MR-ProADM Predicts Mortality and Heart Failure Events in ATTR Cardiac Amyloidosis

BACKGROUND: With the increasing diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) at earlier stages and new therapies, there is a rising demand for tools to stratify risk and prognosis. We evaluated the prognostic value of multiple circulating biomarkers for predicting outcomes in ATTR-CM. METHODS: We evaluated 12 different circulating biomarkers (N-terminal pro-B-type natriuretic peptide NT-proBNP, high-sensitivity troponin I hsTnI, mid-regional pro-adrenomedullin MR-proADM, carbohydrate antigen 125 CA125, soluble suppressor of tumorigenicity 2 sST2, cluster of differentiation antigen 146 CD146, growth/differentiation factor-15 GDF-15, alpha-klotho, fibroblast growth factor 23 FGF-23, galectin-3, insulin-like growth factor-binding protein 7 IGFBP-7, and estimated glomerular filtration rate eGFR) in 337 ATTR-CM patients from Spain. Cox models were employed to determine their predictive abilities. Findings were validated in 2 independent external cohorts of 210 patients from the United States and 416 patients from the ATTR-ACT trial, respectively. RESULTS: Over a median follow-up of 19.7 months (IQR, 6.5–42.3), 67 patients (19.9%) died/underwent heart transplantation, and 81 (24%) had heart failure events. MR-proADM was the biomarker with the strongest prognostic performance, with a C-index of 0.788 (95% CI, 0.723–0.851) for all-cause mortality and 0.721 (95% CI, 0.669–0.772) for the composite endpoint of death and heart failure events. MR-proADM was associated with multiple parameters of ATTR-CM severity and was independently associated with mortality, heart failure events, and the composite endpoint. MR-proADM ≥1.1 nmol/L was identified as the optimal prognostic threshold, and it improved prediction of mortality when added to the National Amyloid Center (area under the curve AUC, 0.682 versus 0.737; P <0.001), Mayo (AUC, 0.659 versus 0.749; P <0.001), and the Columbia staging systems (AUC, 0.699 versus 0.768; P <0.001). In both validation cohorts, patients with MR-proADM ≥1.1 nmol/L had worse outcomes ( P <0.001). This association was also confirmed in patients receiving tafamidis. CONCLUSIONS: In patients with ATTR-CM, MR-proADM levels are associated with disease severity and worse prognosis. MR-proADM improves prediction of all-cause mortality and captures heart failure events.