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

BackgroundSecretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information and influences cardiomyocyte function is unknown.ObjectivesThis study sought to evaluate the merit of SN as a cardiovascular biomarker and assess effects of SN on cardiomyocyte Ca2+ handling.MethodsWe assessed the association between circulating SN levels and mortality in 2 patient cohorts and the functional properties of SN in experimental models.ResultsIn 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 δ (CaMKIIδ) activity via direct SN-CaM and SN-CaMKII binding and attenuated CaMKIIδ-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.ConclusionsSN provided incremental prognostic information to established risk indices in acute HF and ventricular arrhythmia-induced cardiac arrest.