COVID-19 and cardiac manifestations

Subsequent to the COVID-19 pandemic, an increasing body of evidence suggests the existence of cardiac manifestations that can have profound implications for individuals’ cardiovascular health, as shown in Figure 1. ^{Reference Xie, Xu, Bowe and Al-Aly9} Notably, myocarditis, characterized by inflammation of the heart muscle, emerges as a prominent cardiac manifestation. ^{Reference Lampejo, Durkin, Bhatt and Guttmann10} The SARS-CoV-2 virus has been shown to invade cardiac cells and trigger an immunological response, which then causes inflammation of the myocardium. Myocarditis following COVID-19 has been observed in both symptomatic and asymptomatic individuals, and it can give rise to myocardial injury, impaired cardiac function, and the potential development of HF. ^{Reference Italia, Tomasoni and Bisegna11} Studies have demonstrated that individuals in the recovery phase of COVID-19 may experience tenacious myocardial inflammation, emphasizing the necessity for continuous monitoring of cardiac health in these patients. ^{Reference Raman, Bluemke, Lüscher and Neubauer12,Reference Ran and Guy13}

Figure 1. COVID-19 cardiovascular complications; COVID-19 infection is often associated with cardiovascular manifestations such as pulmonary embolism, pericarditis, myocarditis, myocardial infarction, and ischaemic strokes. COVID-19 = coronavirus disease 2019.

Furthermore, in addition to myocarditis, COVID-19 is linked to an augmented risk of thromboembolic events, encompassing venous thromboembolism and arterial thrombosis. ^{Reference Mondal, Quintili, Karamchandani and Bose14} The systemic inflammatory response triggered by the viral infection induces a prothrombotic state, thereby facilitating the formation of blood clots. COVID-19-related thromboembolic events can impact the coronary arteries, leading to myocardial infarction, or affect other blood vessels, resulting in ischaemic stroke or pulmonary embolism. ^{Reference Cheng, Chan and Cheng15} Studies have emphasized the criticality of implementing anticoagulation therapy in the management of COVID-19 patients to mitigate the potential life-threatening complications associated with thromboembolic events. ^{Reference Farkouh, Stone and Lala16, Reference Barnes, Burnett and Allen17}

Moreover, COVID-19 can exacerbate pre-existing cardiovascular conditions or precipitate the development of new cardiac abnormalities. Severe COVID-19 disease course and unfavourable cardiovascular outcomes are more likely to occur in people with underlying CVDs, such as hypertension, coronary artery disease, or HF. ^{Reference Xie, Xu, Bowe and Al-Aly9} The viral infection induces cardiac stress, inflammation, and endothelial dysfunction, which may lead to acute decompensation or deterioration of pre-existing cardiac conditions. ^{Reference Timpau, Miftode and Leca18} Additionally, COVID-19 directly affects the electrical conduction system of the heart, giving rise to arrhythmias such as atrial fibrillation or ventricular tachycardia. ^{Reference Kanuri, Jayesh Sirrkay and Ulucay19,Reference Dherange, Lang and Qian20}

Consequently, in the post-COVID-19 phase, cardiac manifestations, including myocarditis, thromboembolic events, and the exacerbation of pre-existing cardiovascular conditions, impose notable risks to individuals’ cardiovascular health.

Mechanisms of cardiac injury in COVID-19

The mechanisms underlying cardiac injury in COVID-19 involve a multifaceted interplay of direct viral effects, immune response dysregulation, endothelial dysfunction, and thrombotic processes. ^{Reference Tsai, Cˇiháková and Tucker21} These intricate mechanisms contribute to the pathogenesis of myocardial inflammation, myocardial infarction, and exacerbation of pre-existing cardiovascular conditions.

1. 1. Direct viral myocardial injury: The SARS-CoV-2 virus gains entry into cardiac cells by binding to ACE2 receptors, which are abundantly expressed in cardiomyocytes and endothelial cells. ^{Reference Veluswamy, Wacker and Stavridis22} Viral invasion causes cellular damage and disrupts normal functioning of the heart. In addition, the replication of viruses in cardiac cells and their subsequent release triggers local and systemic inflammation. Cardiovascular function may be adversely affected by the combination of direct viral damage and a subsequent inflammatory response. The induction of cytopathic effects is one of the manifestations of direct viral myocardial injury. Studies have shown that SARS-CoV-2 infection in cardiac cells leads to structural and functional changes, such as alterations in cell morphology, disruption of cellular organelles, and impairment of contractile function. ^{Reference Yang, Li, You and Zhou23} These cytopathic effects directly contribute to the dysfunction of cardiac cells and compromise the overall cardiac performance. Moreover, viral infection within cardiac cells can activate apoptotic pathways, leading to programmed cell death. ^{Reference Yang, Li, You and Zhou23} Viral RNA has been detected in myocardial tissue, supporting the notion of viral invasion and replication within the heart. ^{Reference Lindner, Fitzek and Bräuninger24}

