Abstract
Left atrial ligation (LAL) of the chick embryonic heart at HH21 is a model of the hypoplastic left heart syndrome (HLHS) disease, demonstrating morphological and hemodynamic features similar to human HLHS cases. Since it relies on mechanical intervention without genetic or pharmacological manipulations, it is a good model for understanding the biomechanics origins of such HLHS malformations. To date, however, the fluid mechanical environment of this model is poorly understood. In the current study, we performed 4D ultrasound imaging of LAL and normal chick embryonic hearts and 4D cardiac flow simulations to help shed light on the mechanical environment that may lead to the HLHS morphology. Results showed that the HH25 LAL atrial function was compromised, and velocities in the ventricle were reduced. The HH25 LAL ventricles developed a more triangular shape with a sharper apex, and in some cases, the atrioventricular junction shifted medially. These changes led to more sluggish flow near the ventricular free wall and apex, where more fluid particles moved in an oscillatory manner with the motion of the ventricular wall, while slowly being washed out, resulting in lower wall shear stresses and higher oscillatory indices. Consequent to these flow conditions, at HH28, even before septation is complete, the left ventricle was found to be hypoplastic while the right ventricle was found to be larger in compensation. Our results suggest that the low and oscillatory flow near the left side of the heart may play a role in causing the HLHS morphology in the LAL model.
Highlights
Hypoplastic left heart syndrome (HLHS), a type of severe CHD, represents 3% of CHD cases (Reller et al 2008) but accounts for a disproportionate amount of neonatal deaths (Gilboa et al 2010) (10.9%, highest mortality rate among all CHD) (Gilboa et al 2010)
At HH28, the Left atrial ligation (LAL) left ventricle (LV) end-diastolic volume became smaller than the controls end-diastolic volume while the LAL right ventricle (RV) end-diastolic volume became larger than the controls (p < 0.05, Fig. 2a), suggesting that the LV was moving towards being hypoplastic, while the RV was growing larger to compensate for the smaller LV
While the average LV end-diastolic volume increased by 138% in the controls from HH25 to HH28, it had very little increase for LAL LV, increasing only 14% over the same period
Summary
Hypoplastic left heart syndrome (HLHS), a type of severe CHD, represents 3% of CHD cases (Reller et al 2008) but accounts for a disproportionate amount of neonatal deaths (Gilboa et al 2010) (10.9%, highest mortality rate among all CHD) (Gilboa et al 2010). HLHS is characterised by an underdevelopment of the left heart, accompanied by aortic valve stenosis or atresia, and hypoplastic ascending aorta and aortic arch (Franklin et al 2017). HLHS is known to be heritable from parents with atrial-septal defect or ventricular-septal defect at 21 times the estimated population frequency (Nora et al 1969) and is found to be multi-gene and genetically heterogeneous (Liu et al 2017). Known genetic causes are estimated to only account for 20% of CHD cases (Gelb and Chung 2014). It is thought that HLHS can be a result of abnormal hemodynamic loading because physical cardiac aberrations such as premature narrowing of the foramen ovale (Rychik et al 1999), atretic aortic valve (Danford and Cronican 1992) or impaired ventricle function (Allan et al 1989) are observed to precede the HLHS birth morphology
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