3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension.

BACKGROUND: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure. METHODS: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function. RESULTS: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments. CONCLUSIONS: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload.

This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints.

Dynamic Heterogeneities in Liquid Mixtures Confined in Nanopores.

Binary liquid mixtures can exhibit nanosegregation, albeit being fully miscible and homogeneous at the macroscopic scale. This tendency can be amplified by geometrical nanoconfinement, leading to remarkable properties. This work investigates the molecular dynamics of tert-butanol (TBA)-toluene (TOL) mixtures confined in silica nanochannels by quasielastic neutron scattering and molecular dynamics simulation. It reveals a decoupling of the molecular motion of each constituent of the binary liquid, which can be followed independently by selective isotopic H/D labeling. We argue that this behavior is the signature of spatially segregated dynamic heterogeneities, which are due to the recently established core-shell nanophase separation induced by mesoporous confinement.

Free Energy of Nucleation and Interplay between Size and Composition in CuNi Systems.

Using molecular simulation, we shed light on the crystal nucleation process in systems of Cu, Ni, and their nanoalloy. For each system, we simulate the formation of the crystal nucleus along the entire nucleation pathway and determine the free energy barrier overcome by the system to form a critical nucleus. Comparing the results obtained for the pure metals to those for the nanoalloy, we analyze the impact of alloying on the free energy of nucleation, as well as on the size and structure of the crystal nucleus. Specifically, we relate the greater free energy of nucleation, and bigger critical nuclei, obtained for the nanoalloy, to the difference in size and cohesive energy between the two metals. Furthermore, we characterize the dependence of the local composition of the incipient crystal cluster on its size, which is of key significance for the applications of bimetallic nanoparticles in catalysis.