Background: In the era of increasingly successful corrective interventions in patients with congenital heart disease (CHD), global and regional myocardial remodeling are emerging as important sources of long-term morbidity/mortality. Changes in organization of the myocardium in CHD, and in its mechanical properties, conduction, and blood supply, result in altered myocardial function both before and after surgery. To gain a better understanding and develop appropriate and individualized treatment strategies, the microscopic organization of cardiomyocytes, and their integration at a macroscopic level, needs to be completely understood. The aim of this study is to describe, for the first time, in 3 dimensions and nondestructively the detailed remodeling of cardiac microstructure present in a human fetal heart with complex CHD. Methods and Results: Synchrotron X-ray phase-contrast imaging was used to image an archival midgestation formalin-fixed fetal heart with right isomerism and complex CHD and compare with a control fetal heart. Analysis of myocyte aggregates, at detail not accessible with other techniques, was performed. Macroanatomic and conduction system changes specific to the disease were clearly observable, together with disordered myocyte organization in the morphologically right ventricle myocardium. Electrical activation simulations suggested altered synchronicity of the morphologically right ventricle. Conclusions: We have shown the potential of X-ray phase-contrast imaging for studying cardiac microstructure in the developing human fetal heart at high resolution providing novel insight while preserving valuable archival material for future study. This is the first study to show myocardial alterations occur in complex CHD as early as midgestation.

We have developed a novel, high resolution, image acquisition, and quantification approach to study a whole in-vitro heart at myofibre resolution, providing integrated 3D structural information at microscopic level without any need of tissue slicing and processing. This superior imaging approach opens up new possibilities for a systems approach towards analysing cardiac structure and function, providing rapid acquisition of quantitative microstructure of the heart in a near native state.

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Experimental studies on isolated cardiomyocytes from different animal species and human hearts have demonstrated that there are regional differences in the Ca2+ release, Ca2+ decay and sarcomere deformation. Local deformation heterogeneities can occur due to a combination of factors: regional/local differences in Ca2+ release and/or re-uptake, intra-cellular material properties, sarcomere proteins and distribution of the intracellular organelles. To investigate the possible causes of these heterogeneities, we developed a two-dimensional finite-element electromechanical model of a cardiomyocyte that takes into account the experimentally measured local deformation and cytosolic [Ca2+] to locally define the different variables of the constitutive equations describing the electro/mechanical behaviour of the cell. Then, the model was individualised to three different rat cardiac cells. The local [Ca2+] transients were used to define the [Ca2+]-dependent activation functions. The cell-specific local Young’s moduli were estimated by solving an inverse problem, minimizing the error between the measured and simulated local deformations along the longitudinal axis of the cell. We found that heterogeneities in the deformation during contraction were determined mainly by the local elasticity rather than the local amount of Ca2+, while in the relaxation phase deformation was mainly influenced by Ca2+ re-uptake. Our electromechanical model was able to successfully estimate the local elasticity along the longitudinal direction in three different cells. In conclusion, our proposed model seems to be a good approximation to assess the heterogeneous intracellular mechanical properties to help in the understanding of the underlying mechanisms of cardiomyocyte dysfunction.

Echocardiography is the leading imaging modality for cardiac disorders in clinical practice. During an echocardiographic exam, geometry and blood flow are quantified in order to assess cardiac function. In clinical practice, these imagebased measurements are currently performed manually. An automated approach is needed if more advanced analysis is desired. In this article, we propose a new hybrid framework for the construction of a disease-specific atlas to improve Doppler aortic outflow velocity profile segmentation. The proposed method is based on combining realistic computational simulations of the cardiovascular system for common cardiac conditions (using Cir-cAdapt) with a validated image-based atlas construction method. The coupling is realized via model-based generation of echocardiographic images of virtual populations with a statistically approved parameter variation. We created virtual populations of 100 healthy individuals and 100 patients with aortic stenosis, synthesized their aortic Doppler velocity images and constructed the corresponding atlases. We validated atlases' performances by comparing their segmentation of real clinical images with the manually segmented ground truth. The experimental results show that the segmentation accuracy obtained using the proposed atlases is comparable to the accuracy obtained using classical clinical image-based atlases. Moreover, this framework eliminates the time-consuming acquisition of a sufficient number of representative images in clinical practice, offering a substantial time efficiency and flexibility in creating a disease specific atlas and ensuring an observer-independent automated segmentation. The proposed approach can easily be extended towards the creation of atlases for segmenting any Doppler trace in the cardiovascular circulation in a specific disease.