Heart Failure in Pediatric Patients With Congenital Heart Disease

Heart Failure in Pediatric Patients With Congenital Heart Disease

Robert B. Hinton, Stephanie M. Ware

Genes causing congenital heart disease (CHD) and cardiomyopathy form a complex network. The network diagrams were generated using ToppCluster (www.toppcluster.cchmc.org) software. Gene lists were derived from clinically available next-generation sequencing panels for cardiomyopathy genes (n=50) and CHD genes (n=44). A, Abstracted cluster network showing a selected subset of features from the following categories: Gene ontology (GO): molecular function; GO: biological processes; GO: cellular component; human phenotype; mouse phenotype; pathway; disease (cardiomyopathy and CHD). The features are color coded by category and connected to cardiomyopathy (white circle) and CHD gene nodes. B, Gene level network with nodes (blue) selected from features in GO: biological processes category. The network illustrates that regulation of cellular component of movement, actin filament-based processes, and cardiac chamber morphogenesis are shared in common between cardiomyopathy and CHD genes, whereas regulation of force of heart contraction and tube development are unshared. [Powerpoint File]

Noninvasive Imaging in Adult Congenital Heart Disease

Noninvasive Imaging in Adult Congenital Heart Disease

Luke J. Burchill, Jennifer Huang, Justin T. Tretter, Abigail M. Khan, Andrew M. Crean, Gruschen R. Veldtman, Sanjiv Kaul, Craig S. Broberg

Liver imaging in Fontan-associated liver disease. A, Contrast computed tomographic scan of upper abdomen in a patient with heterotaxy and a Fontan circulation demonstrating a well-circumscribed tumor measuring 5 cm in diameter in the right lobe of a midline liver (yellow asterix). B, Fluorodeoxyglucose-positron emission tomographic scan in the same patient demonstrating abnormal uptake in the right lobe of the liver in the region of the tumor. [Powerpoint File]

Noninvasive Imaging in Adult Congenital Heart Disease

Noninvasive Imaging in Adult Congenital Heart Disease

Luke J. Burchill, Jennifer Huang, Justin T. Tretter, Abigail M. Khan, Andrew M. Crean, Gruschen R. Veldtman, Sanjiv Kaul, Craig S. Broberg

Three-dimensional (3D) echocardiographic quantification. In this example, left atrial and left ventricular volumes are measured using semiautomated border detection in a 3D echocardiogram. Ejection fraction can be derived without the geometric assumptions that limited 2D-derived measures, such as Simpson biplane and the area–length method. [Powerpoint File]

Current Interventional and Surgical Management of Congenital Heart Disease: Specific Focus on Valvular Disease and Cardiac Arrhythmias

Current Interventional and Surgical Management of Congenital Heart Disease: Specific Focus on Valvular Disease and Cardiac Arrhythmias

Kimberly A. Holst, Sameh M. Said, Timothy J. Nelson, Bryan C. Cannon, Joseph A. Dearani

Schematic representation of the possible lines of ablation to treat macro reentrant atrial tachycardia in the presence of various atrial anomalies associated with complex congenital heart disease. avn indicates atrioventricular node; CS, coronary sinus; FO, foramen ovale; HV, hepatic vein; IVC, inferior vena cava; LAA, left atrial appendage; LSVC, left superior vena cava; MV, mitral valve; PV, pulmonary valve; RAA, right atrial appendage; RSVC, right superior vena cava; TAPVR, total anomalous pulmonary venous return; and TV, tricuspid valve. Reproduced from Mavroudis et al53 with permission of the publisher. Copyright ©2008, The Society of Thoracic Surgeons. [Powerpoint File]

Current Status and Future Potential of Transcatheter Interventions in Congenital Heart Disease

Current Status and Future Potential of Transcatheter Interventions in Congenital Heart Disease

Damien P. Kenny, Ziyad M. Hijazi

Cartoon illustrating possible future strategies for the surgical management of newborns with congenital heart disease (CHD). If CHD is diagnosed prenatally, fetal cells may be harvested and induced pluripotent stem cells (iPS) generated; as an alternative, umbilical cord stem cells can be isolated at the time of birth. When diagnosis of CHD is made after birth or in babies who require a palliative surgical operation soon after birth, stem cells may be isolated from surgical cardiac leftovers. All these types of cells will allow the generation of a tissue-engineered graft endowed with growth and remodeling potential, necessary for the definitive correction of cardiac defects (Taken from Avolio et al99; Illustration Credit: Ben Smith). [Powerpoint File]

Current Status and Future Potential of Transcatheter Interventions in Congenital Heart Disease

