Abstract
Background:
The relationship between the elevation of cardiac troponin and the increase of mortality and hospitalization rate in patients with heart failure with reduced ejection fraction is clear. This study investigated the association between the extent of elevated levels of high-sensitivity cardiac troponin I (hs-cTnI) and the prognosis in heart failure with preserved ejection fraction patients.
Methods:
A retrospective cohort study consecutively enrolled 470 patients with heart failure with preserved ejection fraction from September 2014 to August 2017. According to the level of hs-cTnI, the patients were divided into the elevated level group (hs-cTnI >0.034 ng/mL in male and hs-cTnI >0.016 ng/mL in female) and the normal level group. All of the patients were followed up once every 6 months. Adverse cardiovascular events were cardiogenic death and heart failure hospitalization.
Results:
The mean follow-up period was 36.2 ± 7.9 months. Cardiogenic mortality (18.6% [26/140] vs. 1.5% [5/330], P <0.001) and heart failure (HF) hospitalization rate (74.3% [104/140] vs. 43.6% [144/330], P <0.001) were significantly higher in the elevated level group. The Cox regression analysis showed that the elevated level of hs-cTnI was a predictor of cardiogenic death (hazard ratio [HR]: 5.578, 95% confidence interval [CI]: 2.995–10.386, P <0.001) and HF hospitalization (HR: 3.254, 95% CI: 2.698–3.923, P <0.001). The receiver operating characteristic curve demonstrated that a sensitivity of 72.6% and specificity of 88.8% for correct prediction of adverse cardiovascular events when a level of hs-cTnI of 0.1305 ng/mL in male and a sensitivity of 70.6% and specificity of 90.2% when a level of hs-cTnI of 0.0755 ng/mL in female were used as the cut-off value.
Conclusion:
Significant elevation of hs-cTnI (≥0.1305 ng/mL in male and ≥0.0755 ng/mL in female) is an effective indicator of the increased risk of cardiogenic death and HF hospitalization in heart failure with preserved ejection fraction patients.
Keywords: Heart failure with preserved ejection fraction, High-sensitivity cardiac troponin I, Cardiogenic mortality, Heart failure hospitalization
Introduction
Heart failure (HF) is an abnormality in the structure and function caused by various etiologies. HF is a syndrome characterized by impaired systolic and/or diastolic function. These abnormal clinical features include long duration, high mortality, and poor prognosis.[1] The state of HF is characterized by recurrence, slow progression, and progressive worsening. Epidemiological studies in China found that the incidence of HF in subjects >65 years of age was 6–10%, while at the age of 35–64 years, the incidence was 0.9%.[2] In developed countries, the incidence of HF is 1–2%, while in adults >70 years old, the incidence of HF is 10%. The all-cause mortality of patients with HF was 17%, and the rate of rehospitalization was 44% in 12-month follow-up.[3] Therefore, early diagnosis of HF and assessment of chronic heart failure (CHF) prognosis are highly important in its treatment and management.
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of all HF patients with the population aging.[4] Although patients with HFpEF and heart failure with reduced ejection fraction (HFrEF) have similar morbidity and mortality rates, therapeutic methods will remain limited.[4,5,6] Biomarkers of myocardial injury have been shown to be effective in risk stratification of cardiovascular events, but there is little data on HFpEF and their prognostic utility in patients with HFpEF is not fully clear.[7,8,9]
Tests for myocardial markers have been widely used in the diagnosis and evaluation of myocardial injury, and cardiac troponin, due to its high sensitivity and specificity, was recommended for the diagnosis of myocardial infarction.[10] High-sensitivity cardiac troponin I (hs-cTnI) detects myocardial injury in a more timely and accurate manner and has shown significant value in the evaluation of prognosis.[11] Previous studies have shown that cardiac troponin may be used to assess the severity and prognosis of HFrEF.[12,13,14] The relationship between the elevation of cardiac troponin and the increase of mortality and hospitalization rates in patients with HFrEF is certain. But the association between the extent of elevated levels of hs-cTnI and the prognosis in HFpEF patients is not fully clear. The objective of this study is to investigate the association between the extent of elevated levels of hs-cTnI and adverse cardiac events in HFpEF patients.
