Abstract
Background
Post-procedural high-sensitivity cardiac troponin T (hs-TnT) is an established prognostic marker in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Current practice applies uniform troponin thresholds regardless of sex, potentially overlooking biological differences in cardiac mass and injury patterns. This study aimed to investigate whether the association between elevated hs-TnT and clinical outcomes differs by sex, and to characterize sex-specific dose–response relationships.
Methods
This retrospective analysis utilized data from a prospective PCI registry enrolling consecutive ACS patients between March 2016 and March 2019. Patients were stratified by post-procedural hs-TnT concentrations measured within 48 h after PCI (< 0.5 vs. ≥ 0.5 ng/mL). The primary outcome was all-cause mortality at 12 months after PCI. The main secondary outcomes included ischemic events (composite of cardiac death, myocardial infarction, or stroke) at 12 months. Multivariable Cox regression models with sex-by-hs-TnT interaction terms and restricted cubic spline (RCS) analyses were performed.
Results
Among 14,214 patients (10,416 males, 3,798 females), elevated hs-TnT (≥ 0.5 ng/mL) was associated with increased 12-month mortality in both sexes, with a stronger association in females (aHR 2.83; 95% CI 1.56–5.13) than in males (aHR 1.63; 95% CI 1.03–2.58; P for interaction = 0.019). For cardiac death, similar differences were observed (P for interaction = 0.023). RCS analysis revealed a nonlinear relationship between hs-TnT and mortality in females (P for nonlinearity = 0.01), whereas the relationship was linear in males (P for nonlinearity = 0.12). The formal test of interaction between continuous hs-TnT and sex confirmed this divergence (P = 0.0042).
Conclusions
The prognostic impact of elevated post-procedural hs-TnT on mortality was substantially greater in female than in male ACS patients. These hypothesis-generating findings suggest that sex-specific approaches to troponin-based risk stratification after PCI warrant further investigation.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12872-026-06079-y.
Keywords: High-sensitivity troponin T, Sex differences, Acute coronary syndrome, Percutaneous coronary intervention, Prognosis, Risk stratification
Introduction
High-sensitivity cardiac troponin T (hs-TnT) is a cornerstone biomarker for assessing myocardial injury and predicting adverse outcomes in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) [1, 2]. Post-procedural hs-TnT concentrations effectively identify patients at elevated risk for both short- and long-term mortality across the spectrum of ACS presentations [2, 3]. According to the Fourth Universal Definition of Myocardial Infarction, procedure-related myocardial injury after PCI is defined using thresholds based on multiples of the assay-specific 99th percentile upper reference limit (URL), whereas type 4a myocardial infarction additionally requires supporting clinical, electrocardiographic, imaging, or angiographic evidence of ischemia [4]. However, current clinical practice applies uniform troponin thresholds for risk stratification regardless of sex [5], an approach that may inadequately capture sex-specific risk heterogeneity.
Substantial sex-based differences exist in demographic characteristics, coronary lesion patterns, and pathophysiology among patients with ACS. Women tend to be older at presentation, have higher prevalences of hypertension and diabetes mellitus, and more frequently present with non-ST-elevation ACS [6–8]. Despite less extensive angiographic coronary artery disease and smaller infarct sizes, female patients experience higher in-hospital and long-term mortality than men [6–8]. Furthermore, women have smaller cardiac volumes and lower left ventricular mass throughout the lifespan [9], and are more likely to present with myocardial infarction with non-obstructive coronary arteries (MINOCA), characterized by underlying mechanisms such as coronary microvascular dysfunction and vasospasm [10]. These differences suggest that a given absolute troponin concentration may represent a proportionally greater degree of myocardial injury relative to total cardiac mass in female patients. Although the Fourth Universal Definition of Myocardial Infarction recommends sex-specific 99th percentile upper reference limits for diagnostic purposes [4, 11, 12], whether the prognostic value of hs-TnT and its dose–response relationship with clinical outcomes differ by sex in patients undergoing PCI remains unclear.
Therefore, leveraging data from a large prospective PCI registry, the present study aimed to investigate whether the association between post-procedural hs-TnT and clinical outcomes differs by sex in patients with ACS undergoing PCI, and to characterize the dose–response relationship between hs-TnT and adverse outcomes in male and female patients separately.
Methods
Study design and population
This study was a retrospective analysis of data prospectively collected from a large-scale PCI registry at the General Hospital of Northern Theater Command. From March 2016 to March 2019, consecutive patients with ACS undergoing PCI were enrolled [13–16]. Inclusion criteria were age ≥ 18 years and PCI performed during the index hospitalization. Patients were excluded if they had missing data for post-procedural hs-TnT. The study protocol was approved by the Institutional Ethics Committee of the General Hospital of Northern Theater Command (approval number: K2018-35) and conducted in accordance with the Declaration of Helsinki. Written informed consent was waived due to the retrospective and observational nature of the study. Clinical trial number: not applicable. This was an observational registry study and did not involve any intervention. Clinical data were collected through a standardized electronic data capture system (CV-NET, Crealife Technology, Beijing, China).
Laboratory assessments
Baseline clinical characteristics and biochemical parameters were obtained from electronic medical records. High-sensitivity cardiac troponin T was measured at admission and after the index procedure within 48 h using the Elecsys high-sensitivity Troponin T assay (Roche Diagnostics) on a Cobas e 411 analyzer. The lower detection limit was 0.003 ng/mL (3 ng/L), and the manufacturer-specified 99th percentile URL for this assay is 14 ng/L (0.014 ng/mL). For clinical risk stratification, our institution adopted an institutional clinical decision cutoff of 100 ng/L (0.1 ng/mL). Patients were stratified according to post-procedural hs-TnT concentrations at ≥ 0.5 ng/mL, corresponding to five times this institutional clinical decision cutoff rather than five times the manufacturer-specified 99th percentile URL. A sensitivity analysis using five times the manufacturer-specified 99th percentile URL (≥ 0.07 ng/mL) was performed to assess the robustness of the findings across threshold definitions. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation [17].