2. 2. Dysregulated immune response and CS: COVID-19 is characterized by dysregulated immune responses and an excessive release of pro-inflammatory cytokines, known as a CS. ^{Reference Bräuninger, Stoffers and Fitzek25,Reference Ye, Wang and Mao26} This dysregulation can lead to an uncontrolled inflammatory response, causing collateral damage to cardiac tissue. The CS is characterized by elevated levels of interleukin-6 (IL-6), tumour necrosis factor-alpha, and other pro-inflammatory molecules. ^{Reference Montazersaheb, Hosseiniyan Khatibi and Hejazi27} These cytokines can directly affect the heart by promoting myocardial inflammation, impairing contractile function, and disrupting the electrical conduction system. ^{Reference Montazersaheb, Hosseiniyan Khatibi and Hejazi27} In addition, the immune response involves the infiltration of immune cells into cardiac tissue, leading to further inflammation and tissue damage. ^{Reference Tan, Komarasamy and Balasubramaniam28}

3. 3. Endothelial dysfunction and thrombotic processes: COVID-19 is associated with widespread dysfunction in the endothelial cells, contributing to vascular abnormalities and thrombotic complications. ^{Reference Otifi and Adiga29} The virus can infect endothelial cells and induce endotheliitis, impairing the normal regulation of vascular tone and promoting vasoconstriction. ^{Reference Canale, Menghini, Martelli and Federici30} This endothelial dysfunction leads to microvascular injury, impaired perfusion, and tissue ischaemia in the heart. ^{Reference Canale, Menghini, Martelli and Federici30} Furthermore, the risk of thromboembolism can increase with systemic inflammation reactions and release of prothrombotic factors in COVID-19. ^{Reference Páramo31} COVID-19-associated coagulopathy, characterized by elevated D-dimer levels, fibrinogen levels, and prolonged prothrombin time, further contributes to the formation of microvascular and macrovascular thrombi, including myocardial infarction and pulmonary embolism. ^{Reference Colling and Kanthi32,Reference Conway, Mackman and Warren33}

Hence, the mechanisms of cardiac injury in COVID-19 involve direct viral myocardial injury, dysregulated immune responses, endothelial dysfunction, and thrombotic processes. These complex mechanisms contribute to myocardial inflammation, myocardial infarction, and the exacerbation of pre-existing cardiovascular conditions. Besides, each mechanism of cardiac injury secondary to COVID-19 infection can be translated into an increase in the level of specific cardiac biomarkers that are shown in the figure (Fig. 2).

Figure 2. Cardiac damage caused by COVID-19 and cardiac biomarkers associated with corresponding mechanisms. COVID-19 = coronavirus disease 2019.

Role of cardiac biomarkers in COVID-19

Cardiac biomarkers have emerged as important tools for risk stratification, diagnosis, monitoring, and prognosis in individuals with COVID-19. The measurement of specific biomarkers allows for the assessment of cardiac injury, myocardial stress, inflammation, and the prediction of adverse cardiovascular outcomes. Figure 2 highlights the corresponding disruption in cardiac biomarkers levels secondary to myocardial injury.

1. 1. Troponin and cardiac injury: Cardiac troponins, particularly high-sensitivity cardiac troponin (hs-cTn), are well-established biomarkers of myocardial injury. ^{Reference Raber, McCarthy Cian and Januzzi James34} A large proportion of patients with COVID-19 have been observed to have higher levels of hs-cTn, and these results are related to an unfavourable clinical outcome. ^{Reference Singh, Anchan and Besser35} The underlying mechanisms of cardiac injury in COVID-19 include direct viral invasion, myocardial oxygen supply-demand mismatch, cytokine-induced inflammation, and microvascular dysfunction. ^{Reference Giustino, Pinney and Lala36} Elevated hs-cTn levels have been associated with increased risk of severe disease, need for ICU admission, and mortality. ^{Reference Larcher, Besnard and Akouz37} Hence, serial monitoring of hs-cTn levels can aid in the early detection of myocardial injury, risk stratification, and guiding therapeutic interventions in individuals with COVID-19.

