Abstract 19517: Circulating Factors Contribute to PDE5-Mediated Pathological Myocardial Remodeling in Single Ventricle Congenital Heart Disease
Introduction: Single ventricle congenital heart disease (SV) is fatal without intervention, and maladaptive myocardial remodeling and eventual heart failure (HF) is a major cause of morbidity and mortality. Our previous studies demonstrated gene expression changes indicative of pathological myocardial remodeling (e.g., up-regulated BNP and MHC isoform switching) and increased PDE5 expression and activity in the systemic right ventricle (RV) of SV patients. Sildenafil, a phosphodiesterase-5 inhibitor (PDE5i), is increasingly utilized for the treatment of SV, with the pulmonary vasculature as the intended target. However, our data suggest potential myocardial effects of PDE5i. Our objective is to determine if myocardial and circulating PDE5 have a role in the induction of pathological gene expression changes seen in SV myocardium.
Methods: Circulating PDE5 levels in non-failing (NF) and SV sera and plasma were measured using an ELISA. Primary cardiomyocytes were isolated from neonatal rat ventricular myocardium (NRVMs) and treated for 72 hours with sera or serum-derived exosomes from NF control and SV patients ± sildenafil. qPCR was performed for the targets of interest.
Results: Circulating levels of PDE5 are significantly higher in SV patients (32±7.8 ng/mL) compared to NF (9±3.1 ng/mL) controls (p<0.05; n=3 SV, n=3 NF).Additionally, treatment of NRVMs with SV serum (n=14 SV and n=3 NF) and exosomes (n=6 SV, n=3 NF) recapitulates the pathological gene expression pattern that is seen in the human SV myocardium. Moreover, inhibition of PDE5 in NRVMs prior to exosome or serum treatment prevents these pathologic gene expression changes (n=9 serum, n=3 exosome).
Conclusions: SV circulating factors contribute to myocyte remodeling, and PDE5i attenuates this response. While additional investigation is necessary, these data suggest that in addition to effects on the pulmonary vasculature, PDE5i may be a direct myocardial target of therapy for the treatment of SV.
Author Disclosures: A.M. Garcia: None. S.J. Nakano: None. B.L. Stauffer: None. C.C. Sucharov: None. S.D. Miyamoto: Consultant/Advisory Board; Modest; Advisor to CoraMir.
- © 2016 by American Heart Association, Inc.