Association of Longitudinal High‐Sensitivity Cardiac Troponin T With Clinical Outcomes in Adult Heart‐Transplant Recipients

Abstract

Background

Cardiac troponin T is associated with mortality in heart transplantation recipients, but the association between its longitudinal measurements and clinical outcomes has not been evaluated. This study aimed to determine whether 3 parameterizations of serial hs‐cTnT (high‐sensitivity cardiac troponin T)—instantaneous concentration, temporal trend, and cumulative exposure—are associated with clinical outcomes in this population.

Methods

In a retrospective analysis, 222 heart transplantation recipients (median age 50 years, 86% men) who survived >30 days post transplant were included. Joint models were used to analyze the association between longitudinal hs‐cTnT and the primary outcome of all‐cause mortality and the secondary outcome of major adverse cardiac events.

Results

Over a median follow‐up of 2.3 years, 32 deaths and 41 major adverse cardiac events occurred. Both instantaneous hs‐cTnT concentration (hazard ratio [HR], 1.85 [95% CI, 1.48–2.31]; P<0.001) and cumulative hs‐cTnT exposure (HR, 1.80 [95% CI, 1.38–2.37]; P<0.001) were strongly associated with mortality. The temporal trend of hs‐cTnT was significantly associated with mortality after adjustment for donor and recipient factors. Similarly, instantaneous concentration and cumulative exposure were associated with major adverse cardiac events incidence (both P<0.05). In contrast, baseline hs‐cTnT lost its significant association with outcomes after multivariable adjustment.

Conclusions

Longitudinally measured hs‐cTnT is independently associated with mortality and major adverse cardiac events in heart transplant recipients.

Nonstandard Abbreviations and Acronyms

cTn

cardiac troponin

hs‐cTnT

high‐sensitivity cardiac troponin T

MACE

major adverse cardiac events

Clinical Perspective.

What Is New?

• By applying joint models to serial measurements of hs‐cTnT (high‐sensitivity cardiac troponin T), this study shows that instantaneous concentration and cumulative exposure—beyond a single baseline value—are strongly and independently associated with all‐cause mortality and major adverse cardiac events in heart transplant recipients.

What Are the Clinical Implications?

• Serial hs‐cTnT monitoring, focusing on both current levels and their cumulative burden over time rather than a single measurement, may help identify heart transplant recipients at high risk of death or major adverse cardiac events and could be incorporated into long‐term surveillance strategies.

Heart transplantation remains the definitive therapy for end‐stage heart failure. However, long‐term survival is still limited by the unpredictable progression of allograft injury. ¹ As a highly specific marker of myocardial injury, cTn (cardiac troponin) is crucial for posttransplant surveillance, with elevated levels linked to early graft dysfunction and acute rejection. ² , ³ , ⁴ Accordingly, international guidelines recommend routine cTn monitoring to aid in rejection screening. ⁵ Moreover, persistent cTn elevation can indicate subclinical myocardial damage, predicting the subsequent development of cardiac allograft vasculopathy and adversely affecting long‐term survival. ⁴ , ⁶

Although cTn is a recognized prognostic marker in heart transplant recipients, research has primarily focused on single measurements, despite the potential of serial monitoring to offer more clinically relevant insights. ⁶ , ⁷ Given the dynamic relationship between cTn levels and disease stability, analyzing changes over time may better reflect the evolving nature of myocardial injury and response to treatment. Although serial cTn monitoring is a common practice post transplantation, the full potential of analyzing its dynamic patterns to improve our understanding of pathophysiology and clinical outcomes remains underexplored. Specifically, the field has often neglected dynamic characteristics such as the rate of change (indicating acute injury) and cumulative exposure (reflecting chronic injury burden), parameters that may more accurately represent ongoing pathological processes within the graft, including subclinical rejection or microvascular injury.

In recent years, high‐sensitivity cTn assays have enabled reliable quantification of very low circulating troponin concentrations and supported longitudinal analysis of troponin dynamics. These assays provide substantially greater analytical sensitivity than conventional methods, permitting detection of minor myocardial injury that may be missed by routine imaging techniques. ² Such capability allows dynamic changes in cTn to be tracked with enhanced precision. Serial measurement of biomarkers has already demonstrated added prognostic value in other cardiovascular settings; for example, monitoring NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) in heart failure and assessing troponin trends in chronic kidney disease improve risk stratification compared with single measurements alone. ⁸ , ⁹ However, within the field of heart transplantation, the relationship between dynamic troponin trajectories and prognosis remains largely unexplored. Beyond considering cTn concentrations at the time of measurement, it remains unclear whether the temporal trend of cTn or cumulative exposure (reflecting a patient’s historical cTn burden) provides clinically meaningful insights. Therefore, this study aims to examine whether (1) longitudinal hs‐cTnT (high‐sensitivity cTnT) instantaneous concentrations, (2) the temporal trend of hs‐cTnT, and (3) cumulative hs‐cTnT exposure are associated with adverse outcomes in heart transplant recipients.

