Abstract 18567: Acute Inhibition of Phosphodiesterase 1 (PDE1) Decreases Tension Generation in Pediatric Heart Failure

Abstract

Introduction: Children with heart failure (HF) due to dilated cardiomyopathy (DCM) or single ventricle congenital heart disease (SV) ultimately require heart transplantation due to the lack of effective medical therapies. Inhibition of PDE1 (PDE1i) is currently being investigated in adult HF, however it is unclear if PDE1i use should be extrapolated to pediatric HF. Objective: To evaluate the acute effect of PDE1i on loaded myocardial contractility in pediatric DCM and SV trabeculae. Methods: Hearts were obtained from DCM (N=25) and SV (N=27) children who underwent transplant between 2010-2020. Right ventricular trabeculae are freshly isolated and mounted in a multi-chamber muscle bath. Ex vivo contractile response of isolated trabeculae was measured in response to 10uM PDE1i, the non-selective β-agonist isoproterenol (Iso), and untreated. To assess contractile response with increased cyclic adenosine monophosphate (cAMP) from β-adrenergic stimulation, a subset of baths received Iso and PDE1i. Percent change in max tension was determined by the difference between max tension and baseline tension, divided by baseline tension. Results: In pediatric DCM and SV trabeculae, acute PDE1i resulted in lower max tension generation when compared to untreated trabeculae (DCM p=0.003 and SV p=0.01). In DCM trabeculae, % change in tension was also lower with PDE1i when compared to Iso (p=0.0053) however there was only a trend toward significance in SV (p=0.06). There was no difference between % change in tension between Iso and PDE1i+Iso in either DCM or SV. Conclusions: Although PDE1 has high expression and activity in human cardiomyocytes, acute PDE1i treatment of explanted trabeculae results in decreased max tension generation. Even in the setting of elevated cAMP, PDE1i does not alter max tension generation. Thus, while there may be beneficial effects of PDE1i in pediatric HF, the consequences are unlikely related to a direct increase in cardiomyocyte contractility.