Adrenomedullin system dysregulation predicts cardiogenic shock and mortality in acute coronary syndromes

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background and Aims</jats:title> <jats:p>Cardiogenic shock (CS) is the most dreadful complication of acute coronary syndromes (ACS). Endothelial dysfunction and vascular leakage are hallmarks of CS pathophysiology; however, biomarkers reflecting these early processes are lacking. The adrenomedullin (ADM) system—the inactive precursor glycine-extended ADM (ADM-Gly), the activating enzyme peptidylglycine α-amidating monooxygenase (PAM), and biologically active ADM (bio-ADM)—modulates vascular tone and permeability. This study investigated associations of ADM system components with CS and 1-year mortality risk after ACS.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>ADM-Gly, PAM, and bio-ADM were assessed in 4098 (Switzerland; SPUM-ACS) and 824 (France; FAST-MI) ACS patients without CS on admission. The primary endpoint was in-hospital CS; the secondary endpoint was 1-year mortality. Biomarker–outcome associations were analysed using multivariable-adjusted regression models, and the incremental predictive value beyond established risk scores was quantified.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Higher ADM-Gly and bio-ADM, but not PAM, were associated with systemic inflammation and haemodynamic compromise. ADM-Gly and bio-ADM independently predicted CS risk in Switzerland (adjusted odds ratio [aOR] per log2 increase, 1.44, 95% confidence interval [CI] 1.22–1.71, P &amp;lt; .001 and aOR 1.37, 95% CI 1.10–1.70, P = .004) and France (adjusted risk ratio [RR] per log2 increase, 1.82, 95% CI 1.34–2.48, P &amp;lt; .001 and aRR 1.55, 95% CI 1.15–2.10, P = .004), and were associated with 1-year mortality risk (adjusted hazard ratio [aHR] per log2 increase, 1.33, 95% CI 1.09–1.61, P = .005 and aHR 1.46, 95% CI 1.15–1.86, P = .002). Addition of ADM-Gly and bio-ADM to the ORBI risk score improved its discrimination (Δ area under the receiver operating characteristic curve 0.02), reclassification (net reclassification improvement 0.229), and model fit (Δ Akaike information criterion −26.9), with consistent results in external validation.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>ADM-Gly and bio-ADM, but not PAM, independently predict in-hospital CS and 1-year mortality risk in initially stable patients with ACS and improve early risk stratification.</jats:p> </jats:sec>