About

Karl Degenhardt, MD, PhD, is a Clinical Associate Professor of Pediatrics (Cardiology) at the Perelman School of Medicine and a clinician in the Division of Cardiology at the Children's Hospital of Philadelphia. He holds a BA in Biology from Washington University, where he graduated magna cum laude in 1990, and earned both his PhD and MD from Mount Sinai School of Medicine in New York, completing his PhD in 2000 and his MD in 2001. His research and clinical work focus on congenital heart disease, with particular interest in fetal cardiovascular development, the mechanisms underlying congenital heart anomalies, and their postnatal management. Degenhardt has contributed to understanding the buffering mechanisms in aortic arch artery formation, the prognostic value of fetal imaging patterns such as the nutmeg lung pattern, and the genetic and developmental pathways involved in cardiovascular development. His work includes investigating the roles of endothelial cells, neural crest cells, and signaling pathways like Pdgfrα and ErbB2 in cardiovascular morphogenesis, aiming to improve diagnostic and therapeutic strategies for congenital heart conditions.

Research topics

• Biology
• Medicine
• Cell biology
• Anatomy
• Internal medicine

Selected publications

• Parental impressions and perspectives of efficacy in prenatal counseling for single ventricle congenital heart disease

  Research Square · 2023-07-07

  preprintOpen access

  Abstract Although commonly performed, optimal techniques, strategies, and content to achieve the most effective prenatal counseling have not been explored. We investigate the efficacy of prenatal counseling via survey feedback of parents of children with prenatally diagnosed single ventricle. Grades of counseling using a Likert scale (1–5) were solicited to assess: 1) overall impression of quantity of counseling, 2) explanation of the heart defect, 3) preparation for heart surgery, 4) preparation for hospital course and care, 5) preparation for complications and outcomes of a Fontan circulation, and 6) preparation for neurological, school related or behavioral problems. Impressions were solicited concerning specific providers. A comprehensive fetal counseling score was calculated for each participant. Burden of care including length of hospitalization was explored as impacting prenatal counseling grades. There were 59 survey respondents. Average age of the children at the time of survey was 4.6 ± 3.3 years (range 1–10 years). Highest grades were for explanation of the heart condition, with lowest grades for preparation for neurological, school related or behavioral problems. Cardiac surgeon received the highest with social worker lowest grade for provider. Negative correlation was found between the composite fetal counseling score and parental recollection of length of hospitalization (Pearson r = − 0.357, p < 0.01). Prenatal counseling for neurological, school related and behavioral problems in single ventricle is deficient. Further studies analyzing prenatal counseling techniques and content, can help improve upon the delivery of this important aspect of prenatal care.

  PublisherOA PDFDOI

• Parental Impressions and Perspectives of Efficacy in Prenatal Counseling for Single Ventricle Congenital Heart Disease

  Pediatric Cardiology · 2023-12-19 · 3 citations

  articleOpen access

  Although commonly performed, optimal techniques, strategies, and content to achieve the most effective prenatal counseling have not been explored. We investigate the efficacy of prenatal counseling via survey feedback of parents of children with prenatally diagnosed single ventricle. Grades of counseling using a Likert scale (1-5) were solicited to assess: (1) overall impression of quantity of counseling, (2) explanation of the heart defect, (3) preparation for heart surgery, (4) preparation for hospital course and care, (5) preparation for complications and outcomes of a Fontan circulation, and (6) preparation for neurological, school-related, or behavioral problems. Impressions were solicited concerning specific providers. A comprehensive fetal counseling score was calculated for each participant. Burden of care including length of hospitalization was explored as impacting prenatal counseling grades. There were 59 survey respondents. Average age of the children at the time of survey was 4.6 ± 3.3 years (range 1-10 years). Highest grades were for explanation of the heart condition, with lowest grades for preparation for neurological, school-related, or behavioral problems. Cardiac surgeon received the highest with social worker lowest grade for provider. Negative correlation was found between the composite fetal counseling score and parental recollection of length of hospitalization (Pearson r = - 0.357, p < 0.01). Prenatal counseling for neurological, school-related, and behavioral problems in single ventricle is deficient. Further studies analyzing prenatal counseling techniques and content can help improve upon the delivery of this important aspect of prenatal care.

  PublisherOA PDFDOI

• New approaches under development: cardiovascular embryology applied to heart disease

  2021-09-22

  article1st authorCorresponding

  Despite many innovative advances in cardiology over the past 50 years, heart disease remains a major killer. The steady progress that continues to be made in diagnostics and therapeutics is offset by the cardiovascular consequences of the growing epidemics of obesity and diabetes. Truly innovative approaches on the horizon have been greatly influenced by new insights in cardiovascular development. In particular, research in stem cell biology, the cardiomyocyte lineage, and the interactions of the myocardium and epicardium have opened the door to new approaches for healing the injured heart.

