Origin Of Congenital Heart Disease Research Articles

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease.

The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic heart has been investigated for over a century, initially focusing on the chick embryo due to the opportunity to isolate and investigate myocardial electromechanical maturation, the ability to directly instrument and measure normal cardiac function, intervene to alter ventricular loading conditions, and then investigate changes in functional and structural maturation to deduce mechanism. The paradigm of “Develop and validate quantitative techniques, describe normal, perturb the system, describe abnormal, then deduce mechanisms” was taught to many young investigators by Dr. Edward B. Clark and then validated by a rapidly expanding number of teams dedicated to investigate CV morphogenesis, structure–function relationships, and pathogenic mechanisms of CHD. Pioneering studies using the chick embryo model rapidly expanded into a broad range of model systems, particularly the mouse and zebrafish, to investigate the interdependent genetic and biomechanical regulation of CV morphogenesis. Several central morphogenic themes have emerged. First, CV morphogenesis is inherently dependent upon the biomechanical forces that influence cell and tissue growth and remodeling. Second, embryonic CV systems dynamically adapt to changes in biomechanical loading conditions similar to mature systems. Third, biomechanical loading conditions dynamically impact and are regulated by genetic morphogenic systems. Fourth, advanced imaging techniques coupled with computational modeling provide novel insights to validate regulatory mechanisms. Finally, insights regarding the genetic and biomechanical regulation of CV morphogenesis and adaptation are relevant to current regenerative strategies for patients with CHD.

Understanding the epigenetic origins of congenital heart disease may lead to its control

Congenital heart disease (CHD), which occurs in about 1 per 100 live births, remains the leading life-threatening abnormality present at birth. It is reasonable to assume that most, if not all, CHD stems from errors or disruptions in the genetic control of heart development, and that a more thorough knowledge of these controlling molecular mechanisms may lead to a better understanding of the origins of CHD. With understanding comes the potential for prevention, and possibly early repair. Our operational research in the Western Cape has identifi ed a severe epidemiological shortfall between the theoretical number of newborns that should present to us with severe CHD and those who actually do - we are referred only 50% of the children that (epidemiologically) should receive heart surgery. Even if we could identify all the missing children, our services would be unable to contend with the consequent demand. This stark dilemma plays itself out in most resource-constrained cardiac health services. It is therefore of utmost importance that the origins of CHD that may be under environmental infl uences - “the epigenetic causes of CHD” - are prioritised in our quest to reduce heart defects. I will outline these infl uences and show how an understanding of them may begin to reduce an enormous health burden.

Prokineticin receptor-1 signaling promotes Epicardial to Mesenchymal Transition during heart development.

The epicardium plays an essential role in coronary artery formation and myocardial development. However, signals controlling the developing epicardium and epicardial-mesenchymal transition (EMT) in the normal and diseased adult heart are studied less rigorously. Here we investigated the role of angiogenic hormone, prokineticin-2 and its receptor PKR1 in the epicardium of developing and adult heart. Genetic ablation of PKR1 in epicardium leads to partial embryonic and postnatal lethality with abnormal heart development. Cardiac developmental defects are manifested in the adult stage as ischemic cardiomyopathy with systolic dysfunction. We discovered that PKR1 regulates epicardial-mesenchymal transition (EMT) for epicardial-derived progenitor cell (EPDC), formation. This event affects at least three consequential steps during heart development: (i) EPDC and cardiomyocyte proliferation involved in thickening of an outer compact ventricular chamber wall, (ii) rhythmicity, (iii) formation of coronary circulation. In isolated embryonic EPDCs, overexpression or activation of PKR1 alters cell morphology and EMT markers via activating Akt signaling. Lack of PKR1 signal in epicardium leads to defective heart development and underlies the origin of congenital heart disease in adult mice. Our mice provide genetic models for congenital dysfunction of the heart and should facilitate studies of both pathogenesis and therapy of cardiac disorders in humans.

Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration.

Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine.

The expanding role of the epicardium and epicardial-derived cells in cardiac development and disease

In this review, we aim at presenting and discussing the cellular and molecular mechanisms of embryonic epicardial development that may underlie the origin of congenital heart disease (CHD). New discoveries on the multiple cell lineages that form part of the original pool of epicardial progenitors and the roles played by epicardial transcription factors and morphogens in the regulation of epicardial epithelial-to-mesenchymal transition, epicardial-derived cell (EPDCs) differentiation, coronary blood vessel morphogenesis and cardiac interstitium formation are presented in a comprehensive manner. We have provided evidence on the critical participation of epicardial cells and EPDCs in normal and abnormal cardiac development, suggesting the implication of defective epicardial development in various forms of CHD.

