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J Cardiovasc Dev Dis. 2020 Jun 12;7(2). doi: 10.3390/jcdd7020023.

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

Journal of cardiovascular development and disease

Bradley B Keller, William J Kowalski, Joseph P Tinney, Kimimasa Tobita, Norman Hu

Affiliations

  1. Cincinnati Children's Heart Institute: Greater Louisville and Western Kentucky Practice, Louisville, KY 40202, USA.
  2. Laboratory of Stem Cell and Neuro-Vascular Biology, Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
  3. Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY 40202, USA.
  4. Department of Medical Affairs, Abiomed Japan K.K., Muromachi Higashi Mitsui Bldg, Tokyo 103-0022, Japan.
  5. Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.

PMID: 32545681 PMCID: PMC7344498 DOI: 10.3390/jcdd7020023

Abstract

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.

Keywords: avian embryo; biomechanics; cardiovascular morphogenesis; computational modeling; congenital heart disease; hemodynamics; impedance; mouse embryo; pressure–volume relations; shear stress; ventricular function; ventricular–vascular coupling; zebrafish embryo

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