  Publisher

• Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections

  2021-09-22

  article1st authorCorresponding

  Total anomalous pulmonary venous connection (TAPVC) is a potentially lethal congenital disorder that occurs when the pulmonary veins do not connect normally to the left atrium, allowing mixing of pulmonary and systemic blood. In contrast to the extensive knowledge of arterial vascular patterning, little is known about the patterning of veins. Here we show that the secreted guidance molecule semaphorin 3d (Sema3d) is crucial for the normal patterning of pulmonary veins. Prevailing models suggest that TAPVC occurs when the midpharyngeal endothelial strand (MES), the precursor of the common pulmonary vein, does not form at the proper location on the dorsal surface of the embryonic common atrium. However, we found that TAPVC occurs in Sema3d mutant mice despite normal formation of the MES. In these embryos, the maturing pulmonary venous plexus does not anastomose uniquely with the properly formed MES. In the absence of Sema3d, endothelial tubes form in a region that is normally avascular, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary. Sequencing of SEMA3D in individuals with anomalous pulmonary veins identified a phenylalanine-to-leucine substitution that adversely affects SEMA3D function. These results identify Sema3d as a crucial pulmonary venous patterning cue and provide experimental evidence for an alternate developmental model to explain abnormal pulmonary venous connections.

  Publisher

• Prognostic value of the nutmeg lung pattern/lymphangiectasia on fetal magnetic resonance imaging

  Pediatric Radiology · 2021-04-15 · 19 citations

  article
  PublisherDOI

• Distinct Compartments of the Proepicardial Organ Give Rise to Coronary Vascular Endothelial Cells

  2021-09-22

  article

  The proepicardial organ is an important transient structure that contributes cells to various cardiac lineages. However, its contribution to the coronary endothelium has been disputed, with conflicting data arising in chick and mouse. Here we resolve this conflict by identifying two proepicardial markers, Scleraxis (Scx) and Semaphorin3D (Sema3D), that genetically delineate heretofore uncharacterized proepicardial subcompartments. In contrast to previously fate-mapped Tbx18/WT-1-expressing cells that give rise to vascular smooth muscle, Scx- and Sema3D-expressing proepicardial cells give rise to coronary vascular endothelium both in vivo and in vitro. Furthermore, Sema3D(+) and Scx(+) proepicardial cells contribute to the early sinus venosus and cardiac endocardium, respectively, two tissues linked to vascular endothelial formation at later stages. Taken together, our studies demonstrate that the proepicardial organ is a molecularly compartmentalized structure, reconciling prior chick and mouse data and providing a more complete understanding of the progenitor populations that establish the coronary vascular endothelium.

  Publisher

• Abstract 10569: Risk Factors for Adverse Outcome in Prenatally Diagnosed Heterotaxy Syndrome in the Current Era

  Circulation · 2021-11-16

  article

  Introduction: Fetuses with heterotaxy syndrome (HS) and congenital heart disease continue to have worse outcomes compared to other lesions. We sought to explore differences between asplenia and polysplenia subtypes and to identify risk factors for poor outcome in the current era. Methods: All cases of fetal HS seen at our center between 1/2005 and 3/2018 were included in this study. Prenatal echocardiographic parameters and clinical outcomes were recorded. Findings were compared between the asplenia and polysplenia subtypes via Chi-square or Fisher’s exact analysis. Univariate logistic regression was utilized to identify prenatal variables predictive of fetal demise. Postnatal survival was examined with Kaplan-Meier curves and univariate Cox proportional hazards models. Results: The cohort consisted of 155 subjects: 86 with asplenia and 69 with polysplenia. There were 36 with biventricular (2V) and 119 with univentricular (1V) physiology. Asplenia subjects were more likely to have 1V physiology, common atrioventricular canal (CAVC), conotruncal anomaly, and pulmonary venous obstruction (all p&lt;0.001). Polysplenia subjects were more likely to have systemic venous anomalies (p&lt;0.001), complete heart block (CHB, p&lt;0.001), ventricular dysfunction (p=.005), and hydrops (p=0.03). There were 105 subjects born alive, 7 fetal demises, 40 terminations, and 3 lost to follow-up prior to birth. Postnatal follow-up data were available for 96/105 (91%) subjects with median follow-up of 5.5 years (IQR 1.2-10.5). Estimated 5-year survival was 72% (95% CI 62-80) for the entire cohort and there was no difference in overall postnatal survival between polysplenia and asplenia subtypes (p=0.24). CHB and ventricular dysfunction were significant risk factors for both fetal demise and postnatal death. Pulmonary venous obstruction and CAVC were additional risk factors for postnatal death. Conclusions: Fetuses with HS continue to have high rates of postnatal mortality, particularly if CHB, ventricular dysfunction, or pulmonary venous obstruction are identified. CHB and ventricular dysfunction are also significant risk factors for fetal demise. Further research is needed to improve management of CHB and pulmonary venous obstruction in this high-risk group.

