|
 
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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 5
| Issue : 3 | Page : 65-72 |
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Possible mechanisms of cardiovascular complications and troponin elevation in coronavirus disease: A narrative review
Saloni Malik1, Manisha Naithani1, Anissa Atif Mirza1, Anshuman Darbari2, Rahul Saxena3
1 Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of CTVS, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 Department of Biotechnology, Amity Institute of Biotechnology, AMITY University, Noida, Uttar Pradesh, India
| Date of Submission | 07-Mar-2021 |
| Date of Acceptance | 07-Jul-2021 |
| Date of Web Publication | 29-Sep-2021 |
Correspondence Address:
Ms. Saloni Malik
M. Sc. Student, Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_16_21
More than 20 million human beings got infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suffered from coronavirus disease 2019 (COVID-19) disease in the current global pandemic. This disease flow showed a heterogeneous spectrum due to various personalized underlying causes and immunogenetics makeup of an individual. Substantial evidence suggests that the severity of pneumonia, acute respiratory distress syndrome, multi-organ failures, and deaths in COVID-19 is attributable to cytokine storm. Thus, in a cytokine storm, the dysregulated immune system is triggered by superantigen of SARS-CoV-2 to release various cytokines with high speed and increased blood circulation concentrations, leading to diverse clinical manifestations of massive multi-organ destruction and death due to exuberant hyperinflammation at a local and systemic level. SARS-CoV-2 can also significantly affect the cardiovascular system of the infected persons through a systemic outburst of the cytokine storm. SARS-CoV-2 infection accompanies many cardiovascular complications that include myocardial infarction, myocarditis, microangiopathy, venous thromboembolism, and a cytokine storm burden resulting in heart failure. This narrative review attempts to gather all recent evidence by Internet-based literature search with relevant keywords related to coronavirus disease with main objective and focus on possible mechanisms of pathophysiology of troponin elevation and cardiovascular complications, with its diagnosis and recent guidelines for its management.
Keywords: Coronavirus, coronavirus disease-19, cytokine storm, microangiopathy, myocardial infarction, myocarditis, troponin
How to cite this article:
Malik S, Naithani M, Mirza AA, Darbari A, Saxena R. Possible mechanisms of cardiovascular complications and troponin elevation in coronavirus disease: A narrative review. Heart Mind 2021;5:65-72 |
How to cite this URL:
Malik S, Naithani M, Mirza AA, Darbari A, Saxena R. Possible mechanisms of cardiovascular complications and troponin elevation in coronavirus disease: A narrative review. Heart Mind [serial online] 2021 [cited 2023 Jun 6];5:65-72. Available from: http://www.heartmindjournal.org/text.asp?2021/5/3/65/326960 |
| Introduction | |  |
The outbreak of unusual pneumonia cases suddenly emerged in Wuhan, Hubei, China, clinically resembled a new type of viral pneumonia in December 2019. Further analysis of lower respiratory tracts samples revealed a novel coronavirus named the 2019 novel coronavirus (2019-nCoV).[1] This name 2019-nCoV has been changed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resultant disease as coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO) on February 11, 2020.[2] COVID-19 was declared to be a pandemic on March 11, 2020. Patients infected with SARS-CoV-2 mainly presented with fever, cough, dyspnea, and pneumonia, which may ultimately progress to acute respiratory distress syndrome (ARDS), multi-organ failure (MOF), and ultimately death.[3] In the current global pandemic, more than 20 million people got infected by SARS-CoV-2 and suffered from COVID-19 with a heterogeneous spectrum of mild, moderate, and severe manifestations.
