The COVID-19 pandemic had emerged as a global health crisis of substantial magnitude. While severe respiratory failure was the primary cause of mortality in patients with coronavirus disease 2019 (COVID-19) (1), a considerable number of patients had also suffered from cardiovascular diseases (2, 3). These included not only cardiac injury but also thromboembolic events (4, 5). Previous research indicated that individuals with severe symptom, pre-existing medical conditions or advanced age were at a higher risk of developing COVID-19-related cardiovascular diseases (6).

Indeed, the impact of COVID-19 extends beyond severe cases, as the cardiovascular health of individuals with mild cases may also be compromised. A previous report indicated that cardiac involvement was present even in COVID-19 patients who exhibited asymptomatic or mild symptom (7). Rajpal and colleagues (8) demonstrated that some young patients continued to experience myocardial inflammation following recovery from COVID-19, despite having initially been asymptomatic or experiencing only mild symptoms. With the emergence of the Omicron variant as the dominant strain in circulation, those infected with the Omicron variant tend to be younger, had fewer comorbidities, and experienced lower disease severity and mortality, with asymptomatic or mild symptom being more prevalent (9–11). This had raised concerns about the potential for cardiovascular system injury in Omicron-infected individuals, particularly those who were asymptomatic or had only mild symptoms. To date, most studies on cardiovascular serum markers associated with Omicron infection have primarily focused on severe cases or elderly patients with chronic diseases. The status of the cardiovascular system in asymptomatic or mild cases remains unknown, and it is still unclear whether these individuals are at risk for cardiovascular complications.

Serum markers such as CK-MB, cTnT, Myo, BNP, and DD offered considerable clinical utility for rapid and precise assessment of the patient's cardiovascular status. In order to fill this gap in relevant knowledge, we conducted a retrospective study that evaluated serum markers suggestive of cardiovascular system injury (CK-MB, cTnT, Myo, BNP, and DD) adjusted for demographic characteristics and other relevant markers, in a cohort of 1,138 asymptomatic or mild patients with Omicron infection.

In this cross-sectional retrospective study, a total of 1,138 COVID-19 patients were included, consisting of 589 asymptomatic and 549 mild cases. The male population constituted approximately 50.42% of the asymptomatic group and 48.63% of the mild group, with mean ages of 32.46 ± 0.61 and 33.94 ± 0.61 years old, respectively (Table 1). Clinical characteristics of biochemistry and hematology were summarized in Table 1, revealing a significant difference only in IgG levels between asymptomatic and mild patients, with mild patients exhibiting higher levels (19.27 ± 1.73 vs. 26.16 ± 2.15) (P < 0.05). Among the total COVID-19 patients, a relatively high proportion had elevated levels of cTnT, BNP, and DD (12.92%, 17.66%, and 19.77%, respectively) (Table 2). In contrast, the proportions of patients with elevated levels of CKMB and Myo were lower, at 1.83% and 2.99%, respectively (Table 2).

A comparative analysis was conducted, examining symptom presentation, gender, and age (older than 35). The results indicated a significantly higher proportion of male patients with elevated Myo levels (4.96%) compared to female patients (1.05%) (Table 2). However, male patients exhibited significantly lower proportions of slight elevated BNP (125–400) (11.88%) and DD (0.55–1.10) (9.22%) compared to female patients (19.34% and 19.69%, respectively) (Table 2). Notably, among patients older than 35, the proportion with slight elevated BNP (125–400) (20.00%) was significantly higher than in those younger than 35 (11.64%) (Table 2). Surprisingly, no significant association was found between the proportion of serum markers for cardiovascular system injury and the presence or absence of symptoms in patients categorized as asymptomatic and mild.

The data indicated that patients with elevated serum markers had a higher proportion of females, higher age, elevated IL6 and PCT levels, and lower IgG levels (P < 0.05) (Table 3). Additionally, the abnormal group exhibited a relatively prolonged nucleic acid clearance time compared to normal patients. Further stratification based on the days for nucleic acid clearance resulted in two groups: those with negative nucleic acid within 14 days (459 patients) and those with negative nucleic acid after 14 days (679 patients). Patients with nucleic acid turning negative after 14 days displayed higher age, increased IL6 levels, elevated BNP and DD levels, and lower IgG levels (P < 0.05) (Table 4).

