Spatial distribution and network morphology of epicardial, endocardial, interstitial, and Purkinje cell-associated elastin fibers in porcine left ventricle.

Cardiac extracellular matrices (ECM) play crucial functional roles in cardiac biomechanics. Previous studies have mainly focused on collagen, the major structural ECM in heart wall. The role of elastin in cardiac mechanics, however, is poorly understood. In this study, we investigated the spatial distribution and microstructural morphologies of cardiac elastin in porcine left ventricles. We demonstrated that the epicardial elastin network had location- and depth-dependency, and the overall epicardial elastin fiber mapping showed certain correlation with the helical heart muscle fiber architecture. When compared to the epicardial layer, the endocardial layer was thicker and has a higher elastin-collagen ratio and a denser elastin fiber network; moreover, the endocardial elastin fibers were finer and more wavy than the epicardial elastin fibers, all suggesting various interface mechanics. The myocardial interstitial elastin fibers co-exist with the perimysial collagen to bind the cardiomyocyte bundles; some of the interstitial elastin fibers showed a locally aligned, hinge-like structure to connect the adjacent cardiomyocyte bundles. This collagen-elastin combination reflects an optimal design in which the collagen provides mechanical strength and elastin fibers facilitate recoiling during systole. Moreover, cardiac elastin fibers, along with collagen network, closely associated with the Purkinje cells, indicating that this ECM association could be essential in organizing cardiac Purkinje cells into "fibrous" and "branching" morphologies and serving as a protective feature when Purkinje fibers experience large deformations in vivo. In short, our observations provide a structural basis for future in-depth biomechanical investigations and biomimicking of this long-overlooked cardiac ECM component.

Investigating the Transient Regenerative Potential of Cardiac Muscle Using a Neonatal Pig Partial Apical Resection Model.

Researchers have shown that adult zebrafish have the potential to regenerate 20% of the ventricular muscle within two months of apex resection, and neonatal mice have the capacity to regenerate their heart after apex resection up until day 7 after birth. The goal of this study was to determine if large mammals (porcine heart model) have the capability to fully regenerate a resected portion of the left ventricular apex during the neonatal stage, and if so, how long the regenerative potential persists. A total of 36 piglets were divided into the following groups: 0-day control and surgical groups and seven-day control and surgical groups. For the apex removal groups, each piglet was subjected to a partial wall thickness resection (~30% of the ventricular wall thickness). Heart muscle function was assessed via transthoracic echocardiograms; the seven-day surgery group experienced a decrease in ejection fraction and fractional shortening. Upon gross necropsy, for piglets euthanized four weeks post-surgery, all 0-day-old hearts showed no signs of scarring or any indication of the induced injury. Histological analysis confirmed that piglets in the 0-day surgery group exhibited various degrees of regeneration, with half of the piglets showing full regeneration and the other half showing partial regeneration. However, each piglet in the seven-day surgery group demonstrated epicardial fibrosis along with moderate to severe dissecting interstitial fibrosis, which was accompanied by an abundant collagenous extracellular matrix as the result of a scar formation in the resection site. Histology of one 0-day apex resection piglet (briefly lain on and accidentally killed by the mother sow three days post-surgery) revealed dense, proliferative mesenchymal cells bordering the fibrin and hemorrhage zone and differentiating toward immature cardiomyocytes. We further examined the heart explants at 5-days post-surgery (5D PO) and 1-week post-surgery (1W PO) to assess the repair progression. For the 0-day surgery piglets euthanized at 5D PO and 1W PO, half had abundant proliferating mesenchymal cells, suggesting active regeneration, while the other half showed increased extracellular collagen. The seven-day surgery piglets euthanized at 5D PO, and 1W PO showed evidence of greatly increased extracellular collagen, while some piglets had proliferating mesenchymal cells, suggesting a regenerative effort is ongoing while scar formation seems to predominate. In short, our qualitative findings suggest that the piglets lose the full myocardial regenerative potential by 7 days after birth, but greatly preserve the regenerative potential within 1 day post-partum.

Using models to advance medicine: mathematical modeling of post-myocardial infarction left ventricular remodeling.

The heart is an organ with limited capacity for regeneration and repair. The irreversible cell death and corresponding diminished ability of the heart to repair after myocardial infarction (MI), is a leading cause of morbidity and mortality worldwide. In this paper, a new mathematical model is presented to study the left ventricular (LV) remodeling and associated events after MI. The model accurately describes and predicts the interactions among heart cells and the immune system post-MI in the absence of medical interventions. The resulting system of nonlinear ordinary differential equations is studied both analytically and numerically in order to demonstrate the functionality and performance of the new model. To the best of our knowledge, this model is the only one of its kind to consider and correctly apply all of the known factors in diseased heart LV modeling. This model has the potential to provide researchers with a predictive computational tool to better understand the MI pathology and develop various cell-based treatment options, with benefits of lowering the cost and reducing the development time.

Epicardial prestrained confinement and residual stresses: a newly observed heart ventricle confinement interface.

The heart epicardial layer, with elastin as the dominant component, has not been well investigated, specifically on how it contributes to ventricular biomechanics. In this study, we revealed and quantitatively assessed the overall status of prestraining and residual stresses exerted by the epicardial layer on the heart left ventricle (LV). During porcine heart wall dissection, we discovered that bi-layered LV surface strips, consisting of an epicardial layer and cardiac muscle, always curled towards the epicardial side due to epicardial residual stresses. We hence developed a curling angle characterization technique to intuitively and qualitatively reveal the location-dependency and direction-dependency of epicardial residual stresses. Moreover, by combining prestrain measurement and biaxial mechanical testing, we were able to quantify the epicardial prestrains and residual stresses on the unpressurized intact LV. To investigate the potential mechanical effect of epicardial prestraining, a finite-element (FE) model has been constructed, and we demonstrate that it is the prestraining of the epicardial layer, not the epicardial layer alone, providing an additional resistance mechanism during LV diastolic expansion and ventricular wall protection by reducing myocardial stress. In short, our study on healthy, native porcine hearts has revealed an important phenomenon-the epicardial layer, rich in elastin, acts like a prestrained 'balloon' that wraps around the heart and functions as an extra confinement and protection interface. The obtained knowledge fills a gap in ventricular biomechanics and will help design novel biomimicking materials or prosthetic devices to target the maintenance/recreation of this ventricle confinement interface.

Heart valve tissue-derived hydrogels: Preparation and characterization of mitral valve chordae, aortic valve, and mitral valve gels.

Heart valve (HV) diseases are among the leading causes of death and continue to threaten public health worldwide. The current clinical options for HV replacement include mechanical and biological prostheses. However, an ongoing problem with current HV prostheses is their failure to integrate with the host tissue and their inability grow and remodel within the body. Tissue engineered heart valves (TEHVs) are a promising solution to these problems, as they are able to grow and remodel somatically with the rest of the body. Recently, decellularized HVs have demonstrated great potential as valve replacements because they are tissue specific, but recellularization is still a challenge due to the dense HV extracellular matrix (ECM) network. In this proof-of-concept work, we decellularized porcine mitral valve chordae, aortic valve leaflets, and mitral valve leaflets and processed them into injectable hydrogels that could accommodate any geometry. While the three valvular ECMs contained various amounts of collagen, they displayed similar glycosaminoglycan contents. The hydrogels had similar nanofibrous structures and gelation kinetics with various compressive strengths. When encapsulated with NIH 3 T3 fibroblasts, all the hydrogels supported cell survivals up to 7 days. Decellularized HV ECM hydrogels may show promising potential HV tissue engineering applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1732-1740, 2019.