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Relevance of developmental studies for clinicians 

Relevance of developmental studies for clinicians
Relevance of developmental studies for clinicians

Cristina Basso

, Deborah J. Henderson

, José Luis de la Pompa

, Robert G. Kelly

, José Maria Pérez-Pomares

, David Sedmera

, and Maurice van den Hoff

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date: 01 March 2021


We, the Editors and Associated Editors of The ESC Textbook of Cardiovascular Development, have been asking ourselves a question for years: how can we make our cardiovascular peers share our enthusiasm for cardiovascular developmental biology? This short chapter is the very specific response to that question.

Many of us have had the great opportunity to participate as members of the Nucleus (board) of the ESC Working Group on Development, Anatomy and Pathology. This working group is composed of a dedicated team of cardiovascular developmental biologists, pathologists, anatomists, geneticists, paediatric cardiologists, and surgeons, interacting to increase our knowledge of the biological bases of abnormal heart formation that leads to congenital heart disease (CHD). However, at least for us, increasing such knowledge is not a goal per se. We have always aimed to contribute to the improvement of clinical practice and care, even if modestly, by identifying new diagnostic markers and therapeutic approaches through the strategy of deciphering the sophisticated but fascinating rules of cardiac embryogenesis. As will be seen in this book, knowledge of developmental mechanisms is also essential for the design of regenerative strategies to repair the damaged adult heart.

In this short chapter we will outline the rationale of this textbook. A rapid inspection of the table of contents shows that we have grouped relevant cardiovascular developmental topics in five different sections, which move progressively from basic research to clinical relevance, concluding with a glance at the near future of this fast-moving field. All these sections deal with concepts that are critical to understanding from where and how cardiac chambers (atria and ventricles), valves (atrioventricular and arterial), great vessels (aortic and pulmonary trunks), cardiac conduction system (nodes, bundles, and Purkinje fibres), and coronary blood vessels form.

Throughout the book there is continuous reference to experimental animal models for developmental processes, including the mouse, chick and zebrafish, often involving the application of state-of-the-art technological innovations. This has allowed us to illustrate the more likely origins of specific forms of CHD, and to elaborate on the developmental substrate of certain forms of adult cardiovascular disease.

To simplify what could be a long and not especially enlightening part of this book, we introduce our arguments as to the relevance of cardiac developmental studies for clinicians as answers to specific questions. We believe that this is a simple and straightforward method of explaining the genesis of this textbook.

The Editors and Associated Editors are most grateful to all the authors who have contributed to the ESC Textbook of Cardiovascular Development.

Why should we study CHD and vascular anomalies?

  • Both CHD and vascular anomalies affect 1–5% of newborns, and have a high social impact.

  • Children’s health is and should remain a priority to health policy makers, scientists, and clinicians.

  • The aetiology of the majority of these diseases remains unknown. Without a deep understanding of the causes of CHD, it will be difficult or impossible to design future therapeutic strategies.

  • CHD affects both the neonate and the adult, and the identification of novel disease markers (i.e. disease-causing genes, secreted factors) will undoubtedly contribute to improving diagnosis and patient stratification.

Why study the embryo if I am interested in adult cardiac diseases only?

  • The embryo and adult constitute a spatiotemporal continuum; adult tissues and organs form in the embryo.

  • Embryonic physiology is similar to the situation in some adult disease conditions (e.g. post myocardial infarction (MI), ventricular septal defect, non-compacted cardiomyopathy).

  • Some adult cardiovascular diseases have a developmental origin.

  • Abnormal cardiac developmental processes result in cardiac defects which may lead to haemodynamic defects/arrhythmias/disease predisposition (e.g. valve anomalies).

  • Fetal gene expression is frequently re-activated in certain adult cardiovascular diseases (e.g. myocardial ischaemia, heart failure).

  • Reprogramming and differentiation strategies for cardiac repair necessitate detailed knowledge of the endogenous processes operating during development.

What can I learn from developmental studies?

  • Many responses of tissues exposed to pathological cues can be explained as the result of the anomalous activity of normal endogenous developmental mechanisms.

  • Knowing more about the genetic regulation of cardiovascular development is likely to be helpful in identifying new causative gene mutations as well as DNA variations with diagnostic and prognostic value, in addition to a variety of post-transcriptional regulatory mechanisms that might be involved in the onset of cardiovascular diseases.

  • The contents of this book might help you to choose an optimal animal model for your cardiovascular research.

  • Full understanding of the origin of different cardiac cell types will allow effective grouping/parsing of pathologies.

What can I learn from the technologies used by cardiovascular developmental biology?

  • Developmental biology is a precise discipline, driven by the necessity of working with small numbers of cells, complex gene regulatory networks, and a highly dynamic system.

  • Comparative analysis of cardiovascular development using different animal models allows investigation of the origin and progression of CHD, and is especially useful in the study of cardiovascular diseases linked to restricted heart domains (e.g. left ventricular non-compaction, Ebstein’s anomaly, arrhythmogenic right ventricle). Developmental studies help to reveal critical functions of cardiac genes. Targeted deletions of candidate genes can confirm these as culprits of heart disease in the young and old (e.g. NKX2-5).

  • The use of animal models is essential for understanding human CHD because in addition to the short generation time of mice as a mammalian model of four-chambered heart formation, experiments with human samples are logically restricted to in vitro cell culture models and tissue from biopsies.

  • Understanding the methods used in cardiovascular developmental research is essential for appreciating the technical limitations of such studies and resolving controversies resulting from divergent interpretations of a single set of results.

Is cardiovascular development relevant for the future of cardiovascular medicine?

  • Mechanistic insight into the origins of congenital heart defects is essential for deconstructing the spectrum of morphological defects for accurate genotyping and for the development of future therapeutic strategies.

  • Developmental studies are the basis of regenerative medicine, including the use of stem and progenitor cells and reprogramming strategies.

  • The Holy Grail of the tissue-engineered heart lies right in front of us—in every embryo, a complete heart forms de novo from a cluster of cells, and the more carefully we observe and understand this process, the more likely we are to be able to reproduce this in vitro.