Abstract
Background
High-sensitivity cardiac troponin T (hs-cTnT) and creatine kinase (CK)-MB are the most commonly used biomarkers for the diagnosis and prognosis of acute myocardial infarction (AMI). Chronic kidney disease (CKD) often leads to elevated hs-cTnT levels in non-AMI patients. However, studies comparing the prognostic value of both hs-cTnT and CK-MB in patients with AMI and CKD are lacking.
Methods
We conducted a retrospective study on AMI patients diagnosed between January 2015 and October 2020. Patients were categorized based on renal function as normal or CKD. Peak hs-cTnT and CK-MB levels during hospitalization were collected, and their diagnostic value was evaluated using receiver operating characteristic (ROC) curves. The impact on in-hospital mortality was analyzed using multivariate logistic regression. The relationship between the hs-cTnT/CK-MB ratio and in-hospital death was examined using a restricted cubic spline (RCS) curve.
Results
The study included 5022 AMI patients, of whom 797 (15.9%) had CKD. The AUCs of Hs-cTnT and CK-MB were higher in the CKD group [0.842 (95% CI: 0.789–0.894) and 0.821 (95% CI: 0.760–0.882)] than in the normal renal function group [0.695 (95% CI: 0.604-0.790) and 0.708 (95% CI: 0.624-0.793)]. After full adjustment for all risk factors, hs-cTnT (OR, 2.82; 95% CI, 1.03–9.86; p = 0.038) and CK-MB (OR, 4.91; 95% CI, 1.54–14.68; p = 0.007) above the cutoff values were independent predictors of in-hospital mortality in patients with CKD. However, in patients with normal renal function, only CK-MB above the cutoff (OR, 2.45; 95% CI, 1.02–8.24; p = 0.046) was a predictor of in-hospital mortality, whereas hs-cTnT was not. There was an inverted V-shaped relationship between the hs-cTnT/CK-MB ratio and in-hospital mortality, with an inflection point of 19.61. The ratio within the second quartile (9.63-19.6) was an independent predictor of in-hospital mortality in patients with CKD (OR 5.3, 95% CI 1.66–16.86, p = 0.005).
Conclusions
Hs-cTnT independently predicted in-hospital mortality in AMI patients with CKD, whereas its predictive value was not observed in patients with normal renal function. CK-MB was an independent predictor of in-hospital mortality regardless of renal function. Moreover, the hs-cTnT/CK-MB ratio may aid in risk stratification of AMI patients with CKD.
1. Introduction
Acute myocardial infarction (AMI) has traditionally been divided into ST elevation or non-ST elevation myocardial infarction, which is the leading cause of morbidity and mortality worldwide [Citation1]. More than 17% of AMI patients have clinically comorbid chronic kidney disease (CKD), and their in-hospital and long-term mortality rates are significantly higher than those of patients with normal renal function [Citation2]. CKD can lead to pathological changes such as vascular calcification, endothelial dysfunction, oxidative stress, and a hypercoagulable state of the blood, which may increase cardiovascular risk [Citation3]. As estimated glomerular filtration rate(eGRF) declines, the risk of cardiovascular death gradually increases, with nearly fifty percent of patients with advanced CKD succumbing to cardiovascular disease.
It is clinically important to find simple and convenient indicators to assess the prognosis of patients with AMI combined with CKD, which can help us better prevent death in this group of patients. High-sensitive cardiac troponin T (hs-cTnT) and creatine kinase (CK)-MB is the most commonly used biomarkers for the clinical diagnosis of AMI [Citation4]. Several studies have demonstrated that they predict immediate and long-term mortality in AMI and are associated with coronary lesion severity and infarct size [Citation5–8]. Hs-cTnT was found to be elevated in patients with CKD without myocardial infarction and was associated with poor prognosis, indicating that renal insufficiency is a factor contributing to troponin elevation [Citation9,Citation10]. The optimal cutoff value for hs-cTnT to diagnose AMI varies at different stages of CKD, and generally increases as eGRF decreases [Citation11,Citation12].
Nevertheless, research on the prognostic significance of hs-cTnT and CK-MB in AMI patients with CKD remains limited. In our clinical observations, hs-cTnT levels were significantly elevated in some AMI patients with CKD, while there was no proportional increase in CK-MB. This discrepancy suggests that the hs-cTnT/CK-MB ratio may also influence the prognosis of this patient group. Therefore, we conducted this retrospective cohort study to evaluate the impact of hs-cTnT and CK-MB on in-hospital mortality in AMI patients with CKD and to explore the potential value of the hs-cTnT/CK-MB ratio in this population.