According to the cohort data, ARDS occurs in nearly 3%–30% of hospitalized patients with COVID-19. An initial mechanism of SARS-CoV-2 infection is the binding of the virus to the membrane-bound angiotensin-converting enzyme 2 (ACE2), which is mainly expressed in the lung and the heart and vessels. Cellular entry of viruses also requires the activity of serine proteases, such as transmembrane protease, serine 2 (TMPRSS2). TMPRSS2 is critical for spike protein activation. It has been found that patients with preexisting heart diseases, hypertension, or diabetes on treatment with ACE2 inhibitors had increased expression of ACE2 and hence at higher risk of getting SARS-CoV-2 infection.[4] A recent meta-analysis including 18,012 COVID-19 patients has shown that a moderate association of severity and mortality is seen with coexisting diabetes mellitus and hypertension, whereas this was a much stronger correlation with preexisting cardiovascular disease (CVD).[5]
Thus, cardiovascular tissues which express ACE2 are at a risk of infection mediating cardiac damage. COVID-19 is associated with many cardiovascular complications, including myocardial infarction (MI), myocarditis, microangiopathy, severe respiratory disease with hypoxia, sepsis, venous thromboembolism, and a cytokine storm burden.[6] Several mechanisms are proposed, which are summarized in [Figure 1]. A substantial number of COVID-19-positive patients have concomitant elevation in cardiac troponin.[7] The main focus is on possible mechanisms of troponin elevations as a diagnostic feature associated with cardiovascular complications and recent guidelines for its management. Since an understanding of these mechanisms is rapidly evolving, this narrative review is our attempt with an object to bring together, in a nutshell, recent pieces of evidence pointing at cardiac implications by an Internet search of various isolated case reports, case series, and original research article available in the standard database with standard keywords of coronary diseases and coronavirus disease in the last 2 years. | Figure 1: The effect of severe acute respiratory syndrome coronavirus 2 and various cardiac complications
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| Myocarditis in Coronavirus Disease 2019 | | |
Inflammation of the myocardium characterized by immunologic, histochemical, and inflammatory infiltrates is referred to as myocarditis. In the United States, the common cause of myocarditis is viral.[8] The cardiotropic viruses can bind directly to receptors in the myocardium, causing myocarditis. There are different reasons for myocardial damage occurrence. Direct virus-mediated cardiomyocyte lysis occurs initially, followed by a vigorous T-cell response. High levels of interleukin-1 (IL-1) lead to further heart injury and ventricular dysfunction. In COVID-19, the mechanism of myocarditis is linked with ACE2.[4]
ACE2, a metallopeptidase, is expressed mainly in the lung and the heart and vessels. Thus any disturbance in the ACE2 signaling pathway will lead to heart injury. By binding its spike proteins to ACE2, SARS-CoV-2 enters into human cells. ACE2 is an enzyme accountable for converting Angiotensin II (Ang-II) into Ang (1–7), which has vasodilator and anti-inflammatory effects. ACE2 is also found in the lungs, heart, and vessels; therefore, it is notable that ACE2 downregulation due to its binding with the virus can disturb the ACE2 signaling or conversion, which will have inflammatory effects, and heart walls are affected and can also lead to inflammation and MOF.[8],[9]
In 35% of COVID-19 patients autopsied after death, myocardium disclosed the presence of viral RNA in them. The presence of viral RNA in the heart was accompanied with a marked reduction of ACE2 expression. The binding mechanism of SARS-CoV and SARS-CoV-2 are almost identical, while SARS-CoV-2 has more affinity toward ACE2 than SARS-CoV, which further increase its efficiency to infect cells.[9] [Figure 2] is showing the comparative effects of SARS-CoV-2 on ACE2 signaling and causing myocarditis. [Table 1] summarizes various cases reported by other authors who presented with myocarditis in COVID-19 patients. A recently published multicenter case series concluded that patients with myocarditis did not differ by sex predilection, morbimortality, or elevations in cardiac markers in serum as compared to those with no documented myocardial involvement. Still, they recorded a higher need for oxygen support. The aged COVID -19 patients are more suspected to myocarditis, specially with previous history of cardiac disease and they have to stay more at hospital with lower value of IL-16 as in comparison of other COVID-19 patients.[10] There have also been reports confirmed by the WHO Global Advisory Committee on Vaccine Safety of myocarditis that predominantly occurred in adolescents and young adults, more frequently in males within 4 days after the second dose of COVID-19 mRNA vaccines.[11] | Table 1: Summary of other reported cases of coronavirus disease-19 who presented with myocarditis
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 | Figure 2: Comparative effects of severe acute respiratory syndrome coronavirus 2 on angiotensin-converting enzyme 2 signaling and causing myocarditis
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| Microangiopathy in Coronavirus Disease 2019 | | |