Methods
Ethical approval
The study protocol conforms to the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Beijing Tiantan Hospital (No. KYSB2018-089). The methods were strictly carried out in accordance with the approved guidelines. Informed consent was obtained from each patient and family member for the use of patients' clinical data.
Patient selection
This retrospective study consecutively enrolled HFpEF patients in the Cardiovascular Department of Beijing Tiantan Hospital from September 2014 to August 2017. The inclusion criteria were age ≥18 years and the etiology of CHF was non-ischemic cardiomyopathy. Exclusion criteria were (1) patients died during the first hospitalization; (2) baseline data were incomplete; (3) patients and their families refused to follow up; (4) patients had cognitive deficits; (5) patients had serious diseases affecting prognosis, such as malignant tumors.
Diagnostic criteria
The diagnosis of HFpEF was made mainly based on the 2019 European Society of Cardiology (ESC) heart failure guideline.[15] HFpEF diagnosis was established in patients with (1) typical and apparent symptoms, such as breathlessness, ankle swelling, and fatigue, and such signs as elevated jugular venous pressure, pulmonary crackles, and peripheral edema; (2) left ventricular ejection fraction (LVEF) ≥50%; (3) the levels of N-terminal pro-B type natriuretic peptide (NT-proBNP) ≥125 pg/mL in patients with sinus rhythm or ≥375 pg/mL in patients with atrial fibrillation; (4) E/e′ ≥ 9 or a mean e′ septal <7 cm/s or lateral wall <10 cm/s; (5) left atrial volume index (LAVI) ≥29 mL/m2 or left ventricular mass index (LVMI) >95 g/m2 in female or >115 g/m2 in male.
Heart Failure Association (HFA)-PEFF score had functional, morphological, and biomarker domains.[15] Within each domain, a major criterion scores 2 points or a minor criterion 1 point. In functional domain, average E/e′ ≥15 or septal e′ <7 cm/s or lateral e′ <10 cm/s was calculated 2 points and average E/e′ 9–14 was calculated 1 point. In morphological domain, LAVI >34 mL/m2 or LVMI ≥122 g/m2 in female or ≥149 g/m2 in male was calculated 2 points and LAVI 29–34 mL/m2 or LVMI >95 and <122 g/m2 in female or >115 and <149 g/m2 in male was calculated 1 point. In biomarker domain, the levels of NT-pro-BNP >220 pg/mL in patients with sinus rhythm or >660 pg/mL in patients with atrial fibrillation were calculated 2 points and 125–220 pg/mL in patients with sinus rhythm or 375–660 pg/mL in patients with atrial fibrillation was calculated 1 point. A total score ≥5 points was considered to be diagnosis of HFpEF.
H2FPEF score was based on body mass index (BMI; >30 kg/m2, 2 points), hypertension (treating more than two antihypertensive medicines, 1 point), paroxysmal or persistent atrial fibrillation (3 points), pulmonary hypertension (pulmonary artery systolic pressure >35 mmHg, 1 point), age (>60 years, 1 point), and Doppler echocardiographic examination (E/e′ >9, 1 point).[16] By establishing the probability of HFpEF, the H2FPEF score may be used to rule out HFpEF among patients with low scores (0–1), to establish the diagnosis HFpEF at higher scores (6–9), and to identify patients for whom additional testing was needed with intermediate scores (2–5).
The etiology of heart failure was considered ischemic cardiomyopathy in the presence of significant coronary artery disease (>50% stenosis or obstruction in one of the major coronary arteries by coronary angiography or computerized tomography angiography, and/or a history of myocardial infarction or previous revascularization). Coronary artery disease was excluded in patients with non-ischemic cardiomyopathy and heart failure by coronary angiography or computed tomography angiograpy.[17]
Acute myocardial infarction was diagnosed if a patient had a rise and/or fall of hs-cTnI with at least one value exceeding the 99th percentile of a normal reference population with one of the following criteria: chest pain lasting 20 min or longer, diagnostic serial electrocardiographic changes consisting of new pathologic Q waves, or ST-segment and T-wave changes, or new left bundle branch block.[18]
Clinical data collection and follow-up
General clinical data, laboratory, and echocardiographic indicators were collected as baseline data at the first hospitalization in HFpEF patients. According to the level of hs-cTnI, the patients were divided into two groups. Levels of hs-cTnI >0.034 ng/mL in male and hs-cTnI >0.016 ng/mL in female were defined as elevated level of hs-cTnI, and levels of hs-cTnI ≤0.034 ng/mL in male and hs-cTnI ≤0.016 ng/mL in female were defined as normal level of hs-cTnI. All patients were followed up once every 6 months.
