336-1339
    CrossrefPubMedGoogle Scholar
  • 69 Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol 2000; 36 (03) 845-851
    CrossrefPubMedGoogle Scholar
  • 70 Akerström S, Gunalan V, Keng CT, Tan YJ, Mirazimi A. Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected. Virology 2009; 395 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 71 Saura M, Zaragoza C, McMillan A. et al. An antiviral mechanism of nitric oxide: inhibition of a viral protease. Immunity 1999; 10 (01) 21-28
    CrossrefPubMedGoogle Scholar
  • 72 Green SJ. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect 2020; 22 (4–5): 149-150
    CrossrefPubMedGoogle Scholar
  • 73 Santovito D, Egea V, Bidzhekov K. et al. Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis. Sci Transl Med 2020; 12 (546) 1-16
    CrossrefPubMedGoogle Scholar
  • 74 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
    CrossrefPubMedGoogle Scholar
  • 75 Xu Z, Shi L, Wang Y. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8 (04) 420-422
    CrossrefPubMedGoogle Scholar
  • 76 Ellinghaus D, Degenhardt F, Bujanda L. et al. Severe Covid-19 GWAS Group. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med 2020; DOI: 10.1056/NEJMoa2020283.
    CrossrefPubMedGoogle Scholar
  • 77 Abd Alla J, Langer A, Elzahwy SS, Arman-Kalcek G, Streichert T, Quitterer U. Angiotensin-converting enzyme inhibition down-regulates the pro-atherogenic chemokine receptor 9 (CCR9)-chemokine ligand 25 (CCL25) axis. J Biol Chem 2010; 285 (30) 23496-23505
    CrossrefPubMedGoogle Scholar
  • 78 Butcher MJ, Wu CI, Waseem T, Galkina EV. CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas. Int Immunol 2016; 28 (05) 255-261
    CrossrefPubMedGoogle Scholar
  • 79 Wein AN, McMaster SR, Takamura S. et al. CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways. J Exp Med 2019; 216 (12) 2748-2762
    CrossrefPubMedGoogle Scholar
  • 80 Tan L, Wang Q, Zhang D. et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther 2020; 5 (01) 33
    CrossrefPubMedGoogle Scholar
  • 81 Diao B, Wang C, Tan Y. et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020; 11: 827
    CrossrefPubMedGoogle Scholar
  • 82 Kalfaoglu B, Almeida-Santos J, Tye CA, Satou Y, Ono M. T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis. bioRxiv 2020; DOI: 10.1101/2020.05.26.115923.
    CrossrefPubMedGoogle Scholar
  • 83 Blanco-Melo D, Nilsson-Payant BE, Liu WC. et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020; 181 (05) 1036.e9-1045.e9
    CrossrefPubMedGoogle Scholar
  • 84 Hadjadj J, Yatim N, Barnabei L. et al. Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients. medRxiv 2020; DOI: 10.1101/2020.04.19.20068015.
    CrossrefPubMedGoogle Scholar
  • 85 McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020; 19 (06) 102537
    CrossrefPubMedGoogle Scholar
  • 86 Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol 2019; 10: 119
    CrossrefPubMedGoogle Scholar
  • 87 Liao M, Liu Y, Yuan J. et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 2020; 26 (06) 842-844
    CrossrefPubMedGoogle Scholar
  • 88 Feng Z, Diao B, Wang R. et al. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes. medRxiv 2020; 2 :2020.03.27.20045427 DOI: 10.1101/2020.03.27.20045427.
    CrossrefPubMedGoogle Scholar
  • 89 Leppkes M, Knopf J, Naschberger E. et al. Vascular occlusion by neutrophil extracellular traps in COVID-19. EBioMedicine 2020; 58: 102925
    CrossrefPubMedGoogle Scholar
  • 90 Zheng HY, Zhang M, Yang CX. et al. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell Mol Immunol 2020; 17 (05) 541-543
    CrossrefPubMedGoogle Scholar
  • 91 Wen W, Su W, Tang H. et al. Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov 2020; 6 (01) 31
    CrossrefPubMedGoogle Scholar
  • 92 Lala A, Johnson KW, Januzzi J. et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID- 19 infection. medRxiv 2020; DOI: 10.1101/2020.04.20.20072702.
