Secretoneurin Is a Novel Prognostic Cardiovascular Biomarker Associated With Cardiomyocyte Calcium Handling

BACKGROUND Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information and influences cardiomyocyte function is unknown. OBJECTIVES This study sought to evaluate the merit of SN as a cardiovascular biomarker and assess effects of SN on cardiomyocyte Ca2_ handling. METHODS We assessed the association between circulating SN levels and mortality in 2 patient cohorts and the functional properties of SN in experimental models. RESULTS In 143 patients hospitalized for acute HF, SN levels were closely associated with mortality (n 66) during follow-up (median 776 days; hazard ratio [ lnSN]: 4.63; 95% confidence interval: 1.93 to 11.11; p 0.001 in multivariate analysis). SN reclassified patients to their correct risk strata on top of other predictors of mortality. In 155 patients with ventricular arrhythmia-induced cardiac arrest, SN levels were also associated with short-term mortality (n 51; hazard ratio [ lnSN]: 3.33; 95% confidence interval: 1.83 to 6.05; p < 0.001 in multivariate analysis). Perfusing hearts with SN yielded markedly increased myocardial levels and SN internalized into cardiomyocytes by endocytosis. Intracellularly, SN reduced Ca2_/ calmodulin (CaM)-dependent protein kinase II d (CaMKIId) activity via direct SN-CaM and SN-CaMKII binding and attenuated CaMKIId-dependent phosphorylation of the ryanodine receptor. SN also reduced sarcoplasmic reticulum Ca2_ leak, augmented sarcoplasmic reticulum Ca2_ content, increased the magnitude and kinetics of cardiomyocyte Ca2_ transients and contractions, and attenuated Ca2_ sparks and waves in HF cardiomyocytes. CONCLUSIONS SN provided incremental prognostic information to established risk indices in acute HF and ventricular arrhythmia-induced cardiac arrest. (J Am Coll Cardiol 2015; 65: 339-51) c 2015 by the American College of Cardiology Foundation.