Revitalizing Our View of Heart Development

paper by Kelly et al., from Margaret Buckingham's group at the Pasteur Institute in Paris, changed the way we think about the developing mammalian heart, as well as the origins of congenital heart disease. Prior to this work, classical studies showing that the heart tube grows in part by the transformation of a noncardiac epithelium into cardiomyocytes had lapsed into obscurity. Kelly et al. and other papers have reinstated the notion that heart growth and morphogenesis are highly dynamic and driven by the recruitment of multipotent heart progenitor cells to a primitive scaffold. It was as if a light went on in the heart development field. This and subsequent work, much of it from Buckingham and colleagues, allows us to understand the cellular and molecular nature of heart growth and to see the origins of congenital heart disease in the aberrant behavior of progenitor cell populations. This PaperPick refers to The Arterial Pole of the Mouse Heart Forms from Fgf10-Expressing Cells in Pharyngeal Mesoderm, by R.G. Kelly, N.A. Brown, and M.E. Buckingham, published in September 2001. Video Abstract Robert Kelly discusses the historical context for the work, outlines how research into the second heart field has progressed in the interim, and highlights the evolutionary and biomedical implications of the resulting changes in our understanding of cardiac development.

Genetic Basis for Congenital Heart Defects: Current Knowledge

The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease.

What’s New In Pediatric Cardiology

1. Phat Pham, MD* 2. Michael Silberbach, MD† 1. *Fellow in Pediatric Cardiology 2. †Associate Professor of Pediatrics, Doernbecher Children’s Hospital, Portland, Ore After completing this article, readers should be able to: 1. Recognize the role of genes in the development of cardiac malformations. 2. Describe advances in noninvasive imaging of congenital heart disease. 3. Characterize the role of interventional catheterization in the treatment of congenital heart disease. 4. Describe emerging concepts for pacemakers and implantable cardioverter defibrillators for use in children. Pediatric cardiology was transformed during the latter half of the 20th century from a field that engendered intense curiosity about the heart in infants and children who had uniformly fatal conditions to an established clinical discipline that routinely offered effective medical and surgical therapies. However, cardiac malformations continue to be the most common birth defects and the leading causes of infant mortality, killing twice the number of children who die from childhood cancer. According to the American Heart Association, more than 2 million Americans are living with congenital heart defects, and more than 91 thousand life-years are lost each year to congenital heart disease (CHD). The Association estimates that the cost of hospital care alone for patients who have CHD exceeds $3 billion per year. Today’s researchers are using the tools of molecular genetics to dissect the circuitry of cardiac embryogenesis and to understand the causes of cardiac malformation. In the 21st century, as the fields of computer technology, information management, and biology become integrated, exciting new approaches to the treatment of childhood heart diseases will become a reality. The following is a brief summary of the recent advances in the understanding of cardiac development, the pathogenesis of heart disease, and the current state of diagnostic modalities and therapies aimed at improving the care of children who have heart disease. Although the “nature versus nurture” debate regarding the origin of CHD continues, it generally is believed that many, if not most, cardiac malformations begin as …

Present Status of Fetal Electrocardiography

Fetal electrocardiography, an infant but vigorous young discipline, seems to be rapidly emerging as a useful tool for that biological research and medical practice which concerns the unborn heart. Based upon wide experience, it will be useful to survey the status of fetal electrocardiography, pointing out the possibilities as well as limitations. The significance in terms of capability for early study of the developing heart, the diagnosis of fetal life, multiple pregnancy, origins of congenital heart disease, as well as the study of intrauterine difficulties as in labor is presented and discussed in detail. On the basis of a discussion of present-day instruments and the types of noise encountered, it is suggested that improved low-noise amplifiers are desirable; it is suggested further that the use of averaging, correlation, and other computer-based techniques may hold substantial promise. 9152.

FETAL ELECTROCARDIOGRAM, SHOWING CARDIAC MALFORMATION, INCLUDING HEART BLOCK

Antenatal electrocardiograms were made from 517 subjects. This has made possible a study of the ECG'S in those cases in which a presumptive diagnosis of congenital heart disease was made antenatally and confirmed postnatally. In three infants heart block was recognized before birth, and two of these died soon after birth; the third survived. In a fourth infant, who died five days after birth, autopsy revealed a coarctation of the aorta and so explained the abnormal ventricular complexes that had been recorded before birth. Antenatal ECG'S not only promise to give information that may help the pediatrician in preparing for postnatal difficulties but also may yield fresh clues to the origin of congenital heart disease.