METHODS

Data supporting the findings of this study are available from the corresponding author upon reasonable request.

Study Cohort and Design

The study was approved by the Institutional Review Board of Guangdong Provincial People’s Hospital (Approval No. KY2025‐761‐01). As this was a retrospective study, the need for written informed consent was waived by the ethics board.

A total of 313 heart transplant recipients who survived >30 days post transplant between January 1, 2015, and March 31, 2024, were initially screened for eligibility. From this initial cohort, we excluded 56 patients who were <18 years old at transplantation, 1 patient who underwent combined heart‐lung transplantation, and 34 patients who had <3 hs‐cTnT measurements during follow‐up. After these exclusions, 222 patients remained and constituted the final analytical cohort. Detailed exclusion counts and the patient flow diagram are provided in Figure 1. Among the 34 patients excluded for insufficient hs‐cTnT data, the reasons were death before a third measurement could be obtained post discharge (n=3), transfer of follow‐up to external institutions (n=26), and insufficient measurements despite survival to study end (n=5). The ≥3 hs‐cTnT measurement requirement was implemented to allow for robust trajectory modeling and reliable assessment of associations with outcomes.

Figure 1. Flow chart of patient inclusion.

Hs‐cTnT indicates high‐sensitivity cardiac troponin T.

Clinical Follow‐Up and Outcomes

The primary outcome was all‐cause mortality. The secondary outcomes comprised major adverse cardiac events (MACE), defined as acute rejection, nonfatal myocardial infarction, ¹⁰ new severe coronary stenosis (≥50%), or heart failure hospitalization. Acute rejection was defined as a composite of biopsy‐proven events and clinically evident rejection. For this study, clinically evident rejection episodes were retrospectively classified using predefined criteria adapted from published definitions, requiring both a clinical suspicion prompting intensified immunosuppression and fulfillment of at least 1 major or 2 minor criteria. ¹¹ Patients were retrospectively analyzed until the occurrence of outcomes or administrative censoring on December 31, 2024.

Data Collection and Procedures

Clinical data were collected by reviewing electronic medical records, focusing on patient demographics, and laboratory results. Additionally, data on preexisting cardiovascular comorbidities, including hypertension, diabetes, cerebrovascular disease, dyslipidemia, and chronic kidney disease, were obtained. As part of routine posttransplant care, a comprehensive transthoracic echocardiography (including left ventricular ejection fraction) was obtained at baseline for descriptive characterization.

High‐sensitivity cTnT was measured using Roche Diagnostics Cobas 602 analyzers (detection limit: 5 ng/L; upper limit: 10 000 ng/L; coefficient of variation: 4%–7%; 99th percentile in healthy individuals: 14 ng/L). To focus on posttransplant injury beyond the perioperative period, hs‐cTnT trajectories were modeled using measurements collected after Day 30. Baseline hs‐cTnT was defined as the first measurement after Day 30. As part of the routine posttransplant follow‐up, hs‐cTnT levels are monitored at fixed intervals. In this cohort, hs‐cTnT measurements were typically obtained monthly within the first 6 months after transplantation and at ∼2‐month intervals thereafter. All hs‐cTnT measurements below the detection limit (<5 ng/L) were assigned a value of 5 ng/L. This decision was made because (1) a value of 5 ng/L indicates low myocardial damage risk, consistent with the clinical status of patients with hs‐cTnT <5 ng/L, given the reference limit of <14 ng/L in healthy subjects; and (2) this approach reduces potential bias from missing data, improving data set completeness for subsequent analyses. ¹²

Statistical Analysis

Patient characteristics were summarized using appropriate descriptive statistics. Continuous variables were presented as means±SD for normally distributed data or as medians with interquartile ranges (IQR) for skewed distributions. Comparisons of continuous variables were performed using an independent Student’s t test or Mann–Whitney U test, depending on the data characteristics. For comparisons of categorical variables, Pearson’s chi‐square test was used when all expected cell counts were ≥5; otherwise, Fisher’s exact test was applied to ensure robustness in tables with small expected frequencies.