Outcome definitions
The primary outcome was all-cause mortality at 12 months after PCI. Secondary endpoints included 12-month ischemic events, defined as a composite of cardiac death, myocardial infarction (MI), or stroke, as well as each individual component. Cardiac death, MI, and stroke were defined according to the Academic Research Consortium-2 (ARC-2) criteria [18]. Deaths of undetermined cause were classified as cardiovascular. Follow-up was conducted via telephone or electronic communication at 1, 6, and 12 months after discharge.
Statistical analysis
Continuous variables were presented as mean ± standard deviation or median (interquartile range), as appropriate. Categorical variables are expressed as counts and percentages. Between-group comparisons were performed using chi-squared tests for categorical variables and Student's t-test or Mann–Whitney U test for continuous variables. Cumulative event rates were estimated using the Kaplan–Meier method, and differences were compared using the log-rank test. Multivariable Cox regression models were constructed to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs), adjusting for covariates listed in Table 2. Missing data proportions for all study variables are reported in Supplementary Table 1. Complete case analysis was used, as missing data for covariates in the primary model were minimal (≤ 0.4%).
Table 2.
Clinical outcomes stratified by sex and hs-TnT levels
| Outcomes | Male | Female | Pinteraction | ||||||
|---|---|---|---|---|---|---|---|---|---|
| < 0.5 ng/mL (n = 8,372) | ≥ 0.5 ng/mL (n = 2,044) | aHR (95% CI) | P | < 0.5 ng/mL (n = 3,155) | ≥ 0.5 ng/mL (n = 643) | aHR (95% CI) | P | ||
| All-cause death | 103 (1.23) | 47 (2.30) | 1.63 (1.03–2.58) | 0.035 | 38 (1.20) | 33 (5.13) | 2.83 (1.56–5.13) | < 0.001 | 0.019 |
| Ischemic events | 147 (1.76) | 78 (3.82) | 2.27 (1.56–3.30) | < 0.001 | 58 (1.84) | 29 (4.51) | 1.94 (1.10–3.44) | 0.023 | 0.951 |
| Cardiac death | 73 (0.87) | 37 (1.81) | 1.69 (1.00–2.87) | 0.049 | 24 (0.76) | 26 (4.04) | 3.01 (1.48–6.12) | 0.002 | 0.023 |
| Non-cardiovascular death | 30 (0.36) | 10 (0.49) | 1.51 (0.59–3.86) | 0.385 | 14 (0.44) | 7 (1.09) | 2.53 (0.82–7.76) | 0.106 | 0.419 |
| MI | 34 (0.41) | 30 (1.47) | 4.32 (2.12–8.83) | < 0.001 | 15 (0.48) | 3 (0.47) | 0.63 (0.16–2.52) | 0.509 | 0.384 |
| Stroke | 45 (0.54) | 12 (0.59) | 1.38 (0.60–3.20) | 0.448 | 25 (0.79) | 2 (0.31) | 0.71 (0.14–3.58) | 0.674 | 0.217 |
Data are presented as n (%)
Abbreviations: aHR adjusted hazard ratio, CI confidence interval, hs-TnT high-sensitivity troponin T, MI myocardial infarction. Model adjusted for age, hypertension, diabetes, previous MI, previous PCI, previous stroke, smoking, type of ACS, anemia, eGFR, arterial access, coronary arteries treated, and number of stents
Sex-stratified analyses were performed for male and female patients separately. Interaction between sex and hs-TnT category was evaluated by adding multiplicative interaction terms. Subgroup analyses assessed the consistency of associations across age (< 65 vs ≥ 65 years), diabetes mellitus, prior cardiovascular disease, anemia, eGFR (< 60 vs ≥ 60 mL/min/1.73 m2), LVEF (< 50% vs ≥ 50%), and type of ACS (UA/NSTEMI/STEMI); additional stratified analyses within NSTEMI/UA and STEMI subgroups included sex interaction tests. Sensitivity analyses further adjusted for log-transformed admission hs-TnT, delta hs-TnT (post-procedural minus admission value), or procedural complexity markers (complex lesion, contrast volume, and multivessel PCI). A time-stratified analysis was performed to evaluate early (≤ 30 days) and late (> 30 days) outcomes separately, with sex-by-hs-TnT interaction tested within each period.
The dose–response relationship between hs-TnT concentration and clinical outcomes was examined using restricted cubic spline (RCS) regression within the Cox regression framework, with 3 knots placed at the 10th, 50th, and 90th percentiles of the hs-TnT distribution. The reference value was set at 0.5 ng/mL. Nonlinearity was tested using the likelihood ratio test. To assess the robustness of the dose–response relationship, RCS analyses were repeated using alternative reference values (0.1 ng/mL and cohort median). The interaction between continuous log-transformed hs-TnT and sex was formally tested using multiplicative interaction terms.
