Abstract 17697: Myocardial Response to Milrinone in Single Ventricle Heart Disease

Abstract

Background: Single ventricle heart disease (SV) is a subset of congenital heart defects characterized by a univentricular circulation. Despite surgical intervention, progressive heart failure (HF) is a common cause of death and indication for heart transplantation in children with SV. The exact mechanisms underlying SV HF are poorly understood, limiting the ability to identify effective therapies. Empiric treatment with milrinone, a phosphodiesterase 3 inhibitor (PDE3i), has become increasingly common in SV HF; however the response to milrinone has yet to be characterized in the pediatric SV population. The purpose of this study was to determine the myocardial response to PDE3i in children with SV. Methods and Results: Cyclic adenosine monophosphate (cAMP) levels, phosphodeisterase (PDE) activity, and phospholamban phosphorylation (pPLB) were determined in explanted human ventricular myocardium from non-failing pediatric donors (n=10) and pediatric patients transplanted secondary to SV HF (of right ventricular [RV] morphology). SV HF subjects were divided into those who received milrinone therapy (n=13) and those who did not (n=12). In comparison to non-failing RV myocardium, cAMP levels are lower in SV HF patients treated with milrinone (ANOVA, p=0.046). Chronic milrinone treatment does not alter total PDE or PDE3 activity in SV myocardium. Additionally, when compared with non-failing RV myocardium, SV myocardium (both with and without milrinone) demonstrates equivalent pPLB at the protein kinase A site (serine 16 residue). Conclusions: As evidenced by preserved pPLB, the molecular adaptation associated with SV HF differs significantly from that demonstrated in pediatric HF due to dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of HF in pediatric SV patients, which has direct implications regarding the putative response to PDE3i treatment in this population.