The Correlation Between Plasma NLRP3 And Cardiac Remodeling And Prognosis In Patients With Non-valvular Atrial Fibrillation

【 Background 】 Atrial fibrillation(AF)is one of the most common clinical arrhythmias and is characterized by high prevalence,disability,and mortality.A large number of studies have found that inflammation is one of the important mechanisms leading to atrial fibrillation.Multiple inflammatory factors in the inflammatory cascade can participate in the occurrence,development,and maintenance of atrial fibrillation by promoting atrial structural remodeling and electrical remodeling.The NLRP3 inflammasome is an important part of the innate immune system and a key molecule in the inflammatory cascade response.Abnormal activation of NLRP3 inflammasome can promote atrial enlargement,atrial fibrosis,and/or atrial electrical remodeling,thereby increasing the susceptibility of atrial fibrillation and promoting the occurrence and maintenance of atrial fibrillation.Although a large number of basic studies have revealed that NLRP3 inflammasome activation promotes electrical and structural remodeling of the atrium,the correlation of NLRP3 inflammasome with cardiac remodeling and prognosis in patients with AF are not elucidated.【Objective】 To explore the relationship between plasma NLRP3 and cardiac remodeling and prognosis in patients with non-valvular atrial fibrillation.【Methods】 This study is a single-center,prospective and observational study.199 patients with non-valvular atrial fibrillation(NVAF)hospitalized in the First Affiliated Department of Cardiology of Kunming Medical University from July 2019 to October 2020 were enrolled.Plasma NLRP3,IL-1β,IL-6,CRP,and s ST2 levels were measured by enzyme-linked immunosorbent assay.Collect baseline clinical data and echocardiography of patients with atrial fibrillation.Echocardiographic indexes reflecting cardiac remodeling include left atrial diameter(LAD),left atrial diameter index(LADI),right atrial length diameter,left ventricular end-diastolic diameter(LVEDD),left ventricular myocardial mass index(LVMI),pulmonary artery systolic pressure(PASP),etc.The patients with atrial fibrillation were followed up 6,12,and24 months after discharge to collect the clinical endpoints(including stroke,massive hemorrhage,and rehospitalization due to cardiovascular disease and death).According to AF type,the patients were divided into the paroxysmal atrial fibrillation(PAF)group and the Continuous atrial fibrillation(CAF)group.The levels of NLRP3,IL-1β,and other inflammatory factors,clinical data,and cardiac remodeling indexes were compared between the two groups.At the same time,patients were divided into LAD ≤ 36 mm group and LAD>36mm group according to the first quartile of left atrial diameter.The levels of inflammatory factors such as NLRP3,clinical data and cardiac remodeling indexes in different groups were compared.In addition,patients were divided into a low-level group and a high-level group using plasma mean NLRP3,and cardiac remodeling indexes,clinical data,and incidence of clinical end events were compared among different groups.The median IL-1βwas used to divide patients into low-level group and high-level group,and the incidence of clinical endpoints in different groups was compared.And according to the plasma IL-1β first and third quartile quantile low-level group,intermediate-level group and high-level group,the cardiac remodeling indexes between the three groups were compared.Finally,NVAF patients were divided into the death group and survival group according to their survival status at the follow-up of 24 months,and the levels of NLRP3 and other inflammatory factors were compared between the two groups.The correlation between plasma levels of NLRP3,IL-1β,s ST2 and cardiac remodeling was analyzed.Pearson/Spearman correlation was used to analyze the correlation between the plasma levels of NLRP3,IL-1β,s ST2 and cardiac remodeling,and the risk factors affecting the size of left atrial diameter were analyzed by multivariate logistic regression.Kaplan-Meier survival analysis was used to evaluate the survival prognosis of NVAF patients in different levels of NLRP3 and IL-1β groups.Cox stepwise regression analysis was used to analyze the relationship between plasma NLRP3 and other inflammatory factors and all-cause death in NVAF patients.