About

Jonathan J Edwards, MD, is an Assistant Professor of Pediatrics (Cardiology) at the Children's Hospital of Philadelphia and a faculty member at the Perelman School of Medicine at the University of Pennsylvania. His clinical expertise includes pediatric cardiomyopathy, heart failure, and transplantation. His research focuses on right ventricular failure, with specific investigations into the cellular and transcriptional landscape of human hypoplastic left heart syndrome, the proteostatic imbalances driving right ventricular heart failure, and the impact of heart transplant allocation changes on patient outcomes. Dr. Edwards has contributed to understanding the molecular mechanisms underlying pediatric heart failure and has been involved in innovative surgical approaches such as hybrid stage 1 palliation with off-pump ventricular assist device placement in neonates with high-risk single ventricle anatomy. His work also explores the activation of metabolic pathways in the human heart, such as the role of SGLT2 inhibitors in activating pantothenate kinase. Dr. Edwards holds a BS in Biology and Chemistry from East Carolina University and earned his MD from Wake Forest School of Medicine.

Research topics

• Medicine
• Chemistry
• Cardiology
• Chromatography
• Internal medicine
• Biochemistry

Selected publications

• “There’s a Little Bit of Watergate in All of Us”: Billy Graham, Richard Nixon, and the Politics of Spiritual Authority in 1973

  Southern Communication Journal · 2026-01-23

  article1st authorCorresponding
  PublisherDOI

• mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation

  Science Signaling · 2026-04-21

  article

  Cardiomyocytes depend on local translation for growth and can undergo directed growth in length or width in response to different stimuli. Protein synthesis is augmented during concentric hypertrophy, which leads to thickening of the heart muscle by increasing cardiomyocyte width. Protein synthesis is controlled at the translation initiation step, when ribosome loading onto transcripts is regulated by the sequential phosphorylation of the eukaryotic initiation factor 4E–binding protein 1 (4EBP1). Here, we identified a mode of 4EBP1 phosphorylation that was associated with concentric hypertrophy in cultured cardiomyocytes and mouse hearts. Whereas canonical phosphorylation of 4EBP1 by mTORC1 regulates global protein synthesis rates, mTORC1- and nuclear ERK–dependent phosphorylation of 4EBP1 was specifically activated during concentric but not eccentric hypertrophy. Nuclear ERK–dependent phosphorylation of 4EBP1 at Ser 64 was necessary and sufficient to relocalize translation initiation sites closer to the nuclei. ERK activation drove redistribution of ribosomes and nascent translation toward the center of the cardiomyocyte without altering global mRNA distribution, leading to spatially enriched deposition of new sarcomeric protein in the cardiomyocyte interior. Together, these findings demonstrate that global protein synthesis can be spatially regulated by the activation of different kinases in distinct subcellular compartments and identify a mechanism that drives concentric hypertrophy.

  PublisherDOI

• Elevated Heart Rate is Associated with Increased Mortality and Rejection in Pediatric Heart Transplant Recipients

  JHLT Open · 2026-05-01

  articleOpen access

  Purpose: Elevated heart rate is associated with adverse outcomes in patients with heart failure.Heart transplant recipients often have elevated heart rate; however, the long-term associations of elevated heart rate with clinical outcomes are unknown. Methods:The records of all pediatric (21 years) heart transplant recipients at our institution were reviewed.Patients who died or lacked a clinic visit within one year following heart transplant were excluded, as were those with a permanent pacemaker.Heart rate was collected from outpatient electrocardiograms and converted to Z-scores using age-specific normative data.The cohort was divided into elevated and normal heart rate groups, with elevated heart rate defined as average HR Z-score 95th percentile during the first post-transplant year.Outcomes, including survival, rejection, and cardiac allograft vasculopathy were compared between groups.Results: A total of 110 pediatric heart transplants were included (median age 11.4 years; 62% male).Thirty-six (33%) had elevated heart rate.The elevated heart rate group was older (15.8 vs.6.1 years, p<0.001) and had shorter follow-up (3.0 vs. 4.7 years, p=0.007).Elevated heart rate was independently associated with increased risk of death (HR 3.98, 95% CI 1.20-13.2,p=0.024) and a composite of death or rejection (HR 3.31, 95% CI 1.47-7.45,p=0.004), but not cardiac allograft vasculopathy. Conclusion:Among patients who survive the first year after pediatric heart transplantation, elevated heart rate during the first post-transplant year is independently associated with increased risk of mortality and rejection.Further work is necessary to determine whether pharmacologic modulation mitigates this risk.