All statistical tests were two-sided, and P < 0.05 was considered statistically significant. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Study population and baseline characteristics
A total of 14,214 patients with ACS undergoing PCI were included in the final analysis (Fig. 1). The cohort comprised 10,416 males (73.3%) and 3,798 females (26.7%). Based on post-procedural hs-TnT concentrations, patients were stratified into two groups: hs-TnT < 0.5 ng/mL and hs-TnT ≥ 0.5 ng/mL. Among males, 8,372 (80.4%) had hs-TnT < 0.5 ng/mL and 2,044 (19.6%) had hs-TnT ≥ 0.5 ng/mL; among females, 3,155 (83.1%) had hs-TnT < 0.5 ng/mL and 643 (16.9%) had hs-TnT ≥ 0.5 ng/mL. The median post-procedural hs-TnT concentration was 0.03 ng/mL (interquartile range [IQR], 0.01–0.09) in males with hs-TnT < 0.5 ng/mL and 1.71 ng/mL (IQR, 0.90–3.00) in those with hs-TnT ≥ 0.5 ng/mL; in females, the corresponding values were 0.03 ng/mL (IQR, 0.01–0.08) and 1.54 ng/mL (IQR, 0.83–2.67), respectively (Table 1).
Fig. 1.
Study flowchart. ACS, acute coronary syndrome; CAD, coronary artery disease; hs-TnT, high-sensitivity troponin T; PCI, percutaneous coronary intervention
Table 1.
Baseline characteristics stratified by sex and hs-TnT Levels
| Characteristics | Male | Female | ||||
|---|---|---|---|---|---|---|
| < 0.5 ng/mL (n = 8,372) | ≥ 0.5 ng/mL (n = 2,044) | P | < 0.5 ng/mL (n = 3,155) | ≥ 0.5 ng/mL (n = 643) | P | |
| Age, years | 59.21 ± 10.03 | 59.27 ± 11.63 | 0.847 | 65.68 ± 8.42 | 67.18 ± 9.40 | < 0.001 |
| Medical history | ||||||
| Hypertension | 5,040 (60.3) | 1,015 (49.8) | < 0.001 | 2,325 (73.8) | 462 (72.2) | 0.410 |
| Diabetes mellitus | 2,488 (29.8) | 495 (24.3) | < 0.001 | 1,183 (37.6) | 212 (33.1) | 0.034 |
| Previous MI | 1,893 (22.7) | 232 (11.4) | < 0.001 | 497 (15.8) | 53 (8.3) | < 0.001 |
| Previous PCI | 2,540 (30.4) | 254 (12.5) | < 0.001 | 833 (26.4) | 70 (10.9) | < 0.001 |
| Previous stroke | 1,139 (13.6) | 299 (14.7) | 0.216 | 559 (17.8) | 109 (17.0) | 0.639 |
| Smoking status | < 0.001 | < 0.001 | ||||
| Never | 2,387 (28.7) | 466 (22.9) | 2,714 (86.1) | 499 (77.9) | ||
| Active | 4,265 (51.2) | 1,323 (65.0) | 314 (10.0) | 123 (19.2) | ||
| Former | 1,680 (20.2) | 247 (12.1) | 123 (3.9) | 19 (3.0) | ||
| Type of ACS | < 0.001 | < 0.001 | ||||
| UA | 5,910 (70.6) | 150 (7.3) | 2,402 (76.1) | 96 (14.9) | ||
| NSTEMI | 1,408 (16.8) | 438 (21.4) | 488 (15.5) | 145 (22.6) | ||
| STEMI | 1,054 (12.6) | 1,456 (71.2) | 265 (8.4) | 402 (62.5) | ||
| Anemia | 977 (11.7) | 364 (17.8) | < 0.001 | 707 (22.4) | 207 (32.2) | < 0.001 |
| eGFR, mL/min/1.73 m2 | 95.11 ± 23.18 | 87.13 ± 23.34 | < 0.001 | 90.26 ± 25.01 | 78.05 ± 24.49 | < 0.001 |
| LVEF, % | 59.37 ± 8.17 | 53.08 ± 8.53 | < 0.001 | 60.59 ± 7.74 | 53.18 ± 9.07 | < 0.001 |
| hs-TnT at admission, ng/mL | 0.01 (0.01–0.06) | 2.46 (0.98–4.74) | < 0.001 | 0.01 (0.01–0.03) | 1.75 (0.46–3.64) | < 0.001 |
| Admission hs-TnT ≥ 0.5 ng/mL | 785 (9.4) | 1,739 (85.1) | < 0.0001 | 210 (6.7) | 474 (73.7) | < 0.0001 |
| hs-TnT post-procedure, ng/mL | 0.03 (0.01–0.09) | 1.71 (0.90–3.00) | < 0.001 | 0.03 (0.01–0.08) | 1.54 (0.83–2.67) | < 0.001 |
| Procedure | ||||||
| Transradial access | 7,771 (92.8) | 1,876 (91.8) | 0.107 | 2,813 (89.2) | 544 (84.6) | 0.001 |
| Coronary arteries treated | ||||||
| LM | 578 (6.90%) | 71 (3.47%) | < 0.0001 | 193 (6.12%) | 31 (4.82%) | 0.2035 |
| LAD | 4661 (55.67%) | 983 (48.09%) | < 0.0001 | 1804 (57.18%) | 321 (49.92%) | 0.0007 |
| LCX | 2180 (26.04%) | 419 (20.50%) | < 0.0001 | 815 (25.83%) | 109 (16.95%) | < 0.0001 |
| RCA | 3029 (36.18%) | 801 (39.19%) | 0.0115 | 1151 (36.48%) | 271 (42.15%) | 0.0068 |
| Number of stents | 1.67 ± 0.91 | 1.34 ± 0.77 | < 0.001 | 1.65 ± 0.88 | 1.40 ± 0.86 | < 0.001 |
| Total length of stents, mm | 46.90 ± 27.02 | 38.66 ± 21.56 | < 0.0001 | 45.16 ± 25.83 | 41.43 ± 22.89 | 0.0004 |
| Average stent diameters, mm | 3.07 ± 0.74 | 3.08 ± 0.66 | 0.6657 | 2.97 ± 0.86 | 2.92 ± 0.35 | 0.0485 |
| Discharge medications | ||||||
