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

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.

Mechanosensitive Pathways in Heart Development: Findings from Chick Embryo Studies

“…The same findings were presented recently, where Salman and colleagues conducted CFD analyses on LAL and control hearts and showed that LAL resulted in a decrease in the left AV canal WSS levels at two time points (pre-and post-septation). This reduction was persistent and was compensated by increased WSS in the right side of the hearts [33]. These sustained hemodynamic alterations following the surgery are thought to be the cause of the cardiac structural defects post LAL.…”

“…Cardiogenesis continues under constantly evolving hemodynamic environment [31]. Previous animal studies from our group and others have shown that surgical interference affecting hemodynamics induce clinically relevant cardiac defects [10,19,21,32,33].…”

Placenta crucially affects formation of fetal congenital heart disease

“…Дифференциация эмбриональной сердечной трубки происходит на 3-й неделе после овуляции, а сердцебиение возникает к 4-й неделе [3]. К этому моменту фетоплацентарное кровообращение состоит из двух компонентов: один направлен к желточному мешку (желточное кровообращение), а другой к плаценте (кровообращение хориона) [4]. Желточное кровообращение формируется первым, и его функция является наиболее важной при развитии сердца плода.…”

“…Нормальное развитие плаценты зависит от адекватной имплантации, иммунотолерантности матери, правильного формирования плацентарного ложа, достаточной оксигенации и обмена веществ через плаценту, который обеспечивается гемохориальной плацентацией. Для этого необходима соответствующая трансформация материнских спиральных артерий 4 Institute for Preventive and Social Medicine; 4 Corresponding author: Valentina I. Tsibizova, e-mail: tsibizova.v@gmail.com…”

Hemodynamic and Structural Comparison of Human Fetal Heart Development Between Normally Growing and Hypoplastic Left Heart Syndrome-Diagnosed Hearts

“…Disturbed hemodynamics has been suggested as an important factor for such cases ( Salman and Yalcin, 2021 ). Compared to healthy fetal hearts, the hemodynamic environment of HLHS hearts shows substantial differences due to the underdevelopment of the left heart ( Salman et al, 2021a ), which results in a significantly deteriorated life quality for the patients with HLHS ( Dempster et al, 2017 ). The blood flow in HLHS hearts is disturbed as a consequence of the developmental disorders.…”