Cardiomyocyte Alpha-1A Adrenergic Receptors Mitigate Postinfarct Remodeling and Mortality by Constraining Necroptosis.

Clinical studies have shown that α1-adrenergic receptor antagonists (α-blockers) are associated with increased heart failure risk. The mechanism underlying that hazard and whether it arises from direct inhibition of cardiomyocyte α1-ARs or from systemic effects remain unclear. To address these issues, we created a mouse with cardiomyocyte-specific deletion of the α1A-AR subtype and found that it experienced 70% mortality within 7 days of myocardial infarction driven, in part, by excessive activation of necroptosis. We also found that patients taking α-blockers at our center were at increased risk of death after myocardial infarction, providing clinical correlation for our translational animal models.

Application of simple biomechanical and biochemical tests to heart valve leaflets: implications for heart valve characterization and tissue engineering.

A simple biomechanical test with real-time displacement and strain mapping is reported, which provides displacement vectors and principal strain directions during the mechanical characterization of heart valve tissues. The maps reported in the current study allow us to quickly identify the approximate strain imposed on a location in the samples. The biomechanical results show that the aortic valves exhibit stronger anisotropic mechanical behavior than that of the pulmonary valves before 18% strain equibiaxial stretching. In contrast, the pulmonary valves exhibit stronger anisotropic mechanical behavior than aortic valves beyond 28% strain equibiaxial stretching. Simple biochemical tests are also conducted. Collagens are extracted at different time points (24, 48, 72, and 120 h) at different locations in the samples. The results show that extraction time plays an important role in determining collagen concentration, in which a minimum of 72 h of extraction is required to obtain saturated collagen concentration. This work provides an easy approach for quantifying biomechanical and biochemical properties of semilunar heart valve tissues, and potentially facilitates the development of tissue engineered heart valves.

Virtual experiments of heart valve tissues.

The heart valve tissue mainly contains collagen fibers and valve interstitial cells (VICs) and constantly experiences different stress states during cardiac cycles. Due to the anisotropic architecture of collagen fibers and highly inhomogeneous cell population, the mechanical behavior of the heart valve becomes more complicated. It is known that external mechanical stimuli can lead to extracellular matrix (ECM) remodeling, cellular mechanotransduction, cell migration, and collagen synthesis; however, the mechanism of matrix-to-cell stress transfer remains unclear. Current study presents heterogeneously distributed collagen fibers responsible for transmitting forces into cells by an image-based finite element analysis incorporating histological photomicrographs of porcine heart valve tissues. Besides, nonlinear and anisotropic material properties tissue models are incorporated to quantify and visualize the overall stress distributions in heart valve tissues. By establishing an effectively predictive method with new computational tools and by performing virtual experiments on the heart valves, the role of load transmission in heart valves is clarified. The current study completely illustrates the stress distribution around cells and demonstrates the force transmission and reception between cells and matrix in the heart valve tissue. Therefore, our developed image-based finite element models provide new insights not only into clarifying the role of the force transmission and reception between heterogeneously distributed collagen fibers, but also a better understanding of relationships between the mechanical stimuli, cellular mechanotransduction, cell migration, matrix synthesis, and tissue remodeling in heart valves.