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

Abstract

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. 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. 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 < .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 < .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. 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.