  PublisherOA PDFDOI

• Abstract 4363274: Evolutionarily Conserved Signatures of Adaptive Right Ventricular Remodeling

  Circulation · 2025-11-03

  article1st authorCorresponding

  Background: Right ventricular failure (RVF) has a high mortality risk across multiple heart diseases, has no proven therapies, and has few identified candidate targets suitable for testing in preclinical models. Research Goal: Identify evolutionarily conserved signatures of adaptive and maladaptive RV responses in human dilated cardiomyopathy (DCM) and mouse pulmonary artery band (PAB). Methods: Total and phosphoproteomics was performed for 56 human RVs (n= 16 nonfailing (NF), n=40 DCM) and 18 mice (n=6 sham, n=12 PAB). We used hemodynamic and echocardiographic assessments of DCM and PAB RVs to differentiate disease-associated from adaptive and maladaptive signatures by Voom/Limma, weighted correlation network analyses, and direct queries for sex-conserved patterns. We performed pathway enrichment analyses in Enrichr. Results: Right ventricular DCM and PAB differential protein abundances were broadly but modestly conserved (rho 0.34, P&lt;0.0001) and revealed loss of mitochondrial/metabolic proteins and increase in extracellular matrix/TGFβ, collagen, and cell junction proteins. Adaptive/maladaptive signatures converged on actin and cell membrane remodeling, metabolic, proteostatic, and fibrotic proteins. Adaptive responses included increase in skeletal muscle ACTA1, enhanced sarcomeric actin treadmilling (e.g. CFL2), and cell membrane repair mechanisms (e.g. PARVA and TRIM72 phosphorylation). Whereas non-sarcomeric actin remodeling was maladaptive driven by a noncanonical WNT signaling axis involving small GTPases, WAVE2 complex, and ARP2/3. Loss/inhibition of oxidative phosphorylation, fatty acid oxidation, and malate-aspartate shuttle occurred in DCM/PAB independent of outcomes, whereas activation of pyruvate metabolism via downregulation of PDK1/4 and disinhibition of PDH1A was adaptive. Adaptive proteostatic signatures included slowed protein synthesis and enhanced folding, with mixed evidence for increase and decreased protein turnover involving autophagy, proteasome, and urea cycle. Maladaptive fibrotic signatures included stepwise increases in COL12A1, COL18A1, FN1, FMOD, LTBP2, and POSTN. Conclusion: Signatures of human adaptive RV remodeling that are conserved in mice—and therefore testable—include enhanced sarcomeric actin turnover, cell membrane repair, activation of pyruvate metabolism, and chaperone capacity exceeding protein synthetic needs.

  PublisherDOI

• CD3-Based Dosing of Antithymocyte Globulin is Effective in Immunologically Low-Risk Pediatric Heart Transplant Recipients

  The Journal of Heart and Lung Transplantation · 2025-04-01

  article
  PublisherDOI

• Impact of Neighborhood Factors on Exercise Capacity in Children With Hypertrophic Cardiomyopathy

