Highlights
High-sensitivity cardiac troponin I (hs-cTnI) is an independent and potent predictor of all-cause mortality in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM).
A standardized threshold of 80 ng/L for hs-cTnI has been identified across three major diagnostic assays (Abbott, Beckman Coulter, and Siemens), simplifying clinical application.
Integrating hs-cTnI into a two-variable staging system alongside natriuretic peptides significantly improves risk stratification, identifying three distinct prognostic groups.
The Growing Burden of Wild-Type Transthyretin Amyloid Cardiomyopathy
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) was once considered a rare cause of heart failure in the elderly. However, with the advent of non-invasive diagnostic techniques such as 99mTc-pyrophosphate scintigraphy, it is increasingly recognized as a prevalent condition, particularly among patients with heart failure with preserved ejection fraction (HFpEF) and severe aortic stenosis. As our ability to diagnose this condition improves, so does the need for precise prognostic tools to guide clinical management and patient counseling.
Risk stratification in cardiac amyloidosis has traditionally relied on biomarkers reflecting myocardial stress and injury, such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponins. While the Mayo Clinic staging system has been a cornerstone in this regard, its application has often been complicated by the use of different troponin assays (Troponin T vs. Troponin I) and varying sensitivities of high-sensitivity assays. Until recently, a clear, assay-independent threshold for hs-cTnI had not been established for ATTRwt-CM patients.
Study Design and Methodology
In a comprehensive multicenter observational study recently published in Circulation: Heart Failure, De Michieli and colleagues sought to address this gap. The researchers aimed to assess the prognostic performance of hs-cTnI across different assays and identify a unifying threshold for risk stratification.
The study utilized data from stable patients with ATTRwt-CM across multiple cohorts. The testing phase involved two cohorts: the Abbott Architect Stat hs-cTnI assay (n=136) and the Beckman Coulter Access hs-cTnI assay (n=98). The validation phase was conducted using an independent cohort (n=345) evaluated with the Siemens Centaur XPT hs-cTnI assay. The primary endpoint for all cohorts was all-cause mortality.
The researchers employed natural log-transformation of hs-cTnI values to account for non-normal distribution and utilized Cox proportional hazards models to determine independent predictors of mortality. By combining the Abbott and Beckman cohorts, they identified the optimal threshold for 18-month mortality through ROC curve analysis, eventually rounding the value for clinical simplicity.
Key Findings: hs-cTnI as a Potent Prognostic Indicator
The results underscore the significant prognostic value of hs-cTnI in this population. In both testing cohorts, hs-cTnI was an independent predictor of mortality, even after adjusting for age and sex. Specifically, the hazard ratio for the Abbott cohort was 1.62 (95% CI, 1.11-2.35; P=0.012), while the Beckman cohort showed an even stronger association with a hazard ratio of 2.47 (95% CI, 1.48-4.14; P<0.001).
The most striking finding was the identification of 81 ng/L as the optimal prognostic threshold for 18-month mortality. For ease of clinical use, the researchers rounded this to 80 ng/L. Patients with hs-cTnI levels above this threshold faced a significantly higher risk of death compared to those below it.
Comparison of Staging Systems
The study went beyond individual biomarker analysis by integrating hs-cTnI into a modified staging system. This system utilized two variables:
- hs-cTnI > 80 ng/L
- Natriuretic Peptides (NT-proBNP > 3000 ng/L or BNP > 250 ng/L)
This approach categorized patients into three stages: Stage I (neither biomarker elevated), Stage II (one biomarker elevated), and Stage III (both biomarkers elevated). The validation cohort using the Siemens assay confirmed the robustness of this system, showing clear survival differences between the groups over a median follow-up of 32 months.
Fig. Prognostic performance of hs-cTnI (high-sensitivity cardiac troponin I) in the combined Abbott/Beckman cohort. A, Receiver-operating characteristic (ROC) curve of hs-cTnI for 18-month mortality in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). B, Kaplan-Meier curves for survival in patients with ATTRwt-CM and hs-cTnI values at baseline below/equal to (blue) or above (red) 80 ng/L. AUC indicates area under the curve; and HR, hazard ratio.
Table 2. Multivariable Cox-Regression Analysis for Mortality in Patients With ATTRwt-CM Evaluated With the Abbott or Beckman Assay
Fig. Kaplan-Meier (KM) curves for survival according to the 2-variable staging system based on hs-cTnI (high-sensitivity cardiac troponin I) >80 ng/L (Abbott/Beckman) and elevated natriuretic peptides (NPs). Elevated NPs are defined as NT-proBNP (N-terminal pro-B-type natriuretic peptide) >3000 ng/L or, if NT-proBNP not available, as BNP (B-type natriuretic peptide) >250 ng/L. Stage I is defined as both variables being below the cutoffs, stage II as 1 variable being above, and stage III as both variables being above. HR indicates hazard ratio.
Expert Commentary and Clinical Implications
The identification of a uniform threshold of 80 ng/L across three major assays is a significant step toward standardizing the management of ATTRwt-CM. Historically, clinicians have struggled with the “inter-assay variability” inherent in troponin testing. By demonstrating that 80 ng/L serves as a reliable cut-off for multiple platforms, this study provides a practical tool for cardiologists to assess risk regardless of their institution’s specific laboratory equipment.
From a pathophysiological perspective, the elevation of hs-cTnI in ATTRwt-CM reflects ongoing cardiomyocyte injury. This injury is likely driven by the mechanical infiltration of amyloid fibrils into the extracellular matrix, which compresses myocytes and compromises microvascular circulation. The fact that hs-cTnI remains an independent predictor after adjusting for natriuretic peptides suggests that it captures a unique facet of disease progression—direct cellular damage—that is distinct from the wall stress reflected by NT-proBNP.
However, clinicians must remain mindful of the study’s limitations. While the 80 ng/L threshold is powerful, it should be interpreted within the context of the patient’s overall clinical status, including renal function and comorbidities like chronic coronary artery disease, which can also elevate troponin levels. Furthermore, while this study focused on mortality, future research should investigate whether these thresholds can predict response to emerging therapies like transthyretin stabilizers or silencers.
Conclusion
In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is more than just a marker of injury; it is a critical prognostic lens. The establishment of an 80 ng/L threshold provides a clear, actionable metric for risk stratification. When combined with natriuretic peptides in a simple staging system, hs-cTnI allows for more accurate identification of high-risk patients who may require more intensive monitoring or earlier therapeutic intervention. As we enter an era of personalized medicine for cardiac amyloidosis, such standardized biomarkers will be essential for optimizing patient outcomes.
References
De Michieli L, Sinigiani G, Guida G, et al. High-Sensitivity Cardiac Troponin I for Risk Stratification in Wild-Type Transthyretin Amyloid Cardiomyopathy. Circ Heart Fail. 2025;18(8):e012816. doi:10.1161/CIRCHEARTFAILURE.125.012816 IF: 8.4 Q1 .
