Acute Coronary Syndrome (ACS) remains a leading cause of morbidity and mortality worldwide, representing a spectrum of conditions including unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI) [1]. Prompt and accurate risk stratification is paramount to guide therapeutic decisions, optimize resource allocation, and improve patient outcomes. Clinical risk scores, such as the GRACE and TIMI scores, are widely used but have limitations in capturing the full extent of individual patient risk [2].

Cardiac biomarkers have revolutionized the diagnosis and management of ACS. High-sensitivity cardiac troponins (hs-cTn) are the cornerstone for the diagnosis of myocardial infarction (MI), offering high sensitivity and precision for detecting myocyte necrosis [3]. Elevated hs-cTn levels are not only diagnostic but also carry significant prognostic weight, correlating with infarct size and subsequent risk of adverse events [4]. However, hs-cTn primarily reflects a single pathophysiological process—myocardial cell death.

In contrast, N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of hemodynamic stress and myocardial wall tension. It is released by cardiomyocytes in response to increased intracardiac pressure and volume overload [5]. While traditionally associated with heart failure, NT-proBNP has emerged as a potent prognostic marker in ACS. Elevated levels are associated with left ventricular dysfunction, larger infarcts, and an increased risk of developing heart failure and mortality post-MI, independent of troponin levels [6].

Given that hs-cTn and NT-proBNP reflect distinct yet complementary pathophysiological pathways—necrosis and hemodynamic stress, respectively—it is hypothesized that their combined measurement could provide a more comprehensive and robust assessment of cardiovascular risk than either marker alone. Several studies have explored this dual biomarker strategy, suggesting an incremental prognostic benefit [7, 8]. However, many of these studies were retrospective, included heterogeneous populations, or were conducted before the widespread implementation of contemporary high-sensitivity troponin assays and intensive modern therapies. A clear research gap exists in prospectively validating this dual biomarker approach in a real-world cohort of ACS patients managed according to current guidelines.

Therefore, the aim of this prospective cohort study was to investigate the combined prognostic value of admission hs-cTn and NT-proBNP for the prediction of 6-month Major Adverse Cardiovascular Events (MACE) in patients with a confirmed diagnosis of ACS.

Study Design and Population: We consecutively enrolled patients aged 18 years or older who presented to the emergency department with symptoms suggestive of ACS and subsequently received a final diagnosis of STEMI or NSTE-ACS, confirmed according to the Fourth Universal Definition of Myocardial Infarction. The study protocol was approved by the Institutional Review Board, and all participants provided written informed consent.

Inclusion and Exclusion Criteria: Inclusion criteria were: (1) age ≥ 18 years; and (2) a final diagnosis of ACS (STEMI or NSTE-ACS).
Exclusion criteria were: (1) severe chronic kidney disease (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²), as this can independently elevate NT-proBNP levels; (2) cardiogenic shock or cardiac arrest at presentation; (3) recent major surgery or trauma (<30 days); (4) active malignancy or other life-limiting non-cardiac disease with a life expectancy of less than one year; and (5) refusal to provide informed consent.

Data Collection and Procedures: Baseline demographic data, medical history, clinical presentation, and electrocardiogram (ECG) findings were recorded for all patients upon enrollment. Blood samples were collected in ethylenediaminetetraacetic acid (EDTA) tubes at the time of initial presentation to the emergency department, prior to the initiation of reperfusion therapy for STEMI patients. Plasma was separated by centrifugation and analyzed immediately.

Biomarker Measurement:Plasma concentrations of hs-cTnT and NT-proBNP were measured using commercially available electrochemiluminescence immunoassays on a Cobas e601 analyzer (Roche Diagnostics, Mannheim, Germany). The hs-cTnT assay has a limit of detection of 5 ng/L and a 99th percentile upper reference limit of 14 ng/L. NT-proBNP was measured with a lower detection limit of 5 pg/mL. For the purpose of this study, "elevated" hs-cTnT was defined as a value >14 ng/L. "Elevated" NT-proBNP was defined as a value >300 pg/mL, a commonly used cut-off for prognostic assessment in ACS.