  PublisherDOI

• Distinct enhancers at the Pax3 locus can function redundantly to regulate neural tube and neural crest expressions

  2021-09-22

  article1st authorCorresponding

  Pax3 is a transcription factor expressed in somitic mesoderm, dorsal neural tube and pre-migratory neural crest during embryonic development. We have previously identified cis-acting enhancer elements within the proximal upstream genomic region of Pax3 that are sufficient to direct functional expression of Pax3 in neural crest. These elements direct expression of a reporter gene to pre-migratory neural crest in transgenic mice, and transgenic expression of a Pax3 cDNA using these elements is sufficient to rescue neural crest development in mice otherwise lacking endogenous Pax3. We show here that deletion of these enhancer sequences by homologous recombination is insufficient to abrogate neural crest expression of Pax3 and results in viable mice. We identify a distinct enhancer in the fourth intron that is also capable of mediating neural crest expression in transgenic mice and zebrafish. Our analysis suggests the existence of functionally redundant neural crest enhancer modules for Pax3.

  Publisher

• Tie2Cre-mediated inactivation of plexinD1 results in congenital heart, vascular and skeletal defects

  2021-09-22

  article

  PlexinD1 is a membrane-bound receptor that mediates signals derived from class 3 secreted semaphorins. Although semaphorin signaling in axon guidance in the nervous system has been extensively studied, functions outside the nervous system including important roles in vascular patterning have also been demonstrated. Inactivation of plexinD1 leads to neo-natal lethality, structural defects of the cardiac outflow tract, peripheral vascular abnormalities, and axial skeletal morphogenesis defects. PlexinD1 is expressed by vascular endothelial cells, but additional domains of expression have also been demonstrated including in lymphocytes, osteoblasts, neural crest and the central nervous system. Hence, the cell-type specific functions of plexinD1 have remained unclear. Here, we describe the results of tissue-specific gene inactivation of plexinD1 in Tie2 expressing precursors, which recapitulates the null phenotype with respect to congenital heart, vascular, and skeletal abnormalities resulting in neonatal lethality. Interestingly, these mutants also have myocardial defects not previously reported. In addition, we demonstrate functions for plexinD1 in post-natal retinal vasculogenesis and adult angiogenesis through the use of inducible cre-mediated deletion. These results demonstrate an important role for PlexinD1 in embryonic and adult vasculature.

  Publisher

• Fetal cardiomyopathy in neurofibromatosis type I: Novel phenotype and review of the literature

  American Journal of Medical Genetics Part A · 2019-03-28 · 12 citations

  review

  Neurofibromatosis type I (NF1) is a relatively common genetic disorder characterized by neurocutaneous lesions, neurofibromas, skeletal anomalies, iris hamartomas, and predisposition to other tumors. NF1 results from heterozygous loss-of-function mutations in neurofibromin (NF1), and diagnosis is most often made using clinical diagnostic criteria. Cardiac manifestations of NF1 include congenital heart disease (such as valvar pulmonary stenosis), left ventricular hypertrophy, and adult-onset pulmonary hypertension. Prenatal features of NF1 are often nonspecific and diagnoses are infrequently made prenatally without a known family history. Herein, we report the first case, to the best of our knowledge, of fetal cardiomyopathy as the presenting feature in NF1 and review NF1-related left ventricular hypertrophy. NF1 should be considered in the differential diagnosis for fetuses with cardiomyopathy, even in the absence of a known family history of the condition.

  PublisherDOI

Recent grants

• NIH Grant K08HL094763

  NIH · $520k · 2016

Frequent coauthors

• Jonathan A. Epstein

  University of Pennsylvania

  32 shared

• Manvendra K. Singh

  Duke-NUS Medical School

  22 shared

• Jack Rychik

  University of Pennsylvania

  13 shared

• Arun Padmanabhan

  City College of San Francisco

  11 shared

• Haig Aghajanian

  9 shared

• Jun Li

  Peking University

  8 shared

• Nicole Antonucci

  7 shared

• Rita C. Milewski

  Yale University

  7 shared

Labs

• Degenhardt LabPI