COVID-19 and cardiovascular diseases: Past, present, and future

Barun Kumar; Abhimanyu Nigam; Shishir Soni; Vikas Kumar; Anupam Singh; Omna Chawla

doi:10.4103/JCDM.JCDM_14_21

REVIEW ARTICLE

Year : 2022 | Volume : 2 | Issue : 2 | Page : 41-46

COVID-19 and cardiovascular diseases: Past, present, and future

Barun Kumar¹, Abhimanyu Nigam¹, Shishir Soni², Vikas Kumar¹, Anupam Singh¹, Omna Chawla³
¹ All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India
² Super-Specialty Hospital (SSH), NSCB Medical College, Jabalpur, MP, India
³ Seema Dental College and Hospital, Rishikesh, Uttarakhand, India

Date of Submission	04-Aug-2021
Date of Acceptance	09-Dec-2022
Date of Web Publication	25-Aug-2023

Correspondence Address:
Shishir Soni
(AIIMS, Rishikesh), Super-Specialty Hospital(SSH), NSCB Medical College, Jabalpur, MP 482003
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCDM.JCDM_14_21

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide adversely affecting the cardiovascular health apart from predominant involvement of the lungs. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which is the agent of COVID-19 can affect various tissues other than lungs including heart and vascular tissues. Thus, cardiovascular diseases are common extra pulmonary manifestations of this illness. This review provides an insight into the cardiovascular manifestations of the COVID-19 disease.

Keywords: Cardiovascular system, coronavirus disease, COVID-19

How to cite this article:
Kumar B, Nigam A, Soni S, Kumar V, Singh A, Chawla O. COVID-19 and cardiovascular diseases: Past, present, and future. J Cardio Diabetes Metab Disord 2022;2:41-6

How to cite this URL:
Kumar B, Nigam A, Soni S, Kumar V, Singh A, Chawla O. COVID-19 and cardiovascular diseases: Past, present, and future. J Cardio Diabetes Metab Disord [serial online] 2022 [cited 2023 Sep 22];2:41-6. Available from: http://www.cardiodiabetic.org/text.asp?2022/2/2/41/384337

Introduction

Coronavirus disease (COVID-19) has been an important concern globally for various reasons and extra pulmonary manifestation is one of them. COVID-19 is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2 virus), which belongs to the genus beta coronavirus.^[1] Cardiac effect of the SARS-CoV-2 virus responsible for this pandemic is a common extra pulmonary manifestation and has worse outcomes.^[1],[2] The effects of COVID-19 infection on cardiovascular systems are acute cardiac injury, arrhythmias, acute coronary syndromes (ACS), and venous thromboembolism.^[3],[4] Acute cardiac injury reflected by elevations in cardiac troponins in patients hospitalized with COVID-19 disease has been associated with larger morbidity and mortality.^[5] Although the case fatality rate is estimated around 4% worldwide, it varies from <0.1% to >20% depending on the data available from different countries.^[6] Variability in these data also depends on the availability of diagnostic testing that defines the affected population. However, a large number of asymptomatic or pauci-symptomatic individuals who did not undergo testing adds to the undiagnosed population that still carries the potential for the late manifestations of this disease. Thus, the overall prevalence is more than estimated and therefore clear understanding of the extra pulmonary manifestation of this disease will help in early identification and proper management of such patients. This review focuses on the cardiovascular manifestation of the COVID-19 disease.

The mechanism of cardiovascular involvement

The etiological agent, that is, SARS-CoV-2, which belongs to the beta coronavirus family, predominantly affects the respiratory system.^[7] The mechanism of cardiovascular involvement has been postulated after the upsurge of such cases being reported with cardiac manifestations. The Interaction between the SARS-CoV-2 and the host cell is shown in [Figure 1]. Following are the important mechanisms involved in cardiovascular manifestation of this virus.