2. 2. Natriuretic peptides and myocardial stress: Natriuretic peptides, including brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP), are released in response to myocardial stress and stretch. ^{Reference Cao, Jia and Zhu38} Elevated levels of BNP and NT-proBNP have been observed in individuals with COVID-19 and are associated with myocardial dysfunction, heart failure, and adverse outcomes. ^{Reference Caro-Codón, Rey and Buño39} The presence of cardiac stress or reduced heart function is reflected in the increased levels of these biomarkers. Numerous scientific investigations have offered proof indicating a connection between higher levels of NT-proBNP and an elevated risk of severe COVID-19 and unfavourable results. ^{Reference Pranata, Huang, Lukito and Raharjo40,Reference Sorrentino, Cacia and Leo41} For example, one study that included 4675 patients hospitalized with COVID-19 discovered that COVID-19 patients with elevated NT-proBNP levels upon admission demonstrated a substantially increased probability of needing ICU admission and had a greater risk of mortality when compared to those with lower NT-proBNP levels. ^{Reference O’Donnell, Ashland and Vasti42} Thus, natriuretic peptides also provide valuable prognostic information and assist in risk stratification. ^{Reference Zinellu, Sotgia, Carru and Mangoni43} Serial measurements of BNP or NT-proBNP can help monitor the progression of myocardial stress.

3. 3. Inflammatory biomarkers and systemic inflammation: Inflammatory biomarkers, such as C-reactive protein (CRP), procalcitonin, and interleukin-6 (IL-6), have been shown to be elevated in individuals with severe COVID-19 and are associated with a higher risk of adverse outcomes. ^{Reference Lee, Lee, Song and Han44} Elevated CRP and IL-6 levels reflect the extent of systemic inflammation, which is associated with disease severity, multiple organ dysfunctions, and increased mortality. ^{Reference Picod, Morisson and de Roquetaillade45} The systemic inflammatory response to COVID-19 can contribute to cardiac injury, myocardial dysfunction, and thrombotic complications.

4. 4. Myoglobin: Myoglobin was shown to be linked to prognosis in patients with COVID-19 in some studies. ^{Reference Ma, Tu and Gu46} Researchers, such as Zhong et al., found that patients with a length of hospital stay fewer than 14 days had lower myoglobin values than patients with a hospital stay longer than 14 days. ^{Reference Wu, Hou, Liu, Chen and Zhong47} Seraji et al. performed a meta-analysis and found that elevated myoglobin was strongly associated with patient mortality (WMD = 159.77 ng/mL; 95% CI = 99.54–220.01; p < 0.001). ^{Reference Parohan, Yaghoubi and Seraji48}

5. 5. Creatine kinase (CK) and creatine kinase MB were also shown to be related to the prognosis of COVID-19. Zinello et al. did a literature review in 2021 on cardiac biomarkers and showed that higher levels of CK-MB and CK were associated with increased severity and poor prognosis in COVID-19 patients. ^{Reference Zinellu, Sotgia, Fois and Mangoni A.A.Serum49}

In a study conducted by Smadja et al., it was demonstrated that increased levels of proBNP and D-dimers were associated with a worse prognosis in COVID-19. ^{Reference Smadja, Fellous and Bonnet50} This was assessed by the need for life-sustaining treatments (LSTs). ^{Reference Mahmoud, Abd El-Hafeez, Ali, Hassan and Seddik51} It was found that, in patients who needed LSTs, the average levels of proBNP were significantly increased compared to the group that didn’t require LST (5115.92 ± 10,865.93 g/mL; 3421.19 ± 6433.58 g/mL; p = 0.037). ^{Reference Mahmoud, Abd El-Hafeez, Ali, Hassan and Seddik51} In this study, patients with lower levels of D-dimers were more likely to not require LSTs wherein out of 135 patients who had D-dimers <1000 μg/L, only 49 required the use of LSTs, which is significantly less than the level in those who didn’t require LSTs which was 86. ^{Reference Mahmoud, Abd El-Hafeez, Ali, Hassan and Seddik51} Stavileci et al. show that troponin I value of ≥16.05 pg/mL on the seventh day were related to the need for intensive care (p < 0.001). ^{Reference Stavileci, Ereren, Özdemir, Özdemir, Cengiz and Enar52} Troponin I value ≥30.25 pg/mL on the ninth day were related to mortality (p < 0.001) in patients with COVID-19. ^{Reference Stavileci, Ereren, Özdemir, Özdemir, Cengiz and Enar52} The association of D-dimers with disease severity and mortality in COVID-19 was assessed, and it showed that D-dimer values ≥878 hg/mL on the second day were associated with intensive care need (p < 0.001). D-dimer values ≥1106 hg/mL on the 10th day were associated with mortality (p < 0.001). ^{Reference Stavileci, Ereren, Özdemir, Özdemir, Cengiz and Enar52}

