This Mentored Patient-Oriented Research Career Development proposal will provide for a structured environment with expert mentorship and an adequate subject population facilitating Dr. Jonathan Soslow's development as an independent clinical investigator. Dr. Soslow is an Assistant Professor of Pediatric Cardiology at Vanderbilt University Medical Center. He trained in pediatric cardiology at Vanderbilt University, including a fourth year in advanced cardiac imaging (complex transthoracic echocardiography, transesophageal echocardiography, and cardiac MRI). Dr. Soslow's long-term goal is to use non-invasive methods to improve diagnosis and monitoring in DMD cardiomyopathy and other forms of pediatric cardiomyopathy. This K23 proposal will strengthen his knowledge of physics and physiology, allowing him to better interface with bioengineers and physicists in the design and implementation of new MRI sequences. He will gain a unique skillset in advanced pediatric cardiac imaging, biomarker evaluation, and statistical analysis that will facilitate his transitionto an independent investigator. Dr. Soslow's mentorship team is uniquely qualified to support him in this endeavor. Strengths include expertise in non-invasive imaging and physiology (Damon), specialist in DMD cardiac care and research and general clinical research design and study conduct (Markham), expertise in heart failure and biomarkers (Sawyer), and expertise in cardiac MRI (Raman and Arai). His mentors have a documented history of successful mentorship of junior faculty. The skills that Dr. Soslow will develop during this award, combined with his current didactic coursework in the Master of Science in Clinical Investigation (MSCI) program, his excellent mentorship, and the research environment at Vanderbilt, will set him on the path towards a career as an independent investigator with R01 funding. Duchenne muscular dystrophy (DMD) is a devastating disease that affects 1 in 3500 boys. Despite significant research advances, patients with DMD continue to die, wheelchair bound, in their twenties. Cardiovascular disease is the leading cause of death in DMD, but the timing and pace of progression to cardiomyopathy is variable. While echocardiographic screening can detect cardiac dysfunction, echocardiography is a poor surrogate marker of disease. Echocardiographic dysfunction likely represents an end stage fibrotic myocardium that is unresponsive to remodeling therapies. Studies demonstrate that early initiation of cardiac specific therapy, prior to manifest systolic dysfunction, can decrease morbidity and delay mortality. Therefore, a better surrogate marker would allow for earlier, focused therapy, potentially altering disease progression and reducing cardiovascular mortality. Fibrosis plays an integral role in the development of DMD cardiomyopathy. Serum and imaging biomarkers of fibrosis are promising methods to identify patients at risk for an accelerated pace of progression to heart failure. Research has demonstrated that proteins secreted by skeletal muscle tissue, or myokines, can modulate the function of distant organs. This concept led us to hypothesize that maintenance of skeletal muscle mass and function, through the secretion of said myokines, is cardioprotective. Our preliminary data fit this model. We have demonstrated a direct relationship between preserved skeletal and cardiac function after loss of ambulation and have established that DMD patients with heart failure have lower levels of neuregulin- 1B (NRG), a candidate myokine. The central hypothesis of this proposal is that serum and imaging biomarkers detect subclinical myocardial fibrosis and can be used as surrogate markers of disease in DMD. We further postulate that maintaining residual skeletal muscle function is cardioprotective, and that this cardioprotection is modulated by NRG and insulin-like growth factor I (IGF-I).
Aim 1 will evaluate serum and imaging biomarkers of fibrosis and assess whether abnormalities in these biomarkers precede left ventricular dysfunction.
This aim will have a direct, meaningful application to clinical care in DMD, allowing for early cardiovascular therapy, assessment and modification of this therapy, and evaluation of novel therapeutic agents.
Aim 2 will evaluate the interaction between skeletal and cardiac muscle function. The results of this aim will inform future studies to prevent DMD cardiomyopathy, including a study evaluating continued corticosteroid therapy after loss of ambulation and a study on the effects of isometric exercise on cardiomyopathy.
Aim 3 will assess the postulated cell-signaling mechanism of skeletal and cardiac interaction by evaluating two candidate myokines, NRG and IGF-I.
This aim will potentially lead to future therapeutic strategies in DMD. This project will advance our understanding of DMD cardiomyopathy and the interaction between skeletal and cardiac muscle, allowing for meaningful changes in DMD care and spring-boarding the candidate to a successful career as an independent investigator.

Public Health Relevance

Heart dysfunction is the leading cause of death in boys with Duchenne muscular dystrophy (DMD), but the timing of onset and pace of progression is variable. This study will evaluate serum and imaging markers of scarring in the heart and the ability to predict heart dysfunction, informing earlier, novel treatments to decrease complications and delay death. In addition, the study will investigate the relationship between skeletal and heart muscle dysfunction and evaluate blood levels of proteins that have the potential to be used as novel medical therapies in patients with DMD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1)
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Scott, Jane
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Vanderbilt University Medical Center
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Godown, Justin; Smith, Andrew H; Thurm, Cary et al. (2018) Mechanical circulatory support costs in children bridged to heart transplantation - analysis of a linked database. Am Heart J 201:77-85
Godown, Justin; Thurm, Cary; Hall, Matt et al. (2018) Changes in Pediatric Heart Transplant Hospitalization Costs Over Time. Transplantation 102:1762-1767
Bradham, William; Ormseth, Michelle J; Elumogo, Comfort et al. (2018) Absence of Fibrosis and Inflammation by Cardiac Magnetic Resonance Imaging in Rheumatoid Arthritis Patients with Low to Moderate Disease Activity. J Rheumatol 45:1078-1084
Godown, Justin; Dodd, Debra A; Stanley, Michael et al. (2018) Changes in left ventricular strain parameters following pediatric heart transplantation. Pediatr Transplant 22:e13166
Simpson, Scott A; Field, Suzanne L; Xu, Meng et al. (2018) Effect of Weight Extremes on Ventricular Volumes and Myocardial Strain in Repaired Tetralogy of Fallot as Measured by CMR. Pediatr Cardiol 39:575-584
Chew, Joshua D; Soslow, Jonathan H; Thurm, Cary et al. (2018) Heart Transplantation in Children with Turner Syndrome: Analysis of a Linked Dataset. Pediatr Cardiol 39:610-616
Chew, Joshua D; Markham, Larry; Smith, Holly M et al. (2018) Assessment of brain-derived neurotrophic factor and osteopontin in a healthy pediatric population. J Circ Biomark 7:1849454418806136
Raucci Jr, Frank J; Parra, David A; Christensen, Jason T et al. (2017) Synthetic hematocrit derived from the longitudinal relaxation of blood can lead to clinically significant errors in measurement of extracellular volume fraction in pediatric and young adult patients. J Cardiovasc Magn Reson 19:58
Soslow, Jonathan H; Godown, Justin (2017) Non-invasive detection of myocardial fibrosis in pediatric heart transplant recipients: The role of cardiovascular magnetic resonance. Pediatr Transplant 21:
Godown, Justin; Thurm, Cary; Dodd, Debra A et al. (2017) A unique linkage of administrative and clinical registry databases to expand analytic possibilities in pediatric heart transplantation research. Am Heart J 194:9-15

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