2. Methods
2.1. Study design and patient population
This retrospective study was conducted at the Yue Bei People’s Hospital, one of the largest cardiac centers in southern China. All study participants were selected from this single center. We consecutively enrolled patients diagnosed with AMI, which includes both acute ST-segment elevation myocardial infarction and acute non-ST-segment elevation acute coronary syndrome. The diagnostic criteria followed the guidelines for myocardial infarction set forth by European and American standards. The study spanned from January 2015 to October 2020. During hospitalization, all patients were confirmed to have their hs-cTnT levels tested above the upper limit of the 99th percentile normal reference value at least once. Detailed clinical data and laboratory test results were meticulously recorded, encompassing demographic information, medical history, comorbidities, coronary interventions, clinical medications, cardiac ultrasound, electrocardiogram, blood test results, and more. We excluded patients without hs-cTnT, CK-MB, or renal function test results, as well as patients with acute renal insufficiency and lost follow-up. Patients with CKD must have an admission diagnosis of chronic kidney disease and have had CKD for more than 3 months. The Ethics Committee of Yuebei People’s Hospital approved the study protocol (Registration Number: ChiCTR2100043135). This study was designed and executed in accordance with applicable rules and regulations (Declaration of Helsinki).
2.2. Definitions
Hs-cTnT was detected using the electrochemiluminescence immunoassay (e602, Roche Diagnostics, Mannheim, Germany, the upper reference limit: 14 pg/mL, range: 3–10 000 pg/mL). CK-MB was measured using immunosuppression assay (LABCO, China, the upper reference limit: 24 U/L, range: 5–2300 U/L). After hospital admission, patients with AMI were typically tested multiple times for hs-cTnT and CK-MB. At our center, blood tests were normally performed immediately after admission, 4 h after PCI, on the mornings of the second and third days of admission. If the patient experiences an episode of chest pain or the condition worsens, blood will be obtained at any time for evaluation. We selected the maximum values of hs-cTnT and CK-MB for analysis and used them to calculate the hs-cTnT/CK-MB ratio. eGFR, calculated by the CKD-Epidemiology Collaboration equation, was used to evaluate renal function. GFR categories were defined as follows: G1: eGFR ≥ 90 mL/min/1.73m2; G2: eGFR = 60–89 mL/min/1.73m2; G3: eGFR = 30–59 mL/min/1.73m2; G4: eGFR = 15–29 mL/min/1.73m2. We classified G1 as the normal renal function group and G2–G4 as the renal insufficiency group (or CKD group, in our study).
2.3. Interventional procedures and medications
Patients diagnosed with AMI received coronary intervention based on their condition, either as an emergency or delayed procedure, performed by three experienced interventional cardiologists. Typically, the surgeon performed simply revascularization of the culprit vessel. Complete revascularization depended on the location of the vascular lesion, its severity, the patient’s overall health, and the surgeon’s strategy. Patients treated with PCI generally received a dual antiplatelet drug regimen consisting of an initial loading dose (LD) of 300 mg aspirin and an LD of 300–600 mg clopidogrel or 180 mg ticagrelor (no history of taking antiplatelet drugs). Starting the following day, patients then took aspirin 100 mg once per day and clopidogrel 75 mg once per day or ticagrelor 90 mg twice per day indefinitely for at least one year. However, in cases where patients had risk factors for bleeding, a single antiplatelet therapy regimen could be considered, or the antiplatelet therapy could be temporarily suspended. In situations where patients were unable to take oral medication, intravenous GP IIbIIIa inhibitors were utilized. Additional medications, such as ACE inhibitors/ARBs, beta-blockers, and antithrombotic drugs, were selected based on the clinical assessment of each patient’s specific situation.
2.4. Study endpoint
The primary endpoint of this study was all-cause death during in-hospital stay (in-hospital death).