Angiotensin – converting enzyme 2 (ACE2) is generally expressed in the lungs, cardiovascular system, gut, kidneys, central nervous system, and in adipose tissue. ACE2 being the probable cellular receptor for the entry of SARS-CoV-2 into the host cells, provides a critical link between immunity, inflammation, and cardio-vascular disease.[12] The renin-Ang system (RAS) is a complex which maintains the blood pressure, tissue perfusion, and extracellular volume through pressor and depressor pathways, and ACE2 is the key counter-regulatory component of RAS. The RAS is a multifaceted mechanism maintaining the blood pressure, tissue perfusion, and extracellular volume through pressor and depressor pathways, and ACE2 is the key counter-regulatory component of RAS. Thus, downregulation of ACE2 due to its binding with SARS-CoV-2 can cause the defect in the normal conversion of Ang-II into Ang (1–7),[6],[7],[13] which opposes the vasoconstrictor, pro-inflammatory, pro-oxidant, proliferative, and pro-fibrotic actions exerted by Ang-II. Downregulated ACE2 expression and high Ang-II levels lead to an added threat of microangiopathy (disease of small blood vessels) in the heart and additionally to other vessels in COVID-19 patients. ACE2 upregulation, oxidative stress, cytokine storm, and endothelial dysfunction lead to coagulopathy and subsequent severity of COVID-19. Some studies are supporting the notion that COVID-19 is highly thrombotic. In the study of Cui et al., 25% of patients with severe COVID-19 had deep vein thrombosis also. Klok et al. reported 31% of critical COVID-19 patients showing the incidence of deep vein thrombosis, pulmonary embolism, and arterial thrombosis, and out of these events, 81% were having pulmonary thromboembolic complications. Laboratory abnormalities in COVID-19 coagulopathy include elevation in D-dimer concentrations and fibrinogen. Elevation in D-dimer is associated with disease severity and higher mortality. This conspicuous elevation in D-dimer is due to the intense inflammation leading to fibrinolysis in the lungs with spillover into the bloodstream.[4] 0.5 μg/mL or a higher level was found in 59.6% of COVID-19 patients with severe disease versus 43.2% of those with mild disease. Vasculitis also contributed to microangiopathy. Endothelial cell inflammation, apoptosis, and dysfunction occur in patients having COVID-19.[14] Lymphocytic vasculitis is seen with skin lesions on the toes, feet, heels, and hands in some COVID-19 patients. In several studies, coronavirus is linked with Kawasaki disease, particularly in children. This may be due to the involvement of the interferon gene pathway, which was known to be inhibited by aspirin and intravenous immunoglobulins. The exact mechanism was found to be activated in COVID-19 by the binding of SARS-CoV-2 with ACE2.[15] In addition, a case series of three SARS patients in 2003 was described with findings of systemic vasculitis of edema, localized necrosis, and monocyte, lymphocyte, and plasma cell infiltration into vessel walls of heart, lung, liver, kidney, adrenal gland, and striated muscles.[16] [Figure 3] is schematically explaining microangiopathy and thrombosis due to SARS-CoV-2. [Table 2] summarizes various cases reported by other authors who presented with microangiopathy in COVID-19 patients. A recent meta-analysis of available literature pointed that in COVID-19, immunothrombotic microangiopathy developed due to it being a hyperinflammatory state. This review also highlighted that massive activation of the immune system and microvascular damage are linked to diffuse alveolar damage that may be accountable for indirect damage to other organs, including the heart[17]. | Table 2: Summary of other reported cases of coronavirus disease 2019 who presented with microangiopathy
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 | Figure 3: Microangiopathy and thrombosis due to severe acute respiratory syndrome coronavirus 2
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| Cytokine Storm and Heart Failure in Coronavirus Disease 2019 | | |
Cytokines play a significant role in immunopathology in viral infections and are deemed the first line of defense combating viruses. COVID-19 is accompanied by an aggressive inflammatory response or “cytokine storm” to release significant quantities of cytokines, particularly of pro-inflammatory type.[18] Substantial evidence suggests that the severity of pneumonia, ARDS, MOFs, and deaths in COVID-19 is attributable to this cytokine storm. Thus, in cytokine storm, the dysregulated immune system is triggered by superantigen of SARS-CoV-2 to release various types of cytokines with high speed and increased concentrations in blood circulation that consequently leads to diverse clinical manifestations, massive multi-organ destruction, and failures due to exuberant hyperinflammation at local and systemic levels.[19]
The upregulation of pro-inflammatory cytokines leads to severe lung inflammation and defective pulmonary gas exchange in COVID-19 patients. Cytokine storm leads to a sudden acute upsurge in circulating levels of pro-inflammatory cytokines such as IL-6, IL-1, TNF-α, and interferon, which results in the influx of macrophages, neutrophils, and T-cells from blood circulation to the site of infection. This accumulation of various immune cells has a destructive effect on human tissue and leads to an impaired vascular barrier, capillary damage, destabilization of cell–cell interaction, damage to alveoli, multiple organ failure, and ultimate demise. The main consequence of cytokine storm is lung injury progressing from acute lung injury to ARDS, resulting in low gas transfer and low arterial oxygen saturation levels, and is the primary cause of death in COVID-19.[19] [Figure 4] is explaining the mechanism of the cytokine storm in COVID-19. There has been anti-cytokine therapy as a treatment option for those unresponsive to standard critical care management. However, diabetes and resulting hyperglycemia with the further generation of pro-inflammatory cytokines set up a vicious cycle that may lead to failure of response to this novel treatment.