In order to assess the value of troponin I in predicting COVID-19-induced myocardial damage, Abdul Rehman et al. studied the relation of troponin I levels with the risk of myocarditis and COVID-19-induced myocardial injury in 104 patients. ^{Reference Rehman, Yousuf, Maken, Naqvi, Murtaza and Ahmad53} In this study, cardiac Tn-I (cTn-I) and CRP were significantly higher in patients with myocarditis (p < 0.01). All patients who died secondary to COVID-19-induced myocardial injury had elevated serum cTn-I. ^{Reference Rehman, Yousuf, Maken, Naqvi, Murtaza and Ahmad53} Additionally, Liu et al. evaluated the role of high-sensitivity cardiac Troponin T (hs-cTnT) in predicting mortality related to COVID-19. ^{Reference Liu, Hammond and Chan54} In this study, on a per-patient level, a normal hs-cTnT had a negative predictive value of 94% (95% CI: 85–98) for ruling out mortality, while an elevated hs-cTnT had a low positive predictive value of 38% (95% CI: 39–47) for ruling in mortality. ^{Reference Liu, Hammond and Chan54}

Mukhopadhyay et al. studied the sex difference in the prognostic value of troponin and D-dimer in COVID-19 illness. ^{Reference Mukhopadhyay, Talmor and Xia55} The initial and peak troponin levels were significantly associated with higher odds of severe COVID-19 (initial: OR = 1.16 per ng/mL, 95% CI = 1.08–1.25; peak: OR = 1.66 per ng/mL, 95% CI = 1.56–1.78, p < 0.001). Similarly, both initial and peak D-dimer levels were associated with higher odds of severe COVID-19 illness (initial: OR = 1.34 per 1000 ng/L, 95% CI = 1.23–1.45, p < 0.001; peak: OR = 2.67 per 1000 ng/mL, 95% CI = 2.46–2.90, p < 0.001). ^{Reference Mukhopadhyay, Talmor and Xia55} These associations were not modified by sex; however, peak D-dimer level was more strongly associated with severe COVID-19 illness in males than females (male: OR = 2.91, 95% CI = 2.63–3.24 versus female: OR = 2.31, 95% CI = 2.04–2.63, p-interaction = 0.005). ^{Reference Mukhopadhyay, Talmor and Xia55}

Bayaz et al. assessed the correlation between cardiac troponin I (TPI) level and the in-hospital mortality in severely ill COVID-19 patients. ^{Reference Javidi Dasht Bayaz, Askari, Tayyebi, Ahmadi, Heidari-Bakavoli and Baradaran Rahimi56} In this study, patients who died in the hospital had higher levels of TPI (2.27 ± 9.58 μg/L) than patients who survived until discharge (0.07 ± 0.06 μg/L), therefore suggesting a valuable role for TPI in early diagnosis of cardiac injury and decreasing mortality in patients with COVID-19. ^{Reference Javidi Dasht Bayaz, Askari, Tayyebi, Ahmadi, Heidari-Bakavoli and Baradaran Rahimi56}

Additionally, the association of right ventricular dysfunction in patients with COVID-19 pneumonitis whose lungs are mechanically ventilated was explored in a multicentre prospective cohort study. ^{Reference McCall, Willder and Stanley57} The results of the study portray that patients with right ventricular dysfunction were more likely to have higher plasma N-terminal pro-B-type natriuretic peptide levels (p = 0.006) and elevated plasma troponin levels (p = 0.048). ^{Reference McCall, Willder and Stanley57} In this study, the prevalence of right ventricular dysfunction of 6% was associated with increased mortality (86%). ^{Reference McCall, Willder and Stanley57}

