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Fetal critical aortic stenosis with evolving hypoplastic left heart syndrome (CAS‐eHLHS) causes biomechanical and functional aberrations, leading to a high risk of progression to hypoplastic left heart syndrome (HLHS) at birth. Fetal aortic valvuloplasty (FAV) can resolve outflow obstruction and may reduce progression risk. However, it is currently difficult to accurately predict which patients will respond to the intervention and become functionally biventricular (BV) at birth, as opposed to becoming functionally univentricular (UV). This prediction is important for patient selection, parental counselling, and surgical planning. Therefore, we investigated whether biomechanics parameters from pre‐FAV image‐based computations could robustly distinguish between CAS‐eHLHS cases with BV or UV outcomes in a retrospective cohort. To do so we performed image‐based finite element biomechanics modelling of nine CAS‐eHLHS cases undergoing intervention and six healthy fetal control hearts, and found that a biomechanical parameter, peak systolic myofibre stress, showed a uniquely large difference between BV and UV cases, which had a larger magnitude effect than echocardiography parameters. A simplified equation was derived for quick and easy estimation of myofibre stress from echo measurements via principal component analysis. When tested on a retrospective cohort of 37 CAS‐eHLHS cases, the parameter outperformed other parameters in predicting UV versus BV outcomes, and thus has a high potential of improving outcome predictions, if incorporated into patient selection procedures. Physiologically, high myocardial stresses likely indicate a healthier myocardium that can withstand high stresses and resist pathological remodelling, which can explain why it is a good predictor of BV outcomes. Key points: Predicting the morphological birth outcomes (univentricular versus biventricular) of fetal aortic valvuloplasty for fetal aortic stenosis with evolving HLHS is important for accurate patient selection, parental counselling and management decisions.Computational simulations show that a biomechanics parameter, pre‐intervention peak systolic myofibre stress, is uniquely robust in distinguishing between such outcomes, outperforming all echo parameters.An empirical equation was developed to quickly compute peak systolic myofibre stress from routine echo measurements and was the best predictor of outcomes among a wide range of parameters tested. [ABSTRACT FROM AUTHOR]

Cardiac trabeculae are uneven ventricular muscular structures that develop during early embryonic heart development at the outer curvature of the ventricle. Their biomechanical function is not completely understood, and while their formation is known to be mechanosensitive, it is unclear whether ventricular tissue internal stresses play an important role in their formation. Here, we performed imaging and image‐based cardiac biomechanics simulations on zebrafish embryonic ventricles to investigate these issues. Microscopy‐based ventricular strain measurements show that the appearance of trabeculae coincided with enhanced deformability of the ventricular wall. Image‐based biomechanical simulations reveal that the presence of trabeculae reduces ventricular tissue internal stresses, likely acting as structural support in response to the geometry of the ventricle. Passive ventricular pressure‐loading experiments further reveal that the formation of trabeculae is associated with a spatial homogenization of ventricular tissue stiffnesses in healthy hearts, but gata1 morphants with a disrupted trabeculation process retain a spatial stiffness heterogeneity. Our findings thus suggest that modulating ventricular wall deformability, stresses, and stiffness are among the biomechanical functions of trabeculae. Further, experiments with gata1 morphants reveal that a reduction in fluid pressures and consequently ventricular tissue internal stresses can disrupt trabeculation, but a subsequent restoration of ventricular tissue internal stresses via vasopressin rescues trabeculation, demonstrating that tissue stresses are important to trabeculae formation. Overall, we find that tissue biomechanics is important to the formation and function of embryonic heart trabeculation. Key points: Trabeculations are fascinating and important cardiac structures and their abnormalities are linked to embryonic demise.However, their function in the heart and their mechanobiological formation processes are not completely understood.Our imaging and modelling show that tissue biomechanics is the key here. We find that trabeculations enhance cardiac wall deformability, reduce fluid pressure stresses, homogenize wall stiffness, and have alignments that are optimal for providing load‐bearing structural support for the heart.We further discover that high ventricular tissue internal stresses consequent to high fluid pressures are needed for trabeculation formation through a rescue experiment, demonstrating that myocardial tissue stresses are as important as fluid flow wall shear stresses for trabeculation formation. [ABSTRACT FROM AUTHOR]

Background: Biomechanical stimuli are known to be important to cardiac development, but the mechanisms are not fully understood. Here, we pharmacologically disrupted the biomechanical environment of wild‐type zebrafish embryonic hearts for an extended duration and investigated the consequent effects on cardiac function, morphological development, and gene expression. Results: Myocardial contractility was significantly diminished or abolished in zebrafish embryonic hearts treated for 72 hours from 2 dpf with 2,3‐butanedione monoxime (BDM). Image‐based flow simulations showed that flow wall shear stresses were abolished or significantly reduced with high oscillatory shear indices. At 5 dpf, after removal of BDM, treated embryonic hearts were maldeveloped, having disrupted cardiac looping, smaller ventricles, and poor cardiac function (lower ejected flow, bulboventricular regurgitation, lower contractility, and slower heart rate). RNA sequencing of cardiomyocytes of treated hearts revealed 922 significantly up‐regulated genes and 1,698 significantly down‐regulated genes. RNA analysis and subsequent qPCR and histology validation suggested that biomechanical disruption led to an up‐regulation of inflammatory and apoptotic genes and down‐regulation of ECM remodeling and ECM–receptor interaction genes. Biomechanics disruption also prevented the formation of ventricular trabeculation along with notch1 and erbb4a down‐regulation. Conclusions: Extended disruption of biomechanical stimuli caused maldevelopment, and potential genes responsible for this are identified. Key Findings: We evaluated the effects of prolonged disruption of heartbeat in the zebrafish embryonic heart (2‐5dpf) on cardiac function, morphology and gene expressions.The disruption led to mal‐development of the heart in terms of abnormal looping angle, smaller ventricle and insufficient heart valves, and it led to poorer cardiac function (lower ejection fraction, regurgitation, slower heart rate, and poorer contractions).Whole transcriptomic analysis showed upregulation of inflammatory and apoptotic genes, downregulation of ECM remodelling and ECM‐receptor interaction.genes, and prevented formation of trabeculation together with not1 and erbb4a downregulation. [ABSTRACT FROM AUTHOR]