Highlights
- MR-proADM has emerged as a superior biomarker for predicting all-cause mortality and heart failure events in transthyretin amyloid cardiomyopathy (ATTR-CM), outperforming established markers like NT-proBNP and high-sensitivity Troponin I.
- A validated prognostic threshold of ≥1.1 nmol/L identifies high-risk patients across diverse clinical settings, including those already receiving disease-modifying therapies like tafamidis.
- Integration of MR-proADM into the National Amyloid Center (NAC), Mayo, and Columbia staging systems significantly improves their predictive accuracy (AUC increases of ~0.05–0.08).
- Validation across three independent international cohorts (Spain, USA, and ATTR-ACT trial) confirms the robust and universal applicability of this biomarker.
Background
Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a prevalent cause of heart failure, particularly heart failure with preserved ejection fraction (HFpEF) in older adults. The clinical landscape of ATTR-CM has shifted dramatically following the approval of transthyretin stabilizers and the development of non-invasive diagnostic pathways (scintigraphy). However, as we identify patients at earlier disease stages, the limitations of current risk-stratification tools become apparent.
Existing staging systems, such as the Mayo 2012 or the National Amyloid Center (NAC) systems, rely heavily on N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponins. While useful, these markers are frequently confounded by renal dysfunction or localized myocardial stretch and may not fully capture the systemic vascular and endothelial stress associated with amyloid infiltration. There is an urgent clinical need for biomarkers that provide independent prognostic value to guide therapeutic intensity and patient counseling.
Key Content
Comparative Analysis of Circulating Biomarkers
In a comprehensive evaluation of 12 distinct circulating biomarkers in a discovery cohort of 337 ATTR-CM patients, mid-regional pro-adrenomedullin (MR-proADM) demonstrated the strongest prognostic performance. Adrenomedullin is a potent vasodilator and regulator of endothelial integrity; its mid-regional pro-hormone fragment (MR-proADM) is more stable in circulation and serves as a reliable surrogate for adrenomedullin levels.
When compared against a panel including GDF-15, sST2, CA125, and standard cardiac markers (NT-proBNP, hsTnI), MR-proADM achieved the highest C-index for all-cause mortality (0.788) and the composite endpoint of death or heart failure events (0.721). Notably, MR-proADM levels correlated significantly with other markers of disease severity, including New York Heart Association (NYHA) class and echocardiographic parameters of restrictive filling, yet maintained independent prognostic power in multivariate Cox models.
Incremental Value Over Existing Staging Systems
One of the most clinically relevant findings in the study by Peiró-Aventín et al. is the additive value of MR-proADM to the “gold standard” staging systems:
- National Amyloid Center (NAC) System: AUC improved from 0.682 to 0.737 (P<0.001).
- Mayo 2012 System: AUC improved from 0.659 to 0.749 (P<0.001).
- Columbia Staging: AUC improved from 0.699 to 0.768 (P<0.001).
This suggest that MR-proADM captures a dimension of risk—likely related to microvascular dysfunction and systemic congestion—not fully addressed by current natriuretic peptide and troponin-based models.
Threshold Validation and Therapeutic Context
A threshold of ≥1.1 nmol/L was identified as optimal for risk stratification. Patients above this level experienced significantly worse outcomes regardless of the ATTR-CM subtype (wild-type vs. hereditary). Importantly, this association remained consistent in the ATTR-ACT trial validation cohort, where MR-proADM predicted outcomes even in patients treated with tafamidis. This indicates that while stabilizers reduce the rate of amyloid deposition, the degree of pre-existing or concurrent endothelial stress (measured by MR-proADM) remains a critical determinant of survival.
Cross-Cohort Reliability
The findings were rigorously validated in two external cohorts:
1. United States Cohort (n=210): Confirming the generalizability of the 1.1 nmol/L threshold in a different healthcare environment.
2. ATTR-ACT Trial Cohort (n=416): Providing high-level evidence from a randomized controlled trial setting, reinforcing that MR-proADM is a robust indicator of heart failure progression and mortality.
Expert Commentary
From a pathophysiological perspective, the success of MR-proADM in ATTR-CM may be attributed to its role as a marker of “endothelial health” and “viral load” of amyloid-induced damage. Adrenomedullin is secreted by vascular endothelial cells and myocytes in response to pressure overload and inflammatory stress. In amyloidosis, where the extracellular matrix is distorted and microvascular resistance is high, MR-proADM likely serves as a more sensitive barometer of systemic hemodynamic compromise than NT-proBNP, which is more specifically a marker of atrial and ventricular wall stretch.
However, clinicians must exercise caution when interpreting MR-proADM in patients with severe sepsis or acute inflammatory states, where adrenomedullin is known to rise sharply. In the chronic management of ATTR-CM, the focus should be on stable, outpatient measurements to guide long-term prognosis. The inclusion of MR-proADM in future updates of clinical guidelines for amyloidosis should be considered, given its superior AUC and consistency across global cohorts.
Conclusion
MR-proADM represents a major advancement in the prognostic toolkit for ATTR cardiac amyloidosis. By providing a clear, reproducible threshold (≥1.1 nmol/L) and significantly enhancing the predictive power of existing staging systems, it allows for more precise risk stratification. Future research should investigate whether changes in MR-proADM levels over time can be used to monitor response to novel gene-silencing therapies or to guide the timing of advanced heart failure interventions such as heart transplantation or mechanical circulatory support.
References
- Peiró-Aventín B, et al. MR-ProADM Predicts Mortality and Heart Failure Events in ATTR Cardiac Amyloidosis. Circulation. 2026; PMID: 41914183.
- Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. PMID: 30145932.
- Gillmore JD, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39(30):2799-2806. PMID: 29479350.
- Grogan M, et al. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016;68(10):1014-1020. PMID: 27585505.