  Circulation Heart Failure · 2025-06-19 · 1 citations

  article

  BACKGROUND: Restricting certain patients with hypertrophic cardiomyopathy (HCM) from exercise likely has negative cardiovascular effects and has not been shown to reduce the risk of sudden cardiac death. Promoting exercise in children with HCM is complex and requires knowledge of the environmental factors that impact exercise capacity in children with HCM. METHODS: This retrospective, cross-sectional analysis includes children with HCM who underwent exercise stress testing at a single, children's tertiary-care center between 2000 and 2023. Addresses from contemporaneous exercise stress testing were accessed and geocoded to census tracts. The child opportunity index was the primary exposure of interest. Granular neighborhood measures including the walkability index, rural-urban commuting area codes, index of concentration at the extremes, and uniform crime reporting rates were measured. The primary outcome measure was peak oxygen consumption. Linear regression and multivariable analyses were performed. RESULTS: A total of 155 patients were identified who met inclusion criteria, 23% (n=35) of whom were female. The mean age at the time of exercise stress testing was 15.8±3.1 years. More than half of the included patients were from a high or very high child opportunity index (30%, n=46, and 35%, n=54, respectively). Most patients lived in urban environments (rural-urban commuting area codes score, 1 or 2, 96.7%, n=150). The mean peak oxygen consumption was 2159±906 mm/min, and the adjusted peak oxygen consumption was 35.5±9.3 mL/kg per min. A multivariate model adjusting for disease severity, age at diagnosis of HCM, race, and accounting for collinearity showed that low child opportunity index, higher levels of urbanization, and lower concentration of neighborhood wealth were independently associated with lower peak oxygen consumption. CONCLUSIONS: Our study identified previously unrecognized environmental determinants of exercise capacity in children with HCM, with lower child opportunity index, increased urbanization, and lower neighborhood wealth independently associated with lower exercise performance. Programs designed to increase physical activity levels and exercise performance in children with HCM should account for neighborhood and economic factors.

  PublisherDOI

• Cardiac Resynchronization Therapy to Aid Ventricular Assist Device Explantation in Infants with Cardiomyopathy and Left Bundle Branch Block

  Pediatric Cardiology · 2025-09-11

  article
  PublisherDOI

• Allosensitization Status Predicts Excess Mortality in Congenital Heart Disease Transplant Recipients in the Current Era: An Analysis of the United Network for Organ Sharing Database

  medRxiv · 2025-02-10

  preprintOpen access

  Abstract Background Allosensitization in pediatric heart transplantation (HT) is a challenging problem, with ongoing uncertainty as to optimal management strategy. Patients with congenital heart disease (CHD) have the highest risk of allosensitization and may be at risk for inferior outcomes following HT due to an accumulation of risk factors. Methods The United Network for Organ Sharing database was studied for all patients &lt;18 years of age with CHD undergoing HT between April 2015 and December 2020. Patients were grouped into three categories of allosensitization status based on calculated panel reactive antibody (cPRA) obtained closest to the time of HT: nonsensitized (cPRA &lt;10%), moderately sensitized (cPRA 10% - &lt;80%), and highly sensitized (cPRA ≥80%). The primary outcome measures of interest were one-year patient and graft survival following HT. Multivariable analysis was used to control for differences in preoperative clinical characteristics among sensitization categories. Results During the study period, 1086 patients with CHD underwent HT at a median of 3 years of age. Nonsensitized patients comprised 70% of the cohort; 22% were moderately sensitized and 9% were highly sensitized. Unadjusted 1-year mortality was 25% in the highly sensitized group compared to 8.7% in the nonsensitized group (P&lt;0.001). After adjustment, highly sensitized patients were &gt;3 times more likely to die within the first year than nonsensitized patients (HR 3.44, 95% CI 2.13 - 5.54, P&lt;0.001). The relationship between cPRA and crossmatch result was also assessed using multivariable regression. A variety of crossmatches were performed, including cytotoxicity and flow cytometry modalities. Regardless of crossmatch result, highly sensitized patients had an increased risk of one-year mortality and graft failure compared to nonsensitized and moderately sensitized patients (HR 3.4, 95% CI 1.98 – 5.84, P&lt;0.001 and HR 3.32, 95% CI 1.94 – 5.67, P&lt;0.001 for one-year mortality and the composite of death or graft failure, respectively). Conclusions Highly sensitized patients with CHD undergoing HT in the current era experience 25% 1-year mortality, which is significantly worse than less sensitized or nonsensitized patients. The magnitude of sensitization as reflected by cPRA, is highly predictive of adverse outcomes. These at-risk patients remain in need of more effective therapies for desensitization and management of the consequences of anti-HLA antibodies following HT. Clinical Perspective What is New? Allosensitization to HLA antigens is a common problem in pediatric heart transplantation, and outcomes remain suboptimal in allosensitized patients undergoing heart transplantation. Patients with CHD are at the highest risk of allosensitization. In the current study, highly sensitized children with CHD undergoing heart transplantation in the current era experience 25% 1-year mortality following heart transplantation, which is significantly higher than in other groups undergoing transplantation. Allosensitization status, regardless of crossmatch result, independently predicted mortality following heart transplantation in this cohort. What are the Clinical Implications? Highly sensitized patients with CHD are much more likely to die in the first year following heart transplantation than less- or nonsensitized patients. They also experience higher rates of rejection, which contributes to morbidity and late mortality. Many efforts are made to minimize the likelihood of a positive crossmatch at the time of transplantation in order to optimize outcomes. However, the results of this study indicate that allosensitization status is the primary driver of outcomes when both allosensitization status and crossmatch result are taken into account. Therefore, continued development of new therapies for desensitization is warranted.

