目的 评估氧化三甲胺(TMAO)对缺血性心力衰竭大鼠预后的影响。方法 SD大鼠随机分为正常对照组、假手术组、模型(HF)组、干预(HF-DMB)组,其中HF组与HF-DMB组大鼠行结扎法模拟心肌梗死,分别于术后4周(4 W)、8周(8 W)、12周(12 W)评估心脏功能,检测血清TMAO、脑钠肽(BNP)、C反应蛋白(CRP)、内毒素(LPS)、白介素-6(IL-6)等水平,心肌组织进行HE染色及Masson染色,取粪便组织进行16S rDNA高通量测序分析。结果 与正常对照组比较,HF组LVEF随时间明显下降,且在8W时下降尤为明显(27.68%±6.41%),HF组各时间点循环TMAO[(9534.02±202.75)nmol/L、(12713.06±243.66)nmol/L、(4970.95±168.15)nmol/L)]、BNP[(37.26±3.41)ng/L、(59.17±3.80)ng/L、(58.83±4.41) ng/L]、CRP[(179.30±13.85)μg/L、(186.40±13.47)μg/L、(187.21±11.35) μg/L]、LPS[(92.45±8.83)ng/L、(90.65±7.5) ng/L、(95.20±4.68) ng/L]、IL-6[(97.57±3.48) pg/ml、(102.60±4.96) pg/ml、(107.70±4.70) pg/ml]等指标浓度较正常对照组明显升高且差异具有统计学意义(P<0.05),HF-DMB组LVEF在各时间点有所回升,且循环中各指标均较HF组有不同程度下降(P<0.05),且TMAO水平变化与其他指标改变一致;心肌病理染色提示HF-DMB组较HF组心肌细胞存活更多且纤维化程度有所减轻;测序分析中,与HF组比较,HF-DMB组菌落丰度增加,HF-8W组厚壁菌门/拟杆菌门比值下降,而HF-DMB-8W组变化与HF-8W组相反。结论 缺血性心力衰竭大鼠循环TMAO变化与传统心力衰竭评价指标变化一致,特异性抑制循环TMAO能够改善心力衰竭多项指标,在心力衰竭的治疗和预后评估中具有一定的临床价值。
Abstract
Objective To evaluate the effect of trimethylamine oxide (TMAO) on the prognosis of ischemic heart failure rats. Methods SD rats were randomly divided into normal control group, sham group, model group (HF) and intervention group (HF-DMB). Rats in HF and HF-DMB groups underwent myocardial infarction simulation via ligation, and cardiac function was assessed at 4 weeks (4 W), 8 weeks (8 W) and 12 weeks (12 W) after surgery, respectively . The levels of Serum TMAO, BNP, CRP, LPS and IL-6 were detected, along with histological examination of myocardial tissue using HE and Masson staining. Fecal samples were also collected for 16S rDNA high-throughput sequencing analysis. Results Compared with Control group, HF group exhibited a significant decline in (LVEF) over time, the difference was most pronounced in the eighth week(27.68±6.41)%,also with a notable increase in circulating TMAO [(9534.02±202.75)nmol/L, (12713.06±243. 66)nmol/L, (4970.95±168.15) nmol/L], BNP[(37.26±3.41)ng/L, (59.17±3.80)ng/L, (58.83±4.41)ng/L], CRP[(179.30±13.85) μg/L, (186.40±13.47) μg/L, (187.21±11.35) μg/L], LPS[(92. 45±8.83)ng/L, (90.65±7.5) ng/L, (95.20±4.68) ng/L], IL-6[(97.57±3.48) pg/ml, (102.60±4.96) pg/ml, (107.70±4.70) pg/ml], levels compared with the control group (P<0.05). Myocardial pathological staining showed that more myocardial cells survived and the degree of fibrosis was reduced in HF-DMB group than in HF group. Sequencing analysis revealed increased microbial richness in the HF-DMB group compared with the HF group with increased Firmicutes and decreased Bacteroidetes at 8 weeks, resulting in a lowered Firmicutes/Bacteroidetes ratio. However, these changes were reversed in the HF-DMB-8W group. Conclusions Changes of circulating TMAO in ischemic heart failure rats are consistent with traditional heart failure evaluation markers. Specific inhibition of circulating TMAO can improve various indexes of heart failure, indicating its potential clinical value in heart failure treatment and prognostic assessment.
关键词
氧化三甲胺 /
心力衰竭 /
3 /
3-二甲基-1-丁醇 /
肠道菌群
Key words
trimethylamine oxide /
heart failure /
3,3-dimethyl-1-butanol /
gut microbiota
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参考文献
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基金
天津市应用基础研究项目(21JCQNJC01230);中心级创新团队课题(KYCXTD0502)
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