2.5. Statistical analysis
Baseline characteristics of the samples were compared between patients with normal and abnormal renal function. The Kolmogorov-Smirnov test was used to determine whether the distribution was normal. Continuous variables are displayed as the mean with standard deviation; the t-test was used to compare the means of two groups, and a one-way ANOVA was used to compare the means of multiple groups. The measurement data of the non-normal distribution, expressed as a median and interquartile range [M(P25, P75)], was checked by the rank-sum test. Receiver operating characteristic (ROC) analysis was used to assess the prognostic value of hs-cTnT and CK-MB. The optimum cutoff value of hs-cTnT and CK-MB was determined by Youden’s index. Multivariate logistic regression analysis was used to assess the association between predictors and in-hospital mortality. The most relevant predictors after univariable screening and some traditional CV risk factors were used in the multivariable logistic regression model, and a backward stepwise procedure was used to choose the final model, with variables significant at p < 0.1 being retained in the model. A restricted cubic spline (RCS) curve was used to depict the continuous relationships between the hs-cTnT/CK-MB ratio and in-hospital death. Subgroup analyses were stratified by some relevant effect covariates. All the analyses were performed with the statistical software packages R (http://www.R-project.org, The R Foundation) and Free Statistics software version 1.7. Two-sided p < 0.05 was considered statistically significant.
3. Results
3.1. Population and baseline characteristics
A total of 5022 patients were enrolled in the study after excluding those who did not meet the enrollment criteria. The flow chart of the study patients’ selection is presented in . provides an overview of the baseline characteristics of all participants. Among them, 797 (15.9%) patients had chronic kidney disease (CKD). Of the enrolled patients, 23 (0.4%) did not receive dual antiplatelet therapy, 386 (7.7%) received single antiplatelet therapy, and the remaining patients received dual antiplatelet therapy. Patients with CKD were older and more likely to have non-ST-elevation myocardial infarction. As eGFR declined, hs-cTnT and in-hospital mortality increased, but CK-MB did not rise proportionally, resulting in a higher hs-cTnT/CK-MB ratio. Furthermore, significant differences were observed between the two groups in several other variables. Patients with CKD exhibited a higher prevalence of hypertension, diabetes, hyperuricemia, NT-proBNP, and narrow coronary arteries. They also had a lower ejection fraction (EF) and a higher Killip classification.
Figure 1. Flowchart of patient selection.
Table 1. Baseline characteristics of the study participants.
3.2. Predictive value of hs-cTnT and CK-MB for in-hospital mortality
The ROC curves of hs-cTnT and CK-MB for predicting in-hospital mortality in patients with normal and abnormal renal function were plotted in . The AUCs of Hs-cTnT and CK-MB were higher in the CKD group [0.842 (95% CI: 0.789–0.894) and 0.821 (95% CI: 0.760-0.882)] than in the normal renal function group [0.695 (95% CI: 0.604–0.790) and 0.708 (95% CI: 0.624–0.793)]. The cutoff values, sensitivity and specificity when the Jorden index was maximum were shown in . It was observed that the optimal cutoff values for hs-cTnT and CK-MB were higher in the normal renal function group compared to the CKD group.
Figure 2. (A) ROC curves of hs-cTnT and CK-MB between normal renal function and CKD groups. (B) The AUC, threshold, sensitivity and specificity of each group.
3.3. Multivariable analysis
According to their respective hs-cTnT and CK-MB cutoff values, patients with CKD and patients with normal renal function were divided into two groups. Multivariate logistic regression analysis was used to assess the association between predictors and in-hospital mortality (). All factors entering the model were first subjected to univariate logistic regression analysis (). After adjusting for age, gender, diagnosis at discharge, hypertension, diabetes, hyperuricemia, current smoker, drinking, stroke history, and history of PCI (model I), elevated levels of hs-cTnT and CK-MB were identified as independent predictors of in-hospital mortality in both patients with normal and abnormal renal function. In the fully adjusted models (model II), hs-cTnT (OR, 2.82; 95% CI, 1.03–9.86; p = 0.038) and CK-MB (OR, 4.91; 95% CI, 1.54–14.68; p = 0.007) above the cutoff values remained independent predictors of in-hospital mortality in patients with CKD. However, in patients with normal renal function, only CK-MB (OR, 2.45; 95% CI, 1.02–8.24; p = 0.046) was a predictor of in-hospital mortality, while hs-cTnT was not. Furthermore, in the subgroup analysis of CKD patients, high levels of CK-MB were identified as an independent risk factor for in-hospital death. On the other hand, high levels of hs-cTnT were found to be an independent risk factor for in-hospital death in CKD patients with eGFR30–89 mL/min/1.73m2, but not in patients with eGFR ≤ 29 mL/min/1.73m2 ().
Figure 3. Forest plot illustrating the adjusted OR for in-hospital deaths in different renal function groups stratified by CK-MB, hs-cTnT and their ratio. The analysis employed a fully adjusted model (adjusts for age, gender, diagnosis at discharge, hypertension, diabetes, hyperuricemia, current smoker, drinking, stroke history, PCI history, Killip classification, heart rate, hemoglobin, ejection fraction, Nt-proBNP, number of diseased vessels, potassium).
