Print this Article 
Send to a FriendDisclaimer: By no means is this an exhaustive or comprehensive review of news related to congenital heart diseases and their surgical management. Similarly, this list or the order of topics is not meant to serve as a “top-ten” list or any equivalent hierarchy of importance. This is merely a sampling of reported results and publications from the prior 3 months, with an inclination to cover journals and publications that perhaps may not be as frequently read or reviewed by the pediatric cardiac surgery community. Certainly, if readers find an article or news item of interest that deserves mention, please forward them to the Research Editor’s attention, pirooz.eghtesady@cchmc.org
Why Is the Aortic Arch Left Sided?
In the embryo, the arterial system initially develops in a symmetrical pattern. Blood flows out of the heart, via five branchial arches (1-4 and 6), to circulate throughout the embryo. In time, however, this pattern is modified with regression of the right fourth and sixth arches and persistence of the left fourth and sixth arches. Why? And why does this sequence break down at times?
Yashiro and colleagues from Osaka University seem to have uncovered an explanation through some elegant experiments described in a recent issue of Nature [1]. Pitx2 transcription factor has long been considered a potential mediator in directing asymmetric development of the branchial arches. Pitx2 itself is known to be induced by Nodal, a key signaling molecule in establishing laterality of the internal organs in the embryo. A deficiency of such signaling has been shown to result in heterotaxy in animal models. Basically, Yashiro and colleagues now show that the underlying mechanism for the asymmetric development of the branchial arches relates to alterations in blood flow through the aortic arches secondary to rotation and realignment of the outflow tract (which in turn occurs in response to expression of Pitx2). Further, they show that the uneven distribution of blood flow results in differential signaling by both the platelet-derived growth factor receptor and vascular endothelial growth factor receptor 2, which is responsible for the stabilization of the left sixth BAA and regression of its right counterpart, to underlie left-sided formation of the aortic arch.
More on Heterotaxy
Continuing on the preceding theme, it is interesting to read the report by Kennedy and colleagues from the University of North Carolina in Chapel Hill that the prevalence of congenital heart disease with heterotaxy (6.3%) is 200-fold higher in patients with primary ciliary dyskinesia (PCD) than in the general population (1:50 versus 1:10 000) [2]. Patients with PCD, a recessive trait, include those with Kartagener’s syndrome, among which only about 50% have situs inversus. These investigators looked at the prevalence of heterotaxy defects among 337 PCD patients, among which nearly half had situs solitus (normal situs). The majority of the patients with heterotaxy had mutations related to ciliary outer dynein arm genes (DNAI1 and DNAH5). These data indicate that patients with PCD should have cardiac evaluation and that screening for PCD mutations is indicated in patients with heterotaxy and congenital heart disease.
Prenatal Tissue-Engineered Valves!
Schmidt and colleagues from the University of Zurich report an exciting and novel concept for prenatally tissue-engineered human autologous heart valves based on routinely obtained fetal amniotic fluid progenitors as single cell source is introduced [3]. Using CD133 magnetic beads (marker for mesenchymal progenitor cells), these investigators were able to isolate, expand, differentiate and then seed heart valve leaflet scaffolds fabricated from rapidly biodegradable polymers with these precursor cells derived from the amniotic fluid. Engineered heart valve leaflets demonstrated endothelialized tissue formation with production of extracellular matrix elements and presence of viable endothelial surfaces. Opening and closing behaviors of these valves were also quite reasonable considering these preliminary studies. It’s not too difficult to see how this technology can have a tremendous impact on congenital heart surgery if further validated.
