==== Front Diseases Diseases diseases Diseases 2079-9721 MDPI 33120956 10.3390/diseases8040040 diseases-08-00040 Brief Report Incidence of Myocardial Injury in COVID-19-Infected Patients: A Systematic Review and Meta-Analysis Prasitlumkum Narut 1* Chokesuwattanaskul Ronpichai 23* Thongprayoon Charat 4 Bathini Tarun 5 Vallabhajosyula Saraschandra 6 https://orcid.org/0000-0001-9954-9711Cheungpasitporn Wisit 4* 1 Department of Medicine, University of Riverside, Riverside, CA 92521, USA 2 Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand 3 Division of Cardiac Electrophysiology, University of Michigan Health Care, Ann Arbor, MI 48109, USA 4 Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; charat.thongprayoon@gmail.com 5 Department of Internal Medicine, University of Arizona, Tucson, AZ 85721, USA; tarunjacobb@gmail.com 6 Department of Cardiovascular Medicine, Emory University, Atlanta, GA 30322, USA; saraschandra.vallabhajosyula@emory.edu * Correspondence: narutprasitlumkum@gmail.com (N.P.); drronpichaic@gmail.com (R.C.); wcheungpasitporn@gmail.com (W.C.) 27 10 2020 12 2020 8 4 4031 8 2020 26 10 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Introduction: The incidence of acute myocardial injury (AMI) among Coronavirus Disease 19 (COVID-19)-infected patients remain unclear. We aimed to conduct a systematic review and meta-analysis to further explore the incidence AMI in these patients. Methods: We comprehensively searched the MEDLINE, EMBASE and Cochrane databases from their inception to August 2020. The included studies were prospective or retrospective cohort studies that reported the event rate of AMI in COVID-19 patients. Data from each study were combined using random-effects to calculate the pooled incidence with 95% confidence intervals. Results: We identified twenty-seven studies consisting of 8971 hospitalized COVID-19-infected patients. The study demonstrated that 20.0% (95% CI 16.1–23.8% with substantial heterogeneity (I2 = 94.9%)) of hospitalized COVID-19 patients had AMI. In addition, our meta-regression suggested that older age, male and comorbidities were associated with a higher risk of AMI. Conclusion: The incidence of COVID-19-related myocardial injury ranges from 16.1–23.8%. Further larger studies are anticipated, as the pandemic is still ongoing. coronavirusCOVID-19myocardial injurymeta-analysissystematic review ==== Body 1. Introduction Coronavirus disease 2019 (COVID-19)-infected patients have shown unique characteristics, with higher infection and mortality rates than prior pandemic-associated respiratory viral infections. However, the incidence and pattern of cardiac involvement for this new emerging respiratory viral infection remains unclear. COVID-19-infected patients have shown unique characteristics, with higher infection and mortality rates than prior pandemic-associated respiratory viral infections. Particularly, myocardial involvement in COVID-19 seems to be common compared to previous coronavirus outbreaks, and is associated with higher morbidity and mortality [1]. As the current pandemic has not yet been resolved, acute myocardial injury (AMI)—which is mostly defined by elevated troponin higher than upper normal limit [2]—is still of importance. The exact incidence is yet to be elucidated, especially from regions other than China. Hence, we aimed to conduct a systematic review and meta-analysis to further explore the incidence of myocardial injury among COVID-19-infected patients. 