Cardiac Adenylyl Cyclase and Phosphodiesterase Expression Profiles Vary by Age, Disease, and Chronic Phosphodiesterase Inhibitor Treatment

Abstract

Background Pediatric heart failure (HF) patients have a suboptimal response to traditional HF medications, although phosphodiesterase-3 inhibition (PDE3i) has been used with greater success than in the adult HF population. We hypothesized that molecular alterations specific to children with HF and HF etiology may affect response to treatment. Methods and Results Adenylyl cyclase (AC) and phosphodiesterase (PDE) isoforms were quantified by means of quantitative real-time polymerase chain reaction in explanted myocardium from adults with dilated cardiomyopathy (DCM), children with DCM, and children with single-ventricle congenital heart disease of right ventricular morphology (SRV). AC and PDE expression profiles were uniquely regulated in each subject group and demonstratde distinct changes in response to chronic PDE3i. There was unique up-regulation of AC5 in adult DCM with PDE3i (fold change 2.415; P = .043), AC2 in pediatric DCM (fold change 2.396; P = .0067), and PDE1C in pediatric SRV (fold change 1.836; P = .032). Remarkably, PDE5A expression was consistently increased across all age and disease groups. Conclusions Unique regulation of AC and PDE isoforms supports a differential molecular adaptation to HF in children compared with adults, and may help identify mechanisms specific to the pathogenesis of pediatric HF. Greater understanding of these differences will help optimize medical therapies based on age and disease process.

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.…”

Heart Failure in Pediatric Patients With Congenital Heart Disease

“…106 Investigation of PDE isoform expression and responsiveness to PDE inhibition also differed in pediatric versus adult samples. 107, 108 While the approach to medical therapy is similar, there are a lack of data on the adaptive responses triggered in patients with structurally abnormal hearts as compared to those with primary heart muscle disease. In the investigation of PDE expression, intriguing differences were noted in samples from DCM explants as compared to single right ventricle CHD hearts in the myocardial response to milrinone.…”

“…In the investigation of PDE expression, intriguing differences were noted in samples from DCM explants as compared to single right ventricle CHD hearts in the myocardial response to milrinone. 108, 109 Additional studies are required to understand the characteristic adaptive programs invoked by ventricular dysfunction of different etiologies. These findings suggest a differential responsiveness to HF medical therapy depending on age, a conclusion that requires more investigation.…”

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.…”