Ultimately, to evaluate the role of cardiac biomarkers in COVID-19 in paediatric children, Ozenen et al. evaluated the troponin levels in 412 paediatric children that were hospitalized and were infected with COVID-19. ^{Reference Guner Ozenen, Akaslan Kara and Kiymet58} They found that troponin I levels were elevated in seven (1.7%) patients and that all of them experienced tachycardia. Out of the seven patients with elevated troponin levels, three (42.9%) required paediatric ICU admission, two (28.6%) required oxygen support, and one (14.3%) required invasive mechanical ventilator. ^{Reference Guner Ozenen, Akaslan Kara and Kiymet58} Out of the patients with normal troponin I levels, 94 (23.2%) had tachycardia, 10 (2.5%) were admitted to ICU, 12 (3%) required oxygen support, and 2 (0.5%) required mechanical ventilation. ^{Reference Guner Ozenen, Akaslan Kara and Kiymet58} Therefore, tachycardia, ICU admission, oxygen support, and mechanical ventilation requirement were more common in children with elevated troponin I levels (p values were 0.020, < 0.001, 0.050, and < 0.001, respectively). ^{Reference Guner Ozenen, Akaslan Kara and Kiymet58}

Furthermore, Zhu et al. assessed the levels of myoglobin in patients with COVID-19 by comparing the levels in patients who died and the survivors. Myoglobin and troponin levels were significantly elevated in the death group (134.4 [interquartile range (IQR) 24.80, 605] versus 38.02 [IQR 3.87, 11.73] ng/mL, p < 0.001), and (0.01 [IQR 0.01, 0.01] versus 0.04 [IQR 0.02, 0.15] ng/mL, p < 0.001), ^{Reference Zhu, Li, Lin, Xu, Du and Li59} respectively. Thus, they concluded that myoglobin levels can be used as a predictor of mortality in patients with COVID-19. ^{Reference Zhu, Li, Lin, Xu, Du and Li59}

In addition, Zinellu et al. reviewed the literature on the role of CK-MB as a prognostic marker for COVID-19 by analysing 55 studies that included 11,791 COVID-19 patients. In this study, high levels of CK-MB were related to poor prognosis and increased mortality in COVID-19. ^{Reference Zinellu, Sotgia, Fois and Mangoni A.A.Serum49}

As it turned out of the 14 papers included in Table 2, 8 studies showed evidence of poor progression of the disease when there is increased troponin. The severity of the disease manifestation was evaluated differently; some studies evaluated the severity of the disease in terms of ICU admission, while others evaluated the severity in terms of mortality, need for ventilators, or myocardial work. This shows that troponin and other cardiac biomarkers may predict poor outcomes of COVID-19 in various aspects.

Table 2. Characteristics of included studies

CRP = C-reactive protein; COVID-19 = coronavirus disease 2019; SARS-CoV-2 = severe acute respiratory coronavirus virus 2; CI = confidence interval; OR = odds ratio.

This shows that elevation in either troponin, proBNP, or D-dimers in the early phases of COVID-19 is a predictor of poor outcomes on various levels.

The worst outcome of COVID-19 is death; 6 studies out of the 14 mentioned in this review showed a positive correlation between mortality and elevation in cardiac biomarkers. This shows the significance of cardiac biomarkers in predicting mortality in patients with COVID-19.

Henceforth, cardiac biomarkers, including troponin, natriuretic peptides, myoglobin, CK, CK-MB, and inflammatory markers, play a crucial role in risk stratification, diagnosis, monitoring, and prognostication in individuals with COVID-19. These biomarkers provide valuable insights into cardiac injury, myocardial stress, inflammation, prediction of adverse cardiovascular outcomes, and optimize therapeutic interventions.

It is important to highlight the half-life and the origin of each cardiac biomarker, as seen in Table 1, in order to understand the relationship between these cardiac biomarkers and the severity of the disease. Additionally, it is important to consider the natural trend of biomarkers levels because some biomarkers, such as myoglobin, peak early after the onset of cardiac injury and decrease directly afterwards, whereas others, for instance, troponin I, peak early after cardiac injury and take a longer period to drop. Each biomarker concentration follows a different trend after the onset of cardiac injury (Graph 1). ^{Reference Galvani, Panteghini and Ottani60} These trends allow us to track the onset of cardiac damage that occurred. In addition, the origin of each cardiac biomarker facilitates the process of determining the location of cardiac injury.

Graph 1. Trend of cardiac biomarkers concentration in time after cardiac injury ^{Reference Galvani, Panteghini and Ottani60} .