General clinical data included gender, age, number of inpatient days, and history of hypertension, diabetes, and atrial fibrillation. Laboratory test indicators included red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), estimated glomerular filtration rate (eGFR), and the peak value of hs-cTnI and NT-proBNP. Echocardiographic findings included left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), LVEF, E/A ratio, E/e′ ratio, LAVI, and LVMI.
Adverse cardiovascular events were (1) cardiogenic death including HF deterioration, myocardial infarction, and fatal arrhythmia and (2) HF hospitalization during the period of follow-up.
Hs-cTnI and NT-proBNP test methods
The ARCHITECT STAT hs-cTnI assay (3P25; Abbott, Chicago, USA) was a chemiluminescent microparticle immunoassay for the quantitative determination of cardiac troponin in human plasma and serum on the ARCHITECT i System with STAT protocol capability. The reference range of hs-cTnI was 0–0.034 ng/mL in male and 0–0.016 ng/mL in female. The ARCHITECT NT-proBNP assay (8K28; Abbott, Chicago, USA) was a chemiluminescent microparticle immunoassay for the quantitative determination of NT-proBNP in human ethylenediaminetetraacetic acid (EDTA) plasma on the ARCHITECT i System.
Statistical analyses
Statistical analyses were performed using SPSS for Windows, version 23.0 (SPSS Inc., Chicago, Illinois, USA). Normally distributed continuous variables were expressed as the mean ± standard deviation and compared using a Student's t-test. Non-normally distributed continuous variables were expressed as median (upper quartile, lower quartile) and compared using the Wilcoxon rank sum test. Normality was tested using the Shapiro–Wilk test. Categorical variables were expressed as a percentage (n/N) and the χ2 test or Fisher's exact test was used for comparison between the two groups. Multivariate Cox regression analyses were performed to identify variables with a predictive value for cardiogenic death and HF hospitalization. In the model, all variables were categorical variables. Age levels were divided into ≥70 years old and <70 years old. Anemia was defined as HGB <120 g/L in males and HGB <110 g/L in females. The levels of hs-cTnI were divided into the normal level (hs-cTnI ≤0.034 ng/mL in male and ≤0.016 ng/mL in female) and the elevated level (>0.034 ng/mL in male and >0.016 ng/mL in female). The receiver operating characteristic (ROC) curve was used to explore the probability of using the extent of the elevated level of hs-cTnI to readily identify the risk of adverse cardiovascular events in patients with HFpEF. The area under the curve represents the predictive value, with an area of 0.5–0.7 indicating a low predictive value, 0.7–0.9 indicating a moderate predictive value, and >0.9 indicating a high predictive value. If the 95% confidence interval (CI) of the area under the curve did not contain 0.5, or if the P value was <0.05, then the tested index was considered to be of predictive value. Based on ROC curve, the cut-off value of hs-cTnI influencing adverse cardiovascular events was determined. Because of the different reference limits of hs-cTnI between male and female, two ROC curves were generated. The Kaplan–Meier method was used to generate survival curves, while the log-rank test was employed for comparison. All statistical tests were run as two-sided tests. For all tests, P < 0.05 was considered to be statistically significant.
Results
Baseline characteristics by the level of hs-cTnI
A total of 470 patients were consecutively enrolled in the cohort study, including 140 patients with an elevated level of hs-cTnI and 330 patients with a normal level of hs-cTnI. There was no significant difference in gender, age, HF duration, and hypertension and diabetes history and eGFR. Patients with an elevated level of hs-cTnI had more inpatient days, lower level of HGB and LVEF, and higher level of NT-proBNP, LAVI, and LVMI. There was no significant difference in HFA-PEFF score and H2FPEF score [Table 1].
