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Abstract Background Diabetes is associated with a cardiomyopathy that is independent of coronary artery disease or hypertension. In the present study we used in vivo magnetic resonance imaging (MRI) and echocardiographic techniques to examine and characterize early changes in myocardial function in a mouse model of type 1 diabetes. Methods Diabetes was induced in 8-week old C57BL/6 mice with two intraperitoneal injections of streptozotocin. The blood glucose levels were maintained at 19–25 mmol/l using intermittent low dosages of long acting insulin glargine. MRI and echocardiography were performed at 4 weeks of diabetes (age of 12 weeks) in diabetic mice and age-matched controls. Results After 4 weeks of hyperglycemia one marker of mitochondrial function, NADH oxidase activity, was decreased to 50% of control animals. MRI studies of diabetic mice at 4 weeks demonstrated significant deficits in myocardial morphology and functionality including: a decreased left ventricular (LV) wall thickness, an increased LV end-systolic diameter and volume, a diminished LV ejection fraction and cardiac output, a decreased LV circumferential shortening, and decreased LV peak ejection and filling rates. M-mode echocardiographic and Doppler flow studies of diabetic mice at 4 weeks showed a decreased wall thickening and increased E/A ratio, supporting both systolic and diastolic dysfunction. Conclusion Our study demonstrates that MRI interrogation can identify the onset of diabetic cardiomyopathy in mice with its impaired functional capacity and altered morphology. The MRI technique will lend itself to repetitive study of early changes in cardiac function in small animal models of diabetic cardiomyopathy.

The tricuspid valve (TV) is composed of three leaflets that coapt during systole to prevent deoxygenated blood from re-entering the right atrium. The connection between the TV leaflets microstructure and the tissue-level mechanical responses has yet to be fully understood in the TV biomechanics society. This pilot study sought to examine the load-dependent collagen fiber architecture of the three TV leaflets, by employing a multiscale, combined experimental approach that utilizes tissue-level biaxial mechanical characterizations, micro-level collagen fiber quantification, and histological analysis. Our results showed that the three TV leaflets displayed greater extensibility in the tissues radial direction than in the circumferential direction, consistently under different applied biaxial tensions. Additionally, collagen fibers reoriented towards the direction of the larger applied load, with the largest changes in the alignment of the collagen fibers under radially-dominant loading. Moreover, collagen fibers in the belly region of the TV leaflets were found to experience greater reorientations compared to the tissue region closer to the TV annulus. Furthermore, histological examinations of the TV leaflets displayed significant regional variation in constituent mass fraction, highlighting the heterogeneous collagen microstructure. The combined experimental approach presented in this work enables the connection of tissue mechanics, collagen fiber microstructure, and morphology for the TV leaflets. This experimental methodology also provides a new research platform for future developments, such as multiscale models for the TVs, and the design of bioprosthetic heart valves that could better mimic the mechanical, microstructural, and morphological characteristics of the native tricuspid valve leaflets.

Atrioventricular heart valves (AHVs) are composed of structurally complex and morphologically heterogeneous leaflets. The coaptation of these leaflets during the cardiac cycle facilitates unidirectional blood flow. Valve regurgitation is treated preferably by surgical repair if possible or replacement based on the disease state of the valve tissue. A comprehensive understanding of valvular morphology and mechanical properties is crucial to refining computational models, serving as a patient-specific diagnostic and surgical tool for preoperative planning. Previous studies have modeled the stress distribution throughout the leaflets thickness, but validations with layer-specific biaxial mechanical experiments are missing. In this study, we sought to fill this gap in literature by investigating the impact of microstructure constituents on mechanical behavior throughout the thickness of the AHVs anterior leaflets. Porcine mitral valve anterior leaflets (MVAL) and tricuspid valve anterior leaflets (TVAL) were micro-dissected into three layers (atrialis/spongiosa, fibrosa, and ventricular) and two layers (atrialis/spongiosa and fibrosa/ventricularis), respectively, based on their relative distributions of extracellular matrix components as quantified by histological analyses: collagen, elastin, and glycosaminoglycans. Our results suggest that (i) for both valves, the atrialis/spongiosa layer is the most extensible and anisotropic layer, possibly due to its relatively low collagen content as compared to other layers, (ii) the intact TVAL response is stiffer than the atrialis/spongiosa layer but more compliant than the fibrosa/ventricularis layer, and (iii) the MVAL fibrosa and ventricularis layers behave nearly isotropic. These novel findings emphasize the biomechanical variances throughout the AHV leaflets, and our results could better inform future AHV computational model developments. STATEMENT OF SIGNIFICANCE: This study, which is the first of its kind for atrioventricular heart valve (AHV) leaflet tissue layers, rendered a mechanical characterization of the biaxial mechanical properties and distributions of extracellular matrix components (collagen, elastin, and glycosaminoglycans) of the mitral and tricuspid valve anterior leaflet layers. The novel findings from the present study emphasize the biomechanical variances throughout the thickness of AHV leaflets, and our results indicate that the previously-adopted homogenous leaflet in the AHV biomechanical modeling may be an oversimplification of the complex leaflet anatomy. Such improvement in the understanding of valvular morphology and tissue mechanics is crucial to future refinement of AHV computational models, serving as a patient-specific diagnostic and surgical tool, at the preoperative stage, for treating valvular heart diseases.