Table 2. Multivariate logistic regression analysis of hs-cTnT and CK-MB on in-hospital deaths between normal renal function and CKD groups.
3.4. Effect of Hs-cTnT/CK-MB ratio on in-hospital mortality
We used RCS to model and visualize the relationship between hs-cTnT/CK-MB ratio and in-hospital death and discovered that it had an inverted V shape with an inflection point of 19.61 (). Both low and high levels of the ratio were associated with a reduced risk of in-hospital death (P-value for non-linearity > 0.05). Next, we divided the hs-cTnT/CK-MB ratio into four quartiles and performed multivariate logistic regression to analyze the effect of different quartiles on in-hospital mortality (). In patients with normal renal function, the quartiles of the hs-cTnT/CK-MB ratio did not show a significant effect on in-hospital mortality. However, in patients with CKD, the second quartile (9.63–19.6) of the ratio was found to be an independent predictor of in-hospital mortality (OR 5.3, 95% CI 1.66–16.86, p = 0.005). Furthermore, subgroup analyses were conducted, and no statistically significant tests of interaction were found ().
Figure 4. Multivariable adjusted odds ratio for in-hospital death according to levels of hs-cTnT/CK-MB ratio on a continuous scale. Solid black lines are multivariable adjusted hazard ratios, with dashed black lines showing 95% confidence intervals derived from restricted cubic spline regressions with four knots. The blue area shows the proportion of different levels of hs-cTnT/CK-MB ratio in all patients with myocardial infarction. 19.61 is the ratio with the highest risk of in-hospital death. The analysis employed a fully adjusted model (adjusts for age, gender, diagnosis at discharge, hypertension, diabetes, hyperuricemia, current smoker, drinking, stroke history, PCI history, Killip classification, heart rate, hemoglobin, ejection fraction, Nt-proBNP, number of diseased vessels, potassium).
Table 4. Multivariate logistic regression analysis of hs-cTnT/CK-MB ratio on in-hospital deaths between normal renal function and CKD groups.
Table 3. Univariate regression analysis of in-hospital deaths.
4. Discussion
In this retrospective cohort study, we observed that peak levels of hs-cTnT and CK-MB demonstrated a stronger predictive value for in-hospital mortality in AMI patients with CKD compared to those with normal renal function. Following adjustment for all relevant risk factors, elevated levels of hs-cTnT and CK-MB above the defined threshold emerged as independent risk factors for in-hospital death specifically in patients with AMI and CKD, while only CK-MB showed predictive value for in-hospital mortality in patients with normal renal function. Notably, the cutoff values for hs-cTnT and CK-MB in assessing in-hospital mortality were higher in the normal renal function group than in the CKD group, which presents an intriguing phenomenon with potential implications for clinical practice. It appears that AMI patients with normal renal function are associated with increased in-hospital mortality when hs-cTnT and CK-MB levels reach higher thresholds, while CKD patients do not require excessively elevated levels for a similar impact on mortality risk. Additionally, we observed a significant association between a hs-cTnT/CK-MB ratio of 19.61 and the highest risk of in-hospital death, whereas lower or higher ratios were associated with a decreased risk of in-hospital mortality. This phenomenon was specific to patients with CKD and not observed in patients with normal renal function.
Hs-cTnT and CK-MB are the most widely used clinical markers for the diagnosis of AMI and play a significant role in the prognostic evaluation of AMI [Citation13,Citation14]. These markers are released into the bloodstream by necrotic cardiomyocytes during myocardial infarction, and their levels are believed to correlate with the infarct size, indicating a poor prognosis [Citation6,Citation15]. However, chronic kidney disease, a significant prognostic factor in AMI, also influences troponin T expression [Citation16]. The mechanism by which troponin T was elevated in patients with CKD without AMI remained unclear, as many CKD patients with low eGFR exhibit normal troponin T levels [Citation17]. Serum troponin is currently thought to be cleared by three main pathways: 1) intracellular cleavage by specific proteases in the reticuloendothelial system; 2) extracellular cleavage by protein hydrolases in serum; and 3) renal (glomerular) filtration [Citation18]. However, since cardiac troponin molecules are not predominantly detected in the urine of most patients, the role of kidneys in eliminating cardiac troponin is uncertain and subject to debate. Some scholars propose that troponin must be broken down into smaller molecular fragments before being excreted through the kidneys [Citation19]. Thus, elevated troponin levels in CKD patients cannot be solely attributed to impaired renal filtration of troponin.