    CrossrefPubMedGoogle Scholar
  • 93 Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004; 351 (25) 2611-2618
    CrossrefPubMedGoogle Scholar
  • 94 Schieffer B, Selle T, Hilfiker A. et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation 2004; 110 (22) 3493-3500
    CrossrefPubMedGoogle Scholar
  • 95 Brånén L, Hovgaard L, Nitulescu M, Bengtsson E, Nilsson J, Jovinge S. Inhibition of tumor necrosis factor-α reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 2004; 24 (11) 2137-2142
    CrossrefPubMedGoogle Scholar
  • 96 Magro C, Mulvey JJ, Berlin D. et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 2020; 220 (June): 1-13
    CrossrefPubMedGoogle Scholar
  • 97 Viedt C, Hänsch GM, Brandes RP, Kübler W, Kreuzer J. The terminal complement complex C5b-9 stimulates interleukin-6 production in human smooth muscle cells through activation of transcription factors NF-κ B and AP-1. FASEB J 2000; 14 (15) 2370-2372
    CrossrefPubMedGoogle Scholar
  • 98 Kang MJ, Jo SG, Kim DJ, Park JH. NLRP3 inflammasome mediates interleukin-1β production in immune cells in response to Acinetobacter baumannii and contributes to pulmonary inflammation in mice. Immunology 2017; 150 (04) 495-505
    CrossrefPubMedGoogle Scholar
  • 99 Wu C, Lu W, Zhang Y. et al. Inflammasome activation triggers blood clotting and host death through pyroptosis. Immunity 2019; 50 (06) 1401.e4-1411.e4
    PubMedGoogle Scholar
  • 100 Jia C, Zhang J, Chen H. et al. Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation. Cell Death Dis 2019; 10 (10) 778
    CrossrefPubMedGoogle Scholar
  • 101 Libby P. Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. J Am Coll Cardiol 2017; 70 (18) 2278-2289
    CrossrefPubMedGoogle Scholar
  • 102 Ridker PM, Everett BM, Thuren T. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
    CrossrefPubMedGoogle Scholar
  • 103 Weber C, von Hundelshausen P. CANTOS trial validates the inflammatory pathogenesis of atherosclerosis: setting the stage for a new chapter in therapeutic targeting. Circ Res 2017; 121 (10) 1119-1121
    CrossrefPubMedGoogle Scholar
  • 104 Cavalli G, De Luca G, Campochiaro C. et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020; 2 (06) e325-e331
    CrossrefPubMedGoogle Scholar
  • 105 Xu X, Han M, Li T. et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020; 117 (20) 10970-10975
    CrossrefPubMedGoogle Scholar
  • 106 McGonagle D, O'Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol 2020; 2 (07) e437-e445
    CrossrefPubMedGoogle Scholar
  • 107 Alessandro A, Thomas T, Dzieciatkowska M. et al. Serum proteomics in COVID-19 patients: Altered coagulation and complement status as a function of IL-6 level. medRxiv 2020; DOI: 10.1101/2020.05.29.20116889.
    CrossrefPubMedGoogle Scholar
  • 108 Boscolo A, Spiezia L, Correale C. et al. Different hypercoagulable profiles in patients with COVID-19 admitted to the internal medicine ward and the intensive care unit. Thromb Haemost 2020; 120 (10) 1474-1477
    Article in Thieme ConnectPubMedGoogle Scholar
  • 109 Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta 2020; 506: 145-148
    CrossrefPubMedGoogle Scholar
  • 110 Weiss E, Roux O, Moyer J-D. et al. Fibrinolysis resistance: a potential mechanism underlying COVID-19 coagulopathy. Thromb Haemost 2020; 120 (09) 1343-1345
    Article in Thieme ConnectPubMedGoogle Scholar
  • 111 Bryce C, Grimes Z, Pujadas E. et al. Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience. medRxiv 2020; DOI: 10.1101/2020.05.18.20099960.