Table 1.
Comparison of the clinical data and adverse cardiovascular events between the two groups.
| Variables | Elevated level of hs-cTnI (n = 140) | Normal level of hs-cTnI (n = 330) | P-value |
|---|---|---|---|
| Male | 78 (55.7) | 208 (63.0) | 0.137 |
| Age (years) | 72.7 ± 12.3 | 70.2 ± 13.9 | 0.061 |
| BMI (kg/m2) | 25.7 ± 2.0 | 26.1 ± 2.0 | 0.079 |
| HF duration (months) | 24.0 (6.0, 96.0) | 24.0 (12.0, 72.0) | 0.977 |
| In-hospital duration (days) | 12.9 ± 7.4 | 10.2 ± 5.0 | <0.001 |
| Hypertension | 104 (74.3) | 236 (71.5) | 0.539 |
| Diabetes | 56 (40.0) | 142 (43.0) | 0.543 |
| Atrial fibrillation | 21 (15.0) | 62 (18.8) | 0.325 |
| RBC (×1012/L) | 4.02 ± 0.79 | 4.24 ± 0.78 | 0.005 |
| HGB (g/L) | 120.2 ± 25.9 | 127.5 ± 24.4 | 0.004 |
| HCT (%) | 36.5 ± 7.3 | 38.5 ± 6.8 | 0.004 |
| eGFR (mL∙min-1∙1.73 m-2) | 73.9 ± 22.6 | 74.9 ± 18.7 | 0.637 |
| NT-proBNP (pg/mL) | 1250.2 (642.3, 2100.0) | 641.0 (261.7, 1285.8) | <0.001 |
| hs-cTnI (ng/mL) | 0.191 (0.072, 0.864) | 0.012 (0.001, 0.028) | <0.001 |
| LVEF (%) | 55.10 ± 4.43 | 61.00 ± 7.21 | <0.001 |
| LVESD (mm) | 34.3 ± 13.7 | 34.7 ± 9.9 | 0.927 |
| LVEDD (mm) | 52.00 ± 9.20 | 51.20 ± 9.76 | 0.580 |
| E/A ratio | 0.70 ± 0.22 | 0.71 ± 0.18 | 0.611 |
| E/e′ ratio | 13.6 ± 1.0 | 13.7 ± 0.6 | 0.694 |
| LAVI (mL/m2) | 35.7 ± 1.0 | 34.9 ± 1.3 | <0.001 |
| LVMI (g/m2) | 122.1 ± 14.4 | 114.3 ± 6.6 | <0.001 |
| HFA-PEFF score | 5.4 ± 4.9 | 5.4 ± 5.0 | 0.284 |
| H2FPEF score | 0.830 | ||
| 0–1 | 9 (6.4) | 19 (5.8) | |
| 2–5 | 115 (82.1) | 267 (80.9) | |
| 6–9 | 16 (11.5) | 44 (13.3) | |
| Follow-up period (months) | 32.7 ± 10.7 | 37.6 ± 5.7 | <0.001 |
| Cardiogenic death | 26 (18.6) | 5 (1.5) | <0.001 |
| HF hospitalization | 104 (74.3) | 144 (43.6) | <0.001 |
Data are presented as n (%), mean (Q1, Q3) or mean ± standard deviation. BMI: Body mass index; eGFR: Estimate glomerular filtration rate; HCT: Hematocrit; HF: Heart failure; HFA-PEEF: Heart Failure Association-PEFF; HGB: Hemoglobin; hs-cTnI: High-sensitivity cardiac troponin I; LAVI: Left atrial volume index; LVESD: Left ventricular end-systolic diameter; LVEDD: Left ventricular end-diastolic diameter; LVEF: Left ventricular ejection fraction; LVMI: Left ventricular mass index; NT-proBNP: N-terminal pro-B type natriuretic peptide; RBC: Red blood cell count.