2. Materials and Methods A systematic literature search of Ovid MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews (from inception to August 2020) was conducted to identify studies evaluating the incidence/prevalence and clinical significance of myocardial injury among COVID-19-infected patients. The systematic literature review was undertaken independently by two investigators (R.C. and N.P.) applying a search approach that incorporated the terms “COVID” or “coronavirus” or “SARS-CoV-2” and “myocardial injury’ or “clinical” (Online Supplementary Data). No language limitation was applied. Eligible studies included cross-sectional, case-control, or cohort studies that assessed the incidence/prevalence and clinical significance of myocardial injury in COVID-19-infected patients. Studies had to provide effect estimates for overall incidence, prevalence, and risk ratios with a 95% confidence interval (CI). Inclusion was not limited by study size. Retrieved articles were reviewed individually for their eligibility by the two investigators noted previously. Analyses were performed using STATA version 14.1. Adjusted point estimates from each study were consolidated using the generic inverse variance approach of DerSimonian and Laird, which designated the weight of each study based on its variance [3]. Meta-regression was also performed to explore risk modifiers. 3. Results The final analysis included 27 observational studies with 8971 hospitalized COVID-19-infected patients (Table 1). Our meta-analysis demonstrated that 20.0% (95% CI 16.1–23.8% with substantial heterogeneity (I2 = 94.9%)) of hospitalized COVID-19 patients had a myocardial injury manifested mainly by elevated cardiac troponin I levels (Online Supplementary Data). To account for demographic data, we performed meta-regression showing that age, gender, region, and CVD comorbidities. Our analysis suggested older age, male, hypertension, diabetes, coronary heart disease and chronic kidney disease correlated with higher incidence of myocardial injury. (all p < 0.01) However, no statistical correlation was found between region, race and incidence of myocardial injury (p > 0.1) (Online Supplementary Data). 4. Discussion Our study highlighted that the incidence of COVID-19 myocardial injury has ranged from 16.1 to 23.8% (Table 2). In comparison with previous epidermic Coronavirus, myocardial injury following COVID-19 seemed to be higher—likely due to underreported incidence of the previous diseases which did not reach pandemic state, suggested by higher mortality rates from those previous diseases limiting their spread. Of note, the diverse incidence of AMI could be explained by differences in demographic data and comorbidities which our study suggested. Despite several studies since the beginning of COVID-19 era, our insight into cardiovascular complications remains limited, warranting further data for better understanding. Based on our meta-regression, our study also supported that older age, male, and comorbidities—particularly hypertension, diabetes, underlying coronary heart disease and chronic kidney disease—were associated with higher risk of myocardial injury incidence. This suggests that these factors may be casual in cardiac injury process. On the other hand, it was deemed primordial to conclude null impact from races and regions, given the paucity of data from countries other than China. Further studies are encouraged to investigate. COVID-19 myocardial injury occurs through several mechanisms. One is direct cardiac injury on different parts of the heart by viral entry into the cardiomyocytes. The second is microvascular dysfunction as a consequence of severe inflammatory reaction to the virus. With this cascade come endothelial dysfunction and endothelitis, which further worsen cardiac function [2]. This phenomenon may lead to several manifestations of myocardial injury, from myocarditis and arrhythmia, to Takotsubo cardiomyopathy [35]. Intriguingly, the hypercoagulability state is one of the most unique pathophysiologies proposed in COVID-19, which leads to generalized arterial and venous thrombosis [36]. Owing to the dysregulated immune system, especially in severe infection, several interplays between cytokine storm, platelet hyperactivation and altered microvascular permeability result in