New Biomarker MR-proADM Outperforms NT-proBNP for Predicting Death in Heart Amyloidosis

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive infiltrative heart disease caused by deposition of misfolded transthyretin protein, leading to restrictive physiology and high mortality. With improved noninvasive diagnosis and new disease-modifying therapies like tafamidis, more patients are being identified at earlier stages — creating an urgent need for better prognostic tools that go beyond predicting survival to also capture heart failure decompensation risk.

This study systematically evaluated 12 circulating biomarkers in a Spanish derivation cohort of 337 ATTR-CM patients enrolled between 2014 and 2022. Biomarkers tested included NT-proBNP, high-sensitivity troponin I, MR-proADM, CA125, sST2, CD146, GDF-15, alpha-klotho, FGF-23, galectin-3, IGFBP-7, and eGFR. Cox proportional hazards models were used to compare predictive performance for all-cause mortality, worsening heart failure events, and a composite endpoint. Results were validated in a U.S. cohort of 210 patients from Oregon and Columbia and in 416 participants from the phase 3 ATTR-ACT tafamidis trial.

Over a median follow-up of 19.7 months, MR-proADM emerged as the strongest prognostic biomarker. Its C-index for all-cause mortality was 0.788 (95% CI 0.723–0.851), substantially outperforming NT-proBNP and troponin. For the composite endpoint of death plus heart failure events, the C-index was 0.721. A threshold of ≥1.1 nmol/L identified patients at significantly elevated risk. Adding MR-proADM to the Mayo staging system improved the AUC from 0.659 to 0.749 (P<0.001); similar improvements were seen for the National Amyloid Center (0.682→0.737) and Columbia (0.699→0.768) systems. MR-proADM was independently associated with outcomes after adjustment for NT-proBNP, eGFR, diuretic dose, and NYHA functional class. Critically, the association held in both external validation cohorts and remained significant among patients receiving tafamidis.

MR-proADM reflects adrenomedullin activity — a vasoactive peptide involved in endothelial function, vascular tone, and fluid homeostasis — and its elevation likely captures hemodynamic congestion and vascular stress dimensions not fully represented by natriuretic peptides. Because current ATTR-CM staging systems were developed in sicker, older cohorts, incorporating MR-proADM could meaningfully sharpen risk stratification in the modern era of earlier diagnosis and active treatment.

The main caveats are the observational, retrospective design and relatively modest cohort sizes, though the multicenter, multinational validation and inclusion of a randomized trial cohort substantially strengthen confidence. Adoption would require clinical labs to routinely offer MR-proADM testing, which is not yet universally available.