Outcome of Pediatric Cardiomyopathy
Since 1993, the Pediatric Heart Transplant Study, a multi-institutional research consortium from three countries, has been working on trying to identify risk factors for various outcomes in children with end-stage heart disease listed for cardiac transplantation. Similarly, the NIH sponsored Pediatric Cardiomyopathy Registry and the National Australian Childhood Cardiomyopathy Study have provided great insights into outcomes of large numbers of children with cardiomyopathy, the majority of which suffer from dilated cardiomyopathy. These studies and registries, however, do not provide as much insight into the numerator of the equation (i.e., they focus on children with established diagnosis of cardiomyopathy). Now a unique prospective, national, multi-center study provides further information on the incidence and outcome of first-time “heart muscle disease-induced” heart failure in children. As Andrews and colleagues from the British Congenital Cardiac Association state, the impetus for this study came from an administrative query in part to assess the needs for heart transplantation and mechanical support in the National Heath Service of UK [4]. Their study involved all 17 pediatric cardiac centers in the United Kingdom and Ireland, and follow-up data were obtained to a minimum of 1 year. These investigators found an incidence of pediatric cardiomyopathy similar to other reports, just shy of 1/100,000. Confirming prior reports, these authors found that once again, older age and reduced systolic function on admission echocardiogram increased risk of death. Importantly, they found that one-third of children die or require transplantation within 1 year of presentation, sobering data that perhaps further justifies aggressive use of ECMO or other assist devices in the clinical management of these children.
The Brain and Congenital Heart Disease and Surgery
Two interesting papers provide further food for thought (no pun intended) on the potential mechanisms leading to brain injury in children with congenital heart disease. Clearly, with improving survival outcomes, “improvement measures” in congenital heart diseases will increasingly focus on decreasing morbidity among children with congenital heart disease, among which preventing or limiting brain injury perhaps is most pressing. While previously, cardiopulmonary bypass and modifications of cerebral perfusion (circulatory arrest vs. cerebral perfusion) were singled out for most of this morbidity, more recent reports suggest that perhaps the underlying congenital heart disease already sets up the milieu for this injury. Miller and colleagues from UCSF now provide more compelling data that term newborns with congenital heart disease have widespread brain abnormalities before they undergo any cardiac surgery [5]. Further, their sophisticated imaging studies, which included magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI), show that in many ways the brains of these newborns are similar to those in premature newborns, with signs of abnormal brain development in utero. These investigators studied the brain of 41 term newborns with congenital heart disease – 29 who had transposition of the great arteries and 12 who had single-ventricle physiology – before cardiac surgery. They also characterized brain metabolism (e.g., the ratio of N-acetylaspartate to choline which increases with brain maturation) and fractional anisotropy of white-matter tracts (which increases with maturation). They found that nearly a third of the newborns with congenital heart disease had evidence of white-matter injury.
At the same time, an incredibly intriguing publication by Stevens and colleagues from Stanford University provides evidence for a novel pathway involved in shaping the developing brain: the classical complement cascade [6]. There is a growing body of evidence that some proteins known for their immune functions also have distinct non-immune functions in the central nervous system. The Stanford investigators have now extended these discoveries to identify an unexpected requirement for molecules of the complement cascade in the remodeling of synaptic connections in the developing nervous system. In essence, the investigators show that C1q, the initiating protein in the classical complement cascade, is expressed by newborn mouse retinal neurons, specifically localizing to synaptic junctions. Further, they show mice deficient in C1q or the downstream complement protein C3 exhibit large defects in proper synapse formation throughout the retinogeniculate connections and the lateral geniculate neurons. Their findings suggest that in the developing brain, unwanted synapses are tagged by complement for elimination (analogous to the role of complement in the immune system). While not discussed by the authors, it is well-known that extracorporeal circulation is a powerful stimulus for up-regulation of the complement cascade, and perhaps responsible for some of the ensuing inflammatory insults from cardiopulmonary bypass. So can cardiopulmonary bypass in the neonate lead to abnormal brain development because of activation of the complement cascade? As of this writing, there is no report in PubMed of either clinical studies or animal experiments looking at concentrations of complement proteins within the cerebrospinal fluid (and perhaps induced changes) during extracorporeal circulation