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. 3
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.
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%.
Pediatric DCM patients
respond well to phosphodiesterase (PDE) 3 inhibition. We have characterized the
mechanisms involved in response to this therapy. Unfortunately, PDE3 inhibition
is delivered in an IV form. We are in the process of further characterizing the
response to PDE3 inhibition, including direct myocardial effects and
mitochondria function, with the intent of developing an oral formulation for
this patient population. 6 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
mechanisms leading to heart failure in pediatric patients with single ventricle
heart disease are largely unknown, although they are likely distinct from those
involved in pediatric dilated cardiomyopathy. Given the increasing use of PDE3
and PDE5 inhibitors in single ventricle heart disease, it is necessary to
develop a comprehensive understanding of various PDE isoforms in the heart,
focusing on their contributions to systolic and diastolic dysfunction.
Phosphodiesterase (PDE) 1 is the predominant cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP) hydrolyzing PDE in the
cytosol, and likely targets unique pools of these second messengers. PDE1 is
uniquely regulated in the hearts of single ventricle patients and our
investigations into the functional role of myocardial PDE1 may provide novel
pharmacologic targets in this population.
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)[add link to http://wiki.oroboros.at/index.php/OROBOROS_INSTRUMENTS]. 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
phosopholipid, 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. Children with Barth Syndrome [link to https://www.barthsyndrome.org/home], a disease affecting cardiolipin, develop cardiomyopathy
and provide a unique clinical population to study the disease process.
can be important biomarkers in several diseases. We have recently identified
four miRNAs that can predict the need for transplant in the pediatric DCM
population. In addition, circulating miRNAs as biomarkers of outcomes are being
study to predict/diagnose:
- Cardiac Allograft
- Right Heart Failure in
Single Ventricle Heart Disease
- Kawasaki Disease
Translation of molecular findings into children
with heart failure requires age-specific preclinical models to test
interventions. There are no pediatric specific animal models of heart failure.
The goal of this program is to be able to model clinically important phenotypes
and test therapeutics prior to implementation in the clinical population. We
have developed several small animal models to study the beta-adrenergic and
phosphodiesterase systems in the failing pediatric heart. These in vivo models
are paired with in vitro experiments to better explore the molecular mechanisms
of pediatric heart failure.
Brian Stauffer, M.D. Shelley Miyamoto, M.D. Carman Sucharov, Ph.D.
Associate Professor Associate Professor Associate Professor
Kathryn Chatfield, M.D. Stephanie Nakano, M.D.
Assistant Professor Assistant Professor
Genevieve Sparagna, Ph.D Kathleen Woulfe, Ph.D.
Assistant Professor Assistant Professor
Lee Toni, Ph.D. Anastacia Garcia, Ph.D.
Professional Research Assistants
Danielle Jeffrey, M.S. Carly Ferguson, B.S.
Karin Nunley, M.S Elisabeth Philips, B.S. Bonnie Neltner, B.S.
Cortney Wilson, B.S.