Immunoinflammatory, Thrombohaemostatic, and Cardiovascular Mechanisms in COVID-19

Selin Gencer; Michael Lacy; Dorothee Atzler; Emiel P. C. van der Vorst; Yvonne Döring; Christian Weber

doi:10.1055/s-0040-1718735

Thrombosis and Haemostasis, Table of Contents

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‡^*

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany

,

Michael Lacy^*

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany

²DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

,

Dorothee Atzler

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany

²DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

³Walther Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-Universität, Munich, Germany

,

Emiel P. C. van der Vorst

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany

²DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

⁴Interdisciplinary Center for Clinical Research (IZKF), Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany

⁵Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

,

Yvonne Döring

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany

²DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

⁶Divison of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Switzerland

,

Christian Weber^**

¹Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany

²DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

⁷Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands

⁸Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

› Author Affiliations

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

Full Text

References

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
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
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
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
5 Lovato A, de Filippis C. Clinical presentation of COVID-19: a systematic review focusing on upper airway symptoms. Ear Nose Throat J 2020;
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
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
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
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
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
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
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
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
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
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
16 Merkler AE, Parikh NS, Mir S. et al. Risk of ischemic stroke in patients with Covid-19 versus patients with influenza. medRxiv 2020;
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
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
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
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
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
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
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
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
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
26 Fountain J, Lappin S. Physiology, Renin Angiotensin System. [Updated July 27, 2020]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing;
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
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
29 Rüster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 2006; 17 (11) 2985-2991
30 Cohn JN. Role of the renin-angiotensin system in cardiovascular disease. Cardiovasc Drugs Ther 2010; 24 (04) 341-344
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
32 Underwood PC, Adler GK. The renin angiotensin aldosterone system and insulin resistance in humans. Curr Hypertens Rep 2013; 15 (01) 59-70
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
34 Umemura S, Nyui N, Tamura K. et al. Plasma angiotensinogen concentrations in obese patients. Am J Hypertens 1997; 10 (06) 629-633
35 Sharma AM, Engeli S. Obesity and the renin- angiotensin-aldosterone system. Expert Rev Endocrinol Metab 2006; 1 (02) 255-264
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
37 Dorresteijn JAN, Visseren FLJ, Spiering W. Mechanisms linking obesity to hypertension. Obes Rev 2012; 13 (01) 17-26
38 Goodfriend TL, Egan BM, Kelley DE. Aldosterone in obesity. In: Endocrine Research. Vol 24. New York, NY: Marcel Dekker Inc.; 1998: 789-796
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
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
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
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
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
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
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
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
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
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
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
50 Satarker S, Nampoothiri M. Structural proteins in severe acute respiratory syndrome coronavirus-2. Arch Med Res 2020; 51 (06) 482-491
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
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
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
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
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
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
57 Wang K, Gheblawi M, Oudit GY. Angiotensin converting enzyme 2: a double-edged sword. Circulation 2020;
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
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
60 Farah C, Michel LYM, Balligand JL. Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol 2018; 15 (05) 292-316
61 Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and endothelial function. Nutrients 2020; 12 (02) 1-17
62 Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS. Nitric oxide and endothelial dysfunction. Crit Care Clin 2020; 36 (02) 307-321
63 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
64 Asadi-Pooya AA, Simani L. Central nervous system manifestations of COVID-19: A systematic review. J Neurol Sci 2020; 413: 116832
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
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;
67 Yetik-Anacak G, Catravas JD. Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascul Pharmacol 2006; 45 (05) 268-276
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
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
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
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
72 Green SJ. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect 2020; 22 (4–5): 149-150
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
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
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
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;
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
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
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
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
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
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;
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
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;
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
86 Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol 2019; 10: 119
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
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
89 Leppkes M, Knopf J, Naschberger E. et al. Vascular occlusion by neutrophil extracellular traps in COVID-19. EBioMedicine 2020; 58: 102925
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
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
92 Lala A, Johnson KW, Januzzi J. et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID- 19 infection. medRxiv 2020;
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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;
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
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
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
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;
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
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
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
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
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
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
118 Ramirez LMP, Caballero MC, de la Torre IM. et al. Hospital readmissions of discharged patients with COVID-19. medRxiv 2020;
119 Chen J, Fan H, Zhang L. et al. Retrospective analysis of clinical features in 101 death cases with COVID-19. medRxiv 2020;
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
121 Costabel JP, Burgos LM, Trivi M. The significance of troponin elevation in atrial fibrillation. J Atr Fibrillation 2017; 9 (06) 1530
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
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
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
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
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
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
128 Ferrari R. RAAS inhibition and mortality in hypertension. Glob Cardiol Sci Pract 2013; 2013 (03) 269-278
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
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
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
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
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
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
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
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
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
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
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
140 Rossi GP, Sanga V, Barton M. Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients. eLife 2020; 9: e57278
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
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
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
144 Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. Nature 2020; 582 (7813): 469
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
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
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
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
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
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