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

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.

Computational Modeling of Blood Flow Hemodynamics for Biomechanical Investigation of Cardiac Development and Disease

“…In order to develop preventive actions, understanding the complete mechanism of CHD initiation and progression is a necessity. Genetic factors are considered as major causes of CHDs, but disturbed hemodynamics also plays a role in development of CHDs [ 151 ]. Altered hemodynamics changes the biomechanical environment and influence the growth and remodeling of cardiac cells since endocardial cells sense the shear stresses generated by the blood flow.…”

Mechanosensitive Pathways in Heart Development: Findings from Chick Embryo Studies

“…The surgery is performed at HH 21 (ED 4 of incubation), where the heart is still not septated (pre-septation stage), ( Figure 1 ). The main defect associated with LAL is left heart hypoplasia (LHH) mimicking human hypoplastic left heart syndrome (HLHS) due to the reduction of blood volume received by the left ventricle from the left atrium [ 9 , 36 ]. The surgery is effective in introducing the HLHS like defect, with 100% of embryos undergone LAL developing hypoplasia at HH34 (ED 8) [ 37 ].…”

“…Technically, the surgery is performed at HH18-HH21 (ED 3~3.5), where the heart is still in its looping stage as visualized in Figure 3 . Similar to the previous surgeries, OTB alters the hemodynamics of the developing heart and leads to cardiac defects changes [ 9 , 52 ].…”

“…The advantages of using embryonic chicks have been reviewed by [ 8 , 9 ]. Briefly, they are easy to access since they develop ex utero.…”

“…Multiple research groups have reviewed the effect of clinically relevant in vivo microsurgeries or similar interferences on changing cardiac hemodynamics and inducing morphological alterations in heart development resembling human CHDs [ 6 , 9 , 16 , 17 ]. Others aimed to synthesize what is known about the genetic pathways for cardiac development and disease [ 18 , 19 , 20 , 21 ].…”