A recent meta-analysis demonstrated the high sensitivity of hs-cTnT in predicting mortality in CKD patients, with each 10 ng/L increase in hs-cTnT being associated with a 14% increase in the risk of all-cause mortality [Citation20]. However, it remains unclear whether hs-cTnT predicts prognosis in CKD patients with concomitant AMI. Our study determined that peak hs-cTnT was an independent predictor of in-hospital mortality in patients with AMI and CKD, but had no independent predictive value in patients with normal renal function during the same study period. We believe this finding can be attributed to the various ways in which CKD exacerbates myocardial damage. Firstly, CKD often coexists with coronary microvascular dysfunction, worsening myocardial ischemia [Citation21]. Secondly, increased blood volume and renal hypertension impose additional loads on the heart, leading to myocardial hypertrophy and further exacerbating myocardial cell damage [Citation22–24]. Thirdly, CKD triggers systemic inflammatory reactions, electrolyte disorders, and disturbances in acid-base balance, all of which contribute to myocardial cell injury [Citation19, Citation25]. Thus, higher troponin levels in CKD patients with AMI are not solely due to coronary artery occlusion but also reflect myocardial injury resulting from CKD.
Multiple prior studies have confirmed that peak CK-MB levels are strong predictors of cardiac infarct size in AMI patients and are associated with mortality [Citation6, Citation26, Citation27]. Our findings align with this evidence as we observed that peak CK-MB was an independent predictor of in-hospital death in AMI patients, both with normal and impaired renal function. We found that renal insufficiency had no effect on CK-MB levels and even showed lower expression in CKD patients, although the difference was not statistically significant. This suggests that CK-MB accurately reflects the extent of myocardial damage resulting from coronary occlusion.
Based on our clinical observations, certain patients with AMI and CKD exhibited significantly elevated troponin levels, while CK-MB levels showed only mild elevations. The prognostic impact of the hs-cTnT/CK-MB ratio in this context remained uncertain. We observed a correlation between the hs-cTnT/CK-MB ratio and eGFR, with the ratio increasing as eGFR decreased. To better understand this relationship, we employed RCS to model and visually represent the association between the hs-cTnT/CK-MB ratio and in-hospital death. Interestingly, we discovered that the relationship followed an inverted V shape. Notably, the second quartile of the hs-cTnT/CK-MB ratio emerged as an independent predictor of in-hospital mortality in CKD patients. This finding suggests that in individuals with AMI and CKD, only corresponding elevations in hs-cTnT and CK-MB have an impact on prognosis. Thus, we propose that the hs-cTnT/CK-MB ratio holds the potential for further risk classification of patients with AMI and CKD.
4.1. Limitations
Several limitations are present in this study. Firstly, due to its retrospective nature, the potential for confounding bias cannot be completely ruled out, and certain risk factors may have been overlooked. Secondly, the collection of hs-cTnT and CK-MB samples was not standardized, leading to variations in testing frequency and potentially missing true peak values in some patients. Thirdly, the limited number of individuals with severe CKD (eGFR < 30 mL/min/1.73 m2) may have influenced the statistical power of the analysis. Lastly, this study was conducted at a single center, and the inclusion of multiple centers in future studies would enhance the reliability of the findings.
5. Conclusion
In conclusion, our study demonstrates that peak hs-cTnT serves as an independent predictor of in-hospital mortality in patients with AMI and CKD, while CK-MB is an independent predictor in patients with both normal and abnormal renal function. Additionally, the hs-cTnT/CK-MB ratio shows potential for risk stratification in patients with AMI and CKD. These findings contribute to a better understanding of the prognostic value of cardiac biomarkers in this specific patient population. Further research involving larger multi-center studies is warranted to validate and expand upon these findings.
Ethical approval
This study protocol was reviewed and approved by the Ethics Committee of our institution (Yue Bei People’s Hospital). Approval Reference: No.2019-28. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Author contributions
Yunxian Chen and Liangqiu Tang designed the study. Xiwen Zhou, Zhixin Chen, Jue Xia, Fenglei Guan, Yue Li, Yanrong Li, Yicai Chen and Yuanlin Zhao collected clinical data. Jiarong Liang and Huayun Qiu analyzed the data. Liangqiu Tang was responsible for the clinical data and critically revised the article. All authors had final approval of the submitted versions.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
Additional information
Funding
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