Adverse cardiovascular events
The mean follow-up time was 36.2 ± 7.9 months. Patients with the normal level of hs-cTnI were followed up longer than those with the elevated level of hs-cTnI. In the entire cohort, 6.6% (31/470) of the subjects died due to cardiogenic death, including 26 patients with an elevated level of hs-cTnI. 52.3% (248/470) were rehospitalized and 104 patients with an elevated level of hs-cTnI. There was a significant difference in cardiogenic mortality and HF hospitalization rate between the two groups [Table 1].
Predictors of cardiogenic death and HF hospitalization
Multivariate Cox regression analysis of the variables including male, age ≥70 years, hypertension, diabetes, atrial fibrillation history, anemia, and elevated level of hs-cTnI in a regression model revealed that elevated level of hs-cTnI was a predictor of cardiac death and HF hospitalization [Table 2]. Considering the interaction between the level of hs-cTnI and other factors influencing adverse cardiovascular events, another multivariate analysis of adverse cardiovascular events stratified by the level of hs-cTnI showed age ≥70 years and the elevated level of hs-cTnI increased the risk of cardiogenic death, but the elevated level of hs-cTnI had no interaction with other factors in HF hospitalization [Table 3].
Table 2.
Multivariate Cox regression model of adverse cardiovascular events.
| Variables | Cardiogenic death | HF hospitalization | ||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P-value | Hazard ratio | 95% CI | P-value | |
| Male | 1.132 | 0.994–1.289 | 0.062 | 1.267 | 0.980–1.638 | 0.071 |
| Age ≥70 years | 2.095 | 0.931–4.716 | 0.074 | 0.843 | 0.686–1.035 | 0.102 |
| Hypertension history | 0.746 | 0.416–1.336 | 0.324 | 1.044 | 0.831–1.311 | 0.712 |
| Diabetes history | 1.565 | 0.913–2.683 | 0.103 | 1.085 | 0.894–1.316 | 0.411 |
| Atrial fibrillation history | 1.473 | 0.747–2.906 | 0.264 | 1.172 | 0.976–1.407 | 0.089 |
| Anemia | 2.888 | 0.871–9.580 | 0.083 | 1.306 | 0.973–1.752 | 0.075 |
| Elevated level of hs-cTnI | 5.578 | 2.995–10.386 | <0.001 | 3.254 | 2.698–3.923 | <0.001 |
CI: Confidence interval; HF: Heart failure; hs-cTnI: High-sensitivity cardiac troponin I.
Table 3.
Multivariate Cox regression model of adverse cardiovascular events stratified by the level of hs-cTnI.
| Variables | Cardiogenic death | HF rehospitalization | ||||||
|---|---|---|---|---|---|---|---|---|
| Normal level of hs-cTnI | Elevated level of hs-cTnI | P-value | P interaction | Normal level of hs-cTnI | Elevated level of hs-cTnI | P-value | P interaction | |
| Gender | 0.502 | 0.071 | ||||||
| Male | 1 | 9.859 (3.458–28.108) | 0.134 | 1 | 4.337 (3.337–5.637) | <0.001 | ||
| Female | 1 | 6.191 (2.897–13.228) | <0.001 | 1 | 2.761 (2.086–3.655) | <0.001 | ||
| Age ≥70 years | 0.025 | 0.373 | ||||||
| Yes | 1 | 14.946 (5.242–42.618) | <0.001 | 1 | 2.778 (2.238–3.449) | <0.001 | ||
| No | 1 | 3.407 (1.595–7.279) | 0.002 | 1 | 5.479 (3.886–7.725) | <0.001 | ||
| Hypertension history | 0.306 | 0.247 | ||||||
| Yes | 1 | 1.311 (0.976–1.761) | 0.072 | 1 | 2.362 (0.968–5.764) | 0.059 | ||
| No | 1 | 1.195 (0.989–1.444) | 0.065 | 1 | 1.795 (0.919–3.508) | 0.087 | ||
| Diabetes history | 0.138 | 0.067 | ||||||
| Yes | 1 | 2.218 (0.980–5.021) | 0.056 | 1 | 3.658 (0.082–15.176) | 0.074 | ||
| No | 1 | 2.236 (0.785–6.371) | 0.132 | 1 | 2.973 (0.824–10.724) | 0.096 | ||
| Atrial fibrillation history | 0.094 | 0.376 | ||||||
| Yes | 1 | 1.986 (1.245–3.169) | 0.004 | 1 | 2.315 (0.956–5.609) | 0.063 | ||
| No | 1 | 1.887 (1.046–3.405) | 0.035 | 1 | 1.974 (0.941–4.141) | 0.072 | ||
| Anemia | 0.793 | 0.450 | ||||||
| Yes | 1 | 5.226 (2.408–11.342) | <0.001 | 1 | 3.071 (2.347–4.017) | <0.001 | ||
| No | 1 | 6.099 (2.386–15.586) | <0.001 | 1 | 3.563 (2.786–4.557) | <0.001 | ||
HF: Heart failure; hs-cTnI: High-sensitivity cardiac troponin I.