Current Status and Future Potential of Transcatheter Interventions in Congenital Heart Disease

Damien P. Kenny, Ziyad M. Hijazi

Series of angiographic images demonstrating hybrid pulmonary valve replacement after plication of the main pulmonary artery in a patient with a significantly dilated right ventricular outflow tract (RVOT) after transannular patch repair of tetralogy of Fallot as an infant. A and B, Initial angiogram demonstrating dilated RVOT measuring 33 mm; (C) RVOT angiogram after main pulmonary artery (MPA) plication and placement of a prestent; and (D) MPA angiogram demonstrating valvular competence with no pulmonary incompetence after Melody valve placement. [Powerpoint File]

Current Status and Future Potential of Transcatheter Interventions in Congenital Heart Disease

Current Status and Future Potential of Transcatheter Interventions in Congenital Heart Disease

Damien P. Kenny, Ziyad M. Hijazi

Series of fetal echocardiography images demonstrating fetal aortic balloon valvuloplasty. A, Initial fetal echocardiogram demonstrating dilated left ventricle (LV) with narrow color jet seen across stenotic aortic valve; (B) introduction of needle into the cavity of the LV (white arrow signifies needle tip); (C) wire seen crossing the aortic valve (white arrow); and (D) inflation of balloon across the aortic valve (white arrow). [Powerpoint File]

Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation

Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation

Paul D. Morton, Nobuyuki Ishibashi, Richard A. Jonas

A, Cortical gyrification increases throughout fetal and perinatal brain development. Legend demarks the 4 lobes of the cortex. B, Gyrification indices and (C) cortical surface areas of fetuses with hypoplastic left heart syndrome (HLHS) compared with normal fetuses. Adapted from Dubois and Dehaene-Lambertz (A)14 and Clouchoux et al (B and C)15 with permission of the publishers. Copyrights © 2015, 2013, Elsevier and Oxford University Press, respectively. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. [Powerpoint File]

Cardiac Regeneration: Lessons From Development

 

Cardiac Regeneration: Lessons From Development

Francisco X. Galdos, Yuxuan Guo, Sharon L. Paige, Nathan J. VanDusen, Sean M. Wu, William T. Pu

Model of the trabeculation process. During trabeulation, a small fraction of cardiomyocytes (CMs) in the compact myocardium (pink) are first specified as trabeculating CMs (brown). These cells delaminate from the compact myocardium and migrate inward to form the first trabecular CMs. CMs in both compacted and trabecular myocardium further proliferate. This proliferation, together with CM migration and rearrangement, results in protrusion and expansion of the trabecular myocardium (illustration credit: Ben Smith). [Powerpoint File]

Cardiac Regeneration: Lessons From Development

Cardiac Regeneration: Lessons From Development

Francisco X. Galdos, Yuxuan Guo, Sharon L. Paige, Nathan J. VanDusen, Sean M. Wu, William T. Pu

Regulation of cardiac progenitor proliferation and differentiation. A, Schematic showing the anterolateral position of first heart field (FHF) progenitors and dorsomedial position of second heart field (SHF) progenitors at embryonic day (E) 7.5. Canonical wingless-type MMTV integration site family member (WNTs), Sonic Hedgehog (SHH), and fibroblast growth factors (FGFs) are expressed dorsally in the region encompassed by the SHF, whereas noncanonical WNTs, BMP2, and FGF8 are expressed ventrally, where the FHF is present. FHF progenitors make up the cardiac crescent and differentiate before the SHF to form the developing heart tube at E8.0. SHF maintains their proliferative state and elongate the heart tube by migrating and differentiating at the inflow and outflow poles of the heart. B, Noncanonical WNTs, BMP2/4, and FGF8 signaling drives FHF progenitors to differentiates toward the myocyte lineage. Meanwhile, canonical WNT/β-catenin, SHH, and FGFs maintain SHF progenitor proliferation. SHF progenitor migration to the outflow and inflow poles of the heart tube exposes them to BMP2/4 and noncanonical WNTs, which drives SHF progenitors to exit their proliferative state and differentiate. C, Canonical WNT/ β-catenin signaling inhibits the differentiation of cardiac progenitors to the myocytes. BMP signaling activates SMAD4 that binds to the transcription factor HOPX to directly inhibit canonical WNT/β-catenin. Moreover, noncanonical WNTs such as WNT5a and WNT11 also inhibit canonical WNT/β-catenin to drive cardiac progenitor differentiation (illustration credit: Ben Smith). [Powerpoint File]

Cardiac Regeneration: Lessons From Development

Cardiac Regeneration: Lessons From Development

Francisco X. Galdos, Yuxuan Guo, Sharon L. Paige, Nathan J. VanDusen, Sean M. Wu, William T. Pu