Based on these cut-offs, patients were stratified into four predefined groups:

• Group 1: Normal hs-cTnT (≤14 ng/L) and normal NT-proBNP (≤300 pg/mL).
• Group 2: Elevated hs-cTnT (>14 ng/L) and normal NT-proBNP (≤300 pg/mL).
• Group 3: Normal hs-cTnT (≤14 ng/L) and elevated NT-proBNP (>300 pg/mL).
• Group 4: Elevated hs-cTnT (>14 ng/L) and elevated NT-proBNP (>300 pg/mL).

Endpoint and Follow-up: The primary endpoint of the study was the 6-month incidence of a composite of MACE, defined as all-cause mortality, non-fatal re-infarction, or urgent unplanned revascularization (percutaneous coronary intervention or coronary artery bypass grafting). All patients were followed up at 1, 3, and 6 months post-discharge via in-person clinic visits or structured telephone interviews conducted by trained research staff blinded to the baseline biomarker levels. Endpoint events were adjudicated by an independent committee of two cardiologists.

Statistical Analysis: Continuous variables were presented as mean ± standard deviation (SD) and compared using one-way analysis of variance (ANOVA). Categorical variables were presented as counts and percentages (n, %) and compared using the Chi-square test or Fisher’s exact test, as appropriate. The cumulative incidence of MACE was estimated using the Kaplan-Meier method, and differences between the four groups were assessed with the log-rank test. A multivariate Cox proportional hazards regression model was used to determine the independent predictive value of the biomarker groups for 6-month MACE. The model was adjusted for established cardiovascular risk factors, including age, sex, diabetes mellitus, hypertension, smoking status, and type of ACS (STEMI vs. NSTE-ACS). A two-sided p-value of < 0.05 was considered statistically significant. All analyses were performed using SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY).

Patient Characteristics: Total 550 patients initially screened for eligibility, 68 were excluded (35 with severe renal dysfunction, 18 with cardiogenic shock, 15 with other reasons or refusal to consent). Thus, a total of 482 patients comprised the final study cohort. The baseline demographic and clinical characteristics of the study population, stratified by the four biomarker groups, are presented in Table 1. Patients in Group 4 (dual biomarker elevation) were significantly older, more likely to have a history of diabetes, hypertension, and prior MI compared to patients in other groups (p < 0.01 for all). The prevalence of STEMI was also highest in Group 4.

Table 1. Baseline Demographics and Clinical Characteristics

Abbreviations: SD, standard deviation; MI, myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome; STEMI, ST-elevation myocardial infarction; LVEF, left ventricular ejection fraction.

Biomarker Concentrations: As per the study design, biomarker levels differed significantly across the four groups. The median concentrations of hs-cTnT and NT-proBNP for each group are detailed in Table 2.

Table 2. Biomarker Concentrations at Presentation (Median [Interquartile Range])

Abbreviations: hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Clinical Outcomes: During the 6-month follow-up period, a total of 73 MACE events (15.1%) occurred in the overall cohort. The incidence of MACE showed a steep, stepwise increase across the four biomarker groups (Table 3). The lowest event rate was observed in Group 1 (3.5%), while the highest was in Group 4 (34.6%). The MACE rate was intermediate for patients with only one elevated biomarker (12.8% for Group 2 and 15.2% for Group 3). The difference in MACE incidence among the four groups was statistically highly significant (p < 0.001).

Table 3. Incidence of 6-Month Major Adverse Cardiovascular Events (MACE)

In the multivariate Cox proportional hazards analysis, after adjusting for age, sex, diabetes, hypertension, smoking, and ACS type, the biomarker groups remained a significant predictor of MACE. Using Group 1 as the reference, the adjusted hazard ratio (HR) for MACE was 3.15 (95% CI: 1.10–9.05; p=0.033) for Group 2, 3.88 (95% CI: 1.25–12.01; p=0.019) for Group 3, and 4.12 (95% CI: 2.55–6.65; p < 0.001) for Group 4. Dual elevation of hs-cTnT and NT-proBNP was the strongest independent predictor of adverse outcomes.

