Julius Hegesh

ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/β-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.

Fetal lung lesions: a spectrum of disease. New classification based on pathogenesis, two‐dimensional and color Doppler ultrasound

Prenatal ultrasound detection of fetal anomalies has not only revolutionized management of the fetus and neonate, it has also transformed our perception of the development and natural history of congenital anomalies throughout gestation1,2. Changes in our understanding of fetal lung anomalies illustrate this concept. Ten years ago, fetal echogenic lung lesions were considered grave fetal malformations and, accordingly, textbooks of that period suggested termination of pregnancy (TOP) before fetal viability3,4. In a large series published by King’s College London in 1994 summarizing 132 cases of congenital cystic adenomatoid malformation (CCAM), 44 (33%) of the cases underwent elective TOP5. Only 4 years later, another study from a very similar tertiary center reported a 10% TOP rate6. We have also learned over the ensuing decade that some of these lesions may display dynamic changes in utero. For example, CCAM Type III was once thought to have a uniformly poor prognosis and as a result prenatal diagnosis would often lead to TOP. However, a proportion of cases of CCAM Type III diagnosed prenatally have been shown to resolve spontaneously. The King’s College London study reported this dynamic process in 9% of its series, while a large Canadian study recently showed that 56% of cases of CCAM regressed spontaneously7. In contrast, tumor growth and hemodynamic deterioration may complicate clinical management of these lesions. To add to the confusion, the two most common pathologies of the fetal lungs, CCAM and bronchopulmonary sequestration (BPS), which seemed to be pathologically and clinically distinct, frequently overlap8, and confused terms such as ‘hybrid form’ and ‘missing link’ appear in the literature9,10. These new and conflicting data are the tip of the iceberg of conjecture and controversy surrounding the etiology and pathogenesis of fetal lung lesions, and classification of a specific lung anomaly according to traditional criteria has become irrelevant. It is time to revise the terminology of congenital lung lesions, not least in light of emerging in-utero treatment modalities for these malformations11. We review here the latest pathological and pathogenic aspects of fetal CCAM and BPS, in an attempt to draw a parallel with prenatal ultrasound technology. Our aim is to propose a new classification system based on the pathogenesis of these malformations and their two-dimensional (2D) and color Doppler ultrasound characteristics. Elsewhere12 we demonstrate the applicability of this classification system in a clinical setting.

Fetal aortic arch measurements between 14 and 38 weeks' gestation: in-utero ultrasonographic study.

Objective To establish in‐utero reference ranges for fetal transverse aortic arch diameter (TAD) and distal aortic isthmus diameter (DAID) using high‐resolution ultrasound techniques.

Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis

The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio-facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects.

Three and four dimensional ultrasound: a novel method for evaluating fetal cardiac anomalies

To evaluate the role of various new models of 3‐ and 4‐dimensional (3D and 4D) ultrasound (US) applications in prenatal assessment of fetal cardiac anomalies.

Prenatal diagnosis of vein of Galen aneurysmal malformation: report of two cases with proposal for prognostic indices

Vein of Galen aneurysmal malformation (VGAM) is a rare, intracranial vascular anomaly that, until recently, has usually been diagnosed postnatally. Today, however, with the advances in high‐resolution ultrasonography and colour Doppler, prenatal diagnosis is relatively easy. Due to novel intravascular embolization techniques, the prognosis of neonates with VGAM has markedly improved. A healthy infant with normal neurodevelopmental and cardiovascular status is now a reality. For the best outcome, however, careful planning of the appropriate time, mode, and place of delivery should be undertaken. To achieve this goal, in utero prognostic factors should be determined. This report illustrates, for the first time, prenatal ultrasonographic indices that may predict the outcome in two cases with a prenatal diagnosis of VGAM. The indices included mapping of intracranial feeding arteries, assessment of the width of the straight sinus, assessment and measurement of flow in the straight sinus, existence of ‘steal’ retrograde aortic flow, and the appearance of high‐output cardiac state. By using these prenatal ultrasonographic parameters, fetal outcome may be predicted and appropriate management decided upon.

Fetal lung dysplasia: clinical outcome based on a new classification system

To evaluate the clinical application of a new classification system of fetal lung anomalies.

Antenatal sonographic findings of right pulmonary agenesis with ipsilateral microtia: a possible new laterality association

Right pulmonary agenesis is a rare congenital malformation which results in secondary dextrocardia in situs solitus. Ipsilateral microtia in this context composes a laterality syndrome. The prenatal sonographic findings of this abnormality have not been previously reported. We describe the association of dextrocardia in situs solitus, intact diaphragm and right microtia. This was sonographically diagnosed at mid‐gestation in an euploid fetus. Surgical evacuation of the pregnancy confirmed the external malformation. Laterality association should be assessed in a fetus with sonographic findings of pulmonary agenesis. The differential diagnosis and updated literature review is presented. Copyright

Left superior vena cava to the left atrium: do we have to change the traditional approach?

Left superior vena cava (LSVC) to the left atrium is a rare congenital cardiac complex, which may appear as an isolated anomaly, or as part of more complex cardiac anomalies. Traditionally, an intraatrial baffle was the preferred surgical technique. Although this technique has proved reliable and successful, acute ligation and extracardiac repair are simpler and easier solutions, requiring less myocardial ischemic time. We present 3 patients who underwent simple ligation and discuss the literature for other extracardiac options of surgical repair. Our patients had short transient congestion in the left upper part of their body that resolved completely after a few weeks, without further complications. We believe that either acute ligation or extracardiac repair is a much simpler yet effective solution to divert the left caval flow to the lesser circulation.

Left main coronary artery atresia : Extremely rare coronary anomaly in an asymptomatic adult and an adolescent soccer player

Left main coronary artery atresia is a very rare coronary anomaly with only 33 cases reported in the literature, of whom only 1 patient is asymptomatic. Pediatric patients are usually very symptomatic early in life (dyspnea, syncope, failure to thrive, ventricular tachycardia, and sudden death), whereas adult patients begin showing symptoms (angina or sudden death) only at an advanced age. Given the high risk related to the presence of left main coronary artery atresia, and in view of the good results obtained by coronary artery bypass surgery, coronary artery revascularization should always be considered as the possible treatment of choice for establishing adequate myocardial blood flow.