Cut-off value of hs-cTnI
The area under the ROC curve was 0.823 (95% CI: 0.772–0.874, P < 0.001) in male and 0.814 (95% CI: 0.751–0.877, P < 0.001) in female, respectively [Figure 1]. According to the ROC curve, the hs-cTnI cut-off value was 0.1305 ng/mL (3.8-fold reference limit) in male and 0.0755 ng/mL (4.7-fold reference limit) in female. The sensitivity and specificity of the cut-off values were 72.6% and 88.6% in males and 70.6% and 90.2% in females, respectively.
Figure 1.
ROC curve of the predictive value to identify the risk for adverse cardiovascular events in male (A) and female (B). The y-axis represents the sensitivity to predict the risk for adverse cardiovascular events; the x-axis represents the false positive rate. AUC: Area under the curve; CI: Confidence interval; ROC: Receiver operating characteristic.
Survival analysis of cardiogenic death and HF hospitalization
According to the cut-off value of hs-cTnI, the level of hs-cTnI was divided into normal hs-cTnI (≤0.034 ng/mL in males and ≤0.016 ng/mL in females), slightly elevated hs-cTnI (0.034<hs-cTnI<0.1305 ng/mL in males and (0.016<hs-cTnI<0.0755 ng/mL in females), and significantly elevated hs-cTnI (≥0.1305 ng/mL in males and ≥0.0755 ng/mL in females). During a follow-up period of 36.2 ± 7.9 months, 1.5% (n = 5) patients with a normal hs-cTnI died and 28.9% (n = 26) patients with a significantly elevated hs-cTnI died [Table 4 and Figure 2A]. There was a significant difference among the three levels of hs-cTnI. A similar situation also occurred in HF hospitalization. Patients with a normal or slightly elevated hs-cTnI had a lower HF hospitalization rate compared to patients with a significantly elevated hs-cTnI [Table 4 and Figure 2B].
Table 4.
Multivariate analysis of cardiac death and heart failure hospitalization.
| Variables | Level of hs-cTnI | ||||
|---|---|---|---|---|---|
| 1 (n = 330) | 2 (n = 50) | 3 (n = 90) | Log-rank χ2 | P-value | |
| Cardiac death (n, %) | 5 (1.5) | 0 (0) | 26 (28.9) | 108.068 | <0.001 |
| Heart failure hospitalization (n, %) | 144 (43.6) | 28 (56.0) | 76 (84.4) | 59.562 | <0.001 |
1: Normal hs-cTnI ≤0.034 ng/mL in males and ≤0.016 ng/mL in females; 2: Slightly elevated hs-cTnI (0.034<hs-cTnI<0.1305) ng/mL in males and (0.016<hs-cTnI<0.0755) ng/mL in females; 3: Significantly elevated hs-cTnI ≥0.1305 ng/mL in males and ≥0.0755 ng/mL in females. hs-cTnI: High-sensitivity cardiac troponin I.
Figure 2.
Kaplan–Meier curve of cardiogenic death (A) and HF hospitalization (B). 1: Normal hs-cTnI ≤0.034 ng/mL in males and ≤0.016 ng/mL in females; 2: Slightly elevated hs-cTnI (0.034<hs-cTnI<0.1305) ng/mL in males and (0.016<hs-cTnI<0.0755) ng/mL in females; 3: Significantly elevated hs-cTnI ≥0.1305 ng/mL in males and ≥0.0755 ng/mL in females; HF: Heart failure; hs-cTnI: High-sensitivity cardiac troponin I.