    CrossrefPubMedGoogle Scholar
  • 112 Trinh M, Chang DR, Govindarajulu US. et al. Therapeutic anticoagulation is associated with decreased mortality in mechanically ventilated COVID-19 patients. medRxiv 2020; :2020.05.30.20117929 DOI: 10.1101/2020.05.30.20117929.
    CrossrefPubMedGoogle Scholar
  • 113 Bikdeli B, Madhavan MV, Gupta A. et al. Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
    Article in Thieme ConnectPubMedGoogle Scholar
  • 114 Zhai Z, Li C, Chen Y. et al. Prevention Treatment of VTE Associated with COVID-19 Infection Consensus Statement Group. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines. Thromb Haemost 2020; 120 (06) 937-948
    Article in Thieme ConnectPubMedGoogle Scholar
  • 115 Wei JF, Huang FY, Xiong TY. et al. Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis. Heart 2020; 106 (15) 1154-1159
    CrossrefPubMedGoogle Scholar
  • 116 Chen T, Wu D, Chen H. et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020; 368: m1091
    CrossrefPubMedGoogle Scholar
  • 117 Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. COVID-19 does not lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med 2020; 201 (10) 1299-1300
    CrossrefPubMedGoogle Scholar
  • 118 Ramirez LMP, Caballero MC, de la Torre IM. et al. Hospital readmissions of discharged patients with COVID-19. medRxiv 2020; DOI: 10.1101/2020.05.31.20118455.
    CrossrefPubMedGoogle Scholar
  • 119 Chen J, Fan H, Zhang L. et al. Retrospective analysis of clinical features in 101 death cases with COVID-19. medRxiv 2020; DOI: 10.1101/2020.03.09.20033068.
    CrossrefPubMedGoogle Scholar
  • 120 Driggin E, Madhavan MV, Bikdeli B. et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020; 75 (18) 2352-2371
    CrossrefPubMedGoogle Scholar
  • 121 Costabel JP, Burgos LM, Trivi M. The significance of troponin elevation in atrial fibrillation. J Atr Fibrillation 2017; 9 (06) 1530
    CrossrefPubMedGoogle Scholar
  • 122 Peretto G, Sala S, Rizzo S. et al. Ventricular arrhythmias in myocarditis: characterization and relationships with myocardial inflammation. J Am Coll Cardiol 2020; 75 (09) 1046-1057
    CrossrefPubMedGoogle Scholar
  • 123 Tavazzi G, Pellegrini C, Maurelli M. et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 2020; 22 (05) 911-915
    CrossrefPubMedGoogle Scholar
  • 124 Zeng JH, Liu YX, Yuan J. et al. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection 2020; 48 (05) 773-777
    CrossrefPubMedGoogle Scholar
  • 125 Doyen D, Moceri P, Ducreux D, Dellamonica J. Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes. Lancet 2020; 395 (10235): 1516
    CrossrefPubMedGoogle Scholar
  • 126 Guzik TJ, Mohiddin SA, Dimarco A. et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020; 116 (10) 1666-1687
    CrossrefPubMedGoogle Scholar
  • 127 Guo T, Fan Y, Chen M. et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; 5 (07) 811-818
    CrossrefPubMedGoogle Scholar
  • 128 Ferrari R. RAAS inhibition and mortality in hypertension. Glob Cardiol Sci Pract 2013; 2013 (03) 269-278
    PubMedGoogle Scholar
  • 129 Bavishi C, Maddox TM, Messerli FH. Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers. JAMA Cardiol 2020; 5 (07) 745-747
    CrossrefPubMedGoogle Scholar
  • 130 Guazzi M, Moroni A. The dilemma of renin-angiotensin system inhibitors in coronavirus disease 2019 (COVID-19): insights into lung fluid handling and gas exchange in heart failure patients. Eur J Heart Fail 2020; 22 (06) 926-928
    CrossrefPubMedGoogle Scholar
  • 131 Kuster GM, Pfister O, Burkard T. et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19?. Eur Heart J 2020; 41 (19) 1801-1803
    CrossrefPubMedGoogle Scholar
  • 132 Keidar S, Gamliel-Lazarovich A, Kaplan M. et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res 2005; 97 (09) 946-953
