How insights from cardiovascular developmental biology have impacted the care of infants and children with congenital heart disease

Abstract

To illustrate the impact developmental biology and genetics have already had on the clinical management of the million infants born worldwide each year with CHD, we have chosen three stories which have had particular relevance for pediatric cardiologists, cardiothoracic surgeons, cardiac anesthesiologists, and cardiac nurses. First, we show how Margaret Kirby’s finding of the unexpected contribution of an ectodermal cell population – the cranial neural crest – to the aortic arch arteries and arterial pole of the embryonic avian heart provided a key impetus to the field of cardiovascular patterning. Recognition that a majority of patients affected by the neurocristopathy DiGeorge syndrome have a chromosome 22q11 deletion, have also spurred tremendous efforts to characterize the molecular mechanisms contributing to this pathology, assigning a major role to the transcription factor Tbx1. Second, synthesizing the work of the last two decades by many laboratories on a wide gamut of metazoans (invertebrates, tunicates, agnathans, teleosts, lungfish, amphibians, and amniotes), we review the >20 major modifications and additions to the ancient circulatory arrangement composed solely of a unicameral (one-chambered), contractile myocardial tube and a short proximal aorta. Two changes will be discussed in detail – the interposition of a second cardiac chamber in the circulation and the septation of the cardiac ventricle. By comparing the developmental genetic data of several model organisms, we can better understand the origin of the various components of the multicameral (multi-chambered) heart seen in humans. Third, Martina Brueckner’s discovery that a faulty axonemal dynein was responsible for the phenotype of the iv/iv mouse (the first mammalian model of human heterotaxy) focused attention on the biology of cilia. We discuss how even the care of the complex cardiac and non-cardiac anomalies seen in heterotaxy syndrome, which have long seemed impervious to advancements in surgical and medical intensive care (Jacobs et al., 2011), may yet yield to strategies grounded in a better understanding of the cilium. The fact that all cardiac defects seen in patients with full-blown heterotaxy can also be seen in patients without obvious laterality defects hints at important roles for ciliary function not only in left-right axis specification but also in cardiovascular morphogenesis. These three developmental biology stories illustrate how the remaining unexplained mortality and morbidity of congenital heart disease can be solved.

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

“…Congenital heart diseases often feature structural abnormalities that arise from defects in the development of the heart during embryogenesis (Chin et al, 2012;Samsa et al, 2013). The heart is the first organ to function, yet the details of its formation are only partly understood.…”

Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2

“…When exposed to appropriate stimuli, progenitors acquire NC fate and express multiple factors that activate downstream genes (3)(4)(5)(6)(7)(8), and several signaling cascades, including bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt), FGF, retinoic acid, and Notch are vital in NC induction (9)(10)(11)(12). Deficits in NC development are responsible for many birth defects (13)(14)(15), broadening the interest in this system.…”

An Uncommon Presentation for Cardiac Melanoma

“…18 This may in part reflect a special tropism of the neural crest cells to the heart; cardiac formation involves a critical neural crest invasion, certainly contributing to the endocardial cushion structures and possibly to other components of the myocardium and epicardium. 19,20 The invasion of the myocardium by the tumor may result in supraventricular and ventricular arrhythmias, primarily monomorphic ventricular tachycardia. Our illustrative case represents an unusual manifestation of cardiac metastasis presenting as PMVT.…”