Figure 1: Interaction between the severe acute respiratory syndrome-coronavirus-2 with the host cell. S1 receptor (spike protein) located over the virus interacts with the angiotensin-converting enzyme 2 receptors and transmembrane protease serine receptors over the cell membranes and facilitates the entry of virus inside the cell

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Direct cardiovascular injury

SARS-CoV-2 can directly affect the cardiac cells resulting in an acute cardiac injury and cardiac dysfunction; however, fulminant myocarditis is uncommon.^[8] Direct angiotensin-converting enzyme 2 (ACE-2)-mediated injury, hypoxia-mediated injury, micro vascular thrombosis, and systemic inflammatory injury are some of the mechanisms involved in acutely infected individuals, out of which ACE-2-mediated injury is a direct mechanism while remaining three are responsible for indirect cardiovascular injury.^[9] ACE-2 which is considered as the cardiac cell target of SARS-CoV-2, has been demonstrated by ribonucleic acid sequencing studies in pericytes, cardiomyocytes, and fibroblasts with its upregulation in failing hearts.^[10] The role of pericytes is supported by the presence of micro vascular injury in autopsy analyses; however, the preceding mechanism can be direct infection or inflammatory mechanism.^[11] Cardiac autopsies have demonstrated cardiomegaly, right ventricular dilatation, lymphocytic myocarditis, endocardial thrombosis, pericarditis, and small vessel thrombosis in affected patients.^[12] The results of the electron microscopy based studies demonstrating virus-like particles in the cardiomyocytes provides a strong evidence of cardiac cellular tropism of this virus.^[13]

Indirect cardiovascular injury

Important mechanisms under this category include hypoxia-induced myocardial injury, microvascular ischemia-thrombosis, and cardiovascular injury due to dysfunctional immune response.^[14] Hypoxia-induced myocardial injury stems from hypoxia resulting from respiratory failure in COVID-19 disease.^[14],[15] Small vessel ischemia occurs due to microvascular injury and thrombosis.^[14],[16] Cardiac injury can also result from dysfunctional immune response.^[17] Such an immune response contributes to the severity of COVID-19 disease. Cytokines storm, a putative phenomenon in COVID-19 disease, may lead to cell death and multigrain dysfunction.

Vascular thrombosis

Both venous and arterial thrombosis occur in SARs-CoV-2 infection and is one of the prominent features of this disease. Electron microscopy based studies have shown viral inflammation of endothelial cells.^[18] Endotheliitis results in degranulation of Weibel Palade bodies which contains Von-will brand factor culminating into cascade of events leading to activation of platelets and thrombus formation.

Others

Altered myocardial demand-supply mismatch, adverse effects of drug therapy, and associated electrolyte imbalance in critically ill patients with COVID-19 disease are other mechanisms contributing to the adverse cardiovascular effects.^[14],[18]

Role of diabetes and other cardiovascular risk factors

Initial reports published from China showed that diabetes and hypertension were common comorbidities in COVID-19 affected patients.^[19],[20] A meta-analysis of COVID-19 patients from China have shown associated diabetes and hypertension in 9.7% and 17.1%, respectively. Moreover, patients who had hypertension and diabetes showed a more severe form of infection and higher mortality rates.^[21] In a single cohort of patients with COVID-19 in Wuhan, 46% patients had comorbidity (72% of patients in intensive care unit (ICU)), 31% of patients had hypertension (58% of ICU patients), 15% had other cardiovascular diseases (25% ICU patients), and 10% had diabetes (22% ICU patients).^[22]

Cardiovascular manifestations

Although COVID-19 predominantly causes viral pneumonia, it is shown to be frequently associated with the occurrence of various cardiac abnormalities.^[22] Complex interaction among underlying risk factors, concomitant drug effects, and systemic inflammation leads to the development of various cardiovascular effects in COVID-19 [see [Figure 2]].