Subsequently, logistic regression analysis was performed to evaluate the risk associated with significant parameters in predicting abnormal elevation in serum markers for cardiovascular system injury. The study focused on identifying the primary factors influencing the occurrence of abnormal elevation. The results revealed that the OR (95% CI) value of IgG was 0.99 (0.98–1.00) (P < 0.001). Additionally, increasing age, female gender, and higher levels of IL6 and PCT were identified as significant risk factors, with ORs (95% CIs) of 1.02 (1.01–1.03), 1.82 (1.40–2.37), 1.03 (1.01–1.04), and 237.95 (18.66–3,034.98), respectively, all achieving statistical significance at P < 0.001 (Table 5). Notably, PCT exhibited the strongest association (OR = 237.95) and emerged as the most impactful single risk factor for predicting abnormal elevation in serum markers for cardiovascular system injury (Table 5).We further made multiple regression analysis to test the combined contribution of several factors, and found the model including age, gender and PCT appeared to be the most combined risk factor for predicting abnormal elevation in serum markers for cardiovascular system injury (OR (95% CI) = 260.59 (34.23–370.34), P < 0.001).

In the current study, we found that during the early stages of Omicron infection, a small percentage of individuals with asymptomatic or mild COVID-19 by the Omicron variant have elevated biomarkers for cardiac and thromboembolic disease. These biomarkers demonstrated a positive correlation with age, female gender, elevated inflammatory factors (PCT and IL-6), and a negative correlation with IgG antibody titers. Notably, high levels of PCT emerged as the most prominent risk factor for the abnormal elevation of serum markers suggestive of cardiovascular system injury. Our data implied that even among asymptomatic or mild Omicron-infected individuals, there may exist a potential risk of subclinical injury in cardiovascular system.

In our results, elevated serum markers (cTnT, BNP, and DD) demonstrated a positive correlation with age, female gender, and levels of inflammatory factors (PCT and IL6), and a negative correlation with IgG antibody levels. Cardiac markers (CKMB, cTnT, and Myo) are crucial in diagnosing and risk stratifying acute myocardial infarction, it was noteworthy that approximately 2% of patients exhibited elevated levels of CKMB and Myo. This finding suggested that myocardial tissue inflammation may occur in asymptomatic or mild cases, albeit relatively infrequently. It led to speculation that, during the initial invasion of the COVID-19 virus into the human body, it targetted myocardial cells, resulting in an increase in myocardial enzyme levels. Compared to cTnT, CKMB and Myo rise earlier in myocardial injury but had a shorter half-life and lower specificity. The levels of CK-MB and Myo might had already returned to normal by the time patients were admitted for testing. Notably, a relatively high proportion of patients with elevated cTnT levels was observed, accounting for 12.92%, which was close to 12% of COVID-19 patients in Wuhan experienced acute heart injuries (14). Among these markers, cTnT was the most specific marker that appears after acute myocardial inflammation or infarction (15). Our results indicated that the Omicron strain did cause subclinical injury to the heart, and even during the early stage of Omicron infection, the viral impact on myocardial tissue was not negligible. Additionally, other studies found that after COVID-19 infection, the levels of hs-TnI, sST-2 and VCAM-1 were closely correlated with major cardiovascular event and mortality (16, 17), which further emphasized clinical significance of abnormally elevated troponin in patients with primary infection.

BNP levels were independent of other clinical factors, rendering it a valuable indicator of cardiac risk, particularly for heart failure (18). DD, a fibrin degradation product resulting from thrombus fibrinolysis, had previously been associated with an increased risk of venous thromboembolism (VTE). Previous studies indicated that cTnT, BNP, and DD levels rise as a late manifestation in severe COVID-19, with markedly elevated levels linked to significant in-hospital mortality (19–21). In this study, the majority patients showed slight elevations in BNP and DD. Additionally, a small percentage of patients with BNP greater than 400 or DD levels exceeding 1.10 are identified as “high risk of heart failure, it still need sufficient clinical attention (12, 13)”.

In terms of gender differences, we noted a significantly higher proportion of male patients with elevated Myo levels compared to female patients. This discrepancy may be attributed to higher androgen levels and increased muscle mass in men, resulting in elevated myoglobin levels (22). Contrary to previous reports (23), our findings regarding BNP and DD differed. Cheng et al. reported higher levels of DD and BNP in men with mild or critically ill COVID-19, while our study indicated significantly lower proportions in male patients. These variations might be linked to the severity of COVID-19 infection and the prevalence of comorbidities, which were more common in males. Excluding comorbidities, our study suggested that BNP and DD were more likely to exhibit slight increases in females in the early stages of Omicron infection. We speculated that higher estrogen levels in women enhanced ACE2 activity and expression, potentially leading to a mild reactive increase in BNP and DD shortly after Omicron infection (24).