Cytokine storm and heart failure (HF) are intricately linked. A study including 5700 patients from multiple cities of the United States of America (USA) reported congestive HF being present in 6.9% of patients.[20] In a smaller comparative study recruiting 53 COVID-19-positive patients with a history of heart diseases and 46 patients without a history of heart diseases, it was found a high prevalence of HF accounting for 21% deaths in the total patients with higher (40%) prevalence of death in those already having cardiac diseases.[21] A retrospective case series including 799 COVID-19 cases of varying severity found that the HF incidence in those having untimely demise was 49%.[22] Thus, worsening COVID-19 may have HF as the most typical complication, more likely in patients with preexisting cardiac disorders, and it dramatically escalates mortality.
Cytokine storm represents a vital aspect responsible for the progression of both COVID-19 and HF. In HF, cytokines are central pathogenic factors, and they also serve as biomarkers of the progression to HF. In turn, HF itself triggers systemic inflammation by releasing large amounts of cytokines.[23] A recent meta-analysis including data from 20 individual studies found that the preexistence of CHF and high serum values of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and CK-MB correlated with poorer outcomes.[24] Another caution mentioned by the European Society of Cardiology (ESC) is the difficulty in diagnosing HF in COVID-19. Acute HF complicating the clinical course may have significantly elevated BNP/NT-proBNP. ESC guidelines mentioned considering the use of bedside transthoracic echocardiography. However, the treatment strategy recommended is common in patients with and without COVID-19.[25]
| Myocardial Infarction in Coronavirus Disease 2019 | | |
MI has main symptoms: chest pain, breath shortness, nausea, sweating, vomiting, abnormal heart rate, anxiety, stress, with diagnostic criteria such as elevated troponin T or troponin I (TnI), and systemic inflammation.[26]
This symptomatology complex of MI overlaps with general complaints of chest pain or tightness in COVID-19. Pain in COVID-19 may be poorly localized, and underlying pneumonia may also cause breathlessness. Differential diagnosis is tricky because shortness of breath and respiratory symptoms may be present and may precede or precipitate cardiac signs and symptoms.[25] Sometimes, COVID-19 presentation could curtail cardiovascular symptoms rather than typical symptoms of fever, cough, and dyspnea. Stefanini et al. detailed that in COVID-19, first manifestation in 81% of patients is with ST-elevation MI, of whom 78.6% had acute chest pain.[27] Those at a high risk of atherosclerotic CVD or history of coronary artery disease (CAD) have a higher chance during this viral infection to develop acute coronary syndrome (ACS). Standardized protocol delays in the treatment of high-risk ACS have been dubbed to cause an increased incidence of short-term MI complications and fatalities. A meta-analysis revealed that at least 8% out of a total of 1527 patients had an acute myocardial injury, with the risk of harm being 13-fold higher in those presenting with severe COVID-19.[28]
Coronavirus entre the host cells via ACE2 receptor, which catalyzes angiotensin II to angiotensin and binding of SARS- CoV-2 with ACE2 affects its regulation and downstream the conversion of Ag II into Ag 1-7 which is expressed in vascular endothelial cells and myocardium. In addition, the suppression of ACE2 expression and Ang-II increase may elevate cardiovascular risk through mechanisms such as endothelial dysfunction, oxidative stress, and vasoconstriction, which amplify the cytokine storm, resulting in a devastating inflammatory response. Thus, direct corona viral infection can lead to plaque instability. Hence in Type-1 MI, where this plaque instability caused by corona virus with subsequent rupture due to thrombus formation, further leads to serious inflammatory response due to the intense release of a cytokine storm. Further hypoxia secondary to lung involvement, fever, and tachycardia participate in Type 2 MI. Coronary artery involvement can also be produced by microangiopathy that has also been described. Chen et al. described the various factors in their cross-sectional study, which relates the COVID-19 with MI, which includes elevation in cardiac troponin I, elevated NT-proBNP, and a rise in the level of high-sensitivity C-reactive protein (hs-CRP).