The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined.

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to over 474 million confirmed cases with 6,098,739 deaths worldwide by March 23rd, 2022.

Patients with preexisting cardiovascular conditions are particularly at risk and have poor prognoses. Clinical characteristics including heart rate, breath rate, fever, cough, and dyspnea at the time of admission were analyzed. Laboratory measurements including neutrophil count, CRP (C-reactive protein), cardiac biomarkers (hs-cTnI, CK-MB, NT-proBNP [N-terminal proB-type natriuretic peptide] or BNP [brain natriuretic peptide], MYO [myoglobin], and CK), and inflammatory cytokine IL (interleukin)-6 at admission and during hospitalization were extracted and analyzed.

Cardiac-specific biomarkers, such as hs-cTnI, CK-MB, and (NT-pro)BNP. Compared with patients without available myocardial biomarkers, patients with measured cardiac injury markers had higher incidences of 28-day all-cause death and the occurrences of Acute Respiratory Distress Syndrome, heart failure, disseminated intravascular coagulation (DIC), sepsis, or multiorgan failure, and acute renal failure.

Prognostic Performance of Cardiac Injury Biomarkers in Predicting 28-Day All-Cause Mortality of COVID-19.

To compare the relative accuracy, sensitivity, specificity, and positive and negative predictive values of each biomarker based on laboratory defined ULN, the prognostic performance of each marker was analyzed. The receiver operating characteristic curve was used to demonstrate the ability of each cardiac biomarker in discrimination of high risk of COVID-19 mortality, which was quantitated as AUC.

Trajectory Patterns of Cardiac Biomarkers and Inflammatory Factor Elevation in Patients With COVID-19.

To further demonstrate the mechanistic cause of cardiac injury in COVID-19 patients, Which determined the temporal relationship of cardiac biomarker elevation with that of the inflammatory markers over time, it has been analyzed the cumulative proportions of patients with increased cardiac biomarkers in association with inflammatory factors of CRP, neutrophil count, and IL-6 elevation during the entire study period. This was based on the laboratory-defined ULN and analyzed from the time of symptom onset (day 0) to the end of follow-up.

In patients showing heart injury during the entire hospitalization, neutrophil percentage and CRP were rapidly and simultaneously increased after disease onset, immediately by the increases of CK-MB, MYO, and hs-cTnI. In contrast, the significant elevation of IL-6 occurred only after the increases of these myocardial markers and was highly elevated mainly in patients with evidence of cardiac injury. The increased inflammatory marker (CRP) and coagulation marker (d-dimer) levels were also significantly associated with an increased risk of 28-day all-cause mortality of COVID-19 and had interactive effects with cardiac injury markers in predicting the poor outcomes of COVID-19.

Elevations of biomarkers such as hs-cTnI, CK-MB, (NT-pro)BNP, or MYO based on reference laboratory normal cutoff values were highly prognostic of 28-day all-cause mortality, including deaths occurring soon after admission. However, standard cutoff values currently used for diagnosis likely underestimated the true extent of cardiac injury. The newly established cutoffs in our study for COVID-19 prognosis were much lower than the currently accepted laboratory cutoff thresholds (by about 50%). The dynamic pattern of cardiac biomarker elevation showed their onset coincided with CRP and neutrophil elevation but preceded the elevation of IL-6.

The company Biotime Biotechnology is a well-known POCT manufacturer that has advanced cardiac markers which are used in the diagnosis and risk stratification of patients with chest pain, suspected Acute Coronary Syndrome(ACS), and Heart Failure(HF). Especially, 5 In 1 biomarker which included 5 items on one cartridge (CTnI/ CK-MB/ Myo/ NT-ProBNP/ D-Dimer), provides results within 15 minutes, has a wide detection range that can accurately verify serious diseases, and is a convenience test with whole blood or plasma without centrifugation. To properly evaluate patients with COVID-19 at admission, the cutoff threshold of abnormality for hs-cTnI, CK-MB, (NT-pro) BNP, and MYO at admission should be lower than the currently recommended laboratory range. Using standard reference laboratory cutoffs might underestimate the extent of cardiac injury. Measurement of cardiac-specific biomarkers like 5 In 1 (CTnI/ CK-MB/ Myo/ NT-ProBNP/ D-Dimer) Rapid Quantitative Test at Biotime and proper interpretation on admission can help to identify COVID-19 patients with a high-risk trajectory. The elevations can help to provide references for the management, monitoring, and enrollment for prospective studies and randomized controlled clinical trials.

In conclusion, the abnormal cardiac biomarker pattern in COVID-19 patients was significantly associated with increased mortality risk, and the newly established COVID-19 prognostic cutoff values of hs-cTnI, CK-MB, (NT-pro)BNP, CK, and MYO were found to be much lower (≈50%) than reference upper normal limits for the general population. It is clinically meaningful that the fluctuating levels of myocardial biomarkers should be intensively monitored, and patients with elevated levels of those biomarkers should be intervened timely to improve the prognosis of COVID-19. Our findings support additional prospective studies and randomized controlled clinical trials to accurately validate the risk thresholds and exact impact of myocardial injury for individuals with COVID-19.

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