Cox regression was used to assess associations between baseline hs‐cTnT and all‐cause mortality/MACE, adjusting for recipient (age, sex, body mass index, comorbidities [hypertension, diabetes, hyperlipidemia, cerebrovascular disease], estimated glomerular filtration rate, creatinine, NT‐proBNP, hematocrit) and donor (age, sex, cold ischemia time) factors. The proportional hazards assumption was checked using Schoenfeld residuals. Kaplan–Meier analysis with log‐rank tests was used to compare cumulative incidence of outcomes, stratified by median baseline hs‐cTnT. Hs‐cTnT and NT‐proBNP were log2‐transformed. Results from the Cox regression analyses are presented as hazard ratios (HR) with 95% CI; specifically, the estimates derived from the multivariable models (adjusted for the aforementioned confounders) are reported as adjusted HRs. All hs‐cTnT measures were log2‐transformed to account for right‐skewness and stabilize variance. Hazard ratios are therefore reported per 1‐log2‐unit increase, which corresponds to a doubling (100% increase) in the hs‐cTnT metric. Missing data were handled as follows, and the extent of missingness for all variables is reported in Table S1. For baseline continuous covariates with low missingness (<5%), missing values were imputed using the mean of the observed values. No imputation was applied to hs‐cTnT because it was the primary longitudinal exposure for the trajectory analyses and inclusion was determined by prespecified measurement criteria.

To characterize longitudinally measured hs‐cTnT, linear mixed‐effects models with random intercepts and slopes were employed, accommodating individual variations in baseline levels and trajectories. Given the nonlinear temporal pattern observed, random effects were modeled using natural cubic splines with 3 knots at the 25th, 50th, and 75th percentiles of follow‐up time, selected based on the lowest Akaike information criterion compared with linear or quadratic terms (Table S2).

To examine the association between hs‐cTnT dynamics and clinical outcomes, the 3 joint models described next were implemented as coprimary analyses, integrating linear mixed‐effects models with Cox regression. These models evaluate 3 dimensions of hs‐cTnT, each in relation to the concurrent risks of mortality and MACE at time t: (1) instantaneous concentration, defined as the model‐estimated hs‐cTnT level at time t; (2) temporal trend, defined as the slope or rate of change estimated at time t; and (3) cumulative exposure, represented by the area under the trajectory curve from transplantation to time t, indicating the long‐term injury burden at that time. This approach was designed to respectively capture the current level, dynamic change, and historical burden of hs‐cTnT.

To explore the robustness of our primary findings, we conducted several sensitivity analyses. We first assessed the impact of the longitudinal model specification by fitting joint models with linear and quadratic terms (Table S3). To evaluate potential selection bias introduced by the ≥3 hs‐cTnT measurement requirement, we repeated the analyses in an expanded cohort that included patients with only 1 or 2 hs‐cTnT measurements (n=227; Tables S4 through S6). We also addressed potential reverse causality by excluding all hs‐cTnT measurements recorded within the 30 days preceding an outcome event (Table S7). Finally, we examined the influence of low‐level imputation by substituting values below the limit of detection (5 ng/L) with limit of detection/√2 (≈3.5 ng/L) in the longitudinal submodel (Table S8).

The Cox model was estimated using the coxph function implemented in the survival R package and the joint models were estimated using the joint model function implemented in the JMBayes2 R package. Statistical analyses were conducted using R (v4.4.1), maintained by the R Foundation for Statistical Computing.

RESULTS

Patient Baseline Characteristics

This study included 222 heart transplant recipients. Table 1 shows the clinical characteristics of the study population (Tables S9 and S10 provide further stratification by all‐cause mortality and MACE, respectively). Baseline hs‐cTnT measurements were performed at a median of 35 days post transplantation (IQR, 32–42 days). The median baseline concentration was 114 ng/L (IQR, 75–196 ng/L); clinical characteristics stratified by levels above and below this median are detailed in Table S11. At transplantation, the median age was 50 years (IQR, 36–57 years) for recipients and 36 years (IQR, 27–42 years) for donors. Dilated cardiomyopathy was the most common primary indication for heart transplantation, accounting for 58.5% of cases. Comorbidities were prevalent (41.9% diabetes, 30.6% hypertension, and 17.1% chronic kidney disease). Patients with preexisting diabetes were more likely to have higher baseline hs‐cTnT levels.

Table 1.

