Cardiovascular Manifestations of COVID-19

Nausharwan Butt¹, Huzaifa Ahmad¹, Nauman Khalid², Sarah Aftab Ahmad³, Nancy Pahwa⁴, Gagandeep Singh Talwar⁴, Lovely Chhabra^5,*

¹Section of Internal Medicine, MedStar Washington Hospital Center, Washington, DC, 20010, USA

²Section of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC, 20010, USA

³Section of Cardiothoracic Surgery, Saint Francis Hospital, Monroe, LA, USA

⁴Tianjin Medical University, Tianjin, China

⁵Division of Invasive Cardiology, Heartland Regional Medical Center, Marion, IL, USA

^*Corresponding author: Dr. Lovely Chhabra, MD, FACC, Division of Invasive Cardiology, Heartland Regional Medical Center, Marion, IL, USA

Received: 24 September 2020; Accepted: 03 October 2020; Published: 20 October 2020

1. Introduction

First described within central China, novel coronavirus 2019 (COVID-19) has rapidly evolved from an initial localized collection of pneumonia cases to a global pandemic [1]. Patients most commonly present with fever, cough, fatigue and shortness of breath although a wide array of clinical signs and symptoms have been reported [2]. COVID-19 enters human cells via the angiotensin-converting enzyme (ACE)-2 receptor within the nasal cavity, it subsequently replicates and spreads throughout the upper conducting airways triggering an immune response which results in mild respiratory symptoms in a majority of patients [3]. Despite this, COVID-19 can also be associated with severe hypoxic respiratory failure from worsening pulmonary infiltrates and alveolar damage leading to acute respiratory distress syndrome (ARDS) [4].

The accurate reporting of COVID-19 infection related mortality has been challenging given the high prevalence of asymptomatic carriers, however initial estimates place the case fatality rate between 0 to greater than 20% based upon predisposing factors including age and underlying medical comorbidities [5]. Unfortunately, treatment options remain limited; although compassionate use of Remdesevir has been associated with some clinical improvement, other tried therapies including lopinavir-ritonavir, hydroxychloroquine and azithromycin have failed to demonstrate any mortality benefit [6-9]. Vaccination development against COVID-19 remains the only proposed definitive prevention at this time, although the process of manufacture is lengthy and complicated with limited detail available on efficacy if successfully produced [10].

Although well known as a respiratory pathogen, COVID-19 has complex interactions with the cardiovascular system; preexisting heart disease leads to increased susceptibility from the virus and cardiac complications from direct infectious insults or due to delay in seeking care [11]. Cardiac injury appears to be common with a reported prevalence of ~20% within hospitalized COVID-19 patients and is independently associated with mortality [12]. We therefore conducted a comprehensive review of cardiac complications with COVID-19 infection.

2. COVID-19 Myocarditis

Myocarditis represents an inflammatory pathology of the heart in the absence of ischemia that can present with a wide variety of clinical signs and symptoms, with chest pain, heart failure and malaise commonly reported [13]. Unfortunately, fulminant myocarditis may also occur on rare occasions which carries an associated mortality ranging between 40 and 70% [14]. Viral infection is a well-established cause of myocarditis as a result of complex multiphasic pathogenesis initially involving direct injury to cardiomyocytes, subsequent immune dysregulation and possible progression to long-term dilated cardiomyopathy [15].

COVID-19 has been reported to instigate cardiac inflammation with suspected myocarditis considered as the likely cause of acute COVID-19 cardiovascular syndrome which comprises of acute cardiac injury, cardiomyopathy, ventricular arrhythmia and hemodynamic instability [16]. COVID-19 patients may also have elevated high-sensitive troponin T and N-terminal (NT)-pro hormone BNP (NT-proBNP), suggesting the development of myocardial injury and ventricular dysfunction [17]. Compared to those with normal troponin T levels, patients with elevated troponin T have been shown to have increased mortality in all patients, more frequently require glucocorticoid therapy and mechanical ventilation, in addition to being at higher risk to developing in-hospital complications such as acute respiratory distress syndrome, malignant arrhythmias, and acute kidney injury [18]. Data on the incidence of COVID-19 related myocarditis is limited however; an initial study reported that 7% of infected patients died of myocarditis related circulatory failure alone whereas 33% lost their lives to both respiratory failure and myocarditis related circulatory failure [19].

