Myocardial Response to Milrinone in Single Right Ventricle Heart Disease

Abstract

Objectives Empiric treatment with milrinone, a phosphodiesterase 3 inhibitor (PDE3i), has become increasingly common in patients with single ventricle heart disease of right ventricular morphology (SRV); our objective was to characterize the myocardial response to PDE3i in the pediatric population with SRV. Study design Cyclic adenosine monophosphate (cAMP) levels, phosphodiesterase (PDE) activity, and phospholamban phosphorylation (pPLN) were determined in explanted human ventricular myocardium from nonfailing pediatric donors (n=10) and pediatric patients transplanted secondary to SRV. SRV subjects were further classified by PDE3i treatment (n=13 with PDE3i and n=12 without PDE3i). Results In comparison with nonfailing RV myocardium, cAMP levels are lower in patients with SRV treated with PDE3i (p=0.021). Chronic PDE3i does not alter total PDE or PDE3 activity in SRV myocardium. When compared with nonfailing RV myocardium, SRV myocardium (both with and without PDE3i) demonstrates equivalent pPLN at the protein kinase A phosphorylation site. Conclusions As evidenced by preserved pPLN, the molecular adaptation associated with SRV differs significantly from that demonstrated in pediatric heart failure due to 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.

Heart Failure in Pediatric Patients With Congenital Heart 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. 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.…”

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

“…For example, despite up-regulation of PDE3A1-1 and PDE3B in SRV disease, PDE3 activity is not significantly changed in either the microsomal or the cytosolic compartments in SRV myocardium. 8 Additionally, the trend toward decreased PDE3A1-1 in SRV myocardium with PDE3i treatment is not reflected in decreased PDE3 activity in this group. 8 In this case, there is some disparity between mRNA expression and enzyme activity, with enzyme activity being the more physiologically relevant measurement.…”

“…8 Additionally, the trend toward decreased PDE3A1-1 in SRV myocardium with PDE3i treatment is not reflected in decreased PDE3 activity in this group. 8 In this case, there is some disparity between mRNA expression and enzyme activity, with enzyme activity being the more physiologically relevant measurement. However, assessment of PDE activity is based on specificity of inhibitors that cannot distinguish between different isoforms of the same family.…”

“…A decrease in global myocardial cAMP level is a common feature across multiple HF populations and phenotypes, specifically adults and children with DCM 7 and children with SRV, 8 suggesting that alterations in cAMP generation via adenylyl cyclases (ACs) or cAMP hydrolysis via phosphodiesterases (PDEs) may be involved in HF. Both ACs and PDEs have numerous isoforms with differing degrees of expression and activity in the myocardium.…”

“…Specifically, our previous work demonstrated that only pediatric DCM patients treated with PDE3i benefit from augmentation of myocardial cAMP and phospholamban phosphorylation, which may contribute to sustained hemodynamic benefits; these changes were not demonstrated in myocardium from adults with DCM 7 or children with SRV. 8 The differential response to PDE3i, both clinically and molecularly, is suggestive of fundamental differences in molecular adaptation to HF secondary to age and disease etiology. AC and PDE isoforms can uniquely target cAMP or cGMP and be present in different compartments.…”