Discussion
Cardiac troponin is composed of three subunits, cardiac troponin T, cardiac troponin I, and cardiac troponin C. During the destruction of cell membrane integrity due to ischemia or hypoxia, free cardiac troponin can penetrate the cell membrane and be released. Cardiac troponin I is a highly specific and sensitive serum marker detected in myocardial injury. This marker plays an important role in the diagnosis of acute coronary syndrome and risk evaluation of cardiac disease and has a significant predictive value in cardiovascular events. The sensitivity of hs-cTnI has significantly improved and is therefore more conducive to early detection of myocardial injury and optimization of clinical treatment. Hs-cTnI has been recommended as the preferred cardiac injury marker in the third definition of myocardial infarction.[10]
However, due to its increased sensitivity, its specificity may be affected. For patients with different degrees of myocardial ischemia and hypoxia, an increase in hs-cTnI may still be detected, which may have an impact on the differential diagnosis of myocardial infarction and myocardial injury.[19,20] Studies have found that patients with low levels of hs-cTnI may suffer from non-myocardial infarction and the clinical diagnostic threshold is determined to be 0.273 ng/mL. This suggests that a low level of hs-cTnI elevation may be detected in patients with non-myocardial infarction, indicating that these patients had various degrees of myocardial injury. Therefore, the causes of hs-cTnI elevation may be classified into ischemic and non-ischemic.[21] Causes of non-ischemic elevations include cardiogenic factors and systemic factors. Cardiogenic factors include heart failure, myocarditis, pericarditis, cardiomyopathy, cardiac ablation, and cardiac malignancies. Systemic factors include CHF, pulmonary embolism, renal failure, stroke, subarachnoid hemorrhage, sepsis, anthracycline antibiotics, and so on. In our study, nearly 30% of patients had an elevated hs-cTnI, which was consistent with previous studies. It was shown that HFpEF patients had myocardial injury at the acute decompensation phase, and that the severity of myocardial injury was related to the level of hs-cTnI.
The essence of hs-cTnI elevation is myocardial injury, and its mechanisms may include (1) primary myocardial ischemia such as coronary plaque rupture or thrombus corrosion caused by myocardial ischemia and injury; (2) imbalance of blood supply and demand leading to myocardial cell apoptosis or necrosis; (3) myocardial injury unrelated to myocardial ischemia, such as viruses, cocaine, and other heart toxic substances directly damaging myocardial cells, and causing changes in cell structure and function; (4) multiple systemic factors such as neuro-endocrine system regulation, the stress-associated system, immune system regulation, and the substance metabolism system, resulting in an absolute or relative increase in the level of hs-cTnI.[10,18] The mechanism by which hs-cTnI is elevated in HF mainly includes cardiac factors and other risk factors, such as kidney disease, lung disease, severe inflammation, and other multisystem diseases.[22,23]
In the pathophysiological process of heart failure, increased volume and pressure load lead to myocardial remodeling.[5,24,25] Ischemic myocardial injury directly causes myocardial cell necrosis and promotes the release of growth factors, extracellular matrix proliferation, and myocardial remodeling. In HF, an increase in the rennin angiotensin aldosterone system and sympathetic nervous system excitability, a variety of neuro-endocrine and cytokine systems activation, directly damage myocardial cells, aggravate cardiac function and promote myocardial remodeling. Myocardial remodeling further activates the neuro-endocrine and cytokine systems, thus forming a vicious circle. Remodeling of the structure and function of the cardiovascular system for physiological reasons or due to pathological myocardial injury plays an irreplaceable role in myocardial injury.[26]
Patients with CHF had elevated hs-cTnI, especially in elderly subjects, males, diabetics, and subjects with renal insufficiency.[27] The proportion of HF caused by ischemic heart disease is higher than that caused by non-ischemic heart disease.[28] At the same time, the positive rate of hs-cTnI detection in patients with acute decompensated CHF was higher than that in patients with chronic stable HF. Similarly, HF patients came to our hospital because of acute decompensation of CHF in our study, and it was useful to detect the levels of hs-cTnI. Risk factors such as being a male, ischemic heart disease, renal insufficiency, hypotension, and hyponatremia were independently associated with elevated hs-cTnI. Regardless of the increase in cardiac troponin, the 1-year mortality of patients increases significantly.[11,28] It was consistent with the results of our study.