The underlying pathogenesis for this cardiac injury is not well understood, however several mechanisms have been proposed including direct myocyte infection, systemic inflammation through increased production of tumor necrosis factor alpha (TNF-α) from ACE-2 receptor downregulation, enhanced activation of transforming growth factor beta (TGF-β) leading to interstitial fibrosis, interferon mediated immune response, hypoxia due to underlying lung dysfunction and cytokine reaction with Type 1 and 2 helper T cells [20].

Current management of COVID-19 related myocarditis is based upon individual case scenarios given that recent literature is limited to only small studies with reported treatment approaches; there remains a lack of high-quality randomized data which is required to determine optimal therapy [21]. However, data from both small and large non-COVID-19 studies has been used to form a set of proposed new guidelines for the management of COVID-19 myocarditis; this includes the utilization of mechanical ventilatory and circulatory support, avoidance of immunosuppression in addition to the possible use of anti-interleukin 6 (IL-6) receptor monoclonal antibody to reduce inflammation such as tocilizumab [22].

3. Pericarditis/Cardiac Tamponade

Up to 90% of pericarditis cases can be attributed to viral causes, most often due to enteroviruses, herpesviruses, and parvovirus B19 [23]. With the ongoing COVID-19 pandemic, cases of pericarditis associated to the coronavirus in addition to its life-threatening sequela of cardiac tamponade have been reported with inflammation of the pericardium likely occurring as a result of direct cytotoxic effects or immune-mediated mechanisms [24]. In addition to blood, feces, and the respiratory tract, isolation and detection of SARS-CoV-2 by reverse transcriptase polymerase chain reaction (PCR) has also been reported within pericardial fluid of a patient undergoing pericardiocentesis for cardiac tamponade, further contributing to the evidence of COVID-19 related myopericarditis [25]. Cardiac tamponade has been witnessed in patients with no prior cardiovascular risk factors, they were found to have significantly elevated troponin T levels after presenting with signs and symptoms of dyspnea, chest pain and hypotension; management with pericardiocentesis resulted in improved hemodynamic parameters, however also exposed a barrier to treatment as isolation may preclude transfer to a cardiac laboratory for fluoroscopic-guided paracentesis and may necessitate paracentesis under echocardiographic guidance [26].

4. STEMI

The COVID-19 pandemic has caused a fear of acquired infection within the general population which in turn has resulted in a reduction of ST-segment elevation myocardial infarction (STEMI) related hospitalizations and consequent increase in morbidity and mortality [27]. In addition, overburdened emergency medical services (EMS), fear of improper medical management, use of personalized protective equipment (PPE), lack of trained EMS paramedics, non-availability of negative pressure cardiac catherization laboratoriesand uncertain diagnosis due to the high incidence of COVID-19 related myocarditis may delay STEMI care [28]. Presumed COVID-19 related myocarditis can mask underlying STEMI, whereas the opposite may also occur given similarly elevated cardiac biomarkers and electrocardiographic changes between the two diseases resulting in a diagnostic challenge; the use of non-invasive imaging modalities such as echocardiography and cardiac magnetic resonance imaging may help to aid in differentiation [29, 30].

