Age-Related Differences in Phosphodiesterase Activity and Effects of Chronic Phosphodiesterase Inhibition in Idiopathic Dilated Cardiomyopathy

Abstract

Background Despite the application of proven adult heart failure (HF) therapies to children with idiopathic dilated cardiomyopathy (IDC), prognosis remains poor. Clinical experience with phosphodiesterase 3 inhibitors (PDE3i) in pediatric IDC patients, however, demonstrates improved HF 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 HF. Methods and Results Cyclic adenosine monophosphate (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 non-failing 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). Additionally, total PDE and PDE3 specific activities were not altered in pediatric IDC patients on PDE3i, while adult IDC patients on PDE3i demonstrated higher total PDE (74.6 pmol/mg/min ± 13.8) and PDE3 (48.2 pmol/mg/min ± 15.9) specific activities in comparison to those of non-failing controls (59.5 pmol/mg/min ± 14.4 and 35.5 pmol/mg/min ± 12.8, 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.

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

“…Therefore, there is a clear need for new approaches to better understand this disease process. Our work has shown differences in the molecular characteristics of pediatric and adult DCM hearts (4)(5)(6)(7)(8). These differences suggest that there are underlying myocardial cellular mechanisms uniquely regulated in children with HF.…”

Genetics of paediatric cardiomyopathies

“…(40) Phosphodiesterase isoform expression and responsiveness to phosphodiesterase inhibition also differed in pediatric versus adult samples. (41, 42) Defining normal transcriptional profiles during infancy and other pediatric age ranges is important to better understand how to optimize treatment approaches.…”

Myocardial Response to Milrinone in Single Right Ventricle Heart Disease

“…Approximately 150 mg of myocardium was homogenized and separated into nuclear, cytosolic and sarcoplasmic reticulum-enriched microsomal fractions by differential sedimentation, as previously described 16 .…”

“…By de-inhibiting SERCA, increased protein kinase A (PKA)-mediated phosphorylation of PLN (pPLN) accelerates calcium re-uptake into the sarcoplasmic reticulum and increases sarcoplasmic reticulum calcium content, contributing to both lusitropic and inotropic effects, respectively 15 . We have previously demonstrated that PKA-mediated pPLN is increased in children with dilated cardiomyopathy (DCM) chronically treated with PDE3i, and may contribute to increased contractility resulting in the sustained clinical benefit of PDE3i treatment in that population 16 . However, it is unlikely that the molecular perturbations in SRV are akin to those in pediatric DCM; thus, given the widespread clinical use our objective was to characterize the molecular response to PDE3i in this unique population.…”