Abstract 18847: Secretoneurin Provides Independent Prognostic Information in Patients with Heart Failure and Cardiac Arrest, and has a Direct Inhibitory Effect on Diastolic Ca2+ Leak and Arrhythmogenic Ca2+ Waves via CaMKIId Inhibition

Background: Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information in cardiovascular disease (CVD) and influences cardiomyocyte function are not known. Methods and Results: Circulating SN was measured 2+ /calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ). SN attenuated CaMKIIδ activity, reduced CaMKIIδ-dependent ryanodine receptor (RyR) phosphorylation, lowered diastolic Ca 2+ leak at different concentrations, and increased sarcoplasmic reticulum Ca 2+ content. These results were also consistent with results from cardiomyocytes of HF animals, as SN reduced RyR leak in HF reflected by less Ca 2+ sparks and waves. SN also reduced basal and isoproterenol (ISO)-induced frequency and dimensions of Ca 2+ sparks and the development of arrhythmogenic Ca 2+ waves, attenuated ISO-induced CaMKIIδ autophosphorylation, and reduced CaMKIIδ-induced RyR phosphorylation in the presence of ISO. Conclusions: SN is a novel CV biomarker that provides independent prognostic information to established risk indices and reduces diastolic Ca 2+ leak and arrhythmogenic Ca 2+ waves via direct CaMKIIδ inhibition, which identifies high SN levels as a compensatory mechanism in the most severely ill patients.