Figure 2: Complex interaction between underlying risk factors, concomitant drug effects and systemic inflammation leading to the development of cardiovascular effects in coronavirus disease 2019

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Common manifestations of cardiac abnormalities in COVID-19 are myocardial injury and infarctions, arrhythmias, ACS, and venous thromboembolism [see [Figure 3]].^[23]

Figure 3: Spectrum of cardiovascular disorders seen with coronavirus disease 2019

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Some patients had cardiac symptoms as the first clinical manifestations,^[23] and the occurrence of myocardial injury during COVID-19 was associated with higher mortality independently.^[24] COVID-19 has been shown to cause cardiovascular involvement in various ways as myocarditis, hypoxic injury, ischemic injury due to microvascular dysfunction, small vessel vasculitis, endothelitis, coronary artery disease, and right heart strain (due pulmonary embolism).^[23],[24]

Acute myocardial injury

Myocardial injury as reflected by elevated cardiac troponins is common in patients with COVID-19.^[25] The exact frequency is difficult to ascertain owing to the use of different assays used for its measurement; however, it ranges from 8% to 22%. With the availability of high sensitivity troponins assays, it is more commonly detected in these patients.^[26] Troponin elevation in these patients can occur from ischemic or non-ischemic causes. Severe hypoxia, sepsis, associated renal failure, inflammatory response, and pulmonary thromboembolism can contribute to non-ischemic myocardial injury. Ischemic myocardial injury results from plaque rupture, coronary spasm, or vascular injury. Up to 22% patients in intensive care unit and up to 59% of the patients who died with COVID-19 disease, myocardial injury was evidenced.^[27] However, myocarditis is uncommon as its diagnosis cannot be based on troponin elevation alone and therefore most of the reported cases include suspected myocarditis case. In a case series from China in which 7% of the patients who died had suspected myocarditis without a definite diagnosis of myocarditis.^[28] Recently cardiac magnetic resonance imaging (CMR) based studies have raised concerns with cardiac involvement in 78% and myocardial inflammation in 60% of patients recovered from COVID-19.^[29] In a review analysis of CMR studies of 199 patients with COVID-19, the features suggestive of myocarditis were seen in 40.2% cases.^[30] Results from a CMR based study in college athletes have found features of myocarditis in 15% and late gadolinium enhancement in 46%.^[31] Such findings suggest cardiovascular involvement in those who recovered from COVID-19 and possibility of future complications in the form of arrhythmia and heart failure.

Acute coronary syndromes

Similar to its precursor virus, SARS-CoV-2 has shown to trigger ACS. The mechanism underlying COVID-19-induced ACS may be due to plaque rupture, coronary spasms or micro thrombi arising from systemic inflammation or cytokine storm.^[32] Inflammation due to COVID-19 infection leads to activation of macrophages which secrete collagenase, which in turn causes the breakdown of the collagenous fibrous cap of the atheromatous plaque. Also, it secretes tissue-factor that triggers prothrombin activation after plaque rupture.^[32] Direct injury to the endothelium and the vasculature by the SARS-CoV-2 might also increase the thrombus formation and ACS [Figure 4].^[33] High variability in the prevalence and presentation was noticed. Non-obstructive coronary artery disease and poor prognosis were common in patients presenting with ACS during COVID-19 pandemic. Management of Myocardial infarction remained unchanged, with timely reperfusion strategy with either fibrinolysis or percutaneous coronary interventions, whichever is readily available.

Figure 4: Mechanism of acute coronary syndromes in coronavirus disease 2019 infection

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Heart failure

With the paucity of data, heart failure has been reported in ~52% in those who died and in ~12% patients who recovered from COVID-19. Exact mechanism remained unclear, and has been related to myocardial lesion and septic shock. Heart failure in COVID-19 may be precipitated by active infection or could be due to worsening of pre-existing heart failure.^[34] In patients with COVID-19, associated other risk factors such as hypertension, diabetes, renal derangements, and coronary artery disease might be contributing to the onset of heart failure which can be triggered by high fever, tachycardia, excessive hydration, and impaired renal function.^[35] Acute myocardial injury, secondary to ACS and cardiac damage, can also aggravate pre-existing heart disease and cause systolic or diastolic dysfunction. In the advanced stages of COVID-19, it can exacerbate the immune system’s response and may lead to the development of stress-induced cardiomyopathy.^[36]

Heart failure could be due to acute right heart failure, which in itself occurs secondary to acute pulmonary embolism. Or it could be due to acute left ventricular failure due to acute myocardial infarction. It may involve both the ventricles in myocarditis or stress cardiomyopathy. Heart failure may also present as cardiogenic shock occurring due to severe impairment of left ventricular function during cytokine storm. However, sudden cardiac death may occur due to the development of fatal arrhythmias.

