Heart Failure (HF) is one of the leading causes of death in the developed world. In children, dilated cardiomyopathy (DCM) is the most common indication for heart transplant in children older than 1 year of age. Unfortunately, therapy developed in adults with DCM may not translate directly to efficacy in pediatric DCM populations. To better understand the molecular mechanisms involved in pediatric DCM, we have identified molecular pathways specifically dysregulated in this patient population. Transcriptome profile and target gene approach of pediatric and adult DCM patients revealed dysregulation of age-specific genes, suggesting that pediatric DCM is a unique disease process.

A novel approach, developed by our group, consists of treatment of primary cardiomyocytes with serum and exosomes from pediatric DCM patients. Serum treatment results in pathologic remodeling of these cells. We are in the process of identifying factors present in the serum of these patients. We recently showed that serum exosomes can induce a pathologic response in primary cardiomyocytes.

Single ventricle congenital heart disease (SV) is the leading cause of cardiovascular death and indication for heart transplantation in infancy. SV comprises a spectrum of cyanotic congenital cardiac malformations that are defined by hypoxia and a univentricular circulation. These defects are universally fatal without intervention and despite advances in medical and surgical therapies, the 1-year survival for SV in the current era is only 68.7%.

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There are currently no proven therapies for SV heart failure (HF) and identification of targeted therapies specific to the failing SV are needed in order to improve outcomes. Phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are used for the treatment of primary pulmonary hypertension in children due to their proven vasodilatory effects. Over the past few years, use of PDE5i in those with SV HF has increased dramatically. While the stated target of therapy in SV patients is the pulmonary vascular bed, there is increasing evidence that PDE5i has beneficial myocardial remodeling and functional effects. The central hypothesis of this project is that PDE5i has direct myocardial effects in SV that result in augmented cardiac function, effects on cGMP-regulated signaling pathways and altered sarcomeric protein phosphorylation. This project is the first to determine myocardial effects of PDE5i in pediatric SV hearts and will correlate molecular findings with function.

Abnormalities in mitochondria are well demonstrated in cardiovascular disease and may lead to functional impairments in the myocardium. Our laboratory studies mitochondrial function in the human heart using spectrophotometric methods and high resolution respirometry (Oroboros O2K). We are interested in how the mitochondrial electron transport system supercomplex affects the mitochondria's ability to function properly in both electron transport and beta oxidation. Changes in mitochondrial membrane phospholipids have been linked to mitochondrial function in several model systems. We can determine the cardiac mitochondrial phospholipid, cardiolipin and the acyl CoA content in the human heart tissue using liquid chromatography coupled to electrospray ionization mass spectrometry and are interested in understanding the association between changes and clinical pathology in humans and in our age-specific animal models of heart failure.

Circulating miRNAs and proteins can be important biomarkers in several diseases. We have recently identified miRNAs and proteins that can predict the need for transplant in the pediatric DCM population. We are now exploring the biological effect of these circulating factors in cardiac myocytes and cardiac fibroblasts.

Translation of molecular findings into children with heart failure requires age-specific preclinical models to test interventions. We now developed two pediatric specific animal models of heart failure. The goal of this program is to understand disease mechanisms, to model clinically important phenotypes and test therapeutics prior to implementation in the clinical population. These in vivo models are paired with in vitro experiments to better explore the molecular mechanisms of pediatric heart failure.

Link to Sucharov publications:

https://www.ncbi.nlm.nih.gov/myncbi/carmen.sucharov.1/bibliography/public/

Links to Miyamoto publications:

Miyamoto: https://www.ncbi.nlm.nih.gov/myncbi/shelley.miyamoto.1/bibliography/public/

Links to Stauffer publications:

Stauffer: https://www.ncbi.nlm.nih.gov/myncbi/brian.stauffer.1/bibliography/public/

Link to Sparagna publications:

Sparagna: https://www.ncbi.nlm.nih.gov/myncbi/genevieve.sparagna.2/bibliography/public/