The Society for Cardiovascular Angiography and Interventions (SCAI), American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP) recommend the continued use of percutaneous coronary intervention (PCI) as the mainstay of treatment for STEMI in the COVID-19 pandemic. If PCI is not available, thrombolytic therapy can be considered [31]. In addition, the following interventions are recommended during the COVID-pandemic: EMS should use personal protective equipment (PPE) in all patients regardless of symptoms and should rapidly preform an electrocardiogram (ECG) if heart disease is suspected; once in the emergency department, patients should be triaged to COVID-19 possible or negative pressure areas where testing may be considered although not at the expense of a delay to revascularization, low threshold intubation may be performed in patients at risk for respiratory decompensation. PPE should be used by all individuals in contact with the patient regardless of COVID-19 status. Lastly, post-procedure care should consist of an extended decontamination time of the cardiac catherization laboratories, plans for early discharge, use of negative pressure rooms if available and rationing of critical-care beds to those requiring intensive care [31, 32].

Broader goals include the initiation of a campaign on public awareness to remind the general population of seeking help immediately if they have symptoms indicative of a heart attack [32]. Additionally, regional STEMI systems of care should be considered including the establishment of macro-hubs to converge time-sensitive emergencies and dedicated personal; these changes may also simultaneously decompress smaller spoke hospitals [33, 34]. Finally, the implementation of telemedicine and virtual cardiac rehabilitation may be considered to help aid and follow-up patient recovery [32].

5. NSTEMI and Unstable Angina

A reduction in the number of observed non-ST segment elevation myocardial infarction (NSTEMI) cases presenting to hospital has been witnessed during the COVID-19 pandemic, as patients tend to stay at home given fear of infection and may only present to hospitals once symptoms worsen or remain persistent, with this unfortunately leading to a delay in treatment and subsequently results in adverse outcomes [35].

Management recommendations for NSTEMI remain largely similar but have also been adapted to reduce the risk of virus exposure to patients and health care professionals; all hospital personal should wear PPE based upon established institution guidelines, COVID-19 testing for suspected patients is recommended if available locally, medical management should be commenced at local non-PCI capable hospitals with avoidance of routine transfer to a designated PCI center unless patients have high risk electrocardiographic features orhemodynamic instability. Lastly, high-risk transferred patients or those who present at designated PCI centers should be treated based upon standard revascularization protocols with either conservative or invasive therapies [36].

Of note, patients with NSTEMI and COVID-19 infection have a higher reported incidence of myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) suggesting that some cases of reported NSTEMI may in fact be secondary to viral mediated myocardial inflammation [37]. A careful review of risks and benefits for acute coronary intervention in NSTEMI is required before proceeding to reduce risk of transmission of COVID-19 to patients and health care workers, in those who require intervention isolated culprit vessel PCI is recommended [38].

6. Takotsubo Cardiomyopathy

The COVID-19 pandemic has resulted in significant stress within the general population with more than half of the general population describing a moderate to severe psychologic impact due to the disease; this may result in emotional triggers and subsequent takotsubo cardiomyopathy [39]. Post-menopausal women are considered to be most susceptible to takotsubo cardiomyopathy due to possible lack of estrogen replacement and may be at the highest risk for takotsubo cardiomyopathy during the course of  COVID-19 infection [40, 41]. Most reported cases of takotsubo cardiomyopathy from COVID-19 infectionare of post-menopausal women; several mechanisms of pathogenesis have been proposed including an adrenergic response to stress, though little is known about any specific pathologic changes which may occur with COVID-19 resulting in takotsubo cardiomyopathy [42, 43]. Treatment of takotsubo cardiomyopathy predominantly consists of symptom management until left ventricular function has recovered [41].

7. Arrhythmias

Patients suffering from COVID-19 are at risk to suffer from arrhythmias as a result of hypoxia, fever, severe electrolyte abnormalities in addition to the adverse effects of medications used within management [44, 45]. Hydroxychloroquine, azithromycin and lopinavir-ritonavir are used for off-label treatment of COVID-19 but are all associated with significant risk of arrhythmia and QTc prolongation [46]. More recent studies have failed to demonstrate any significant clinical benefit with these medications which may result in a decline of their usage [7-9]. Currently remdesevir remains the only pharmacologic therapy which has shown promising results with severe COVID-19 infection,nonetheless information of the effect of the drug on QTc prolongation and arrhythmias remains limited, and further data is required to mitigate the risk of arrhythmia in patients with COVID-19 [6].

