Volume Load-Induced Right Ventricular Failure in Rats Is Not Associated With Myocardial Fibrosis

Background Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction. Methods Wistar rats were subjected to aorto-caval shunt (ACS, n = 23) or sham (control, n = 15) surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed. Results At 6 months, 6/8 ACS-rats (75%) showed clinical signs of RV failure (pleural effusion, ascites and/or liver edema), whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGF beta 1 and pSMAD2/3), or fibrosis were present at any time point. Conclusions In the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model

Cellular senescence impairs the reversibility of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH

Permeation of probe molecules into alginate microbeads: Effect of salt and processing

International audienceThe ability to exclude harmful factors from a hydrogel microbead is important for the degree of protection the beads offers to what is encapsulated within. The permeability of alginate microbeads, prepared by water-in-oil emulsification, was investigated by their ability to exclude FITC-labelled protein probes. The influence of alginate concentration, calcium concentration and method of addition, and salt content of the environment was investigated. The permeability was also compared to the permeability of beads made by the traditional method of dripping an alginate solution into a CaCl2 solution. Beads produced with low amounts of CaCl2 show a significant degree of swelling and are therefore very permeable (C/C0 (BSA) = 0.62, where C is the final concentration of BSA-FITC in the bead, and C0 the concentration of BSA-FITC in the continuous phase). With additional calcium, either by adding more calcium crystals after the emulsification step or by washing with a CaCl2 solution, beads swell less and are less permeable (C/C0 (BSA) = 0.13 and 0.12). Beads made by dripping are very permeable (C/C0 (BSA) ∼ 0.60). Because in this process the droplets of alginate are not constrained by a water-oil boundary, the beads can swell during gelation. The salt concentration in the continuous phase influences the strength of the electrostatic repulsion between the probes and the alginate network and hence affects the permeation of the probes into the beads. In the absence of salt, even FITC (389Da) is mostly excluded from the interior of the beads (C/C0 (FITC) ∼ 0.09)