Elucidating the Role of Cardiac Biomarkers in COVID-19: A Narrative Evaluation with Clinical Standpoints and a Pragmatic Approach for Therapeutics

Abstract

With the incidence of the unabated spreading of the COVID-19 (coronavirus disease 2019) pandemic with an increase in heart-related complications in COVID-19 patients, laboratory investigations on general health and diseases of heart have greater importance. The production of a higher level of clots in the blood in COVID-19 individuals carries a high risk of severe lethal pneumonia, pulmonary embolism, or widespread thromboembolism. The COVID-19 pandemic has raised awareness regarding the severe consequences for the cardiac system that might cause due to severe acute respiratory distress syndrome (SARS-CoV-2). COVID-19 causes acute respiratory distress syndrome (ARDS), acute myocardial infarction, venous thromboembolism, and acute heart failure in people with preexisting cardiac illness. However, as COVID-19 is primarily a respiratory infectious disease, there is still a lot of debate on whether and how cardiac biomarkers should be used in COVID-19 patients. Considering the most practical elucidation of cardiac biomarkers in COVID-19, it is important to note that recent findings on the prognostic role of cardiac biomarkers in COVID-19 patients are similar to those found in pneumonia and ARDS studies. The use of natriuretic peptides and cardiac troponin concentrations as quantitative variables should help with COVID-19/pneumonia risk classification and ensure that these biomarkers sustain their high diagnostic precision for acute myocardial infarction and heart failure. Serial assessment of D-dimers will possibly aid clinicians in the assortment of patients for venous thromboembolism imaging in addition to the increase of anticoagulation from preventive to marginally higher or even therapeutic dosages because of the central involvement of endothelitis and thromboembolism in COVID-19. Therefore, cardiac biomarkers are produced in this phase because of some pathological processes; this review will focus on major cardiac biomarkers and their significant role in COVID-19.

1. INTRODUCTION

COVID-19 is an incipient infectious respiratory disease that has caused a pandemic worldwide, with more than 193,359,380 cases and more than 4,142,769 deaths as of July 22^nd, 2021. SARS-CoV-2 (causative agent of COVID-19) enters the host cell through the direct fusion of the viral envelope with the host cell membrane or membrane fusion within the endosome following endocytosis. The S protein's receptor-binding protein (RBD) binds to the human host cell receptors on the cell surface, allowing the virus to enter the cell. Angiotensin-converting enzyme 2 (ACE2), neuropilin-1, Tyrosine-protein kinase receptor UFO (AXL), and antibody-FcR complexes are among the receptors that SARS-CoV-2 uses to connect to the surface of host cells. Current evidence specifies that a massive proportion of deaths from COVID-19 may be attributed to cardiac disease [1]. Although some patients, particularly children, might have a mild or even asymptomatic course of COVID-19, many others develop a problematical course of COVID-19 that includes viral pneumonia, acute respiratory distress syndrome (ARDS), acute myocardial infarction (AMI), stroke, tachyarrhythmias, venous thromboembolism (VTE), acute heart failure (AHF), and cardiac arrest [2, 3]. Cardiac biomarkers have been recommended as a valuable help to doctors in COVID-19 by perceiving and measuring cardiac hemodynamic stress, cardiomyocyte injury, as well as intravascular coagulation, as the heart can play a more significant role in COVID-19 [2, 4]. Cardiac markers may be classified as assessing acute cardiac injury or those used to identify long-term risks. However, there is still a lot of confusion about using cardiac biomarkers in people who have COVID-19. It is worth noting that current findings regarding the predictive importance of cardiac biomarkers in patients hospitalised with COVID-19 are comparable to those found in research on viral pneumonia caused by influenza and ARDS in general, despite minor differences. Here, we outline the potential involvement of recently discovered cardiac biomarkers in COVID-19 and their unique characteristics.

The specific mechanisms causing various cardiac difficulties in COVID-19 patients are still being debated as they are the most effective treatments for COVID-19 patients with underlying heart disease [5]. As a result, an enhanced understanding of how COVID-19 affects the human cardiac system, mainly in those with heart disease, is critical to developing approaches for early recognition of cardiac injury and adequate cardiomyocyte protection in mild and severe COVID-19 cases to prevent heart failure in these patients [6, 7]. Furthermore, cardiac difficulties in COVID-19 infected patients appear to be alarming, given the growing number of COVID-19 patients, in addition to the prevalent clinical presentations of the disease [8].

