Levels of cardiac troponin-T and LDL-C to HDL-C ratio of hospitalized COVID-19 patients: A case-control study

Expression of Concern

Expression of Concern (20^th October 2023): We, the Publisher and Editor of F1000Research, are issuing an Expression of Concern for the following article:

Sabah Khalid S, Mohamed Ali Z and Shareef LG. Levels of cardiac troponin-T and LDL-C to HDL-C ratio of hospitalized COVID-19 patients: A case-control study [version 1; peer review: awaiting peer review]. F1000Research 2022, 11:860 (https://doi.org/10.12688/f1000research.123619.1).

After publication of this article, questions about the integrity of the ethical approval and methodology were brought to the attention of the F1000 Editorial Team. We have reached out to the authors requesting that they respond to the concerns raised and provide additional information to support the integrity of the content. However, despite multiple attempts to contact the authors, and their institution, they have not responded to our queries within the requested timeframe. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. The authors have been sent notification about this Expression of Concern.

Editorial note

Editorial Note (13^th July 2023): Since publication, concerns have been raised to the Editorial Team regarding the ethical approval for this study, as well as overlap in the sample and methods to other papers by these authors. The Editorial Team requested explanations regarding the similarities on 19^th May and 6^th June 2023, and the institution was contacted on 21^st March, 6^th April and 25^th April 2023 to verify the ethical approval. Neither the author nor institution have provided responses to our requests. The Editorial Team will update this Editorial Note as the situation progresses. Peer review activity has been suspended for this article until we receive an explanation from the authors/institution.

Introduction

Coronavirus initially arose in 2019 in Wuhan, China, and subsequently spread around the globe. The virus belong to the family of positive single-stranded RNA (+ssRNA) with diameters in the range from (60–140 nm).^1–6 Troponin is the most extensively utilized biomarker in diagnosing acute myocardial injury (AMI).⁷ Troponin is present both in cardiac as well as the skeletal muscles. Troponin unit is made up of three subunits: troponin T (TnT), a tropomyosin-binding subunit, troponin I (Tn-I), an inhibitory subunit, and troponin C (TnC), a calcium-binding subunit. Troponin monitors the interaction of actin and myosin through the calcium influence, which causes muscle fibers contraction and relaxation.⁸ Troponin is detected in the bloodstream four to six hours after an AMI and reaches a maximum after 24 h. It may persist for up to 14 days. The automated detection of cardiac troponin I (cTnI) or cardiac troponin-T (cTnT) is presently the much more sensitive and specific method for detecting AMI. Nevertheless, every scenario that causes or contributes to cardiac damage, including decompensated heart failure, pulmonary embolism, end-stage renal disease, and stroke, raises cTn.^8,9

A low level of high-density lipoprotein cholesterol (HDL-C) is a powerful and reliable predictor of cardiac disease.¹⁰ Also, elevated levels of low-density lipoprotein cholesterol (LDL-C) have an essential role in the emergence and progression of atherosclerosis.¹¹ Furthermore, it has been shown that a high LDL-C:HDL-C ratio is a stronger predictor than either HDL-C or LDL-C alone for cardiovascular events.¹²

The research aimed to evaluate cTnT and LDL-C:HDL-C ratio levels in the blood of severe coronavirus disease 2019 (COVID-19) infected patients and compare them to healthy controls to determine whether there is an association between these markers and COVID-19 infection severity.

Methods

Results

This was a case-control study with 90 participants, including 45 hospitalized patients with COVD-19 who had a positive result of nucleic acid amplification testing by reverse transcription-quantitative PCR (RT-qPCR) of respiratory samples, which were nasal/oropharyngeal swabs for COVID-19 infection, and 45 healthy volunteers as a control group. Female participants made up 53% of the study population. The study showed significant increases in cTnT levels in patients compared with controls (P-value 0.025 in which alpha was < 0.05, median (IQR) was 0.0121 (0.0159) (ng/ml) while median (IQR) for control was 0.0187 (0.0227) (ng/ml)). LDL-C:HDL-C ratio also showed a significantly higher level in the COVID-19 infected group compared with controls (P-value < 0.001, median (IQR) for patients was 1.5919 (1.08) while for controls it was 0.7346 (0.67)), as shown in Table 2.

cTnT had an AUC of 0.363, which made it fail as a predictive marker for COVID-19 infection; it had an optimal cut-off of 0.167 (ng/ml) with sensitivity and specificity of 42.2% and 37.8%, as shown in Table 3 and Figure 1. In this study, the optimal cut-off value of LDL-C:HDL-C ratio was 1.0089 with sensitivity and specificity of 86.7% and 77.8%, respectively, with an AUC of 0.888, as shown in Table 3 and Figure 2.

Figure 1. ROC curve for measuring the AUC of cardiac troponin-T analysis.

ROC, receiver operating characteristic; AUC, area under the curve.

Figure 2. ROC curve for measuring the AUC of LDL-C:HDL-C analysis.