| Aspirin | 8,253 (98.6) | 1,947 (95.3) | < 0.001 | 3,107 (98.5) | 604 (93.9) | < 0.001 |
| P2Y12 inhibitors | < 0.001 | 0.113 | ||||
| Clopidogrel | 5,507 (66.0) | 1,199 (59.1) | 2,423 (77.1) | 468 (74.2) | ||
| Ticagrelor | 2,833 (34.0) | 830 (40.9) | 720 (22.9) | 163 (25.8) | ||
| Statins | 7,854 (93.8) | 1,845 (90.3) | < 0.001 | 2,954 (93.6) | 566 (88.0) | < 0.001 |
| ACEI/ARB | 5576 (66.60%) | 1362 (66.63%) | 0.9787 | 2068 (65.55%) | 420 (65.32%) | 0.9118 |
| β-blockers | 5,814 (69.5) | 1,323 (64.7) | < 0.001 | 2,232 (70.7) | 435 (67.7) | 0.118 |
Data are presented as mean ± SD or n (%)
Abbreviations: ACEI angiotensin-converting enzyme inhibitor, ACS acute coronary syndrome, ARB angiotensin receptor blocker, eGFR estimated glomerular filtration rate, hs-TnT high-sensitivity troponin T, LAD left anterior descending artery, LCX left circumflex artery, LM left main artery, LVEF left ventricular ejection fraction, MI myocardial infarction, NSTEMI non-ST-elevation myocardial infarction, PCI percutaneous coronary intervention, RCA right coronary artery, STEMI ST-elevation myocardial infarction, UA unstable angina
Baseline characteristics stratified by sex and hs-TnT level are presented in Table 1. In males, mean age was similar between hs-TnT groups (59.21 ± 10.03 vs. 59.27 ± 11.63 years; P = 0.847), whereas females with hs-TnT ≥ 0.5 ng/mL were older than those with hs-TnT < 0.5 ng/mL (67.18 ± 9.40 vs. 65.68 ± 8.42 years; P < 0.001). Patients with hs-TnT ≥ 0.5 ng/mL exhibited a higher proportion of ST-elevation myocardial infarction (males: 71.2% vs. 12.6%; females: 62.5% vs. 8.4%; both P < 0.001), and lower LVEF (males: 53.08 ± 8.53% vs. 59.37 ± 8.17%; females: 53.18 ± 9.07% vs. 60.59 ± 7.74%; both P < 0.001). The hs-TnT ≥ 0.5 ng/mL group also had lower eGFR (males: 87.13 ± 23.34 vs. 95.11 ± 23.18 mL/min/1.73 m2; females: 78.05 ± 24.49 vs. 90.26 ± 25.01 mL/min/1.73 m2; both P < 0.001) and higher prevalence of anemia (males: 17.8% vs. 11.7%; females: 32.2% vs. 22.4%; both P < 0.001). Conversely, rates of previous MI and prior PCI were lower in patients with hs-TnT ≥ 0.5 ng/mL (previous MI: males 11.4% vs. 22.7%, females 8.3% vs. 15.8%; prior PCI: males 12.5% vs. 30.4%, females 10.9% vs. 26.4%; all P < 0.001). Among patients with post-procedural hs-TnT ≥ 0.5 ng/mL, admission hs-TnT was already ≥ 0.5 ng/mL in 85.1% of males and 73.7% of females.
Clinical outcomes
At 12-month follow-up, 221 deaths occurred (150 [1.44%] in males, 71 [1.87%] in females). Associations between hs-TnT elevation and clinical outcomes are presented in Table 2. Elevated hs-TnT was associated with increased risk of all-cause death in both males (1.23% vs. 2.30%; aHR, 1.63; 95% CI, 1.03–2.58; P = 0.035) and females (1.20% vs. 5.13%; aHR, 2.83; 95% CI, 1.56–5.13; P < 0.001), with a significant sex-by-hs-TnT interaction (P for interaction = 0.019). Similarly, elevated hs-TnT was associated with increased risk of cardiac death in males (0.87% vs. 1.81%; aHR, 1.69; 95% CI, 1.00–2.87; P = 0.049) and females (0.76% vs. 4.04%; aHR, 3.01; 95% CI, 1.48–6.12; P = 0.002), with a significant interaction (P for interaction = 0.023). Non-cardiovascular death was not significantly associated with elevated hs-TnT in either sex (males: aHR 1.51, 95% CI 0.59–3.86, P = 0.385; females: aHR 2.53, 95% CI 0.82–7.76, P = 0.106; P for interaction = 0.419).
For ischemic events, elevated hs-TnT was associated with increased risk in both males (1.76% vs. 3.82%; aHR, 2.27; 95% CI, 1.56–3.30; P < 0.001) and females (1.84% vs. 4.51%; aHR, 1.94; 95% CI, 1.10–3.44; P = 0.023), with no significant interaction (P for interaction = 0.951). For MI, elevated hs-TnT was associated with increased risk in males (0.41% vs. 1.47%; aHR, 4.32; 95% CI, 2.12–8.83; P < 0.001) but not in females (0.48% vs. 0.47%; aHR, 0.63; 95% CI, 0.16–2.52; P = 0.509). No significant associations were observed between elevated hs-TnT and stroke in either sex (males: 0.54% vs. 0.59%; aHR, 1.38; 95% CI, 0.60–3.20; P = 0.448; females: 0.79% vs. 0.31%; aHR, 0.71; 95% CI, 0.14–3.58; P = 0.674).
