Bio-Adrenomedullin Predicts Death and Major Adverse Cardiovascular Events in Cardiac Amyloidosis A Cross-Continental Multi-Centre Study

BackgroundBioactive adrenomedullin (bio-ADM) is a vasoactive peptide hormone that predicts clinical outcomes in heart failure - the main driver of adverse outcomes in cardiac amyloidosis (CA). This prospective observational study sought to assess the prognostic role of bio-ADM in CA. MethodsCA patients were enrolled from amyloid centres in Germany (observation cohort), Japan and the U.S. (combined validation cohort). Bio-ADM was quantified using the sphingotest(R) bio-ADM(R) assay. Associations of bio-ADM with all-cause death and major adverse cardiovascular events (MACE) over two years were assessed using Kaplan-Meier and Cox regression analyses. Likelihood ratio chi-squared tests for nested models evaluated whether adding bio-ADM improves validated prognostic staging systems. ResultsIn both the German observation cohort (n=86) and the combined validation cohort from Japan and the U.S. (n=124), elevated bio-ADM (>29 pg/mL) was associated with more frequent all-cause death and MACE. Bio-ADM remained independently associated with impaired overall (p<0.001) and MACE-free survival (p<0.001) after adjustment for age, sex, and established prognostic biomarkers in the entire cohort. Adding categorised bio-ADM (>29 pg/mL) significantly improved the prognostic accuracy of the National Amyloidosis Centre (C-index 0.674 to 0.787; p=0.002) and MayoATTR (C-index 0.662 to 0.757; p<0.001) staging systems for cardiac transthyretin amyloidosis (ATTR-CA). Adding bio-ADM to staging systems for cardiac immunoglobulin light chain amyloidosis (AL-CA) yielded no significant changes. ConclusionsBio-ADM is a promising prognostic biomarker, especially in ATTR-CA, where it improved risk stratification when added to established staging systems. Further research is needed to clarify its role as part of staging systems for AL-CA. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIBioactive Adrenomedullin (bio-ADM) is a novel prognostic biomarker for all-cause mortality and major adverse cardiovascular events (MACE) in patients with cardiac amyloidosis. C_LIO_LIIncorporating bio-ADM into established staging systems for cardiac transthyretin amyloidosis (ATTR-CA) improves their prognostic performance. Further research is required to determine the role of bio-ADM as part of staging systems for cardiac immunoglobulin light chain amyloidosis (AL-CA). C_LI What Are the Clinical Implications?O_LIUsing bio-ADM as an additional prognostic biomarker allows for more accurate risk-stratification and may thereby enhance individualized clinical management in patients with ATTR-CA. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/25341962v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@5a4b27org.highwire.dtl.DTLVardef@1fc0d6corg.highwire.dtl.DTLVardef@d53ac7org.highwire.dtl.DTLVardef@10619b7_HPS_FORMAT_FIGEXP M_FIG C_FIG This cross-continental multi-centre study, comprising a German observation cohort (n=86) and a combined validation cohort from Japan and the United States (n=124), sought to assess the prognostic value of bioactive Adrenomedullin (bio-ADM) in patients with cardiac amyloidosis (CA) and evaluate whether its incorporation into established staging systems improves risk-stratification. Therefore, patients were stratified into groups with low (i.e., [&le;]29pg/mL; n=43, 20.5%) and high (i.e., >29pg/mL; n=167, 79.5%) bio-ADM plasma levels at baseline and were then followed for the occurrence of major adverse cardiovascular events (MACE) or all-cause death over a period of up to two years. High bio-ADM plasma levels were associated with an elevated risk for MACE and all-cause death in both the observation and the validation cohort. Integrating bio-ADM into validated prognostic staging systems for cardiac transthyretin amyloidosis (ATTR-CA; NAC and MayoATTR staging systems) led to significant improvements in their prognostic accuracy. No such improvements were observed when adding bio-ADM to staging systems for cardiac immunoglobulin light chain amyloidosis (AL-CA; Mayo2004 and Mayo2012 staging systems). In conclusion, bio-ADM is a promising novel prognostic biomarker, especially in ATTR-CA, where it allows for improved risk-stratification and may thereby enhance individualized clinical management. Further research is needed to clarify the role of bio-ADM as part of staging systems for AL-CA.