| Background Chronic heart failure(CHF)is a disease end-state in which the heart gradually loses its normal pumping function with symptoms of cardiac insufficiency due to various organic heart diseases,and it has been a public health problem that has been difficult to be completely solved in the medical field all over the world.Therefore,the active search for ways to improve cardiac remodeling in patients with heart failure is a major clinical challenge and a focus of the cardiovascular field at this stage.Studies have shown that reduced cardiac pumping causes redistribution of blood flow to systemic organs,with localized insufficiency of the intestinal tract and mucosal edema of the intestinal wall,a condition that causes displacement of intestinal flora,as well as elevated levels of endotoxins in the circulation,which can stimulate the release of excessive proinflammatory cytokines.Pro-inflammatory cytokines,in turn,further enhance the body’s immune inflammatory response by producing more pro-inflammatory cytokines,a phenomenon that mediates and precipitates the process of myocardial fibrosis and dysfunction,exacerbating the progression of heart failure.At the same time,the relationship between metabolite disorders following intestinal flora dysbiosis and heart failure is also very close and is a factor that cannot be ignored in the pathogenesis of heart failure.Phenylacetylglutamine(PAGln),one of the common chronic kidney disease toxins,was previously thought to be produced by the combination of phenylacetate or its precursors,namely phenylbutyrate and glutamine,under the action of catalase.In contrast,recent studies have revealed that phenylalanine can be synthesized into PAGln via conversion by intestinal microorganisms.The higher the plasma level of PAGln,the higher the probability of major adverse cardiovascular events(MACE).However,there are few studies on the changes of PAGln concentration in plasma of CHF patients.In this study,we investigated the changes and effects of intestinal flora and its metabolites in heart failure by detecting serum PAGln and sequencing the intestinal flora to provide new ideas for the diagnosis and treatment of heart failure.Objective By analyzing the changes of intestinal flora and its metabolite PAGln in CHF patients,we explored(1)the relationship between intestinal flora diversity in patients with varying grades in CHF and that in the healthy controls,(2)the changes in the PAGln levels in patients with varying grades in CHF and the healthy controls,and(3)the effects of intestinal flora diversity and PAGln on CHF.Methods 58 patients with heart failure admitted in the department of cardiology of Shanghai Fengxian District Central Hospital were selected as the CHF group,among which the number of NYHA class Ⅲ patients and NYHA class Ⅳ patients were 29 cases,respectively.In addition,22 patients with the same CHF risk factors but without clinical symptoms and past medical history of CHF were selected as the control group.The diversity and abundance of intestinal flora in the three groups of patients were analyzed by 16 S rRNA sequencing technology.Liquid chromatography tandem mass spectrometry(LC-MS/MS)was used to detect the level of PAGln in the plasma of the specimens from the three groups.Results 1.There were significant differences in heart rate,blood creatinine,urea nitrogen,and diuretics among control,NYHA class Ⅲ,and NYHA class Ⅳ patients(P<0.01).The differences in LVEF,LVESD,LVEDD,BNP and PAGln between the three groups were statistically significant(P<0.001).The results of the two-way comparison showed that the differences in LVEF between the three groups were statistically significant(P<0.01).There were statistically significant differences in LVESD and LVEDD between the control group and NYHA class Ⅳ(P<0.01),LVESD and LVEDD between NYHA class Ⅲ and NYHA class Ⅳ(P<0.01),and no statistically significant differences between LVESD and LVEDD between the control group and NYHA class Ⅲ(P>0.05).Meanwhile,there were statistically significant differences in BNP and PAGln levels between the three groups(P<0.01).Spearman correlation analysis showed that BNP(r=0.924,P<0.001),LVESD(r=0.529,P<0.001),and LVEDD(r=0.477,P<0.001)were positively correlated with PAGln,and LVEF(r=-0.587,P<0.001)was negatively correlated with PAGln.2.The Venn diagram shows that at the phylum level,the total number of OTUs in the three groups was 16,the number of NYHA class Ⅲ-specific OTUs was 1,the number of NYHA class Ⅳ-specific OTUs was 2,and the number of control group-specific OTUs was 6.At the genus level,the total number of OTUs in the three groups was 221,the number of OTUs specific to NYHA class Ⅲ was 7,the number of OTUs specific to NYHA class Ⅳ was 12,and the number of OTUs specific to the control group was 113.Both NYHA class Ⅲ and NYHA class Ⅳ had significantly fewer unique OTUs than the control group.The α-diversity index indicated that the difference in Chao 1 index between NYHA class Ⅲ and NYHA class Ⅳ was not statistically significant(P>0.05);the Chao 1 index of both NYHA class Ⅲ and NYHA class Ⅳ was lower than that of the control group,and the difference was statistically significant(P<0.05).NMDS demonstrated that the sample points in the heart failure and control groups were clearly separated,while NYHA class Ⅲ and NYHA class Ⅳ had some degree of overlap,with sample points clustered within the respective ranges of the three groups.Community composition analysis showed that the most dominant species in the control,NYHA class Ⅲ and NYHA class Ⅳ at the phylum level were Firmicutes,with statistically significant differences between groups(60.5%:48.8%:51.1%,P<0.05);Bacteroidetes was the second most abundant species in all three groups,with no statistically significant differences between groups(P> 0.05).At the genus level,the differences in the abundance percentages of Escherichia-Shigella,Agathobacter,Megamonas,Bifidobacterium,Klebsiella,Streptococcus,and Lactobacillus in the control group,NYHA class Ⅲ and NYHA class Ⅳ were statistically significant(P<0.05).LEf Se indicated that the bacterial species with the largest differences were Lachnospiraceae in control group,Enterobacteriaceae in NYHA class Ⅲ,and Escherichia in NYHA class Ⅳ.CCA analysis showed that BNP,PAGln,LVEDD and LVESD were significantly correlated with the flora of CHF group,among which BNP had the greatest influence on the change of the community;both BNP and PAGln had similar effect on the flora of CHF group;the angle of the line connecting the two arrows was acute,which indicated that BNP and PAGln were positively correlated with each other.Spearman correlation analysis indicated that Parabacteroides was negatively correlated with BNP and PAGln,and Romboutsia was negatively correlated with PAGln.Klebsiella was positively correlated with BNP and Escherichia-Shigella was positively correlated with BNP and PAGln.Alistipes was negatively correlated with BNP,Bacteroides was negatively correlated with BNP and PAGln,Blautia was negatively correlated with PAGln,and Parabacteroides was negatively correlated with LVEDD.Conclusion There were differences in the structural composition of the intestinal flora in the three groups of patients.Patients in the CHF group showed significantly lower diversity and significantly higher abundance of intestinal pathogenic bacteria compared to the control group.It may lead to an increase in the concentration of PAGln in CHF patients,which is involved in the development of CHF.Figure 8 Table 5 Reference 86... |
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