2. BIOLOGY OF SARS-COV-2

Coronaviruses, a broad family of single-stranded enclosed RNA viruses [9], were not previously recognised as particularly dangerous in humans until the SARS outbreak during 2002-2003, caused by SARS-CoV [10,11]. Given the genomic sequence similarity, SARS-CoV-2 is believed to have many biological characteristics with SARS-CoV, implying that we may use our fundamental knowledge of SARS-CoV biology and pathophysiology to understand SARS-CoV-2 better [12]. Coronaviruses have a crown-like exterior, with four structural proteins, namely, spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins that make up the virus [9, 13].

The viral genome enclosed by N protein is a single-stranded, positive-sense RNA that serves as a genome and an mRNA. Coronaviruses are classified into four genera, namely, α, β, γ, and δ, of which only α and β coronaviruses are known to infect humans. The genome of SARS-CoV-2, similar to other coronaviruses, is around 30 kb long and comprises 10 open reading frames (ORFs) that encode 24–27 genes [14, 15] and polyproteins pp1a and pp1ab that are cleaved into 16 non-structural proteins, including RNA-dependent RNA polymerase (RdRP).

Structural proteins S, E, M, and N are encoded in the 3′-terminal third of the genome. The S protein is a structural protein that plays a crucial function in virus attachment and entrance and disease pathogenesis [16-18]. Viral S protein binds to angiotensin-converting enzyme 2 (ACE2) on the host cell surface after infection with SARS-CoV-2. The virus attaches to ACE2 through the receptor-binding region on the surface component S1 of the S protein. The transmembrane serine protease TMPRSS2 cleaves the S protein once it binds to it, allowing the viral membrane to fuse with the host cell membrane as well as the virus to enter the cytoplasm directly [19, 20]. A possible therapeutic target can be provided for each phase of the viral life cycle, including protein S priming by TMPRSS2, membrane fusion and endocytosis, and RNA replication by RdRP [21].

3. COVID-19 INFECTION AND CARDIAC INVOLVEMENT

COVID-19 is a viral infection in which the lungs are the primary and seriously impacted target; it is a kind of infection in which most organ systems are afflicted with variable degrees. The severity of the condition is determined by various factors, including the patient's age, immunological status, and prior comorbidities. The disease progresses over time, and indications and symptoms are determined by viral invasion and replication and the host's immunological response [22]. The body's immune system strives to control and restrict viral damage as the disease progresses, but this regrettably results in an exaggerated hyper-inflammatory response, which causes widespread collateral tissue injury and severely affects numerous organs. COVID-19 may affect the cardiac system in various ways [23-25] and concerning time (Fig. 1).

Fig. (1).

Disease severity and SARS-CoV-2 induced cardiac problems concerning time.

COVID-19 related cardiac disorders include myocarditis, acute coronary syndrome (ACS), arrhythmias, and secondary cardiac disorders are cardiac injury during SARS-CoV-2 septic shock and multiple organ failure. Direct or indirect methods can cause cardiac damage.

Viral penetration into cardiac tissue causes cardiomyocyte loss and inflammation as a direct mechanism. Cardiac stress caused by respiratory failure and hypoxia and heart inflammation caused by severe systemic hyper inflammation are examples of indirect processes [26]. Viral penetration into cardiac tissue causes cardiomyocyte loss and inflammation as a direct mechanism. Moreover, cardiac stress caused by respiratory failure and hypoxia and heart inflammation caused by severe systemic hyper inflammation are examples of indirect processes [1, 27]. Moreover, cardiac complications include myocardial injury, arrhythmias, myocardial infarction, and heart failure (Fig. 2).

Fig. (2).

COVID-19 and cardiac injury with the clinical sequel.

Congenital cardiac disease is a significant and fast-growing global health issue for children. Unfortunately, children with acquired heart disease, such as children who do not have heart disease at birth but develop it after, are far more uncommon. Inflammatory heart disease, such as rheumatic heart disease, which develops after rheumatic fever, and infectious heart diseases, such as endocarditis or cardiac trauma, are examples of these disorders.

3.1. Acute Coronary Syndrome (ACS)

Virus infections have been linked to coronary plaque inflammation, plaque rupture, and the initiation of thrombosis, according to research. COVID19 is thought to behave similarly, and people with COVID19 may experience ACS symptoms [28].