Kaplan–Meier survival curves stratified by sex and hs-TnT category are displayed in Fig. 2.
Fig. 2.
Kaplan–Meier curves for clinical outcomes stratified by sex and hs-TnT Levels. Kaplan–Meier estimates of cumulative incidence of all-cause death (A) and ischemic events (B) according to sex and hs-TnT levels. Patients were stratified into four groups: male with hs-TnT < 0.5 ng/mL (blue dashed line), male with hs-TnT ≥ 0.5 ng/mL (red dashed line), female with hs-TnT < 0.5 ng/mL (blue solid line), and female with hs-TnT ≥ 0.5 ng/mL (red solid line). P values were calculated using the log-rank test
Dose response relationship
Sex-specific RCS curves for all-cause death and ischemic events are presented in Fig. 3. The formal test of interaction between continuous log-transformed hs-TnT and sex was significant for all-cause death (P for sex interaction = 0.0042) but not for ischemic events (P for sex interaction = 0.5773). For all-cause death, the association was significant in both males (P for overall = 0.02; P for nonlinearity = 0.12) and females (P for overall < 0.0001; P for nonlinearity = 0.01). The nonlinear pattern in females was consistent across alternative reference values including the institutional cutoff (0.1 ng/mL) and the cohort median (Supplementary Fig. 1).
Fig. 3.
Restricted cubic spline analysis of hs-TnT and clinical outcomes: sex-specific curves. Restricted cubic spline curves showing the association between hs-TnT levels and hazard ratios for all-cause death (A) and ischemic events (B) in male (blue) and female (red) patients. The analysis used 3 knots placed at the 10th, 50th, and 90th percentiles of the hs-TnT distribution. The reference value was set at 0.5 ng/mL (vertical dashed line). Solid lines represent hazard ratios, and shaded areas represent 95% confidence intervals. Rug plots along the x-axis indicate the distribution of hs-TnT values. Models were adjusted for covariates listed in Table 2. P values for sex interaction, overall association, and nonlinearity are shown for each sex
Subgroup analyses
Subgroup analyses for all-cause death are presented in Fig. 4 (males) and Fig. 5 (females). In males, the association between elevated hs-TnT and mortality was consistent across all prespecified subgroups, including age (< 65 vs. ≥ 65 years), diabetes mellitus, prior cardiovascular disease, anemia, renal function (eGFR < 60 vs. ≥ 60 mL/min/1.73 m2), LVEF < 50% vs. ≥ 50%, and ACS subtype (all P for interaction > 0.05).
Fig. 4.
Forest plot of subgroup analyses for all-cause death in male patients. Forest plot showing adjusted hazard ratios with 95% confidence intervals for all-cause death associated with hs-TnT ≥ 0.5 ng/mL versus < 0.5 ng/mL across prespecified subgroups in male patients. Subgroups were defined by age (< 65 vs ≥ 65 years), diabetes mellitus, prior cardiovascular disease (previous myocardial infarction, percutaneous coronary intervention, or stroke), anemia, estimated glomerular filtration rate (< 60 vs ≥ 60 mL/min/1.73 m2), left ventricular ejection fraction (< 50% vs ≥ 50%), and type of acute coronary syndrome. The number of events and total patients at risk (events/n) are displayed. P values for interaction are shown. The vertical dashed line indicates a hazard ratio of 1.0
Fig. 5.
Forest plot of subgroup analyses for all-cause death in female patients. Forest plot showing adjusted hazard ratios with 95% confidence intervals for all-cause death associated with hs-TnT ≥ 0.5 ng/mL versus < 0.5 ng/mL across prespecified subgroups in female patients. Subgroups were defined as in Fig. 4. The number of events and total patients at risk (events/n) are displayed. P values for interaction are shown. The vertical dashed line indicates a hazard ratio of 1.0
In females, significant heterogeneity was observed across several subgroups. The prognostic impact of elevated hs-TnT was more pronounced in patients aged ≥ 65 years (aHR 5.71; 95% CI: 3.25–10.02) compared with those aged < 65 years (aHR 1.06; 95% CI: 0.31–3.63; P for interaction = 0.01). The association was also stronger in patients with diabetes (aHR 8.07; 95% CI: 3.95–16.47) versus those without (aHR 2.25; 95% CI: 1.13–4.47; P for interaction = 0.01), and in those with eGFR < 60 mL/min/1.73 m2 (aHR 5.02; 95% CI: 2.50–10.09) versus ≥ 60 mL/min/1.73 m2 (aHR 1.51; 95% CI: 0.66–3.49; P for interaction = 0.03). No significant interactions were observed for prior cardiovascular disease (P for interaction = 0.20) left ventricular ejection fraction (P for interaction = 0.42), or ACS subtype (P for interaction = 0.58).
Stratified analyses by ACS subtype with sex-by-hs-TnT interaction tests are presented in Supplementary Table 2. In the NSTEMI/UA subgroup, the aHR for all-cause death associated with hs-TnT ≥ 0.5 ng/mL was 1.34 (95% CI: 0.75–2.39; P = 0.316) in males and 2.49 (95% CI: 1.24–4.99; P = 0.010) in females (P for sex interaction = 0.128). In the STEMI subgroup, the corresponding aHRs were 2.21 (95% CI: 0.99–4.93; P = 0.052) in males and 6.05 (95% CI: 1.25–29.36; P = 0.026) in females (P for sex interaction = 0.284). The STEMI female < 0.5 ng/mL subgroup contained only 2 deaths, and a model convergence warning was noted for this stratum.