Management of heart failure in COVID-19 is similar to general heart failure management protocol, with the primary aim to reduce congestion, increase myocardial contractility, and reduce left ventricular remodeling.

Arrhythmias and sudden cardiac arrest

Arrhythmias and sudden cardiac arrest are common manifestations of COVID-19. Overall prevalence of arrhythmia in these patients is ~16.7% with ~44.4% in those with severe illness and ~8.9% in mild disease.^[37] Both bradyarrhythmia and tachyarrhythmias can occur. Palpitations have been reported as a common and significant symptom in patients with COVID-19 without fever or cough.^[37] However, the exact incidence and cause of arrhythmias in patients with COVID-19 are unknown. Atrial and ventricular arrhythmias may be triggered by myocardial injury or other generalized causes such as fever, sepsis, hypoxia, and electrolyte abnormalities.^[38] Furthermore, patients with COVID-19 are treated with various antiviral agents, which have their pro-arrhythmic effects and may result in multiple ventricular arrhythmias.

Coagulation abnormalities and thrombosis

COVID-19 is primarily thought to be an endothelial disease rather than a respiratory virus due to thromboembolic events.^[39] Pulmonary thrombosis, arterial thrombosis, and venous thrombosis were reported in 16–49% cases in intensive care unit in one case series. Clinical observations of increased thromboembolic events in COVID-19 suggests the presence of a hypercoagulable state. Various studies have demonstrated higher D-dimer level and slightly prolonged prothrombin time. Also, elevated fibrinogen and factor VIII levels are seen in COVID-19. Venous thromboembolism is a common complication in critically ill patients with COVID-19. The mechanism of coagulation abnormalities in COVID-19 is unclear. One hypothesis is that severe inflammatory response and damage to the endothelium induced by COVID-19 combined with underlying comorbidities might predispose patients to a hypercoagulable state. Certain antiviral medications and investigational therapies are given to patients that might promote thrombosis or bleeding events through drug–drug interactions with antiplatelet and anticoagulants.

Multi-system inflammatory syndrome

Multi-system inflammatory syndrome in children was initially described in the pediatric population, affected with COVID-19. The presenting features mimicked Kawasaki disease, including fever, gastrointestinal symptoms, shock, left ventricle dysfunction, and elevated inflammatory markers. Recently, a similar syndrome has been observed in adult populations, which is termed as multi-system inflammatory syndrome-A, causing fever, gastrointestinal symptoms, shock, left ventricle dysfunction, and elevated inflammatory markers. COVID-19 has been reported to have severe inflammatory symptoms in some population of patients. Studies from the UK reported a cluster presenting with a hyperinflammatory syndrome with features of Kawasaki disease.^[40]

Antiviral drugs and cardiovascular effects

Hydroxychloroquine and azithromycin

Chloroquine and hydroxychloroquine (HCQ) have been widely proposed as a treatment for COVID-19 in the initial days of the pandemic.^[41] The principal mode of action of these drugs was blocking the vial entry into the cell. In addition, HCQ had an additional immunomodulatory effect. However, in the light of the recent evidence, the effect of chloroquine and HCQ has shown inconsistent results in the prevention and treatment of COVID-19.^[42] In addition, these agents are also known to induce arrhythmias.