Baseline Characteristics of the Study Cohort

	Heart transplant recipients (n=222)
Recipient characteristics
Age, y	50 (36–57)
Male, n (%)	190 (85.6)
Body mass index, kg/m2	22.9±3.6
Heart rate, bpm	86 (78–93)
Systolic blood pressure, mm Hg	110 (101–120)
Diastolic blood pressure, mm Hg	70 (64–78)
Comorbidities
Hypertension, n (%)	68 (30.6)
Diabetes, n (%)	93 (41.9)
Cerebrovascular disease, n (%)	14 (5.4)
Hyperlipidemias, n (%)	15 (6.8)
Chronic kidney disease, n (%)	38 (17.1)
Reason for heart transplant
Dilated cardiomyopathy, n (%)	130 (58.5)
Ischemic heart disease, n (%)	53 (23.9)
Hypertrophic cardiomyopathy, n (%)	4 (1.8)
Arrhythmogenic right ventricular cardiomyopathy, n (%)	6 (2.7)
Other, n (%)	29 (13.1)
Hospital stay
D in intensive care unit	7 (5–12)
D in hospital	19 (13–30)
Donor characteristics
Age, y	36 (27–42)
Male, n (%)	206 (92.8)
Cold ischemia time, min	192 (168–217)
Sex mismatch, n (%)	29 (13.1)
Blood chemistry
Total cholesterol, mg/dL	5.4 (4.2–6.6)
Low‐density lipoprotein cholesterol, mmol/L	3.4 (2.6,4.3)
High‐density lipoprotein cholesterol, mmol/L	1.2 (1.0–1.4)
Triglycerides, mmol/L	1.7 (1.3–2.6)
Fasting blood glucose, mmol/L	5.3 (4.8–6.5)
Estimated glomerular filtration rate, mL/min per 1.73 m2	55.6 (38.0–80.2)
Creatinine, μmol/L	102.9 (76.9–142.6)
Blood urea nitrogen, mmol/L	10.7 (8.1–15.9)
Hemoglobin, g/L	116 (97–134)
Hematocrit, %	35.4±6.9
N‐terminal pro‐B‐type natriuretic peptide, pg/mL	1393 (714–2695)
Echocardiography
Left ventricular end diastolic diameter, mm	42.4±3.9
Left ventricular ejection fraction, %	65 (61–68)

Variables are expressed as means±SDs; numbers, with percentage in parentheses; or medians, with interquartile ranges in parentheses.

Association Between Baseline Hs‐cTnT and Clinical Outcomes

During a median follow‐up of 2.3 years (IQR, 0.8–4.5 years), 73 patients (32.9%) experienced clinical outcomes, including 32 deaths (14.4%; 25 cardiovascular, 4 noncardiovascular, and 3 undetermined), 2 nonfatal myocardial infarctions, 14 acute rejections (6 biopsy‐proven and 8 clinically evident), 9 new severe coronary stenoses, and 16 heart failure hospitalizations. The overall 5‐year event‐free survival was 58.0% (95% CI, 50.5%–66.7%), showing an inverse relationship with baseline hs‐TnT (P<0.001). When stratified by the median baseline hs‐cTnT concentration, unadjusted analyses showed that a level above the median was significantly associated with increased risks of both all‐cause mortality (HR, 2.82 [95% CI, 1.30–6.08]; P=0.009) and MACE (HR, 2.46 [95% CI, 1.51–4.02]; P<0.001). These associations were substantially attenuated and became nonsignificant after multivariable adjustment (Table S12). Consistently, Kaplan–Meier analysis confirmed significantly worse outcomes for recipients with hs‐cTnT above the respective median thresholds: for all‐cause mortality (≥114 ng/L, log‐rank P=0.006) and for MACE (≥105 ng/L, log‐rank P=0.026; Figure S1). In continuous analyses, each unit increase in baseline hs‐cTnT was associated with a significantly higher risk of all‐cause mortality in the unadjusted model (HR, 1.74 [95% CI, 1.32–2.29]; P<0.001), the donor‐adjusted model (HR, 1.75 [95% CI, 1.32–2.33]; P<0.001), and the recipient‐adjusted model, though the latter was not statistically significant (HR, 1.39 [95% CI, 0.94–2.06]; P=0.096). A similar pattern was observed for MACE, with significant associations in the unadjusted (HR, 1.66 [95% CI, 1.28–2.14]; P<0.001), donor‐adjusted (HR, 1.63 [95% CI, 1.26–2.11]; P<0.001), and recipient‐adjusted models (HR, 1.43 [95% CI, 1.02–2.01]; P=0.040). However, in the fully adjusted model that accounted for both donor and recipient factors, the associations were attenuated and lost formal statistical significance for both all‐cause mortality (HR, 1.46 [95% CI, 0.98–2.18]; P=0.063) and MACE (HR, 1.36 [95% CI, 0.97–1.92]; P=0.073) (Table 2).

