Functional Characterization of Phosphodiesterase 1 in Single Ventricle Heart Disease

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Project Summary This Mentored Clinical Scientist Development Award proposal describes a 5-year training program to allow Dr. Nakano (PI) the opportunity to develop an academic career in the field of pediatric heart failure. Dr. Nakano has completed clinical pediatric cardiology fellowship at the University of Colorado and basic cardiovascular research training through a T32 mechanism. Dr. Nakano’s career aspiration is to become an independent physician scientist and improve outcomes in pediatric heart failure through molecular investigations. Single ventricle heart disease (SV) is a subset of congenital heart defects that are universally fatal without intervention. Progressive heart failure (HF) is a common cause of death and indication for heart transplantation in children with SV. The exact mechanisms underlying SV HF are poorly understood, limiting the ability to identify effective therapies. The extrapolation of proven adult HF medications to the pediatric SV HF population has been unsuccessful, consequently novel treatment paradigms are needed. Pharmacologic inhibition of select phosphodiesterase (PDE) enzymes has become increasingly common therapy for SV HF, with the primary goal of augmenting contractility through increasing cyclic adenosine monophosphate (cAMP) with PDE3 inhibition (PDE3i). However our studies suggest that, on a molecular level, PDE3i is not effective therapy in SV HF; this is in stark contrast to what is found with PDE3i in pediatric patients with HF due to dilated cardiomyopathy. Thus, it is necessary to elucidate the role of other PDEs in the heart, particularly PDE1: 1) PDE1 is the predominant cAMP- and cyclic guanosine monophosphate (cGMP)- hydrolyzing PDE in the cytosol, 2) PDE1 is localized to the sarcomere and likely targets a unique pool of cAMP, and 3) PDE1 inhibition (PDE1i) decreases hypertrophy mediated through cGMP pathways. In this proposal, we will determine: 1) PDE1 localization and activity in explanted SV myocardium, and measure the functional effects of acute PDE1i in SV trabeculae; 2) the role of PDE1 in calcium sensitivity and relaxation kinetics in myocytes and myofibrils isolated from SV myocardium; and 3) the contribution of PDE1 in pathologic remodeling using neonatal rat ventricular myocytes treated with sera from SV subjects. Elucidating the molecular and functional role of PDE1 in the SV myocardium would provide justification for developing PDE1i for clinical use in this population, where current outcomes are unacceptably poor. PDE1i therapy could potentially prevent HF development or delay the need for heart transplantation in these high-risk, SV patients. Within an optimal, mentored environment, Dr. Nakano will gain new research expertise that will be essential to conducting future translational cardiovascular research as an independent investigator. Dr. Nakano has the support of clinical, research, pediatric, and adult cardiology expertise and resources at the University of Colorado, including the University’s large human heart tissue bank. Dr. Nakano will continue to work with her current mentor team at the University of Colorado, who are committed to her success.