Effect of left atrial ligation-driven altered inflow hemodynamics on embryonic heart development: clues for prenatal progression of hypoplastic left heart syndrome

Huseyin Enes Salman,Jonathan T. Butcher,Russell A. Gould,Fatiha M. Benslimane,Akshay Shekhar,Huseyin C. Yalcin,Maha Alser

doi:10.1007/s10237-020-01413-5

Abstract

Congenital heart defects (CHDs) are abnormalities in the heart structure present at birth. One important condition is hypoplastic left heart syndrome (HLHS) where severely underdeveloped left ventricle (LV) cannot support systemic circulation. HLHS usually initiates as localized tissue malformations with no underlying genetic cause, suggesting that disturbed hemodynamics contribute to the embryonic development of these defects. Left atrial ligation (LAL) is a surgical procedure on embryonic chick resulting in a phenotype resembling clinical HLHS. In this study, we investigated disturbed hemodynamics and deteriorated cardiac growth following LAL to investigate possible mechanobiological mechanisms for the embryonic development of HLHS. We integrated techniques such as echocardiography, micro-CT and computational fluid dynamics (CFD) for these analyses. Specifically, LAL procedure causes an immediate flow disturbance over atrioventricular (AV) cushions. At later stages after the heart septation, it causes hemodynamic disturbances in LV. As a consequence of the LAL procedure, the left-AV canal and LV volume decrease in size, and in the opposite way, the right-AV canal and right ventricle volume increase. According to our CFD analysis, LAL results in an immediate decrease in the left AV canal WSS levels for 3.5-day (HH21) pre-septated hearts. For 7-day post-septated hearts (HH30), LAL leads to further reduction in WSS levels in the left AV canal, and relatively increased WSS levels in the right AV canal. This study demonstrates the critical importance of the disturbed hemodynamics during the heart valve and ventricle development.

Highlights

The mammalian heart is the first functional organ that develops during embryogenesis
Less is known about how intracardiac hemodynamic forces contribute to heart development and function, and how the dysregulation of such forces can contribute to the formation of congenital heart defects (CHDs)
Previous studies have shown that perturbation of blood flow in the embryonic heart results in a spectrum of cardiac defects (Miller et al 2003; Sedmera et al 1999; Yalcin 2014), suggesting that disturbed hemodynamic environment is an important source for Congenital heart defects (CHDs)

Summary

Introduction

The mammalian heart is the first functional organ that develops during embryogenesis. It is well-understood that the Ithaca, NY, USA 4 Regeneron Pharmaceuticals, Tarrytown, NY, USA heart pumps a continuous supply of blood and nutrients to extracardiac tissues. Less is known about how intracardiac hemodynamic forces contribute to heart development and function, and how the dysregulation of such forces can contribute to the formation of congenital heart defects (CHDs). The heart continually pumps blood while growing and remodeling, which suggests that hemodynamic stresses within the heart may provide morphogenic cues to guide chamber development (Culver and Dickinson 2010; Forouhar et al 2006; Hove et al 2003; Yalcin et al 2011). Several studies have cataloged the increasing hemodynamic burden on cardiac morphogenesis during which the heart grows over 100-fold in size

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Conclusion