Table 2.

Association of Baseline Hs‐cTnT With Mortality and Major Adverse Cardiac Events: Comparisons by Continuous Analysis

	Baseline hs‐cTnT increment	P value
All‐cause mortality
Unadjusted	1.74 (1.32–2.29)	<0.001
Recipient‐adjusted model	1.39 (0.94–2.06)	0.096
Donor‐adjusted model	1.75 (1.32–2.33)	<0.001
Fully adjusted model	1.46 (0.98–2.18)	0.063
Major adverse cardiac events
Unadjusted	1.66 (1.28–2.14)	<0.001
Recipient‐adjusted model	1.43 (1.02–2.01)	0.040
Donor‐adjusted model	1.63 (1.26–2.11)	<0.001
Fully adjusted model	1.36 (0.97–1.92)	0.073

Cox proportional hazards models were used to estimate hazard ratios and 95% CIs for the association between hs‐cTnT and clinical outcomes (all‐cause mortality and major adverse cardiac events), using three sequential adjustment strategies: (1) recipient factors (age, sex, body mass index, comorbidities, baseline blood parameters); (2) donor factors (age, sex, cold ischemia time); and (3) all recipient and donor factors in a fully adjusted model. Hs‐cTnT indicates high‐sensitivity troponin T.

Different Temporal Evolution of Hs‐cTnT in Patients With and Without Clinical Outcomes

This analysis included 3694 hs‐cTnT measurements from 222 heart transplant recipients. Participants underwent a median of 14 measurements (IQR, 9–22) during follow‐up, with a median interval of 30 days (IQR, 9–61 days) between consecutive measurements. Temporal analysis revealed nonlinear patterns in hs‐cTnT levels over time, with spline functions identifying knots positioned approximately at 3, 6, and 26 months post transplantation.

During follow‐up, patients who experienced all‐cause mortality exhibited significantly higher baseline hs‐cTnT levels (170 ng/L [IQR, 106–365] versus 105 ng/L [IQR, 71–172], P=0.002) compared with survivors. This difference persisted longitudinally, with mean hs‐cTnT levels remaining elevated in the mortality group (100 ng/L [IQR, 62–362] versus 29 ng/L [IQR, 22–63]; P<0.001). Similarly, patients who developed MACE showed markedly higher baseline concentrations (156 ng/L [IQR, 85–219] versus 102 ng/L [IQR, 68–158], P=0.007) compared with those without MACE. This trend was consistently observed throughout longitudinal assessments, with individual mean hs‐cTnT levels remaining significantly higher in patients who developed MACE (68 ng/L [IQR, 32–120] versus 29 ng/L [IQR, 20–53], P<0.001).

Longitudinal hs‐hs‐cTnT trajectories demonstrated distinct patterns across clinical outcomes. In the first 3 months post transplant, patients who died had significantly less hs‐cTnT decline than survivors (−0.57 versus −2.31 log₂ units/year, P<0.001). This corresponds to an approximate annualized decline to about two thirds (∼2^–0.57) of the baseline value in those who died, in contrast to a decline to roughly one fifth (∼2^–2.31) of baseline in survivors. From 3 to 6 months, whereas survivors continued to show a decline (−2.86 log₂ units/year), patients with subsequent mortality showed a significant hs‐cTnT elevation (+0.35 log₂ units/year, P<0.001), equivalent to an annualized increase of ∼1.27‐fold (∼2^0.35). From 6 to 26 months, decline rates were similar in both groups (P=0.112) (Figure 2A).

Figure 2. Hs‐cTnT trajectory patterns and clinical outcomes.

Hs‐cTnT trajectory patterns are shown, stratified by all‐cause mortality (A) and MACE (B). The figure displays individual hs‐cTnT measurements (points), individual patient trajectories (thin lines), and population‐average trends (bold lines, with the surrounding shaded band indicating its 95% CI). Note that patients who experienced all‐cause mortality or MACE exhibited higher hs‐cTnT levels and less pronounced declines in hs‐cTnT slopes. Hs‐cTnT indicates high‐sensitivity troponin T; and MACE, major adverse cardiac events.