[22] These biomarkers of myocardial injury and inflammation are correlated with the severity and mortality of the disease.[29] An initial study in Wuhan, China by Haung et al. reported hypersensitive cardiac troponin I (hs-cTnI) was increased substantially in 5 patients of total 41 patients, in whom the diagnosis of virus-related cardiac injury was made. Out of five patients with elevated hs-cTnI, four show disease severity and required intensive care unit admission. Thus, increased troponin I is associated with higher mortality of CVD patients in COVID-19. Infectious states are characterized by fever, tachycardia, and endocrine dysregulation, leading to a severe increase in the oxygen requirement of myocardial tissue. Hypoxemia also leads to excessive intracellular calcium resulting in cardiac myocyte apoptosis.[30] Type 2 MI can occur with or without underlying CAD. However, considering the higher prevalence of elevated troponin levels in patients with COVID-19 with previous CVD, in some cases, unexpected MI occured in patients of stable coronary diseases due to acute infection and associated inflammation. In the study of Guo et al., it was found that plasma troponin levels correlated significantly and positively with plasma hs-CRP levels, signifying that myocardial injury may be closely connected to inflammation.[31] [Figure 5] is explaining the mechanism of MI in COVID-19. [Table 3] summarizes clinical signs in the various cases reported with MI in COVID-19 patients by other authors. | Table 3: Summary of other reported cases of coronavirus disease-19 who presented with myocardial infarction
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 | Figure 5: Myocardial infarction mechanism in patients of coronavirus disease 2019
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It is imperative to note that cardiac biomarker elevations in COVID-19 could either be nonspecific elevation, a complication of sepsis, acute kidney injury, or stroke.[32],[33] Troponin elevation in patients with COVID-19 infection has been documented to be lesser than in classic ACS or acute myocarditis; the European Association of Percutaneous Cardiovascular Interventions suggests considering marked elevation (e.g. >5 times the standard upper limit) in a patient who is not critically ill to suspect COVID with MI.[34],[35] Treatment, however, remains unchanged in these cases. Finally, it is paramount to emphasize that differential diagnosis of COVID-AMI is a challenge for clinicians. It is of utmost importance to use clinical judgment and collaborate biomarker elevation with symptoms and signs and ECG changes.[36],[37],[38]
| Conclusion | | |
Substantial recent pieces of evidence depicted cardiac morbimortality associated with current coronavirus disease. Cytokine storm is attributable to cascades of hypercoagulability that deprive blood supply to the myocardium, leading to MI. Utmost caution must be taken to diagnose common cardiac manifestations in COVID-19, as symptoms may overlap with other presentations. A personalized approach toward COVID-19 patients will be of great value to track diagnosis, monitor patients' presentations, and plan and implement treatment regimes. Troponin elevation in patients with COVID-19 infection has been documented to be lesser than in classic ACS or acute myocarditis. Marked elevation may strengthen the suspicion of COVID-AMI. Biomarkers of diagnosis of these cardiac manifestations also labeled as prognostic markers in COVID-19. Further robust, well-designed multicenter studies are still warranted, to clarify the pathogenic mechanisms to unveil novel inflammatory and vascular biomarkers.[37],[38]
Ethical statement
Ethical statement is not applicable for the article as it is a Review Article.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]
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