ROC, receiver operating characteristic; AUC, area under the curve; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

Discussion

Cardiovascular injury is a common cause of heart disease in COVID-19 patients. COVID-19 individuals with elevated cTn levels have one of three primary pathologies: myocarditis, microangiopathy, or myocardial infarction (MI).¹⁶ Myocarditis may be caused by either a direct viral invasion or injury to cardiomyocytes, which causes T-cell excitability and subsequent cardiac inflammation, or by indirect inflammation caused by the cytokine storm response as a result of the infection.^17,18 The myocardium may have a high viral load or extensive inflammatory multifocal inflammatory cells on biopsy. Microangiopathy may also be caused by direct viral invasion of the endothelium through the angiotensin-converting enzyme 2 (ACE2) receptor, resulting in endothelial dysfunction. It may also occur indirectly as a result of these patients’ hypercoagulable and prothrombotic states, which produce endothelial dysfunction and, finally, cardiac damage as a result of perfusion deficits, vascular hyperpermeability, and vasospasms.¹⁹ cTnT levels rise 3 to 6 h after ischemic injury and peak between 12 and 24 h, with thresholds remaining elevated for four to five days.^20,21 Admission levels are therefore useful for determining the presence of myocardial injury but not for determining the severity of the myocardial injury, which is more invariably related to the greatest rise in cTnT level.²² Thus, in this study we observed higher cTnT levels in the patient group than in the controls. The COVID-19 group showed a P-value of 0.025 (alpha 0.05) and the median (IQR) for cTnT levels was 0.0121 (0.0159) (ng/ml) compared to 0.0187 (0.0227) (ng/ml) for the control group, which was in agreement with a retrospective study done by Guo et al., in which patients with COVID-19 who had increased TnT levels had a 13% mortality rate during hospitalization.²³ The rising mechanism of cTn in COVID-19 disease seems to represent non-coronary artery disease rather than acute coronary artery disease including MI. Furthermore, the underlying pathophysiology may be an inflammatory reaction, since in severe circumstances many people with COVID-19 have an increase in inflammation markers like C-reactive protein (CRP), which may manifest clinically as fulminant myocarditis.²⁴ According to a prior study that examined the relationship among both AMI and COVID-19, there is also an influential independent association between increased cTn concentrations and COVID-19 disease severity, including death, and the relationship of varying degrees of severity with rising cTn concentrations may assist in determining how to treat a patient in the emergency department, and if cTn is raised. Even if the patient is not hospitalized, outpatient treatment may be considered.²⁵ The intensity level of both hypolipidemia and COVID-19 displayed a parallel correlation.²⁶ Furthermore, low HDL-C levels in COVID-19 are likely to cause severe complications.²⁷ In COVID-19 infection, significant inflammatory process may develop, leading to a shift in lipid metabolism and vascular permeability that results in the transfer of cholesterol particles into the lungs, generating exudate, and causing a decrease in plasma LDL-C and cholesterol levels.²⁸ There is additional evidence that COVID-19 can be triggered by sterol regulatory element-binding protein-2 inhibiting cholesterol biosynthesis, which results in a cytokine storm; therefore, the ratio of LDL-C to HDL-C is a powerful predictor of coronary heart disease and has greater predictive power than HDL-C and LDL-C alone for cardiovascular diseases (CVD).^29,30 The LDL-C:HDL-C ratio was considerably higher in the COVID-19 infected group than in the controls (P-value = 0.00 0.05), with the median (IQR) for patients being 1.5919 (1.08) and 0.7346 for controls (0.67). The optimal LDL-C:HDL-C ratio cut-off value had a sensitivity and specificity of 86.7% and 77.8%, respectively; thus, the severity of patients in this study was associated with LDL-C:HDL-C ratio levels greater than 1.0089; the AUC for LDL-C:HDL-C ratio was 0.888, making it an excellent predictive marker for severe COVID-19 infection.³¹ In an investigation about the optimal cut-off value for LDL-C:HDL-C ratio in cardiovascular and metabolic disease, Chen et al. (2016) described 2.5 as an optimal cut-off point for LDL-C:HDL-C ratio to predict CVD risk factors in Uygur subjects over 35 years old and provided evidence that a higher LDL-C:HDL-C ratio was related to an undesirable cardio-metabolic risk level.³² This variation in optimal cut-off values may be due to a variety of factors, including genetic factors, especially those genes involved in lipid metabolism and overweight, such as apolipoprotein A-V (APOA5) and peroxisome proliferator-activated receptor (PPAR) genetic genotyping, as well as environments, race, lifestyle, and living habits. As a result, the optimal cut-off point of the LDL-C:HDL-C ratio may differ depending on a variety of factors, as discussed above.³²

Conclusions

Because cTn is a marker of severity of illness and a strong independent predictor of unfavorable outcomes, it may aid in deciding how to manage a patient in the emergency room. Ambulatory treatment may be used if cTn is high but the patient is not hospitalized. The fluctuation of the LDL-C:HDL-C ratio level in COVID-19 patients’ blood suggested a significant association with the condition. Because the lipid profile is inexpensive and simple to do in all facilities, it may aid the clinician in determining the degree of COVID-19 infection.

Data availability