Azithromycin was used initially in combination with HCQ for treating COVID-19. It increases the chances of ventricular arrhythmias as it prolongs QT-interval. In a cohort study of 90 patients with COVID-19 treated with HCQ (with or without azithromycin), patients receiving a combination of HCQ and azithromycin had prolonged QTc-interval than patients receiving HCQ alone.^[43] In another cohort study of 1438 patients admitted with COVID-19, treatment with HCQ, azithromycin or both was compared with neither therapy.^[43] All groups were comparable in terms of mortality, with no increase in mortality, but the occurrence of cardiac arrest was higher in patients receiving the combination of HCQ and azithromycin.^[43]

Ritonavir–lopinavir

These are primarily protease inhibitors used in HIV and were introduced for the treatment of COVID-19. A randomized controlled trial (RCT), including 199 patients with COVID-19, showed no benefit with lopinavir–ritonavir therapy compared with symptomatic care.^[44] Lopinavir–ritonavir should be used with caution because this drug combination might interact with common cardiovascular drugs metabolized by cytochrome P450 3A4, including drugs such as clopidogrel, anticoagulants, and antiarrhythmics.^[45]

Conclusion

SARS-CoV-2 has commonly shown its association with cardiovascular effects in patients, which has higher morbidity and mortality and increased hospital stay duration. Myocardial injury is a prevalent complication among hospitalized patients, with or without previous cardiovascular disease, and has a worse outcome. In addition to myocardial injury, ventricular arrhythmias, and ACS have significantly contributed to the mortality in COVID-19. Early detection of cardiovascular complications helps in timely interventions and thus better management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Sharma A, Ahmad Farouk I, Lal SK COVID-19: A review on the novel coronavirus disease evolution, transmission, detection, control and prevention. Viruses 2021;13:202.
2.	Bonow RO, O’Gara PT, Yancy CW Cardiology and COVID-19. JAMA 2020;324:1131-2.
3.	Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC COVID-19 and cardiovascular disease: From basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020;17:543-58.
4.	Long B, Brady WJ, Koyfman A, Gottlieb M Cardiovascular complications in COVID-19. Am J Emerg Med 2020;38:1504-7.
5.	Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;5:802-10.
6.	Khafaie MA, Rahim F Cross-country comparison of case fatality rates of COVID-19/SARS-COV-2. Osong Public Health Res Perspect 2020;11:74-80.
7.	Hu B, Guo H, Zhou P, Shi ZL Characteristics of SARS-cov-2 and COVID-19. Nat Rev Microbiol 2021;19:141-54.
8.	Luo J, Zhu X, Jian J, Chen X, Yin K Cardiovascular disease in patients with COVID-19: Evidence from cardiovascular pathology to treatment. Acta Biochim Biophys Sin (Shanghai) 2021;53:273-82.
9.	Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-converting enzyme 2: SARS-cov-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20^th anniversary of the discovery of ACE2. Circ Res 2020;126:1456-74.
10.	Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. COVID-19 and the cardiovascular system: Implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020;116:1666-87.
11.	Roshdy A, Zaher S, Fayed H, Coghlan JG COVID-19 and the heart: A systematic review of cardiac autopsies. Front Cardiovasc Med 2020;7:626975.
12.	Bulfamante GP, Perrucci GL, Falleni M, Sommariva E, Tosi D, Martinelli C, et al. Evidence of SARS-CoV-2 transcriptional activity in cardiomyocytes of COVID-19 patients without clinical signs of cardiac involvement. Biomedicines 2020;8:626.
13.	Zhu H, Rhee JW, Cheng P, Waliany S, Chang A, Witteles RM, et al. Cardiovascular complications in patients with COVID-19: Consequences of viral toxicities and host immune response. Curr Cardiol Rep 2020;22:32.
14.	Yang LC, Zhang RT, Guo LJ, Xiao H, Zu LY, Zhang YY, et al. Hypoxia and inflammation are risk factors for acute myocardial injury in patients with coronavirus disease 2019. Beijing Da Xue Xue Bao Yi Xue Ban 2020;53:159-66.