In the first 3 months, hs‐cTnT reduction rates were comparable between patients who developed MACE and event‐free patients (−1.90 versus ‐2.11 log₂ units/year, P>0.05). From 3 to 6 months, patients with MACE showed a numerically faster reduction rates (−3.32 versus −2.74 log₂ units/year, P>0.05), but this difference was not statistically significant. From 6 to 26 months, the difference widened, with patients with MACE showing a slower decline (−3.72 versus −5.39 log₂ units/year, P<0.001) (Figure 2B). A slope of −3.72 log₂ units/year corresponds to an annual decline to about one thirteenth of the baseline value, compared with a slope of −5.39 log₂ units/year (≈one fortieth per year) in event‐free patients. This markedly slower decline in hs‐cTnT from 6 to 26 months post transplant illustrates a substantially blunted resolution of myocardial injury in patients who experienced MACE.

Association of Longitudinal Hs‐cTnT With Clinical Outcomes

Longitudinal hs‐cTnT trajectories confirmed its associations with both all‐cause mortality and MACE. At any given time, each unit increase in hs‐TnT instantaneous concentration was associated with an 85% higher risk of all‐cause mortality (HR, 1.85 [95% CI, 1.48–2.31]) and a 47% higher risk of MACE (HR, 1.47 [95% CI, 1.13–1.91]). As a summary measure of a patient’s hs‐cTnT history (cumulative exposure), each 1‐unit increment in the area under the trajectory was associated with an 80% higher risk of all‐cause mortality (HR, 1.80 [95% CI, 1.38–2.37]) and a 48% higher risk of MACE (HR, 1.48 [95% CI, 1.12–1.94]). Instantaneous concentration and cumulative exposure effect estimates remained robust after adjusting for confounders (Table 3). A 1‐unit increase in the log₂‐transformed hs‐cTnT slope（Temporal trend)—indicating a slower decline or rise in levels—was significantly associated with all‐cause mortality risk after adjustment. Although initially showing a nonsignificant trend toward increased all‐cause mortality (HR, 1.09 [95% CI, 1.00–1.18]; P=0.062), this association between the hs‐cTnT slope and all‐cause mortality strengthened significantly after adjustment for recipient and donor factors (P<0.05).

Table 3.

Association of Longitudinal Hs‐cTnT With Mortality and Major Adverse Cardiac Events

Longitudinal hs‐cTnT	Instantaneous concentration	P value	Temporal trend	P value	Cumulative exposure	P value
All‐cause mortality
Unadjusted	1.85 (1.48–2.31)	<0.001	1.09 (1.00–1.18)	0.062	1.80 (1.38–2.37)	<0.001
Adjusted recipient factors	2.04 (1.61–2.60)	<0.001	1.12 (1.03–1.22)	0.011	1.82 (1.38–2.36)	<0.001
Adjusted donor factors	2.05 (1.68–2.53)	<0.001	1.16 (1.06–1.29)	0.001	1.91 (1.52–2.42)	<0.001
Fully adjusted model	2.37 (1.76–3.28)	<0.001	1.18 (1.06–1.33)	0.005	1.94 (1.44–2.67)	<0.001
MACE
Unadjusted	1.47 (1.13–1.91)	0.004	1.03 (0.93–1.11)	0.328	1.48 (1.12–1.94)	0.007
Adjusted recipient factors	1.45 (1.13–1.87)	0.006	1.04 (0.96–1.11)	0.301	1.38 (1.05–1.83)	0.021
Adjusted donor factors	1.48 (1.20–1.85)	<0.001	1.06 (0.97–1.13)	0.154	1.45 (1.15–1.81)	<0.001
Fully adjusted model	1.49 (1.15–1.92)	0.006	1.05 (0.95–1.13)	0.304	1.39 (1.01–1.88)	0.042

Joint models were used to evaluate the impact of longitudinal hs‐cTnT on all‐cause mortality and MACE, with sequential adjustments for confounders as outlined in Table 2. The unit for instantaneous hs‐cTnT concentration is defined as a doubling of the current value of hs‐cTnT. The temporal trend represents a unit increase in the slope (hs‐cTnT per y) of longitudinal hs‐cTnT. Cumulative exposure corresponds to a unit increase in the area under the trajectory curve of longitudinal hs‐cTnT. Hs‐cTnT indicates high‐sensitivity troponin T; and MACE, major adverse cardiac events.