【Results】1.Compared with the PAF group,there are more patients with heart failure in the CAF group,and plasma levels of NLRP3,IL-1β,IL-6,and s ST2 were higher,the indexes of cardiac structural remodeling LAD,LVDI,right atrial length diameter,right ventricular length diameter,LVEDD,LVMI were higher,and LVEF was lower,the difference was statistically significant(P<0.05).2.There were more patients with LAD≤36mm combination and heart failure,higher age,NLRP3,IL-1βand s ST2 levels,and higher right atrial length diameter,right ventricular length diameter,LVMI,LVEDD,and lower LVEF compared with LAD>36mm group,the difference was statistically significant(P<0.05).3.Multivariate logistic regression analysis showed that age,continuous atrial fibrillation,serum creatinine,plasma NLRP3,and PASP were independent risk factors for left atrial dilation(P<0.05).4.There were more patients with high-level NLRP3 combination with coronary heart disease and heart failure,higher IL-1 β and IL-6 levels,higher CHA2DS2-VASc scores,and higher right atrial mid-transverse diameter and right ventricular long diameter indexes of cardiac structural remodeling compared with the low-level NLRP3 group,and the differences were statistically significant(P<0.05).5.Compared with the high-level of IL-1β,the LADI was lower in the IL-1βlow-level group and the intermediate-level group,and the right atrial length diameter was lower in the low-level group(P<0.05).6.The plasma NLRP3 level was positively correlated with LAD,right ventricular long diameter,and right atrial middle transverse diameter(r=0.143,P=0.044;r=0.167,P=0.019;r=0.18,P=0.011).7.The plasma IL-1 β level was positively correlated with LAD,LADI,and right atrial length diameter(r=0.153,P=0.031;r=0.148,P=0.037;r=0.142,P=0.046).8.The plasma s ST2 level was positively correlated with LAD,LADI,right atrial long diameter,right ventricular basal segment transverse diameter,LVMI,LVEDD,PASP(r=0.24,P=0.001;r=0.2,P=0.005;r=0.228,P=0.001;r=0.195,P=0.006;r=0.181,P=0.01;r=0.172,P=0.015;r=0.283,P<0.001);and negatively correlated with LVEF(r=-0.229,P=0.001).9.Following up for 24 months,32 patients died,with a mortality rate of 16.1%(32/199).39 patients were hospitalized for cardiovascular diseases,with a rehospitalization rate of 19.6%(39/199).10.The NLRP3 high-level group was higher than the low-level group due to cardiovascular mortality(17.3% vs.7.4%,P=0.035).There was no significant difference in the rate of re-hospitalization for cardiovascular reasons between the high NLRP3 group and the low NLRP3 group(15.4% vs.24.2%,P>0.05).11.The IL-1 β high-level group was higher than the low-level group due to cardiovascular mortality(18.2% vs.7%,P=0.017).There was no significant difference in the rate of re-hospitalization for cardiovascular reasons between the high IL-1β group and the low IL-1β group(16.2% vs.23%,P>0.05).12.Compared with the survival group,NLRP3 and s ST2 levels in the death group were higher,and the difference was statistically significant(P<0.05).13.Kaplan-Meier survival analysis showed that the incidence of all-cause mortality in the NLRP3 group was lower than that in the high group,and the Log-rank test statistic was 6.013(P=0.014).The incidence of all-cause mortality in the IL-1βgroup was lower than in the high-level group,and the Log-rank test statistic was3.946(P=0.047).14.Multivariate Cox stepwise regression analysis showed that hypertension,serum creatinine,RDW,plasma NLRP3 and PASP were independent risk factors for all-cause mortality in patients with NVAF(P<0.05).【Conclusions】1.The level of plasma NLRP3 is closely associated with atrial remodeling in NVAF patients.The higher of the plasma NLRP3 level,the more severe of the left atrial dilatation,and the elevated plasma NLRP3 level maybe an independent risk factor for left atrial remodeling.2.Elevated plasma NLRP3 level is an independent risk factor for all-cause death in NVAF patients,the level of NLRP3 has reference value in predicting the risk of death in patients with NVAF.