8. Conclusion

In summary, COVID-19 can present with a wide array of cardiovascular signs and symptoms which may be difficult to dissect from one another resulting in increased morbidity and mortality. Physicians should be aware of the cardiac manifestations of COVID-19 including myocarditis, pericarditis and cardiac tamponade, STEMI and NSTEMI, takotsubo cardiomyopathy and arrhythmias. Further guidelines and literature arerequired to allow for optimal cardiovascular management of COVID-19 patients.

Conflict-of-Interest Statement

The authors have no conflict of interest to declare.

References

1. Cucinotta D, Vanelli M. WHO Declares COVID-19 a Pandemic. Acta Bio-Medica Atenei Parm 91 (2020): 157-160.
2. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 382 (2020): 1708-1720.
3. Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. J Adv Res 24 (2020): 91-98.
4. Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J 55 (2020).
5. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA 323 (2020): 1775-1776.
6. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. Published online April 10 (2020).
7. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382 (2020): 1787-1799.
8. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med (2020).
9. Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. Published online May 11 (2020).
10. Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. Published online March 30 (2020).
11. De Rosa S, Spaccarotella C, Basso C, et al. Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era. Eur Heart J. Published online May 15 (2020).
12. 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. Published online March 25 (2020).
13. Mahrholdt Heiko, Wagner Anja, Deluigi Claudia C., et al. Presentation, Patterns of Myocardial Damage, and Clinical Course of Viral Myocarditis. Circulation 114 (2006): 1581-1590.
14. Chen C, Zhou Y, Wang DW. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz. Published online March 5 (2020): 1-3.
15. Dennert R, Crijns HJ, Heymans S. Acute viral myocarditis. Eur Heart J 29 (2008): 2073-2082.
16. Fried JA, Ramasubbu K, Bhatt R, et al. The Variety of Cardiovascular Presentations of COVID-19. Circulation. Published online April 3 (2020).
17. Chen C, Chen C, Yan JT, Zhou N, Zhao JP, Wang DW. [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 48 (2020): E008.
18. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Published online March 27 (2020).
19. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. Published online March 3 (2020): 1-3.
20. Babapoor-Farrokhran S, Gill D, Walker J, Rasekhi RT, Bozorgnia B, Amanullah A. Myocardial injury and COVID-19: Possible mechanisms. Life Sci 253 (2020): 117723.
21. Hendren NS, Drazner MH, Bozkurt B, Cooper LT. Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome. Circulation. Published online April 16 (2020).
22. Siripanthong B, Nazarian S, Muser D, et al. Recognizing COVID-19-related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm. Published online May 5 (2020).
23. Imazio M, Gaita F, LeWinter M. Evaluation and Treatment of Pericarditis: A Systematic Review. JAMA 314 (2015): 1498-1506.
24. Dabbagh MF, Aurora L, D’Souza P, Weinmann AJ, Bhargava P, Basir MB. Cardiac Tamponade Secondary to COVID-19. JACC Case Rep. Published online April 22 (2020).
25. Farina A, Uccello G, Spreafico M, Bassanelli G, Savonitto S. SARS-CoV-2 detection in the pericardial fluid of a patient with cardiac tamponade. Eur J Intern Med. Published online April 23 (2020).
26. Hua A, O’Gallagher K, Sado D, Byrne J. Life-threatening cardiac tamponade complicating myo-pericarditis in COVID-19. Eur Heart J. Published online March 30 (2020).
27. Lazzerini M, Barbi E, Apicella A, Marchetti F, Cardinale F, Trobia G. Delayed access or provision of care in Italy resulting from fear of COVID-19. Lancet Child Adolesc Health. Published online April 9 (2020).