To evaluate the robustness of our primary findings, we performed several sensitivity analyses. First, when assessing different functional forms for the longitudinal trajectory including natural cubic spline, linear, and quadratic terms, all models indicated that instantaneous concentration and cumulative exposure remained significantly associated with increased risks of both all‐cause mortality and MACE (Table S3). However, the temporal trend of hs‐cTnT was not significantly associated with all‐cause mortality in the linear or quadratic models. Second, analyses conducted in an expanded cohort that included patients with only 1 to 2 hs‐cTnT measurements (Table S5 and S6, n=227) yielded results largely consistent with the primary analysis. Third, when hs‐cTnT measurements within the 30 days preceding an outcome were excluded (Table S7), the association between longitudinal hs‐cTnT and all‐cause mortality persisted, indicating that hs‐cTnT serves as a robust marker of longer‐term risk. In contrast, the association with MACE was attenuated in this analysis, suggesting that its predictive value for these events is more concentrated in the immediate preevent period. Finally, using an alternative substitution method (limit of detection/√2) for values below the limit of detection did not materially change the conclusions (Table S8).

DISCUSSION

This study shows that longitudinal hsTnT trajectories—specifically cumulative exposure and instantaneous concentration—exhibit robust associations with adverse outcomes in heart transplant recipients, independent of clinical confounders. Specifically, temporal trends displayed a distinct pattern: the association with all‐cause mortality was of borderline significance before adjustment, this association strengthened significantly after covariate adjustment. In contrast, baseline hs‐cTnT lost its association after adjustment, highlighting notable differences between static and dynamic biomarker assessments.

Adjusting for recipient factors, including comorbidities, weakened the association between baseline hs‐cTnT levels and outcomes. This probably occurred because baseline hs‐cTnT constitutes a confounding signal, reflecting both transplant injury and preexisting comorbidities; statistical adjustment may thus partially remove this shared prognostic information. Conversely, adjustment strengthened the association between hs‐cTnT temporal trends and outcomes. This suggests that noninjury‐related physiological variations in hs‐cTnT—particularly those common among patients with similar comorbidities—initially obscured the true relationship between increasing hs‐cTnT trends and adverse outcomes. Statistical adjustment reduced this background variation, revealing the underlying transplant‐specific pathological signal within the trends, potentially indicating subclinical rejection progression. However, we acknowledge that these explanations are hypothesis generating and cannot be definitively proven within the current observational design.

Cumulative exposure and instantaneous concentration showed generally consistent associations before and after adjustment, suggesting their potential role as markers of sustained injury burden. This divergence may help resolve the apparent contradiction: early, isolated measurements might reflect heterogeneous posttransplant conditions influenced by comorbidities, whereas longitudinal dynamics could capture early pathological evolution. Clinically, serial monitoring beyond the perioperative period might help stratify patients into distinct risk groups. Trajectories showing persistently elevated or rising hs‐cTnT may be associated with active injury processes warranting intensified surveillance, and rapidly declining slopes could reflect uncomplicated recovery.

Longitudinal monitoring showed that elevated serum hs‐cTnT levels were significantly associated with adverse clinical outcomes, which may be closely related to underlying myocardial injury mechanisms. cTn remains the gold‐standard biomarker for detecting acute myocardial necrosis and serves as an important parameter in posttransplant rejection surveillance. ¹³ However, elevations of serum hs‐cTnT in asymptomatic transplant recipients may signal underlying subclinical myocardial injury. Our cohort analysis demonstrated an 85% mortality risk increment per doubling of hs‐cTnT concentration—substantially surpassing the 1.3 to 1.5‐fold HRs documented in cohorts with chronic heart failure. ¹⁴ , ¹⁵ , ¹⁶ This discrepancy likely reflects the distinct pathophysiological mechanisms operating in transplant recipients. These include immunosuppressive therapy‐related cardiotoxicity (eg, calcineurin inhibitor regimens impairing coronary endothelial function) ¹⁷ and chronic biomechanical stress from donor‐recipient size mismatch, which induces persistent myocardial strain. ¹⁸ These concurrent mechanisms may synergistically elevate hs‐cTnT levels while remaining clinically silent during early disease progression.