3.2. Acute Myocardial Injury

Numerous overlapping elements, such as a strong inflammatory response with direct cytokine stimulation, are thought to have a role in heart damage. Atherosclerotic plaques can become unstable and break, triggering a thromboembolic cascade that leads to myocardial infarction. Myocardial damage can be caused by an imbalance between oxygen supply and demand, electrolyte abnormalities, or arrhythmia [29].

SARS-COV-2 can cause direct harm to vascular endothelial cells and cardiomyocytes because it enters through ACE 2 receptors prevalent in lungs, vascular endothelial cells, and myocytes [30].

3.3. Heart Failure

Patients with congestive heart failure (CHF) are more likely to contract SARS-CoV-2, which is concerning because severe respiratory sickness might trigger CHF decompensation [31]. CHF in COVID 19 sufferers could be caused by a variety of factors. Cardiomyopathies have been described in some cases. However, the specific pathophysiology of ventricular failure remains unknown. Increased serum brain natriuretic peptide (BNP) levels may indicate a role for cardiac failure in the pulmonary edema seen in COVID-19 patients [32], which is mainly due to ARDS.

3.4. Arrhythmias and Sudden Cardiac Arrest

COVID-19 is known to cause arrhythmias and sudden cardiac arrest. In patients without fever or cough, heart palpitation has been recorded as the main presenting symptoms of COVID-19 [33]. In addition, patients with increased troponin T levels were more likely to progress to malignant arrhythmias than those with normal troponin T levels [34]; for instance, ventricular tachycardia and fibrillation were reported in a study involving COVID-19 patients. However, because arrhythmias, including atrial and ventricular tachycardia and fibrillation, may be caused by myocardial damage [34], the actual contribution of COVID-19 to cardiac arrhythmias is unknown.

3.5. Thrombosis and Coagulation Abnormalities

COVID-19 is linked to coagulation problems that may lead to thromboembolic events [35]. According to clinical observations, increased thromboembolic events in COVID-19 patients suggest the existence of a hypercoagulable state. Venous thromboembolism, which comprises deep vein thrombosis and pulmonary embolism, is a common complication in COVID-19 patients. In the case of COVID-19, the mechanisms driving these coagulation abnormalities, particularly hypercoagulation, are unknown. COVID-19-induced significant inflammatory response and endothelial damage, in combination with primary comorbidities, may lead individuals to a hypercoagulable condition [36].

3.6. ACE2 and Cardiac Manifestations of COVID-19

The link between cardiac risk factors and COVID-19 mortality has been proven in multiple case series and retrospective studies. The first extensive investigations were conducted in China, followed by Italy and the United States, confirming the link between COVID-19 mortality and cardiac risk factors. Microvascular inflammation and thrombosis were seen in COVID-19 patients' pathological specimens. The release of cytokines, like interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), by activated macrophages, causes hyper inflammation and endothelial dysfunction. Myocardial damage in severe COVID-19 patients [37, 38] is caused by thrombus formation in the coronary microcirculation and endothelial dysfunction.

The mechanisms which cause COVID-19 related heart damage are unknown. One of the primary elements hypothesised to be involved in the molecular mechanism underpinning tissue-specific infection is ACE2 expression. Given that ACE2 is known to have critical functions in both the cardiac and immunological systems [39], the interaction between S protein and ACE2 has piqued researchers' curiosity. The renin-angiotensin-aldosterone system (RAAS) contains ACE2, which has a role in developing hypertension and heart failure. ACE2 is extensively expressed in heart and blood arteries in tissues [39]. According to single-cell RNA sequencing data, cardiomyocytes express ACE2 at a lesser level than pericytes; besides, neither pericytes nor cardiomyocytes express TMPRSS2 [40]. However, both cell have significant levels of types cathepsin B and cathepsin L, which aid in S protein priming and may help the virus enter the cell via the endocytic pathway. As a result, SARS-CoV-2 may be proficient indirectly infecting cardiomyocytes, pericytes, and endothelial cells, among other cardiac cell types.