28. Roffi M, Guagliumi G, Ibanez B. The Obstacle Course of Reperfusion for STEMI in the COVID-19 Pandemics. Circulation. Published online April 21 (2020).
29. Yousefzai R, Bhimaraj A. Misdiagnosis in the COVID era: When Zebras are Everywhere, Don’t Forget the Horses. Jacc Case Rep. Published online April 27 (2020).
30. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Published online March 27 (2020).
31. Mahmud E, Dauerman HL, Welt FGP, et al. Management of acute myocardial infarction during the COVID-19 pandemic: A Consensus Statement from the Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP). Catheter Cardiovasc Interv Off J Soc Card Angiogr Interv. Published online April 20 (2020).
32. The American Heart Association’s Get With The Guidelines-Coronary Artery Disease Advisory Work Group And Mission Lifeline Program null, The American Heart Association’s Council On Clinical Cardiology  null, The American Heart Association’s Council On Clinical Cardiology’s Committee On Acute Cardiac Care And General Cardiology Committee  null, The American Heart Association’s Council On Clinical Cardiology’s Committee Interventional Cardiovascular Care Committee  Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic: AHA’s Mission: Lifeline. Circulation. Published online May 2 (2020).
33. Mahmud E, Dauerman HL, Welt FG, et al. Management of Acute Myocardial Infarction During the COVID-19 Pandemic. J Am Coll Cardiol. Published online April 21 (2020).
34. Ferlini M, Andreassi A, Carugo S, et al. Centralization of the ST elevation myocardial infarction care network in the Lombardy region during the COVID-19 outbreak. Int J Cardiol. Published online April 24 (2020).
35. Tam C-CF, Cheung K-S, Lam S, et al. Impact of coronavirus disease 2019 (COVID-19) outbreak on outcome of myocardial infarction in Hong Kong, China. Catheter Cardiovasc Interv. n/a(n/a).
36. Abdelaziz HK, Patel B, Chalil S, Choudhury T. COVID-19 Pandemic and Acute Myocardial Infarction: Management Protocol From a British Cardiac Centre. Crit Pathw Cardiol. Published online April 27 (2020).
37. Trabattoni D, Montorsi P, Merlino L. Late STEMI and NSTEMI patients’ emergency calling in CoVID-19 outbreak. Can J Cardiol. Published online May 8 (2020).
38. Zeng J, Huang J, Pan L. How to balance acute myocardial infarction and COVID-19: the protocols from Sichuan Provincial People’s Hospital. Intensive Care Med. Published online March 11 (2020): 1-3.
39. Wang C, Pan R, Wan X, et al. Immediate Psychological Responses and Associated Factors during the Initial Stage of the 2019 Coronavirus Disease (COVID-19) Epidemic among the General Population in China. Int J Environ Res Public Health 17 (2020).
40. Khalid N, Ahmad SA, Shlofmitz E, Chhabra L. Racial and Gender Disparities Among Patients With Takotsubo Syndrome. Clin Cardiol 42 (2019): 19.
41. Gowdar S, Chhabra L. Microvascular Dysfunction in Takotsubo Cardiomyopathy. International CardiovascularForum Journal 5 (2016): 40-49.
42. Minhas AS, Scheel P, Garibaldi B, et al. Takotsubo Syndrome in the Setting of COVID-19 Infection. JACC Case Rep. Published online May 1 (2020).
43. Nguyen D, Nguyen T, De Bels D, Castro Rodriguez J. A case of Takotsubo cardiomyopathy with COVID 19. Eur Heart J Cardiovasc Imaging. Published online May 12 (2020).
44. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Published online May 1 (2020).
45. Lakkireddy DR, Chung MK, Gopinathannair R, et al. Guidance for Cardiac Electrophysiology During the Coronavirus (COVID-19) Pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association. Heart Rhythm. Published online April 1 (2020).
46. Gérard A, Romani S, Fresse A, et al. Off-label use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers. Therapie. Published online May 7 (2020).