Sensitivity analysis
Additional Cox regression models were constructed with further adjustment for log-transformed admission hs-TnT or delta hs-TnT (post-procedural minus admission value). After adjustment for admission hs-TnT, the aHR for all-cause death associated with hs-TnT ≥ 0.5 ng/mL was 1.13 (95% CI 0.69–1.87; P = 0.627) in males and 2.75 (95% CI 1.44–5.25; P = 0.002) in females (P for interaction = 0.016). After adjustment for delta hs-TnT, the corresponding aHRs were 1.64 (95% CI 1.04–2.60; P = 0.034) in males and 2.40 (95% CI 1.31–4.40; P = 0.004) in females (P for interaction = 0.020; Supplementary Table 3). The sex-by-hs-TnT interaction for all-cause death remained statistically significant across both sensitivity models.
Additionally, a sensitivity analysis was performed using the manufacturer's 99th percentile URL (14 ng/L) as the basis for threshold definition, with patients stratified at ≥ 0.07 ng/mL (5 × the manufacturer's 99th percentile). This lower threshold classified a substantially larger proportion of patients as elevated (males: 4,511/10,416 [43.3%]; females: 1,517/3,798 [39.9%]) compared with the primary analysis (males: 19.6%; females: 16.9%). Despite this dilution, the sex-by-hs-TnT interaction for all-cause death remained significant (female aHR 1.94; 95% CI 1.07–3.52; P = 0.029; male aHR 1.42; 95% CI 0.95–2.13; P = 0.086; P for interaction = 0.048; Supplementary Table 4).
Time-stratified analysis showed that during the early period (≤ 30 days), the aHR for all-cause death was 4.03 (95% CI 1.46–11.14; P = 0.007) in males and 7.47 (95% CI 1.74–32.14; P = 0.007) in females (P for sex interaction = 0.123). During the late period (> 30 days), the aHR was 1.25 (95% CI 0.74–2.14; P = 0.404) in males and 2.13 (95% CI 1.05–4.30; P = 0.035) in females (P for sex interaction = 0.119; Table 3).
Table 3.
Time-stratified analysis: early (≤ 30 Days) and Late (> 30 Days) clinical outcomes
| Outcomes | Male | Female | Pinteraction | ||||||
|---|---|---|---|---|---|---|---|---|---|
| < 0.5 ng/mL (n = 8,372) | ≥ 0.5 ng/mL (n = 2,044) | aHR (95% CI) | P | < 0.5 ng/mL (n = 3,155) | ≥ 0.5 ng/mL (n = 643) | aHR (95% CI) | P | ||
| Early (≤ 30 days) | |||||||||
| All-cause death | 12 (0.14) | 16 (0.78) | 4.03 (1.46–11.14) | 0.007 | 3 (0.10) | 14 (2.18) | 7.47 (1.74–32.14) | 0.007 | 0.123 |
| Ischemic events | 22 (0.26) | 38 (1.86) | 6.64 (3.25–13.57) | < 0.0001 | 12 (0.38) | 15 (2.33) | 3.16 (1.16–8.63) | 0.025 | 0.421 |
| Cardiac death | 11 (0.13) | 15 (0.73) | 3.76 (1.32–10.70) | 0.013 | 3 (0.10) | 12 (1.87) | 6.21 (1.37–28.25) | 0.018 | 0.222 |
| Late (> 30 days)† | |||||||||
| All-cause death | 91 (1.09) | 31 (1.53) | 1.25 (0.74–2.14) | 0.404 | 35 (1.11) | 19 (3.02) | 2.13 (1.05–4.30) | 0.035 | 0.119 |
| Ischemic events | 125 (1.50) | 40 (2.00) | 1.40 (0.87–2.25) | 0.163 | 46 (1.46) | 14 (2.24) | 1.47 (0.70–3.06) | 0.306 | 0.898 |
| Cardiac death | 62 (0.74) | 22 (1.08) | 1.23 (0.65–2.33) | 0.518 | 21 (0.67) | 14 (2.23) | 2.36 (0.99–5.63) | 0.053 | 0.096 |
Data are presented as n (%)
Abbreviations: aHR adjusted hazard ratio, CI Confidence interval, MI Myocardial infarction, NA Not applicable (no events in the ≥ 0.5 ng/mL group)
†For the late period (> 30 days), patients with events or loss to follow-up within 30 days were excluded; event rates were calculated using the landmark cohort as denominator. Model adjusted for age, hypertension, diabetes mellitus, previous myocardial infarction, previous percutaneous coronary intervention, previous stroke, smoking status, type of ACS (UA/NSTEMI/STEMI), anemia, estimated glomerular filtration rate, arterial access site, coronary arteries treated, and number of stents
Discussion
Using data from a large prospective PCI registry in China, this study analyzed 14,214 patients with ACS to investigate whether the prognostic value of elevated hs-TnT for clinical outcomes differs by sex in patients with ACS undergoing PCI. The principal findings are as follows. First, elevated hs-TnT was associated with increased 12-month mortality in both sexes, but the magnitude of association was significantly greater in female patients (aHR 2.83 vs 1.63; P for interaction = 0.019). Second, the RCS analysis revealed distinct dose–response patterns, with a nonlinear relationship in females and a linear relationship in males. Third, the sex-specific prognostic signal demonstrated differential sensitivity to adjustment for baseline troponin levels, suggesting distinct underlying mechanisms between sexes. These findings extend prior observations of sex-based disparities in ACS outcomes by suggesting that troponin-based risk stratification may benefit from sex-specific interpretation.