Specification of mesodermal precursors. Schematic representing the signaling events leading to mesodermal specification during early development. NODAL (nodal growth differentiation factor) is first expressed proximally at embryonic day (E) 5.0. Through an autoregulatory loop, NODAL activates its own expression throughout the epiblast (shown in light purple) and goes on to induce the expression of NODAL antagonists, LEFTY1 and CER1, in the distal visceral endoderm at E5.5 (DVE). The DVE migrates anteriorly where it specifies the anterior portion of the embryo as shown in the yellow hues at E6.5 to 7.5. The anterior visceral endoderm (AVE, yellow) limits NODAL signaling to the posterior of the embryo. Along with wingless-type MMTV integration site family member 3 (WNT3) and bone morphogenic protein (BMP) signaling, NODAL specifies early primitive streak progenitors to the mesoderm fate. [Powerpoint File]

Genetics and Genomics of Congenital Heart Disease

Genetics and Genomics of Congenital Heart Disease

Samir Zaidi, Martina Brueckner

NOTCH signaling in congenital heart disease (CHD) (A) the outline of NOTCH signaling pathway showing signal-sending cell in yellow and signal receiving cell in green. B, Syndromes and CHD associated with NOTCH pathway gene mutations. BAV indicates bicuspid aortic valve; CoA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; HTX, heterotaxy-associated defects; NA, not applicable; NICD, Notch intracellular domain; VSD, ventricular septal defect; TA, truncus arteriosus; and TOF, tetralogy of Fallot. [Powerpoint File]

Genetics and Genomics of Congenital Heart Disease

Genetics and Genomics of Congenital Heart Disease

Samir Zaidi, Martina Brueckner

A, Outline of human heart development. The x axis displays days of human and mouse gestation. B, The spectrum of congenital heart disease from mild to severe. The lesions indicated as “severe” are expected to require intervention in the first year of life. Classes of CHD based on proposed developmental-genetic mechanisms are indicated in parentheses. C, Genetic causes of CHD identified to date. ASD indicates atrial septal defect; CHD, congenital heart disease; CoA, coarctation of the aorta; CTD, conotruncal defect; HLHS, hypoplastic left heart syndrome; HTX, heterotaxy; LVO, left ventricular outflow obstruction; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; and VSD, ventricular septal defect. [Powerpoint File]

Gene Editing With CRISPR/Cas9 RNA-Directed Nuclease

Gene Editing With CRISPR/Cas9 RNA-Directed Nuclease

Thomas Doetschman, Teodora Georgieva

Large deletions, marker insertions, and single-nucleotide polymorphism (SNP) insertions. A, Multiple exons can be deleted by nonhomologous end joining (NHEJ) by designing single-guide RNAs (sgRNAs) that flank the region to be deleted. In the presence of Cas9 double-strand DNA breaks (DSBs) will occur resulting in small indels at the site of end joining. The double bar at the sgRNA:gene hybridization site represents the DSB caused by Cas9. Cas9 can be introduced as either mRNA or recombinant protein. B, Marker gene insertion can be achieved through homology-directed repair (HDR) in which the homologous regions are introduced in a plasmid as would be done by gene targeting. C, A chromosomal region deletion has been done using HDR in which 2 sgRNAs were designed at each end of the region to be deleted. The homology template was an single-strand DNA (ssDNA) oligo with homology at each end of the region to be deleted. D, SNP insertion using HDR with ssDNA oligo as homology template. [Powerpoint File]

Gene Editing With CRISPR/Cas9 RNA-Directed Nuclease

Gene Editing With CRISPR/Cas9 RNA-Directed Nuclease

Thomas Doetschman, Teodora Georgieva

Cas9 RNA-guided nuclease system. Schematic representation of the Streptococcus pyogenes Cas9 nuclease (green) targeted to genomic DNA by a single-guide RNA (sgRNA) consisting of an ≈20-nt guide sequence (blue) and a scaffold (red). The guide sequence is directly upstream of the protospacer adjacent motif (PAM), NGG (orange circles). Cas9 mediates a double-strand DNA break (DSB) ≈3 bp upstream of the PAM (red triangles). The break is repaired by 1 of 2 mechanisms: nonhomologous end joining (NHEJ) that creates random insertions or deletions at the target site or homology-directed repair (HDR). Two types of template can be used for HDR: small single-stranded DNA (ssDNA) oligonucleotide donor with short 60- 70-bp homology arms and a linear or circular dsDNA plasmid with long homology arms of 1 to 3 kb. [Powerpoint File]