    CrossrefPubMedGoogle Scholar
  • 133 Zhong JC, Ye JY, Jin HY. et al. Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression. Regul Pept 2011; 166 (1–3): 90-97
    CrossrefPubMedGoogle Scholar
  • 134 Ferrario CM, Jessup J, Chappell MC. et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005; 111 (20) 2605-2610
    CrossrefPubMedGoogle Scholar
  • 135 Zheng Y-Y, Ma Y-T, Zhang J-Y, Xie X. Reply to: ‘Interaction between RAAS inhibitors and ACE2 in the context of COVID-19’. Nat Rev Cardiol 2020; 17 (05) 313-314
    CrossrefPubMedGoogle Scholar
  • 136 Albini A, Di Guardo G, Noonan DM, Lombardo M. The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies. Intern Emerg Med 2020; 15 (05) 759-766
    CrossrefPubMedGoogle Scholar
  • 137 Milne S, Yang CX, Timens W, Bossé Y, Sin DD. SARS-CoV-2 receptor ACE2 gene expression and RAAS inhibitors. Lancet Respir Med 2020; 8 (06) e50-e51
    CrossrefPubMedGoogle Scholar
  • 138 Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin–angiotensin–aldosterone system blockers and the risk of COVID-19. N Engl J Med 2020; 382 (25) 2431-2440
    CrossrefPubMedGoogle Scholar
  • 139 Reynolds HR, Adhikari S, Pulgarin C. et al. Renin–angiotensin–aldosterone system inhibitors and risk of covid-19. N Engl J Med 2020; 382 (25) 2441-2448
    CrossrefPubMedGoogle Scholar
  • 140 Rossi GP, Sanga V, Barton M. Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients. eLife 2020; 9: e57278
    CrossrefPubMedGoogle Scholar
  • 141 ClinicalTrials.gov. A study to evaluate the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia. US National Library of Medicine. Accessed September 28, 2020 at: https://clinicaltrials.gov/ct2/show/NCT04320615
    PubMedGoogle Scholar
  • 142 ClinicalTrials.gov. observational study, use of canakinumab administered subcutaneously in the treatment COVID-19 pneumonia. US National Library of Medicine. Accessed September 28, 2020 at: https://www.clinicaltrials.gov/ct2/show/NCT04348448
    PubMedGoogle Scholar
  • 143 ClinicalTrials.gov. Efficacy and safety of emapalumab and anakinra in reducing hyperinflammation and respiratory distress in patients with COVID-19 infection. US National Library of Medicine. Accessed September 28, 2020 at: https://www.clinicaltrials.gov/ct2/show/NCT04324021
    PubMedGoogle Scholar
  • 144 Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. Nature 2020; 582 (7813): 469
    CrossrefPubMedGoogle Scholar
  • 145 Vandevyver S, Dejager L, Tuckermann J, Libert C. New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology 2013; 154 (03) 993-1007
    CrossrefPubMedGoogle Scholar
  • 146 Johannesdottir SA, Horváth-Puhó E, Dekkers OM. et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 2013; 173 (09) 743-752
    CrossrefPubMedGoogle Scholar
  • 147 van Giezen JJJ, Brakkee JGP, Dreteler GH, Bouma BN, Jansen JWCM. Dexamethasone affects platelet aggregation and fibrinolytic activity in rats at different doses which is reflected by their effect on arterial thrombosis. Blood Coagul Fibrinolysis 1994; 5 (02) 249-255
    CrossrefPubMedGoogle Scholar
  • 148 Violi F, Pastori D, Cangemi R, Pignatelli P, Loffredo L. Hypercoagulation and antithrombotic treatment in coronavirus 2019: a new challenge. Thromb Haemost 2020; 120 (06) 949-956
    Article in Thieme ConnectPubMedGoogle Scholar
  • 149 Jin HM, Pan Y. Angiotensin type-1 receptor blockade with losartan increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetes and nephropathy. Nephrol Dial Transplant 2007; 22 (07) 1943-1949
    CrossrefPubMedGoogle Scholar
  • 150 Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, Michel JB. Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol 2000; 20 (03) 645-651
    CrossrefPubMedGoogle Scholar