Several biological mechanisms may underlie the observed sex differences, although these were not directly assessed in the present study and should be considered hypothesis-generating. Women have lower left ventricular mass and smaller cardiac volumes throughout the lifespan [9], a structural difference reflected in the systematically lower female-specific 99th percentile upper reference limits across more than 90% of high-sensitivity troponin assays [11]. Consequently, a given absolute troponin concentration may represent a proportionally greater degree of myocardial damage relative to total cardiac mass in female patients, a distinction that sex-neutral thresholds cannot capture. Additionally, women are more likely to present with MINOCA, with underlying mechanisms including microvascular dysfunction and vasospasm that may result in distinct troponin release patterns [10]. Canton et al. reported that among patients with MINOCA, women aged 70 years or younger had a threefold increased risk of major adverse events compared with male counterparts [19]. Furthermore, de Bakker et al. demonstrated that the slope of troponin change with advancing age was steeper in women and independently predictive of cardiovascular outcomes in women but not in men [20]. These observations collectively suggest that the biological significance of troponin elevation may be inherently different between sexes [21].
The sensitivity analyses provide further insight into the nature of the post-procedural hs-TnT signal. After adjustment for log-transformed admission hs-TnT, the male-specific association with mortality was attenuated and no longer statistically significant (aHR 1.13; P = 0.627), whereas the female-specific association remained significant (aHR 2.75; P = 0.002), with the sex-by-hs-TnT interaction preserved (P for interaction = 0.016). A similar but less pronounced attenuation was observed after adjustment for delta hs-TnT. These findings suggest that, in males, the prognostic signal of post-procedural hs-TnT may be more closely related to the severity and kinetics of the presenting ischemic event. In contrast, the persistent female-specific association after adjustment for admission hs-TnT suggests that post-procedural hs-TnT may carry prognostic information beyond the baseline troponin trajectory, potentially reflecting cumulative myocardial vulnerability from both the presenting event and superimposed procedural injury. However, post-procedural hs-TnT elevation should be interpreted differently across ACS subtypes. In STEMI, it may predominantly reflect index infarct burden and biomarker kinetics, whereas in NSTEMI/UA it may also capture superimposed periprocedural myocardial injury. Recent NSTEMI data showed that periprocedural myocardial injury and type 4a myocardial infarction after PCI are common and prognostically relevant, particularly when accompanied by clinical, electrocardiographic, imaging, or angiographic evidence of ischemia [22]. Given the recognized procedural and microvascular vulnerability of women undergoing PCI, these NSTEMI data support the plausibility that post-procedural hs-TnT elevation in women may reflect not only the presenting ischemic event but also superimposed procedure-related myocardial injury. Emerging evidence also links glucometabolic dysregulation, especially stress hyperglycemia ratio, with type 4a myocardial infarction and adverse outcomes in NSTEMI patients undergoing PCI [23]. These findings may partly contextualize the stronger association observed in women with diabetes in our subgroup analysis. However, because type 4a myocardial infarction was not adjudicated in our registry, this interpretation should be considered hypothesis-generating.
The absence of a sex interaction for ischemic events (P = 0.951) reflects opposing directions of the component-specific interactions: the female-predominant cardiac death signal (P for interaction = 0.023) was counterbalanced by a reversed, male-predominant MI signal (male aHR 4.32 vs. female aHR 0.63), resulting in a null composite interaction. This contrast may relate to the greater burden of epicardial coronary artery disease in men, as reflected by the higher prevalence of previous MI, previous PCI, and STEMI presentation in the male cohort. The RCS analyses revealed fundamentally different dose–response architectures between sexes. In females, the hazard ratio rose steeply at lower hs-TnT concentrations before reaching a plateau, whereas in males a more gradual, linear increase was observed. The formal test of interaction between continuous log-transformed hs-TnT and sex confirmed this divergence (P for sex interaction = 0.0042), and the nonlinear pattern in females was robust across alternative reference values including the median and the institutional cutoff (0.1 ng/mL). While the Fourth Universal Definition recommends sex-specific 99th percentile thresholds for diagnostic purposes [12], the translation to prognostic risk stratification remains underexplored. Lehmacher et al. compared the prognostic performance of sex-specific 99th percentiles across four high-sensitivity assays and found that sex-specific cutoffs did not significantly affect prognostic value [24]. However, this study did not specifically examine sex differences in the shape of the dose–response relationship. Current risk stratification models for non-ST-elevation acute coronary syndrome have limited applicability to female patients and older individuals with frailty [25]. Similarly, contemporary accelerated diagnostic algorithms incorporating hs-cTnT alone or in combination with novel biomarkers such as cardiac myosin-binding protein C and copeptin have achieved high diagnostic accuracy for NSTEMI rule-out [26–29], yet these algorithms have primarily been validated using sex-neutral thresholds, and whether sex-based stratification could further refine their diagnostic or prognostic performance remains to be determined. Our findings suggest that the prognostic interpretation of troponin concentrations may require not only sex-specific thresholds but also consideration of the fundamentally different dose–response patterns between sexes, particularly in the context of post-procedural risk assessment following PCI. Notably, the RCS curves suggest that in females, the hazard ratio begins to rise at hs-TnT concentrations well below the 0.5 ng/mL threshold, with a notable inflection at approximately 0.1–0.2 ng/mL, whereas males demonstrated a more gradual increase without a clear inflection point. While these observations raise the possibility that lower sex-specific thresholds may have prognostic utility in women, the present study was not designed to derive or validate such cutoffs, and future studies employing dedicated threshold derivation with independent validation and reclassification metrics are warranted.
Subgroup analyses revealed notable heterogeneity in the prognostic effect of elevated hs-TnT among females, with significant effect modification by age, diabetes, and renal function, whereas the association was consistent across all male subgroups. However, these subgroup analyses involved multiple comparisons without adjustment for multiplicity, and event numbers were limited in several female strata, contributing to extreme hazard ratios with wide confidence intervals. These findings should therefore be considered exploratory and hypothesis-generating, and require independent validation.
