Myocardial Response to Milrinone in Single Right Ventricle Heart Disease

• Published in: The Journal of pediatrics 2016-07, Vol.174, p.199-203.e5
• Main Authors: Nakano, Stephanie J., MD, Nelson, Penny, MS, Sucharov, Carmen C., PhD, Miyamoto, Shelley D., MD
• Format: Article
• Language: English
• Subjects: Adenosine Monophosphate - metabolism; Calcium-Binding Proteins - metabolism; Cardiomyopathy, Dilated - drug therapy; Cardiomyopathy, Dilated - etiology; Cardiomyopathy, Dilated - metabolism; Child; Child, Preschool; cyclic adenosine monophosphate; Female; Heart Transplantation; Heart Ventricles - abnormalities; Humans; Infant; Male; Milrinone - therapeutic use; Myocardium - metabolism; pediatric heart failure; Pediatrics; phosphodiesterase; Phosphodiesterase 3 Inhibitors - therapeutic use; phospholamban; Phosphoric Diester Hydrolases - metabolism
• ISSN: 0022-3476; 1097-6833
• DOI: 10.1016/j.jpeds.2016.04.009

Objectives Empiric treatment with milrinone, a phosphodiesterase (PDE) 3 inhibitor, has become increasingly common in patients with single ventricle heart disease of right ventricular (RV) morphology (SRV); our objective was to characterize the myocardial response to PDE3 inhibition (PDE3i) in the pediatric population with SRV. Study design Cyclic adenosine monophosphate levels, PDE activity, and phosphorylated phospholamban (PLN) were determined in explanted human ventricular myocardium from nonfailing pediatric donors (n = 10) and pediatric patients transplanted secondary to SRV. Subjects with SRV were further classified by PDE3i treatment (n = 13 with PDE3i and n = 12 without PDE3i). Results In comparison with nonfailing RV myocardium (n = 8), cyclic adenosine monophosphate levels are lower in patients with SRV treated with PDE3i (n = 12, P  = .021). Chronic PDE3i does not alter total PDE or PDE3 activity in SRV myocardium. Compared with nonfailing RV myocardium, SRV myocardium (both with and without PDE3i) demonstrates equivalent phosphorylated PLN at the protein kinase A phosphorylation site. Conclusions As evidenced by preserved phosphorylated PLN, the molecular adaptation associated with SRV differs significantly from that demonstrated in pediatric heart failure because of dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of heart failure in pediatric patients with SRV, which has direct implications regarding the presumed response to PDE3i treatment in this population.