The atrioventricular heart valve (AHV) leaflets have a complex microstructure composed of four distinct layers: atrialis, ventricularis, fibrosa and spongiosa. Specifically, the spongiosa layer is primarily proteoglycans and glycosaminoglycans (GAGs). Quantification of the GAGs mechanical contribution to the overall leaflet function has been of recent focus for aortic valve leaflets, but this characterization has not been reported for the AHV leaflets. This study seeks to expand current GAG literature through novel mechanical characterizations of GAGs in AHV leaflets. For this characterization, mitral and tricuspid valve anterior leaflets (MVAL and TVAL, respectively) were: (i) tested by biaxial mechanical loading at varying loading ratios and by stress-relaxation procedures, (ii) enzymatically treated for removal of the GAGs and (iii) biaxially mechanically tested again under the same protocols as in step (i). Removal of the GAG contents from the leaflet was conducted using a 100 min enzyme treatment to achieve approximate 74.87% and 61.24% reductions of all GAGs from the MVAL and TVAL, respectively. Our main findings demonstrated that biaxial mechanical testing yielded a statistically significant difference in tissue extensibility after GAG removal and that stress-relaxation testing revealed a statistically significant smaller stress decay of the enzyme-treated tissue than untreated tissues. These novel findings illustrate the importance of GAGs in AHV leaflet behaviour, which can be employed to better inform heart valve therapeutics and computational models.

The collective data associated with this article presents the biaxial mechanical behavior for six smaller, delimited regions of the mitral valve and tricuspid valve anterior leaflets. Each data set consists of five columns of data, specifically: (i) biaxial testing protocol ID, (ii) circumferential stretch, (iii) radial stretch, (iv) circumferential membrane tension, and (v) radial membrane tension. For further elaboration regarding methodologies or results of the biaxial mechanical characterization please refer to the companion article Laurence, 2019.

Proper tricuspid valve (TV) function is essential to unidirectional blood flow through the right side of the heart. Alterations to the tricuspid valvular components, such as the TV annulus, may lead to functional tricuspid regurgitation (FTR), where the valve is unable to prevent undesired backflow of blood from the right ventricle into the right atrium during systole. Various treatment options are currently available for FTR; however, research for the tricuspid heart valve, functional tricuspid regurgitation, and the relevant treatment methodologies are limited due to the pervasive expectation among cardiac surgeons and cardiologists that FTR will naturally regress after repair of left-sided heart valve lesions. Recent studies have focused on (i) understanding the function of the TV and the initiation or progression of FTR using both in-vivo and in-vitro methods, (ii) quantifying the biomechanical properties of the tricuspid valve apparatus as well as its surrounding heart tissue, and (iii) performing computational modeling of the TV to provide new insight into its biomechanical and physiological function. This review paper focuses on these advances and summarizes recent research relevant to the TV within the scope of FTR. Moreover, this review also provides future perspectives and extensions critical to enhancing the current understanding of the functioning and remodeling tricuspid valve in both the healthy and pathophysiological states.

The facilitation of proper blood flow through the heart depends on proper function of heart valve components, and alterations to any component can lead to heart disease or failure. Comprehension of these valvular diseases is reliant on thorough characterization of healthy heart valve structures for use in computational models. Previously, computational models have treated these leaflet structures as a structurally and mechanically homogenous material, which may not be an accurate description of leaflet mechanical response. In this study, we aimed to characterize the mechanics of the heart valve leaflet as a structurally heterogenous material. Specifically, porcine mitral valve and tricuspid valve anterior leaflets were sectioned into six regions and biaxial mechanical tests with various loading ratios and stress-relaxation test were performed on each regional tissue sample. Three main findings from this study were summarized as follows: (i) the central regions of the leaflet had a more anisotropic nature than edge regions, (ii) the mitral valve anterior leaflet was more extensible in regions closer to the annulus, and (iii) there was variance in the stress-relaxation behavior among all six regions, with mitral valve leaflet tissue regions exhibiting a greater decay than the tricuspid valve regions. This study presents a novel investigation of the regional variations in the heart valve biomechanics that has not been comprehensively examined. Our results thus allow for a refinement of computational models for more accurately predicting diseased or surgically-intervened condition, where tissue heterogeneity plays an essential role in the heart valve function.