This prospective cohort study demonstrates that a dual biomarker strategy, integrating admission levels of hs-cTn and NT-proBNP, significantly enhances risk stratification in patients with ACS. The principal finding is that patients with concurrent elevation of both biomarkers are at a substantially higher risk for 6-month MACE compared to those with elevation in only one or neither marker. This relationship persisted after adjusting for traditional cardiovascular risk factors, highlighting the independent and synergistic prognostic value of this approach.

Our findings are consistent with and expand upon previous research. Studies by Januzzi et al. have shown that NT-proBNP adds prognostic information to troponin levels in patients with NSTE-ACS [9]. Similarly, a meta-analysis by Lemos et al. confirmed that natriuretic peptides are powerful predictors of death and heart failure in ACS patients [10]. Our study contributes to this body of evidence by prospectively evaluating this dual strategy in a contemporary cohort that includes both STEMI and NSTE-ACS patients managed with modern invasive strategies and medical therapies. The stepwise gradient of risk we observed—from 3.5% in the dual-negative group to 34.6% in the dual-positive group—provides a clear and clinically intuitive framework for risk assessment.

The pathophysiological rationale for this synergistic effect is compelling. Hs-cTn is a specific marker of myocyte necrosis, quantifying the extent of the initial ischemic insult [11]. NT-proBNP, on the other hand, is a marker of ventricular strain and neurohormonal activation, reflecting the heart's hemodynamic response to that injury [12]. An ACS event with minimal troponin release and no significant wall stress (Group 1) carries a good prognosis. An event causing significant necrosis but with preserved ventricular function (Group 2) carries an intermediate risk. Conversely, a patient with pre-existing or acutely induced ventricular stress but minimal necrosis (Group 3) also has an intermediate risk, likely driven by underlying comorbidities or diffuse coronary disease [13]. The highest-risk scenario (Group 4) represents a patient with substantial myocardial necrosis superimposed on, or resulting in, significant hemodynamic compromise. This combination captures both the acute damage and the heart’s failing ability to cope, explaining the markedly worse outcomes [14, 15].

The clinical implications of our findings are significant. The simple, four-group stratification can be easily implemented in routine clinical practice, as both hs-cTn and NT-proBNP are widely available assays. Identifying the dual-positive, very high-risk group at the time of admission could trigger a more aggressive management pathway. This might include earlier consideration for advanced imaging to assess viability and ventricular function, more intensive medical therapy (e.g., early initiation of SGLT2 inhibitors or sacubitril/valsartan), closer in-hospital monitoring, and more rigorous follow-up post-discharge to mitigate the risk of subsequent heart failure and mortality. Conversely, patients in the dual-negative group could potentially be candidates for earlier, safe discharge and less intensive follow-up.

This study has several strengths, including its prospective design, the inclusion of a broad and contemporary ACS population, adjudicated clinical endpoints, and analysis of a combined MACE endpoint relevant to clinical practice. However, some limitations must be acknowledged. First, it was a single-center study, which may limit the generalizability of our findings to other populations and healthcare systems. Second, the 6-month follow-up period is relatively short; longer-term studies are needed to assess if this prognostic value persists. Third, we did not measure serial biomarker levels, which might provide additional dynamic risk information. Finally, despite multivariate adjustment, the possibility of residual confounding from unmeasured variables cannot be entirely excluded.

In conclusion, this study provides strong evidence that the combined measurement of hs-cTn and NT-proBNP on admission is a powerful and independent tool for risk stratification in patients across the entire spectrum of acute coronary syndrome. This dual biomarker approach effectively distinguishes patients at low, intermediate, and very high risk for future adverse cardiovascular events. Integrating this strategy into routine clinical assessment can help clinicians tailor therapeutic intensity and monitoring, ultimately contributing to more personalized and effective management of ACS patients.

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