15.	Montone RA, Iannaccone G, Meucci MC, Gurgoglione F, Niccoli G Myocardial and microvascular injury due to coronavirus disease 2019. Eur Cardiol 2020;15:e52.
16.	Mitrani RD, Dabas N, Goldberger JJ COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Heart Rhythm 2020;17:1984-90.
17.	Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8.
18.	Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, et al. China medical treatment expert group for COVID-19. Comorbidity and its impact on 1590 patients with COVID-19 in China: A nationwide analysis. Eur Respir J 2020;55:2000547.
19.	Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol 2020;109:531-8.
20.	Sanyaolu A, Okorie C, Marinkovic A, Patidar R, Younis K, Desai P, et al. Comorbidity and its impact on patients with COVID-19. SN Compr Clin Med 2020;25:1-8.
21.	Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. COVID-19 and cardiovascular disease. Circulation 2020;141:1648-55.
22.	Kang Y, Chen T, Mui D, Ferrari V, Jagasia D, Scherrer-Crosbie M, et al. Cardiovascular manifestations and treatment considerations in COVID-19. Heart 2020;106:1132-41.
23.	Gu ZC, Zhang C, Kong LC, Shen L, Li Z, Ge H, et al. Incidence of myocardial injury in coronavirus disease 2019 (COVID-19): A pooled analysis of 7,679 patients from 53 studies. Cardiovasc Diagn Ther 2020;10:667-77.
24.	Zou F, Qian Z, Wang Y, Zhao Y, Bai J Cardiac injury and COVID-19: A systematic review and meta-analysis. CJC Open 2020;2:386-94.
25.	Prasitlumkum N, Chokesuwattanaskul R, Thongprayoon C, Bathini T, Vallabhajosyula S, Cheungpasitporn W Incidence of myocardial injury in COVID-19-infected patients: A systematic review and meta-analysis. Diseases 2020;8:40.
26.	Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052-9.
27.	Laganà N, Cei M, Evangelista I, Cerutti S, Colombo A, Conte L, et al. Suspected myocarditis in patients with COVID-19: A multicenter case series. Medicine (Baltimore) 2021;100:e24552.
28.	Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:1265-73.
29.	Ojha V, Verma M, Pandey NN, Mani A, Malhi AS, Kumar S, Jagia P, et al. Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): A systematic review of cardiac magnetic resonance imaging findings in 199 patients. J Thorac Imaging 2021;36:73-83.
30.	Rajpal S, Tong MS, Borchers J, Zareba KM, Obarski TP, Simonetti OP, et al. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. JAMA Cardiol 2021;6:116-8.
31.	Libby P, Tabas I, Fredman G, Fisher EA Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 2014;114:1867-79.
32.	Bentzon JF, Otsuka F, Virmani R, Falk E Mechanisms of plaque formation and rupture. Circ Res 2014;114:1852-66.
33.	Calabretta E, Moraleda JM, Iacobelli M, et al. COVID-19-induced endotheliitis: Emerging evidence and possible therapeutic strategies. Br J Haematol 2021;193:43.
34.	Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth universal definition of myocardial infarction (2018). Circulation 2018;138:e618-51.
35.	Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ 2020;368:m1091.
36.	Mehra MR, Ruschitzka F COVID-19 illness and heart failure: A missing link? JACC Heart Fail 2020;8:512-4.
37.	Fried JA, Ramasubbu K, Bhatt R, Topkara VK, Clerkin KJ, Horn E, et al. The variety of cardiovascular presentations of COVID-19. Circulation 2020;141:1930-6.
38.	Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:811-8.
39.	Siddiqi HK, Libby P, Ridker PM COVID-19—A vascular disease. Trends Cardiovasc Med 2021;31:1-5.
40.	Hennon TR, Yu KOA, Penque MD, Abdul-Aziz R, Chang AC, McGreevy MB, et al. COVID-19 associated multisystem inflammatory syndrome in children (MIS-C) guidelines; revisiting the Western New York approach as the pandemic evolves. Prog Pediatr Cardiol 2021;62:101407.
41.	Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: A randomized clinical trial. JAMA 2020;324:2165-2176.
42.	Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro. Cell Res 2020;30:269-71.
43.	Fihn SD, Perencevich E, Bradley SM Caution needed on the use of chloroquine and hydroxychloroquine for coronavirus disease 2019. JAMA Netw Open 2020;3:e209035.
44.	Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006;27:1166-1173.
45.	Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe covid-19. N Engl J Med 2020;382:1787-99.