  PublisherOA PDFDOI

• ROR2 drives right ventricular heart failure via disruption of proteostasis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-02 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Background: No therapies exist to reverse right ventricular failure (RVF), and the molecular mechanisms that drive RVF remain poorly studied. We recently reported that the developmentally restricted noncanonical WNT receptor ROR2 is upregulated in human RVF in proportion to severity of disease. Here we test mechanistic role of ROR2 in RVF pathogenesis. Methods: ROR2 was overexpressed or knocked down in neonatal rat ventricular myocytes (NRVMs). ROR2-modified NRVMs were characterized using confocal microscopy, RNAseq, proteomics, proteostatic functional assays, and contractile properties with pacing. The impact of cardiac ROR2 expression was evaluated in mice by AAV9-mediated overexpression and by AAV9-mediated delivery of shRNA to knockdown ROR2 in a pulmonary artery banded pressure overload RVF model. ROR2-modified mice were evaluated by echocardiography, RV protein synthetic rates and proteasome activity. Results: In NRVMs, we find that ROR2 profoundly dysregulates the coordination between protein translation and folding. This imbalance leads to excess protein clearance by the ubiquitin proteasome system (UPS) with dramatic impacts on sarcomere and cytoskeletal structure and function. In mice, forced cardiac ROR2 expression is sufficient to disrupt proteostasis and drive RVF, while conversely ROR2 knockdown partially rescues proteostasis and cardiac function in a pressure overload model of RVF. Conclusions: In sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and, thus, provides a promising target to treat RVF.

  PublisherOA PDFDOI

• Allosensitization status predicts excess mortality in pediatric congenital heart disease transplant recipients in the current era: An analysis of the United Network for Organ Sharing database

  JHLT Open · 2025-10-11 · 1 citations

  articleOpen access

  Background: Patients with congenital heart disease are at high risk of allosensitization and as such may be at risk for inferior outcomes following heart transplantation. Methods: The United Network for Organ Sharing database was studied for patients <18 years with congenital heart disease undergoing heart transplantation from April 2015 to December 2020. Patients were grouped into 3 categories of allosensitization status based on % calculated panel reactive antibody at transplant: non- (<10%), moderately- (10%-<80%), and highly sensitized (≥80%). Primary outcome measures were 1-year patient and graft survival. Multivariable analysis controlled for differences in preoperative clinical characteristics among categories. Results: < 0.001) compared to nonsensitized and moderately sensitized patients. Conclusions: Highly sensitized patients with congenital heart disease undergoing heart transplantation in the current era experience 25% 1-year mortality. The magnitude of sensitization predicts adverse outcomes.

  PublisherOA PDFDOI

Recent grants

• Defining the Role of ROR2 in Right Ventricular Failure Pathogenesis

  NIH · $657k · 2021–2026

Frequent coauthors

• Jonathan B. Edelson

  Children's Hospital of Philadelphia

  94 shared

• Kimberly Y. Lin

  Children's Hospital of Philadelphia

  90 shared

• Bruce D. Gelb

  Child Health and Development Institute

  76 shared

• Joseph W. Rossano

  Children's Hospital of Philadelphia

  74 shared

• Matthew J. O’Connor

  Children's Hospital of Philadelphia

  70 shared

• Lisa Edelmann

  Icahn School of Medicine at Mount Sinai

  66 shared

• Wendy K. Chung

  Harvard University

  65 shared

• Jane W. Newburger

  Harvard University

  65 shared

Labs

• Edwards Laboratory for Pediatric Heart FailurePI

Education

• MD

  Wake Forest University School of Medicine

  2013