The association between elevated hs‐cTnT levels during long‐term monitoring and adverse events may further reflect or be influenced by chronic immune activation against the graft. By implementing longitudinal rather than single‐point hs‐cTnT monitoring, this study revealed that cumulative hs‐cTnT exposure significantly associated with adverse outcomes. Notably, unlike the abrupt elevation characteristic of acute coronary syndromes, persistent hs‐cTnT elevations in transplant patients suggest distinct injury mechanisms. It is plausible that immune‐mediated myocardial damage may be partially responsible, as chronic immune activation induces subclinical injury through endothelial dysfunction and cardiomyocyte apoptosis. It is crucial to consider that sustained hs‐cTnT elevations may signify multiple pathologies including early cardiac allograft vasculopathy and rejection. Pathological evidence supports this relationship: patients with persistently elevated hs‐cTnT within 12 months post transplantation showed significantly increased myocardial microvascular fibrin deposition, which was closely associated with increased risk of subsequent cardiac allograft vasculopathy development. ⁴ Additionally, a study involving 98 heart transplant recipients (with 408 myocardial biopsies) found that patients experiencing acute cellular rejection had significantly higher median cTnI levels (57.1 ng/L) compared with those without rejection (10.2 ng/L), with cTnI concentrations showing clear correlation with histological rejection grades. ¹⁹ Although this study specifically assessed cTnI, the pathophysiological implications may extend to TnT given their shared role as biomarkers of myocardial injury in transplant rejection contexts. ²⁰ Based on available evidence, longitudinal hs‐cTnT trajectories we observed are likely a composite signal, reflecting microvascular ischemia, cardiac allograft vasculopathy progression, and subclinical rejection. Methodologically, the distinct temporal nature of these risks was supported by a sensitivity analysis excluding measurements from the 30 days preceding an event. The persistence of the association with mortality underscores hs‐cTnT’s role as a marker of sustained risk, consistent with the chronic pathologies discussed previously. Conversely, the attenuation of the association with MACE indicates that the original association was substantially driven by acute biomarker changes occurring in the immediate preevent period. Furthermore, the observed nonlinear temporal trajectory of hs‐cTnT may indicate threshold effects in myocardial injury progression, potentially reflecting a transition from subclinical graft compromise to overt dysfunction—a phenomenon observed in serial echocardiographic study. ²¹

Although the adjusted rate of change (slope) in hs‐cTnT was significantly associated with all‐cause mortality, it was not a significant predictor of MACE. This may be attributable to the greater statistical noise inherent in estimating individual slopes, particularly over varying follow‐up periods. The stronger and more consistent associations observed for instantaneous concentration and cumulative exposure—metrics that are more robust to measurement variability—suggest these parameters hold greater prognostic utility. The dose–response relationship between cumulative hs‐cTnT exposure and mortality risk underscores the potential clinical value of serial monitoring.

Limitations

This study has several limitations. First, as a retrospective single‐center analysis, detailed treatment data were unavailable to evaluate whether interventions influenced the association between longitudinal hs‐cTnT changes and outcomes. Second, coronary assessment was restricted to patients eligible for contrast‐based coronary imaging. Third, acute rejection was ascertained as a composite of biopsy‐proven and clinically evident events, with the latter classified retrospectively using predefined criteria. Fourth, requiring at least 3 hs‐cTnT measurements may have excluded some high‐risk patients with very early events, and symptom data were not systematically collected; however, sensitivity analyses including patients with 1 to 2 measurements showed consistent results. Finally, the intervals between hs‐cTnT measurements were not uniform across patients, which could affect the precision of trajectory estimates. However, we addressed this by using linear mixed‐effects models that are robust to irregular time intervals, and all patients followed a similar posttransplant surveillance schedule.

CONCLUSIONS

In heart transplant recipients, longitudinal hs‐cTnT trajectories were independently associated with all‐cause mortality and MACE. These findings suggest that serial troponin monitoring may serve as a valuable tool for identifying high‐risk individuals who could benefit from intensified surveillance. Although requiring validation in prospective cohorts, these results support the potential of integrating dynamic biomarker trajectories with established clinical indicators to refine posttransplant risk stratification.

Sources of Funding

This research was supported by the National Natural Science Foundation of China (Grant No. 82502289 to Yuelong Yang, 82371903 to Hui Liu), Basic and Applied Basic Research Foundation of Guangdong Province (Grant No. 2024A1515012087 to Hui Liu), Medical Scientific Research Foundation of Guangdong Province (Grant No. A2025146 to Yuelong Yang), Science and Technology Projects in Guangzhou (Grant No. 2025A04J4778 to Yuelong Yang), Guangzhou Clinical High‐tech, Major, and Distinctive Technology Projects (Grant No. 2023P‐TS43 to Hui Liu), and Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis Application (Grant No. 2022B1212010011).

Disclosures

None.

Supporting information

Tables S1–S12

Figure S1

Data S2