Study On The Pathogenesis Of Degenerative Aortic Stenosis And Treatment Strategy Of Bioprosthetic Valve Calcificatio

Porphyromonas gingivalis Systemic Infection is Associated with Calcific Aortic Valve Stenosis Through IL-1β-dependent Signaling PathwaysDegenerative aortic valve stenosis(DAVS)is the most common valvular heart disease drastically increased with aging.However,due to our poor understanding of its pathological mechanisms,there are currently no effective medical treatments capable of altering its course.We show that Porphyromonas gingivalis,a keystone pathogen of human periodontitis,is differentially enriched in human aortic valves extirpated from DAVS patients.Intravenously injected live Porphyromonas gingivalis,but not other live bacteria,preferentially infiltrates into mouse aortic valves,where it invades into the cytoplasm of valvular interstitial cells,causing osteoblast-like phenotypic switching via IL-1β-mediated inflammation,leading to accelerated valvular calcification and hemodynamically significant aortic stenosis,with or without the presence of hyperlipidemia.Metronidazole prophylaxis significantly reduces P.gingivalis transmission and the development of DAVS in the murine models.These results provide new insights into the potential bacterial etiology of DAVS that may lead to early prevention of human DAVS in the future.Sevelamer attenuates bioprosthetic heart valve calcificationObjective:Sevelamer hydrochloride is a phosphate binder used to treat hyperphosphatemia in chronic kidney disease(CKD)patients that can reduce valvular and vascular calcification.The aim of this study was to examine the effects of sevelamer treatment on calcification in bioprosthetic heart valves(BHVs).Methods:Wister rats were randomly divided into three groups according to sevelamer intake and implantation(sham-sham operation;implant-implantation and normal diet,implant+S implantation,and sevelamer diet).Two kinds of BHVs—bovine pericardium treated with glutaraldehyde(GLUT)or non-GLUT techniques—were implanted in rat dorsal subcutis at 4 weeks.After implantation,sevelamer was administered to the implant+S group.The animals were executed at days 0(immediately after implantation),7,14,28,and 56.Calcium levels were determined by atomic absorption spectroscopy and von Kossa staining.Serum biochemistry analysis,Western blotting,real-time quantitative polymerase chain reaction,alkaline phosphatase activity measurement,histopathologic analysis,immunohistochemistry,and enzyme-linked immunosorbent assay were conducted to identify the anti-calcification mechanism of sevelamer.Results:Non-GLUT crosslinking attenuates BHV calcification.Serum phosphate and calcium remained unreactive to sevelamer after a 14-day treatment.However,the mean calcium level in the implant+S group was significantly decreased after 56 days.In addition,the PTH level,inflammatory cell infiltration,system and local inflammation,and expression of Bmp2,Runx2,Alp,IL1b,IL6,and TNFa were significantly reduced in the implant+S group.Conclusion:Sevelamer treatment significantly attenuated the calcification of BHVs and had anti-inflammation effects that were independent from serum calcium and phosphate regulation.Thus,sevelamer treatment might be helpful to improve the longevity of BHVs.