The objective of this study was to evaluate the long term performance of cell-free vascular grafts made from a fast-degrading elastic polymer. We fabricated small arterial grafts from microporous tubes of poly(glycerol sebacate) (PGS) reinforced with polycaprolactone (PCL) nanofibers on the outer surface. Grafts were interpositioned in rat abdominal aortas and characterized at 1 year post-implant. Grafts remodeled into “neoarteries” (regenerated arteries) with similar gross appearance to native rat aortas. Neoarteries mimic arterial tissue architecture with a confluent endothelium and media and adventita-like layers. Patent vessels (80%) showed no significant stenosis, dilation, or calcification. Neoarteries contain nerves and have the same amount of mature elastin as native arteries. Despite some differences in matrix organization, regenerated arteries had similar dynamic mechanical compliance to native arteries in vivo. Neoarteries responded to vasomotor agents, albeit with different magnitude than native aortas. These data suggest that an elastic vascular graft that resorbs quickly has potential to improve the performance of vascular grafts used in small arteries. This design may also promote constructive remodeling in other soft tissues.

In pre-clinical models of PH CD47 targets cMyc to increase ET-1 signaling. In clinical PH TSP1-CD47 is upregulated, and in both, contributes to pulmonary arterial vasculopathy and dysfunction.

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF; World Health Organization Group II) secondary to left ventricular (LV) diastolic dysfunction is the most frequent cause of PH. It is an increasingly recognized clinical complication of the metabolic syndrome. To date, no effective treatment has been identified, and no genetically modifiable mouse model is available for advancing our understanding for PH-HFpEF. To develop a mouse model of PH-HFpEF, we exposed 36 mouse strains to 20 weeks of high-fat diet (HFD), followed by systematic evaluation of right ventricular (RV) and LV pressure-volume analysis. The HFD induces obesity, glucose intolerance, insulin resistance, hyperlipidemia, as well as PH, in susceptible strains. We observed that certain mouse strains, such as AKR/J, NON/shiLtJ, and WSB/EiJ, developed hemodynamic signs of PH-HFpEF. Of the strains that develop PH-HFpEF, we selected AKR/J for further model validation, as it is known to be prone to HFD-induced metabolic syndrome and had low variability in hemodynamics. HFD-treated AKR/J mice demonstrate reproducibly higher RV systolic pressure compared with mice fed with regular diet, along with increased LV end-diastolic pressure, both RV and LV hypertrophy, glucose intolerance, and elevated HbA1c levels. Time course assessments showed that HFD significantly increased body weight, RV systolic pressure, LV end-diastolic pressure, biventricular hypertrophy, and HbA1c throughout the treatment period. Moreover, we also identified and validated 129S1/SvlmJ as a resistant mouse strain to HFD-induced PH-HFpEF. These studies validate an HFD/AKR/J mouse model of PH-HFpEF, which may offer a new avenue for testing potential mechanisms and treatments for this disease.

BackgroundRight ventricular (RV) diastolic function has been associated with outcomes for patients with pulmonary hypertension; however, the relationship between biomechanics and hemodynamics in the right ventricle has not been studied.Methods and ResultsRat models of RV pressure overload were obtained via pulmonary artery banding (PAB; control, n=7; PAB, n=5). At 3 weeks after banding, RV hemodynamics were measured using a conductance catheter. Biaxial mechanical properties of the RV free wall myocardium were obtained to extrapolate longitudinal and circumferential elastic modulus in low and high strain regions (E1 and E2, respectively). Hemodynamic analysis revealed significantly increased end‐diastolic elastance (Eed) in PAB (control: 55.1 mm Hg/mL [interquartile range: 44.7–85.4 mm Hg/mL]; PAB: 146.6 mm Hg/mL [interquartile range: 105.8–155.0 mm Hg/mL]; P=0.010). Longitudinal E1 was increased in PAB (control: 7.2 kPa [interquartile range: 6.7–18.1 kPa]; PAB: 34.2 kPa [interquartile range: 18.1–44.6 kPa]; P=0.018), whereas there were no significant changes in longitudinal E2 or circumferential E1 and E2. Last, wall stress was calculated from hemodynamic data by modeling the right ventricle as a sphere: )(stress=Pressure×radius2×thickness.Conclusions RV pressure overload in PAB rats resulted in an increase in diastolic myocardial stiffness reflected both hemodynamically, by an increase in Eed, and biomechanically, by an increase in longitudinal E1. Modest increases in tissue biomechanical stiffness are associated with large increases in Eed. Hemodynamic measurements of RV diastolic function can be used to predict biomechanical changes in the myocardium.

Background Pulmonary hypertension ( PH ) results in increased right ventricular ( RV ) afterload and ventricular remodeling. Sacubitril/valsartan (sac/val) is a dual acting drug, composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, that has shown promising outcomes in reducing the risk of death and hospitalization for chronic systolic left ventricular heart failure. In this study, we aimed to examine if angiotensin receptor‐neprilysin inhibition using sac/val attenuates RV remodeling in PH . Methods and Results RV pressure overload was induced in Sprague–Dawley rats via banding the main pulmonary artery. Three different cohorts of controls, placebo‐treated PH , and sac/val‐treated PH were studied in a 21‐day treatment window. Terminal invasive hemodynamic measurements, quantitative histological analysis, biaxial mechanical testing, and constitutive modeling were employed to conduct a multiscale analysis on the effects of sac/val on RV remodeling in PH . Sac/val treatment decreased RV maximum pressures (29% improvement, P =0.002), improved RV contractile (30%, P =0.012) and relaxation (29%, P =0.043) functions, reduced RV afterload (35% improvement, P =0.016), and prevented RV ‐ pulmonary artery uncoupling. Furthermore, sac/val attenuated RV hypertrophy (16% improvement, P =0.006) and prevented transmural reorientation of RV collagen and myofibers ( P =0.011). The combined natriuresis and vasodilation resulting from sac/val led to improved RV biomechanical properties and prevented increased myofiber stiffness in PH (61% improvement, P =0.032). Conclusions Sac/val may prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen, and myofiber reorientation as well as tissue stiffening both at the tissue and myofiber level.