4. VARIOUS CARDIAC MARKERS WITH THEIR IMPORTANCE IN COVID-19

In light of the continuing expansion of the COVID-19 pandemic and the rise in heart-related problems among COVID-19 patients, laboratory investigations regarding general health and heart disorders are becoming increasingly important [41]. Cardiac indicators are divided into two categories: those used to assess acute cardiac injury and those used to identify long-term concerns. Some common cardiac biomarkers are:

1. Cardiac markers of myocardial infarction (MI).

   1. Cardiac troponins (cTnT and cTnI).

   2. High sensitivity troponin (hscTnT and hscTnI).

   3. Creatine kinase isoenzyme (CK-MB).

   4. Myoglobin

2. Markers for risk prediction

   1. Total cholesterol level in serum.

   2. LDL cholesterol and Apo B-100 level.

   3. HDL cholesterol and Apo A-1 level.

   4. Lp(a) level.

   5. Serum Triglycerides.

   6. Plasma hsCRP.

   7. Lipoprotein-Associated Phospholipase A2.

3. Markers of Myocardial Stress

   1. BNP and NTproBNP (N-terminal proB-type natriuretic peptide).

Myocardial infarction markers are cardiac markers (Table 1) that are used to rapidly diagnose myocardial ischemia. Cardiac troponins (cTnI and cTnT) and creatine kinase isoenzyme are two frequent indicators [42]. In addition, risk variables, such as cholesterol, lipoproteins, and hs-CRP in plasma, are used as markers for risk prediction.

Table 1.

Most used cardiac biomarkers and their pathogenic significance.

Biomarker Source	Biomarker	Pathogenic Significance
Cardiomyocytes	BNP and NTproBNP	Cardiac biomechanical stress
	GDF-15	Cardiomyocytes inflammation
	cTnT and cTnI	Cardiac myocyte necrosis
Cardiomyocytes, Fibroblasts, Endothelial cells	ST2 (suppression of tumorigenicity 2) and sST2 (soluble ST2)	Cardiomyocytes inflammation
Endothelial cells, Epithelial cells, Macrophages, Neutrophils	Galectin-3	Cardiomyocytes fibrosis
Vascular smooth muscle cells	Matrix Gla protein (MGP)	Cardiac calcification and injury

5. CLINICAL CONSEQUENCES OF CARDIAC BIOMARKERS IN COVID-19

COVID-19 investigations conducted during the initial wave of the pandemic, primarily in healthcare settings stunned by large numbers of severe patients, have provided current evidence about the likely relevance of cardiac biomarkers [43]. Unfortunately, this has ensued in occasionally high mortality rates in patients emerging respiratory failure as well as ARDS, whereas mortality rates of around 20% have been reported in ICUs with better resources [44]. This raises doubts about the data's applicability to patients with severe COVID-19 treated in hospitals during the second wave when healthcare systems are more prepared.

The finding that biomarkers measuring cardiac pathophysiology, for instance, cardiomyocyte injury and cardiac hemodynamic stress, are sturdily connected with the threat of death in patients with primarily noncardiac complaints, like pneumonia caused by SARS-CoV-2 or other causes, could have significant clinical implications. In addition, several other cardiac biomarkers are being investigated in COVID-19 studies, including growth differentiation factor 15 (GDF-15) [45, 46], a member of the transforming growth factor β (TGF-β) superfamily that appears to be unconfined by both hemodynamic and inflammatory stress and may provide even better predictive accuracy in patients with COVID-19 than the more established biomarkers [47].

C-reactive protein (CRP) is a liver-generated plasma protein that is triggered by inflammatory mediators, like IL-6. Despite its lack of specificity, this acute phase reactant is utilized therapeutically as a biomarker for various inflammatory disorders; an increase in CRP levels is linked to a worsening of the disease. While further research on the use of serum amyloid A (SAA) as a biomarker for COVID-19 is needed, CRP and SAA are widely used together to monitor inflammatory disorders. The neutrophil: lymphocyte ratio (NLR) is a well-known biomarker that is elevated in many inflammatory disorders and can be used to assess disease severity. However, more investigations are required to determine the efficacy of NLR as a biomarker.

When type-1 AMI is assumed concerning the clinical background of patients without pneumonia, cardiac troponin should be tested. Traditional diagnostic algorithms for prompt rule-out and/or rule-in of myocardial infarction in patients with acute chest anxiety and patients with COVID-19 are expected to perform similarly to other stimulating subgroups with state-of-the-art baseline cardiac troponin concentrations, like high rule-out safety but lower efficacy [48, 49]. Possible mechanisms underlying advancements in cardiac troponin along with myocardial injury in COVID-19 are shown in Fig. (3).