This dataset contains the anisotropic tissue responses of porcine atrioventricular valve leaflets to force-controlled biaxial mechanical testing. The set includes the first Piola-Kirchhoff Stress and the specimen stretches (λ) in both circumferential and radial tissue directions (C and R, respectively) for the mitral valve anterior and posterior leaflets (MVAL and MVPL), and the tricuspid valve anterior, posterior, and septal leaflets (TVAL, TVPL, and TVSL) from six porcine hearts at five separate force-controlled biaxial loading protocols. This dataset is associated with a companion journal article, which can be consulted for further information about the methodology, results, and discussion of this biaxial mechanical testing (Jett et al., in press) [1].

Valvular heart diseases are complex disorders, varying in pathophysiological mechanism and affected valve components. Understanding the effects of these diseases on valve functionality requires a thorough characterization of the mechanics and structure of the healthy heart valves. In this study, we performed biaxial mechanical experiments with extensive testing protocols to examine the mechanical behaviors of the mitral valve and tricuspid valve leaflets. We also investigated the effect of loading rate, testing temperatures, species (porcine versus ovine hearts), and age (juvenile vs adult ovine hearts) on the mechanical responses of the leaflet tissues. In addition, we evaluated the structure of chordae tendineae within each valve and performed histological analysis on each atrioventricular leaflet. We found all tissues displayed a characteristic nonlinear anisotropic mechanical response, with radial stretches on average 30.7% higher than circumferential stretches under equibiaxial physiological loading. Tissue mechanical responses showed consistent mechanical stiffening in response to increased loading rate and minor temperature dependence in all five atrioventricular heart valve leaflets. Moreover, our anatomical study revealed similar chordae quantities in the porcine mitral (30.5 ± 1.43 chords) and tricuspid valves (35.3 ± 2.45 chords) but significantly more chordae in the porcine than the ovine valves (p

It is well established that diabetes mellitus accelerates atherosclerotic vascular disease. Endothelial injury has been proposed to be the initial event in the pathogenesis of atherosclerosis. Endothelium not only acts as a semi-selective barrier but also serves physiological and metabolic functions. Diabetes or high glucose in circulation triggers a series of intracellular responses and organ damage such as endothelial dysfunction and apoptosis. One such response is high glucose-induced chronic endoplasmic reticulum stress in the endothelium. The unfolded protein response is an acute reaction that enables cells to overcome endoplasmic reticulum stress. However, when chronically persistent, endoplasmic reticulum stress response could ultimately lead to endothelial dysfunction and atherosclerosis. Herein, we discuss the scientific advances in understanding endoplasmic reticulum stress-induced endothelial dysfunction, the pathogenesis of diabetes-accelerated atherosclerosis and endoplasmic reticulum stress as a potential target in therapies for diabetic atherosclerosis.

Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium-targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin-interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium-specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy.

We previously reported on the experimental validation of several in silico-predicted glioma biomarkers (e.g., Plexin-B2 (PLXNB2), SLIT3, and Spondin-1 (SPON1)) that were found to be higher in human high-grade gliomas (HGGs). In this study, we validated their therapeutic potential by investigating antibody therapies against these three biomarkers in a preclinical mouse GL261 high-grade glioma model. Efficacies for antibody therapies against these biomarkers were assessed by survival and tumor volumes, biomarker expressions, cell invasion and proliferation, and bioinformatics gene/protein associations. Antibodies against PLXNB2, SLIT3, or SPON1 were effective in significantly reducing tumor volumes and increasing animal survival. With immunohistochemistry (IHC), these biomarkers were highly expressed in human HGGs, as well as in mice tumors. From IHC, CD44v6 was significantly decreased for all three antibody treatments, compared to UT GL261 tumors. Bioinformatics suggested that targeting either PLXNB2 or SPON1 may have a major effect on HGG cell migration and invasion (validated with CD44v6 IHC), whereas targeting SLIT3, in addition to affecting cell invasion, may also affect cell proliferation (not validated with Ki67 IHC). These results indicate that targeting these three biomarkers could add to the therapeutic arsenal against high-grade gliomas and that antibodies against them could be considered for clinical translation. [ABSTRACT FROM AUTHOR]