abnormal coagulation cascades which promote coronary thrombosis, plaque thrombosis, and even stent thrombosis [37]. Recent studies provided data that support this theory, demonstrating massively elevated Von Willebrand factor, D-Dimer and abnormal procoagulant factors, and even the presence of antiphospholipid antibodies [38,39,40]. Another mechanism is indirect involvement through imbalance between metabolic demand and cardiac reserve in patients with preexisting cardiac disease. Based on Choundry et al. [41], we can infer that COVID-19 posed patients at higher risks for acute coronary events. Exaggerated inflammatory responses following the infection can stimulate acute plaque rupture, leading to demand-supply mismatch [42]. As a result, acute myocardial infarction ensues, complicating the patient’s prognosis and clinical course. Nevertheless, data paucity has remained in regard to the true incidence between AMI by microvascular dysfunction and coronary thrombosis among COVID-19 patients, given the difficulty in designing such dedicated studies. Given the consequent high fatality rate, several clinical trials have been investigated to treat and prevent its progression. Combined antibiotics with Azithromycin and Chloroquine, however, did not improve mortality outcomes but lengthened QT interval, posing significant arrhythmias [43]. For novel therapies such as Remdesevir and IL-6 inhibitors, the data are still limited. Recently, Sheng et al. began a clinical trial using Canakinumab to minimize the risk of myocardial injury, which is currently in the enrolling state [44]. At the moment, we do not have any effective treatments which reduce COVID-19 complications. Though informative, our study has certain limitations. First, the statistical heterogeneity is sizable. Thus, meta-regression was performed elucidating the contributions from demographical data and patients’ comorbidities. Moreover, the lack of echocardiographic parameters is cumbersome, further precluding proper variable adjustment. However, the use of echocardiograms in COVID-19-infected patients remains limited due to the disease’s high transmission rate. Second, most studies were from China; thus, real-world incidence may be diverse. Nevertheless, our preliminary analysis suggested no significant difference in myocardial injury incidence. Many more studies from countries other than China are required to demonstrate such diversity. Lastly, true incidence could be overestimated, as most studies used troponin as a marker of cardiac injury, which is not specific to COVID-induced cardiac injury alone, but also to ACS, heart failure, arrhythmia, and so on. Thus, interpretation should be carefully discerned. 5. Conclusions Our study showed the most updated incidence of COVID-19-related myocardial injury, which ranges from 16.1–23.8%. However, as the pandemic has not yet reached the turning point, further studies investigating this relationship with a larger sample size are anticipated. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Materials The Supplementary Materials are available online at https://www.mdpi.com/2079-9721/8/4/40/s1. Click here for additional data file. Author Contributions N.P., R.C., and W.C. contributed to the conception or design of the work. C.T., T.B. and S.V. contributed to the acquisition, analysis, or interpretation of data for the work. N.P., W.C. and R.C. drafted the manuscript. R.C. and W.C. critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Conflicts of Interest The authors have declared that no competing interests exist. diseases-08-00040-t001_Table 1Table 1 Study characteristics. Study Name Country Total Numbers (n) Mean Age (Years Old) Sex (Male%) Hypertension (%) DM (%) CHD (%) CKD (%) Myocardial Injury Incidence (%) He [4] China 54 68 n/a 24.1 14.8 5.3 n/a 44 Huang [5] China 41 49 73 15 20 15 n/a 12 Wang [6] China 138 56 54.3 31.2 10.1 14.5 2.9 7 Zhou [7] China 191 56 62 30 19 8 1 17 Liu [8] China 56 53.75 55 18 7 3.6 1 13 Chen [9] China 150 59 44 33 13 6 n/a 20 Shi [10] China 416 64 49.3 31 14 16 3.4 20 Deng [11] China 225 54 55 26 12 8 n/a 29 Yang [12] China 52 59.7 67 n/a 9 5 n/a 23 an [13] China 135 47 53.3 9.6 8.9 5.2 n/a 7 Cao [14] China 102 54 52 27.5 10.8 4.9 3.9 15 Guo [15] China 187 58.5 n/a 32.6 15 11.2 3.2 28 Tao [16] China 312 69.2 60 57.1 38.8 29.8 3.21 33 Tu [17] China 174 53.7 45.4 21.2 9.8 9.2 n/a 14 Du [18] China 179 58 54.2 32.4 18.4 16.2 n/a 23 Xu [19] China 88 57.1 40.91 23 12.5 7.95 n/a 8 Wu [20] China 201 51 63.1 19.4 10.9 8 n/a 4 Wei [21] China 101 49 53.5 21 13.9 5 n/a 16 Ni [22] China 176 67 57.39 49 26 14 n/a 28 Li [23] China 548 60 50.9 30.3 15.1 6.2 1.8 22 Yu [24] China 226 64 61.5 42.5 20.8 9.7 0.35 27 Feng [25] China 476 53 56.9 23.7 10 8 0.8 11 Lombardi [26] Italy 614 67 70.8 57 24 22.3 17.9 45 Javanian [27] Iran 100 60 51 32 27 20 12 14 Saleh [28] Iran 386 59.5 61.1 36.8 34.5 25.1 4.1 30 Chung [29] South Korea 110 56.9 43.6 33.6 16.3 9.1 n/a 12 Richardson [30] USA 3533 63 60.3 56.6 33.8 11.1 8.5 23 Abbreviations: CVD: Coronary heart disease; CKD: Chronic kidney disease; DM: Diabetes. n/a: Not applicable. diseases-08-00040-t002_Table 2Table 2 Cardiovascular manifestation among recent epidermic/pandemic Coronavirus. Summary of Cardiovascular Presentations among Outbreak Coronavirus Outbreak Period 2003 2015 Current Comparison SARS MERS COVID-19 Pathophysiology Exaggerated immune response [31] Unclear Cytokine storm, direct viral injury, plaque instability Myocardial injury incidence No clear data Varied from 16.1–23.8% Cardiovascular manifestation Subclinical diastolic dysfunction, tachycardia, hypotension, cardiomegaly, atrial fibrillation, myocardial ischemia, elevated troponin [31,32,33] Acute myocarditis, Acute heart failure [34] Shock, Acute myocarditis, Acute heart failure, Elevated troponin, Arrhythmia [6,30] ==== Refs References 1. Bonow R.O. Fonarow G.C. O’Gara P.T. Yancy C.W. Association of Coronavirus Disease 2019 (COVID-19) with Myocardial Injury and Mortality JAMA Cardiol. 2020 5 751 753 10.1001/jamacardio.2020.1105 32219362 2. Bavishi C. Bonow R.O. Trivedi V. Abbott J.D. Messerli F.H. Bhatt D.L. Acute myocardial injury in patients hospitalized with COVID-19 infection: A review Prog. Cardiovasc. Dis. 2020 10.1016/j.pcad.2020.05.013 32512122 3. DerSimonian R. Laird N. Meta-analysis in clinical trials Control. Clin. Trials 1986 7 177 188 10.1016/0197-2456(86)90046-2 3802833 4. He X.W. Lai J.S. Cheng J. Wang M.W. Liu Y.J. Xiao Z.C. Xu C. Li S.S. Zeng H.S. [Impact of complicated myocardial injury on the clinical outcome of severe or critically ill COVID-19 patients] Zhonghua Xin Xue Guan Bing Za Zhi 2020 48 456 460 10.3760/cma.j.cn112148-20200228-00137 32171190 5. Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 497 506 10.1016/S0140-6736(20)30183-5 31986264 6. Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. Wang B. Xiang H. Cheng Z. Xiong Y. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China JAMA 2020 323 1061 1069 10.1001/jama.2020.1585 32031570 7. Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study Lancet 2020 395 1054 1062 10.1016/S0140-6736(20)30566-3 32171076 8. Liu K. Chen Y. Lin R. Han K. Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients J. Infect. 2020 80 e14 e18 10.1016/j.jinf.2020.03.005 9. Chen C. Chen C. Yan J.T. Zhou N. Zhao J.P. Wang D.W. [Analysis of myocardial injury in patients with COVID-19 and association between concomitant cardiovascular diseases and severity of COVID-19] Zhonghua Xin Xue Guan Bing Za Zhi 2020 48 567 571 10.3760/cma.j.cn112148-20200225-00123 32141280 10. Shi S. Qin M. Shen B. Cai Y. Liu T. Yang F. Gong W. Liu X. Liang J. Zhao Q. Association of Cardiac Injury with Mortality in Hospitalized Patients With COVID-19 in Wuhan, China JAMA Cardiol 2020 5 802 810 10.1001/jamacardio.2020.0950 32211816 11. Deng Y. Liu W. Liu K. Fang Y.Y. Shang J. Zhou L. Wang K. Leng F. Wei S. Chen L. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: A retrospective study Chin. Med. J. (Engl.) 2020 133 1261 1267 10.1097/CM9.0000000000000824 32209890 12. Yang X. Yu Y. Xu J. Shu H. Xia J. Liu H. Wu Y. Zhang L. Yu Z. Fang M. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study Lancet Respir. Med. 2020 8 475 481 10.1016/S2213-2600(20)30079-5 32105632 13. Wan S. Xiang Y. Fang W. Zheng Y. Li B. Hu Y. Lang C. Huang D. Sun Q. Xiong Y. Clinical features and treatment of COVID-19 patients in northeast Chongqing J. Med. Virol. 2020 92 797 806 10.1002/jmv.25783 32198776 14. Cao J. Hu X. Cheng W. Yu L. Tu W.J. Liu Q. Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit Intensive Care Med. 2020 46 851 853 10.1007/s00134-020-05987-7 32123993 15. Guo T. Fan Y. Chen M. Wu X. Zhang L. He T. Wang H. Wan J. Wang X. Lu Z. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19) JAMA Cardiol. 2020 5 811 818 10.1001/jamacardio.2020.1017 32219356 16. Li T. Lu L. Zhang W. Tao Y. Wang L. Bao J. Liu B. Duan J. Clinical characteristics of 312 hospitalized older patients with COVID-19 in Wuhan, China Arch. Gerontol. Geriatr. 2020 91 104185 10.1016/j.archger.2020.104185 32688107 17. Tu W.J. Cao J. Yu L. Hu X. Liu Q. Clinicolaboratory study of 25 fatal cases of COVID-19 in Wuhan Intensive Care Med. 2020 46 1117 1120 10.1007/s00134-020-06023-4 32253448 18. Du R.H. Liang L.R. Yang C.Q. Wang W. Cao T.Z. Li M. Guo G.Y. Du J. Zheng C.L. Zhu Q. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: A prospective cohort study Eur. Respir. J. 2020 55 10.1183/13993003.00524-2020 19. Xu X. Yu M.Q. Shen Q. Wang L.Z. Yan R.D. Zhang M.Y. Liu J.Y. Qu Y.Q. Analysis of inflammatory parameters and disease severity for 88 hospitalized COVID-19 patients in Wuhan, China Int. J. Med. Sci. 2020 17 2052 2062 10.7150/ijms.47935 32788884 20. Wu C. Chen X. Cai Y. Xia J. Zhou X. Xu S. Huang H. Zhang L. Zhou X. Du C. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China JAMA Intern. Med. 2020 180 934 943 10.1001/jamainternmed.2020.0994 32167524 21. Wei J.F. Huang F.Y. Xiong T.Y. Liu Q. Chen H. Wang H. Huang H. Luo Y.C. Zhou X. Liu Z.Y. Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis Heart 2020 106 1154 1159 10.1136/heartjnl-2020-317007 32354798 22. Ni W. Yang X. Liu J. Bao J. Li R. Xu Y. Guo W. Hu Y. Gao Z. Acute Myocardial Injury at Hospital Admission Is Associated With All-Cause Mortality in COVID-19 J. Am. Coll. Cardiol. 2020 76 124 125 10.1016/j.jacc.2020.05.007 32407771 23. Li X. Xu S. Yu M. Wang K. Tao Y. Zhou Y. Shi J. Zhou M. Wu B. Yang Z. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan J. Allergy Clin. Immunol. 2020 146 110 118 10.1016/j.jaci.2020.04.006 32294485 24. Yu Y. Xu D. Fu S. Zhang J. Yang X. Xu L. Xu J. Wu Y. Huang C. Ouyang Y. Patients with COVID-19 in 19 ICUs in Wuhan, China: A cross-sectional study Crit. Care 2020 24 219 10.1186/s13054-020-02939-x 32410714 25. Feng Y. Ling Y. Bai T. Xie Y. Huang J. Li J. Xiong W. Yang D. Chen R. Lu F. COVID-19 with Different Severities: A Multicenter Study of Clinical Features Am. J. Respir. Crit. Care Med. 2020 201 1380 1388 10.1164/rccm.202002-0445OC 32275452 26. Lombardi C.M. Carubelli V. Iorio A. Inciardi R.M. Bellasi A. Canale C. Camporotondo R. Catagnano F. Dalla Vecchia L.A. Giovinazzo S. Association of Troponin Levels with Mortality in Italian Patients Hospitalized with Coronavirus Disease 2019: Results of a Multicenter Study JAMA Cardiol. 