A previous study demonstrated that men aged 54 or older with SARS-CoV-2 infection and mild to moderate COVID-19 exhibited significantly increased troponin levels early after infection (25). Our study results showed that patients older than 35 years had a higher proportion of abnormally elevated BNP, with no significant difference in abnormal cTnT proportions across different age groups. However, there was no significant association between the proportion of abnormal increased serum markers for the cardiovascular system injury and the presentation of patient symptoms (asymptomatic or mild). This suggested that the degree of abnormal increased serum markers for the cardiovascular system caused by the virus might not be significantly linked to cardiovascular symptoms. Reports of sudden cardiac death following uneventful COVID-19 raise concerns about potential enduring myocardial damage (26). This was supported by the detection of persistent SARS-CoV-2 RNA in various organs, including the heart (27, 28). Our results contributed additional insights by highlighting gender and age differences. These differences suggested that there may exist subclinical cardiovascular system injury, degree of elevation of clinical serum markers varied depending on gender and age. Furthermore the influence in COVID-19 infection might extend to non-cardiac entities such as pulmonary hypertension due to acute pulmonary embolism (29).

In cases of moderate or severe COVID-19, cardiac injury and thromboembolic events were common occurrence, which was likely a result of a combination of cytokine release, inflammation, and viral damage (30). Among the five indicators examined in our study, CKMB, Myo and cTnT are directly associated with myocardial damage, BNP is linked to heart failure, and DD is correlated with cardiovascular thrombotic events. Our results revealed that patients with abnormal combination of indicators (CKMB, cTnT, Myo, BNP, and DD) exhibited significantly lower levels of IgG and higher levels of inflammatory factors (IL6 and PCT). The positive association between cardiac biomarkers and PCT and IL-6 represents tissue damage caused by an excessive inflammatory reaction (31). Contrastingly, IgG antibodies might provide protection to organs by neutralizing a portion of the virus, binding to the viral S-protein, and interfering with its interaction with the ACE2 receptor (32). Our findings aligned with this, indicating that normal patients exhibit higher serum IgG levels.

Previous studies had linked PCT, the precursor of the hormone calcitonin, with the severity of COVID-19 (33). Notably, an increasing number of researchers advocated for PCT testing in patients with cardiovascular diseases, including those with shortness of breath, possible heart failure, suspected endocarditis, and acute coronary syndrome (34). Our results suggested that elevated PCT levels in early-stage Omicron infection patients were associated with an abnormal increased serum markers for the cardiovascular system most significantly. Another noteworthy observation was that patients with abnormal indicators required a longer time for viral RNA clearance, resulting in an overall extension of the infection duration, patients with clearance times exceeding 14 days exhibited significantly elevated levels of BNP and DD. This implied that patients with abnormal increased serum markers for the cardiovascular system might experience a longer period of Omicron infection.

To the best of our knowledge, this study is the first to analyze five serum markers for cardiovascular system injury (CK-MB, cTnT, Myo, BNP, and DD) in the early stages of Omicron infection. Nevertheless, there are several limitations to this study. Firstly, it is a retrospective study conducted in a single medical center. Secondly, due to the challenges associated with emergency measurements, data such as the presence of underlying diseases were self-reported, potentially introducing recall biases. Thirdly, the study is limited by the availability of relevant research, and our focus is solely on specific markers, with all serum samples collected in the early stages of hospitalization. Lastly, there is no follow-up of patients about cardiac testing or echocardiogram to assess cardiovascular function. Future studies should conduct a comprehensive analysis of additional test results, and long-term follow-up studies on Omicron patients to explore the specific impacts on the cardiovascular system.

Our findings suggested that even among asymptomatic or mild patients with Omicron infection, there might be an occurrence of abnormally elevated levels of cardiovascular indicators, signifying a certain degree of risk for subclinical cardiovascular damage. The abnormal cardiovascular markers were strongly associated with increased PCT levels. Female gender and age over 35 years old were also identified as contributing risk factors. We believed that this knowledge will play a crucial role in developing early intervention strategies to effectively address these risks.