Fig. (3).

Elevations in cardiac troponin and myocardial injury in COVID-19 patients.

In patients hospitalised with confirmed or suspected COVID-19, Hs-cTn may be a valuable associate to combat against the virus, and it would be evaluated systematically as part of routine clinical care. Finally, because blood tests are routinely implemented in these patients, no further procedures are necessary, making cardiac biomarkers the cheapest, most straightforward, and further accessible for cardiac investigations and an appropriate gatekeeper for cardiac imaging, which can be logistically challenging at times.

Intra-cardiac filling pressure, end-diastolic wall stress, and hypoxaemia appear to be the most common drivers of BNP/NT-proBNP production as quantitative biomarkers of hemodynamic stress as well as heart failure [50]. As a result, BNP/NT-proBNP values in COVID-19 patients should be interpreted as a combination of preexisting cardiac illness and hypoxaemic and acute hemodynamic stress caused by COVID-19 [51]. During the COVID-19 epidemic, hospitalised patients were observed to have a coagulopathy marked (Table 2) by minor lengthening of the triggered partial thromboplastin time and prothrombin time, increasing fibrin breakdown products, and varied, i.e., mild to significant elevations of D-dimers [52].

Table 2.

Possible mechanisms that represent coagulopathy in COVID-19.

Primary Factor	Potential Mechanism
Sepsis-induced	Disseminated intravascular coagulation (DIC)- consumptive coagulopathy
Cytokine	Cytokine-mediated DIC
Fibrinogen	Increased levels of fibrinogen and an excessive fibrin polymerization
Thrombin	Activation of thrombin and suppression of fibrinolysis
Urokinase plasminogen activator	Inhibition of urokinase plasminogen activator leads to fibrinolysis
Plasmin	Plasmin-mediated increased binding of SARS-CoV-2 to ACE-2 receptors
Antiplasmins	Inhibition of plasmin by antiplasmins

D-Dimer is a protein fragment that occurs in the blood after a blood clot breaks down. Once the damage is healed, the body will generally eliminate the clot. However, higher blood clots in the blood will cause severe deadly pneumonia, pulmonary embolism, or widespread thromboembolism in patients with COVID-19 [53, 54]. The D-Dimer test could detect these dangers. People who have a propensity for blood clotting disorders should do a D-Dimer test to determine the amount of clot formation [55]. Approximately 3-5 percent of severe COVID-19 instances have been known to result in fatal consequences due to excessive blood clotting, imminent pneumonia, and consequent ARDS, which necessitates ICU admission with ventilator assistance [56]. Based on the indications existing at the period of this write-up, the following clinical ideas have been developed [2]:

1. Cardiac troponin, D-dimer, and natriuretic peptides can aid clinicians in early assessing COVID-19 patients with chest discomfort or dyspnoea [57].

2. Minor elevations in cardiac troponin concentrations are common and can be caused by various factors, such as an imbalance between myocardial oxygen demand and supply, myocarditis, or a general inflammatory response disorder [58].

3. If COVID-19 patients' symptoms worsen, D-dimer, natriuretic peptide, and cardiac troponin testing should be done.

4. Due to confusion in DIC, ARDS, and shock, these cardiac indicators are easy to understand in steady patients than in unfavorably ill individuals [59, 60].

5. Patients should be treated with acute coronary syndrome if there is a strong indication of myocardial ischemia, based on all available clinical data.

CONCLUSION AND FUTURE OUTLOOK

The COVID-19 pandemic has let a great deal of new research, yielding important insights into the disease's aetiology. Following a review of the findings from most current COVID-19 research, it is clear that direct or indirect cardiac association is not unusual in COVID-19 individuals. The severity of cardiac damage depends on the patient's age, pre-existing heart condition, and intricated pathophysiology of cardiac injury. Cardiac biomarkers rise maximum in patients with COVID-19, yet their predictive potential for the worse outcome increases with disease severity. In patients with COVID-19, elevated hs-TnI and BNP at admission can predict mortality. Therefore, cardiac biomarkers must be examined in COVID-19 patients at hospital admission. As SARS-CoV-2 septic shock is commonly coupled with multiorgan damage, a combined study on cardiac biomarkers with biomarkers of additional organ damage is expected to provide a clear picture for future observation.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.