2020 10.1001/jamacardio.2020.3538 27. Javanian M. Bayani M. Shokri M. Sadeghi-Haddad-Zavareh M. Babazadeh A. Yeganeh B. Mohseni S. Mehraeen R. Sepidarkish M. Bijani A. Clinical and laboratory findings from patients with COVID-19 pneumonia in Babol North of Iran: A retrospective cohort study Rom. J. Intern. Med. 2020 58 161 167 10.2478/rjim-2020-0013 32396143 28. Karbalai Saleh S. Oraii A. Soleimani A. Hadadi A. Shajari Z. Montazeri M. Moradi H. Talebpour M. Sadat Naseri A. Balali P. The association between cardiac injury and outcomes in hospitalized patients with COVID-19 Intern. Emerg. Med. 2020 10.1007/s11739-020-02466-1 29. Chung S.M. Ahn J.H. Moon J.S. Response: The Risk of Diabetes on Clinical Outcomes in Patients with Coronavirus Disease 2019: A Retrospective Cohort Study (Diabetes Metab J 2020;44:405-13) Diabetes Metab. J. 2020 44 625 626 10.4093/dmj.2020.0167 32856805 30. Richardson S. Hirsch J.S. Narasimhan M. Crawford J.M. McGinn T. Davidson K.W. The Northwell COVID-19 Research Consortium Barnaby D.P. Becker L.B. Chelico J.D. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized with COVID-19 in the New York City Area JAMA 2020 323 2052 2059 10.1001/jama.2020.6775 32320003 31. Peiris J.S. Chu C.M. Cheng V.C. Chan K.S. Hung I.F. Poon L.L. Law K.I. Tang B.S. Hon T.Y. Chan C.S. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study Lancet 2003 361 1767 1772 10.1016/S0140-6736(03)13412-5 12781535 32. Yu C.M. Wong R.S. Wu E.B. Kong S.L. Wong J. Yip G.W. Soo Y.O. Chiu M.L. Chan Y.S. Hui D. Cardiovascular complications of severe acute respiratory syndrome Postgrad. Med. J. 2006 82 140 144 10.1136/pgmj.2005.037515 16461478 33. Pan S.F. Zhang H.Y. Li C.S. Wang C. [Cardiac arrest in severe acute respiratory syndrome: Analysis of 15 cases] Zhonghua Jie He He Hu Xi Za Zhi 2003 26 602 605 14633442 34. Alhogbani T. Acute myocarditis associated with novel Middle east respiratory syndrome coronavirus Ann. Saudi Med. 2016 36 78 80 10.5144/0256-4947.2016.78 26922692 35. Montone R.A. Iannaccone G. Meucci M.C. Gurgoglione F. Niccoli G. Myocardial and Microvascular Injury Due to Coronavirus Disease 2019 Eur. Cardiol. 2020 15 e52 10.15420/ecr.2020.22 32617121 36. Tedeschi D. Rizzi A. Biscaglia S. Tumscitz C. Acute myocardial infarction and large coronary thrombosis in a patient with COVID-19 Catheter Cardiovasc. Interv. 2020 10.1002/ccd.29179 32767631 37. Sardu C. Gambardella J. Morelli M.B. Wang X. Marfella R. Santulli G. Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence J. Clin. Med. 2020 9 1417 10.3390/jcm9051417 32403217 38. Zhang Y. Xiao M. Zhang S. Xia P. Cao W. Jiang W. Chen H. Ding X. Zhao H. Zhang H. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19 N. Engl. J. Med. 2020 382 e38 10.1056/NEJMc2007575 32268022 39. Escher R. Breakey N. Lammle B. Severe COVID-19 infection associated with endothelial activation Thromb. Res. 2020 190 62 10.1016/j.thromres.2020.04.014 32305740 40. Samidurai A. Das A. Cardiovascular Complications Associated with COVID-19 and Potential Therapeutic Strategies Int. J. Mol. Sci. 2020 21 6790 10.3390/ijms21186790 41. Choudry F.A. Hamshere S.M. Rathod K.S. Akhtar M.M. Archbold R.A. Guttmann O.P. Woldman S. Jain A.K. Knight C.J. Baumbach A. High Thrombus Burden in Patients With COVID-19 Presenting With ST-Segment Elevation Myocardial Infarction J. Am. Coll. Cardiol. 2020 76 1168 1176 10.1016/j.jacc.2020.07.022 32679155 42. Sheth A.R. Grewal U.S. Patel H.P. Thakkar S. Garikipati S. Gaddam J. Bawa D. Possible mechanisms responsible for acute coronary events in COVID-19 Med. Hypotheses 2020 143 110125 10.1016/j.mehy.2020.110125 32763657 43. Rosenberg E.S. Dufort E.M. Udo T. Wilberschied L.A. Kumar J. Tesoriero J. Weinberg P. Kirkwood J. Muse A. DeHovitz J. Association of Treatment with Hydroxychloroquine or Azithromycin with In-Hospital Mortality in Patients with COVID-19 in New York State JAMA 2020 323 2493 2502 10.1001/jama.2020.8630 32392282 44. Sheng C.C. Sahoo D. Dugar S. Prada R.A. Wang T.K.M. Abou Hassan O.K. Brennan D. Culver D.A. Rajendram P. Duggal A. Canakinumab to reduce deterioration of cardiac and respiratory function in SARS-CoV-2 associated myocardial injury with heightened inflammation (canakinumab in Covid-19 cardiac injury: The three C study) Clin. Cardiol. 2020 10.1002/clc.23451