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BackgroundPulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are not well understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH in HFpEF, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.MethodsEight week old male and female C57/BL6J mice were given either L-NAME and high fat diet (HFD) or control water/diet for 2,5, and 12 weeks. Bulk RNA sequencing and single cell RNA sequencing was performed to identify early and cell-specific pathways that might regulate pulmonary vascular remodeling in PH-HFpEF. Finally, clodronate liposome and IL1β antibody treatments were utilized to deplete macrophages or IL1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF.ResultsMice given L-NAME/HFD developed PH, small vessel muscularization, and right heart dysfunction after 2 weeks of treatment. Inflammation-related gene ontologies were over-represented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling of mouse lung and plasma showed an increase in IL1β, which was confirmed in plasma from patients with HFpEF. Single cell sequencing of mouse lungs also showed an increase in M1-like, pro-inflammatory populations of Ccr2+ monocytes and macrophages, and transcript expression of IL1β was primarily restricted to myeloid-type cells. Finally, clodronate liposome treatment prevented the development of PH in L-NAME/HFD treated mice, and IL1β antibody treatment also attenuated PH in L-NAME/HFD treated mice.ConclusionsOur study demonstrated that a well-accepted model of HFpEF recapitulates features of pulmonary vascular remodeling commonly seen in patients with HFpEF, and we identified myeloid cell derived IL1β as an important contributor to PH in HFpEF.

Various damage formulations have been used to simulate the inelastic behavior of granular composite materials, e.g., concrete, under cyclic loadings, but the results obtained differ from experimental data. The aim of this study is to develop general nonlinear damage formulations, with calibration capabilities, on the basis of two nonlinear indices, namely the tension and compression states, covering all cyclic loading conditions, including partial and complete unloading/reloading ones. Using verification procedures, the efficiency of calibration ability of the formulations, especially for computer programming, is illustrated.

To the article “Modeling the damage characteristics of concrete subjected to cyclic loading” by P. Chatee, M. S. Jaafar, A. Ibrahim, and H. Talati, Vol 53, No. 5, p. 670, 2017.