In patients with HF, the detection rate of hs-cTnI was higher than that of traditional cardiac troponin I, and it had a high sensitivity beyond the traditional cardiac troponin I for the detection of myocardial injury.[27,29] In our study, elevated levels of hs-cTnI were able to indicate the severity of myocardial injury in CHF. Hs-cTnI for the assessment of rehospitalization and mortality in patients with heart failure has shown the superior prognostic value and is an important marker for assessing the prognosis of heart failure.[30] Previous research has confirmed that the level of cTnI also increases as the severity of HF increases.[31] This increase is inversely related to the LVEF value. These results are consistent with other studies in the literature, suggesting that the level of cTnI may be a useful marker in the diagnosis and evaluation of severity of HF.
Compared with chronic stable HF, hs-cTnI levels were significantly elevated in patients with acute decompensated CHF. Pascual-Figal et al[30] found an average high-sensitivity cardiac troponin T (hs-cTnT) level of 0.35 ng/mL in patients with acute HF. Parissis et al[32] also found that patients with hs-cTnT >0.077 ng/mL had a 7.2-fold mortality in patients with hs-cTnT <0.077 ng/mL in acute HF. Univariate analysis found that hs-cTnT was significantly associated with mortality. Except for confounding factors such as age, gender, LVEF, and creatinine level, hs-cTnT still had important predictive significance. Similarly, in our study, patients with hs-cTnI ≥0.1305 ng/mL (3.8-fold reference limit) in male and hs-cTnI ≥0.0755 ng/mL (4.7-fold reference limit) in female had an increased risk of cardiogenic death and HF hospitalization. It was obvious that a significantly elevated level of hs-cTnI was closely related to the occurrence of cardiogenic death or other cardiovascular adverse events.
In our study, HFA-PEFF score ≥5 was adopted as the diagnostic criterion for HFpEF, while H2FPEF scores were found to be 2–5 in >80% of patients. One of the possible reasons was that the BMI level of the enrolled population in our study was 25.9 ± 2.0 kg/m2, and significantly <30 kg/m2 (2 points), resulting in low H2FPEF score. In addition to the BMI factor, there may be other factors leading to the difference between the two score systems. In future studies, patients were further examined with their informed consent to explore the reasons for the difference in scores. It may be important to improve the diagnostic efficiency and investigate the correlation with major adverse events of the two score systems.
This study was conducted at a single center, hence limiting its generalizability. Importantly, however, our study cohort is truly representative of a real-world population with HFpEF. In multivariate analysis, a parsimonious model was generated because of a small sample size, which may have an impact on the strength of the association of hs-cTnI and the clinical outcome. Of note, although the patients included in the study were all followed systematically within our hospital system, there was low cardiogenic mortality compared to previous studies which may be related to the severity of HFpEF. The survival curves of cardiogenic death and HF hospitalization did not look perfect, probably due to the small sample size and short follow-up period. Large-scale, multicenter, and prospective studies should be conducted in the future, and subgroup analyses stratified by hs-cTnI should be performed.
HFpEF patients with the elevated level of hs-cTnI increase the risk of cardiogenic death (5.578-fold) and HF hospitalization (3.254-fold). Significant elevation of hs-cTnI (3.8-fold reference limit in male and 4.7-fold reference limit in female) is an effective indicator of the increased risk of cardiogenic death and HF hospitalization in HFpEF patients. Meanwhile, among these patients, those >70 years of age should receive a close follow-up because of the increasing risk of adverse cardiovascular events. Large-scale, multicenter, and prospective studies should be conducted in the future to investigate the significance of hs-cTnI in HFpEF patients.
Footnotes
How to cite this article: Hu HY, Li JJ, Wei X, Zhang J, Wang JY. Elevated level of high-sensitivity cardiac troponin I as a predictor of adverse cardiovascular events in patients with heart failure with preserved ejection fraction. Chin Med J 2023;136:2195–2202. doi: 10.1097/CM9.0000000000002639
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