Circ Heart Fail 2015 Jan 2;8(1):57-63. Epub 2014 Oct 2.
From the Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora (S.J.N., S.D.M.); Cardiology Section, Veterans Affairs Salt Lake City Health Care System and the Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah School of Medicine (M.M.); Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora (P.N., B.L.S., C.C.S.); and Division of Cardiology, Department of Medicine, Denver Health and Hospital Authority, CO (B.L.S.).
Background: Despite the application of proven adult heart failure therapies to children with idiopathic dilated cardiomyopathy (IDC), prognosis remains poor. Clinical experience with phosphodiesterase 3 inhibitors (PDE3i) in pediatric patients with IDC, however, demonstrates improved heart failure symptoms without the increased incidence of sudden death seen in adults treated with PDE3i. We sought to determine age-related differences in PDE activity and associated intracellular signaling responsible for the efficacy and relative safety of chronic PDE3i in pediatric heart failure.
Methods And Results: cAMP levels, PDE activity, and phospholamban phosphorylation (pPLB) were determined in explanted human left ventricular myocardium (pediatric n=41; adult n=88). Adults and children with IDC (not treated with PDE3i) had lower cAMP and pPLB compared with nonfailing controls. In contrast to their adult counterparts, pediatric IDC patients chronically treated with PDE3i had elevated cAMP (P=0.0403) and pPLB (P=0.0119). In addition, total PDE- and PDE3-specific activities were not altered in pediatric IDC patients on PDE3i, whereas adult IDC patients on PDE3i demonstrated higher total PDE-specific (74.6±13.8 pmol/mg per minute) and PDE3-specific (48.2±15.9 pmol/mg per minute) activities in comparison with those of nonfailing controls (59.5±14.4 and 35.5±12.8 pmol/mg per minute, respectively).
Conclusions: Elevated cAMP and higher pPLB may contribute to sustained hemodynamic benefits in pediatric IDC patients treated with PDE3i. In contrast, higher total PDE and PDE3 activities in adult IDC patients treated with PDE3i may perpetuate lower myocardial cAMP and pPLB levels, limiting the potential benefits of PDE3i therapy.