Abstract 185: Chromogranin A is a Potent Prognostic Biomarker in Acute Heart Failure, and its Fragment Catestatin Regulates Cardiomyocyte Calcium Homeostasis by Camkiiδ Inhibition

Abstract

Background: Circulating chromogranin A (CgA) levels have been found associated with clinical outcomes in cardiovascular disease, but whether the CgA fragment catestatin (CST) may directly modulate cardiomyocyte Ca 2+ handling is not known. Methods: The prognostic utility of circulating CgA levels were compared between patients with acute HF (n=143) and chronic acute obstructive pulmonary disease (COPD, n=84). Functional effects of CST were assessed in isolated cardiomyocyte and explanted hearts. Results: CgA levels were associated with mortality in acute HF patients, but not in acute COPD. (Figure; patients stratified according to CgA quartiles on hospital admission). Admission CgA levels were also associated with mortality after adjusting for other risk factors in multivariate analysis. We found CST to interact with Ca 2+ /calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ) and to inhibit CaMKIIδ activity. CST also reduced CaMKIIδ-dependent phosphorylation of the ryanodine receptor 2 and phospholamban. In line with CaMKIIδ inhibition, CST reduced Ca 2+ spark and wave frequency, attenuated Ca 2+ sparkdimensions, increased sarcoplasmic reticulum Ca 2+ content, andaugmented magnitude and kinetics of cardiomyocyte Ca 2+ transients and contractions. Frequency dependent acceleration of relaxation was most pronounced in the Control group, an indication of CaMKIIδ activation, and this was attenuated by CST. Conclusions: CgA regulates cardiomyocyte Ca 2+ handling via CaMKIIδ inhibition, which makes CgA an interesting CV biomarker and potential compensatory mechanism in situations of enhanced CaMKIIδ activity.