Myocardial injury remains a critical challenge in clinical cardiology, necessitating both refined risk stratification and potential therapeutic interventions [30]. From a clinical perspective, these findings raise the possibility that uniform troponin thresholds may underestimate mortality risk in women with modest hs-TnT elevations, particularly in those with concomitant risk modifiers such as advanced age, diabetes, or renal dysfunction. However, given the observational design, single-center setting in an East Asian population, modest event numbers in women, and the attenuation of the sex interaction in time-stratified analysis, these findings should not be interpreted as practice-changing evidence. Multicenter studies in ethnically diverse populations are needed to validate these sex-specific associations and to determine whether incorporating sex into troponin-based algorithms can improve clinical decision-making following PCI.
Limitations
Several limitations should be acknowledged. First, this was a single-center retrospective analysis of an exclusively East Asian cohort, which may limit generalizability; ethnic differences in cardiac mass, coronary vessel size, and CYP2C19 allele prevalence may modify troponin-outcome relationships across populations. Second, given the high STEMI prevalence (> 60%) in the hs-TnT ≥ 0.5 ng/mL group and the fact that admission hs-TnT had already exceeded 0.5 ng/mL in 85.1% of males and 73.7% of females, post-procedural hs-TnT reflects a composite of presenting infarct severity and procedural injury; definitive separation of these components requires prospective studies with standardized serial sampling. Additionally, residual confounding from procedural complexity variables, including lesion complexity, and periprocedural hemodynamic compromise, cannot be fully excluded despite sensitivity adjustment for available procedural characteristics. Third, the modest number of female deaths (n = 71; events-per-variable ratio = 4.2) may compromise the precision of sex-specific estimates, and subgroup interactions in women should be regarded as hypothesis-generating; furthermore, multiple subgroup and interaction analyses were performed without adjustment for multiplicity, and the possibility of type I error inflation should be considered. Fourth, post-procedural hs-TnT represents the last recorded value within 48 h and does not necessarily represent the peak concentration; sex differences in troponin kinetics may have influenced observed values. Fifth, LVEF data were missing in 15.8% of patients and were therefore excluded from the primary model, though subgroup analyses showed no significant interaction with hs-TnT in either sex. Sixth, restriction to hs-TnT alone precludes a comprehensive multi-biomarker assessment of periprocedural myocardial injury. Seventh, the stratification threshold (≥ 0.5 ng/mL) was derived from 5 × the institutional clinical decision cutoff (0.1 ng/mL) rather than 5 × the manufacturer-specified 99th percentile URL (14 ng/L); however, a sensitivity analysis using the manufacturer's 5 × URL threshold (≥ 0.07 ng/mL) confirmed that the sex-by-hs-TnT interaction for all-cause death remained significant (P for interaction = 0.048; Supplementary Table 4).
Conclusions
In this large prospective registry of 14,214 patients with ACS undergoing PCI, elevated hs-TnT was associated with increased 12-month mortality in both sexes, but the magnitude of association was significantly greater in females than in males. The dose–response relationship differed between sexes. Females exhibited a nonlinear pattern with steep risk escalation at lower troponin concentrations followed by a plateau, whereas males demonstrated a linear increase across the troponin spectrum. These hypothesis-generating findings suggest that uniform troponin thresholds may inadequately capture mortality risk in women and warrant further investigation of sex-specific approaches to troponin-based risk stratification in patients with ACS undergoing PCI.
Supplementary Information
Acknowledgements
The authors appreciate the dedicated efforts of clinical research coordinators and staff at the General Hospital of Northern Theater Command for their contributions to patient enrollment and data collection.
Clinical trial number
Not applicable. This was an observational registry study and did not involve any intervention.
Abbreviations
- ACEI
Angiotensin-converting enzyme inhibitor
- ACS
Acute coronary syndrome
- aHR
Adjusted hazard ratio
- ARB
Angiotensin receptor blocker
- ARC-2
Academic Research Consortium-2
- CI
Confidence interval
- eGFR
Estimated glomerular filtration rate
- hs-TnT
High-sensitivity cardiac troponin T
- IQR
Interquartile range
- LAD
Left anterior descending artery
- LCX
Left circumflex artery
- LM
Left main artery
- LVEF
Left ventricular ejection fraction
- MI
Myocardial infarction
- MINOCA
Myocardial infarction with non-obstructive coronary arteries
- NSTEMI
Non-ST-elevation myocardial infarction
- PCI
Percutaneous coronary intervention
- RCA
Right coronary artery
- RCS
Restricted cubic spline
- STEMI
ST-elevation myocardial infarction
- UA
Unstable angina
- URL
Upper reference limit
Authors’ contributions
Xueqing Yang: Conceptualization, Formal analysis, Visualization, Writing – original draft. Kun Na: Data curation, Formal analysis, Methodology, Software. Miaohan Qiu: Data curation, Formal analysis, Methodology, Writing – review & editing. Jing Li: Investigation, Writing – review & editing. Yi Li: Investigation, Resources, Writing – review & editing. Chenghui Yan: Supervision, Validation, Writing – review & editing. Yaling Han: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – review & editing.
Funding
This study was supported by the National Natural Science Foundation of China (82470303) and the Independent Research Project of the General Hospital of Northern Theater Command (ZZKY2024008).
Data availability
The datasets generated and analyzed during the current study are available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the Institutional Ethics Committee of the General Hospital of Northern Theater Command (approval number: K2018-35) and conducted in accordance with the Declaration of Helsinki. Written informed consent was waived due to the retrospective and observational nature of the study.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xueqing Yang, Kun Na and Miaohan Qiu contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding authors on reasonable request.