| Objective:(1)To assess the relationship between plasma aldosterone concentration(PAC)and the occurrence of white matter lesions(WMLs),to analyze the mediating effect of blood pressure levels in patients with hypertension,and to analyze the correlation between PAC and white matter lesion load.(2)To evaluate whether mineralocorticoid receptor antagonists can affect the progression of white matter lesion load on cerebral magnetic resonance imaging(MRI).(3)To explore the plasma proteomics of WMLs in patients with hypertension,so as to obtain the spectrum of differentially expressed proteins between two groups,to analyze the biological functions and pathways,and further to analyze the relationship between differentially expressed proteins and PAC.At the same time,the relationship between aldosterone and WMLs and key differential proteins was confirmed by animal model.Methods:(1)A cross-sectional study design was used to screen patients with secondary hypertension in the Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region from January 2011 to April2021.We collected basic patient information and clinical data through electronic medical record system.The Scheltens scale was used to score the white matter lesion load.The logistic regression model was used to analyze the relationship between PAC and the risk of WMLs.The association between white matter lesion load and PAC was analyzed by linear regression model.Meanwhile,mediating effect analysis was used to evaluate the mediated effect between PAC and white matter lesion load at blood pressure levels.Finally,stratification analysis and interaction analysis were carried out to explore whether stratification factors interacted in the relationship between PAC and WMLs.(2)In the retrospective cohort study,patients with WMLs who were hospitalized in the Hypertension Center and completed cerebral MRI from January 2011 to December 2020 were divided into treatment with mineralocorticoid receptor antagonists(spironolactone)and without mineralocorticoid receptor antagonists according to clinical decisions,and included patients who completed brain MRI again before December 2021.The white matter lesion load on twice cerebra MRIs of the subjects were scored according to the Scheltens scale.A mixed linear model was used to analyze whether spironolactone could affect the progression of WMLs.The effects of spironolactone oral daily dose and oral duration on the progression of WMLs were analyzed.(3)Among patients with hypertension hospitalized in the Hypertension Center from July 2019 to April 2020,20 patients with WMLs were selected as the case group,and 20 patients without WMLs hospitalized during the same period were selected as the control group according to age,gender,blood pressure level and other factors.Based on the 4D-DIA detection method,the qualitative and quantitative detection of plasma proteome was carried out.The differentially expressed proteins between the two groups were obtained by t-test,and the biological information was analyzed according to the differentially expressed proteins.Correlation analysis assessed the relationship between aldosterone and differentially expressed proteins.C57BL/6 mice were randomly divided into control and aldosterone group.WML was observed by luxol fast blue staining.Results:(1)A total of 10,033 patients with hypertension were included in the study,with an average age of 47.9±8.3years and 62.2% male.In the multivariable logistic model,the risk of WMLs increased with tertile PAC(P for trend <0.05),each 1,5,and 10 units increase in PAC was associated with a 2%,7% and 15% increased risk,respectively(P<0.05).The OR value for the third quartile was 1.27(95%CI: 1.02-1.59,P<0.05)compared with the first tertile.The multivariate restricted cubic spline showed that PAC had a dose-response relationship with the risk of WMLs.The result showed that PAC≥19.15 ng/d L increased the risk of WMLs by 37% compared with aldosterone <19.15ng/d L(OR=1.37,95%CI: 1.13-1.66).The results of multivariable linear regression models showed that PAC was positively correlated with white matter lesion load.Mediation-effect analysis showed that systolic and diastolic blood pressure mediated 18.8% and 16.5% of the total effects of aldosterone and WMLs,respectively(P<0.001).(2)A total of 412 hypertensive patients with WMLs were included in this study,with a median follow-up time of 41 months on cerebral MRI,an average age of 60.2±8.7 years,and 53.4% were male.According to the doctors’ prescriptions,a total of 126 people were divided into spironolactone treatment group and286 people in control group.There was no significant difference in blood pressure levels at baseline and the degree of blood pressure reduction between the two groups.The mean Scheltens scale score for white matter lesion load in spironolactone group increased from baseline 13.67 to 16.06(difference 2.38,95%CI: 1.82-2.94),the control group increased from 10.50 to 14.77(difference 4.27,95%CI: 3.94-4.60),and the difference between the two groups was-1.70(95%CI:-2.46～-0.93).The progression of white matter lesion load slowed with increasing daily oral dose(P for trend <0.001);compared with the control group,the difference between the 20 mg/day dose group and its progression of white matter lesion load was-1.49(95%CI:-2.39 ～-0.58),the between-group difference between the 40 mg/day dose group was-1.91(95%CI:-2.66～-1.16),and the difference between the 60 mg/day dose group was-3.25(95%CI:-5.45 ～-1.06).Further analysis of spironolactone oral duration and white matter lesion progression showed that each increase in oral time of 1,12 and 24 months,the mean progression of white matter lesion load score slowed down by 0.02,0.20 and 0.40(P for all values <0.001).Sensitivity analysis showed no significant change in the results of above model analysis after excluding patients with intermittent oral spironolactone and primary aldosteronism,respectively.(3)There were 42 differentially expressed proteins between WMLs and no-WMLs in patients with hypertension.The biological functions involved were mainly calcium ion-mediated signaling,and the main biological pathway was synaptic vesicle cycle.Correlation analysis showed that amyloid-beta precursor protein(APP)was positively correlated with plasma aldosterone concentration.Subcellular localization of differentially expressed proteins suggested that the extracellular matrix was the primary cellular localization.The results of differential protein-protein interaction network analysis showed that APP was the protein with high connectivity in the entire protein network.Animal models confirmed that aldosterone intervention increased the expression level of APP in plasma,aggravated the degree of white matter lesions.Conclusions:(1)In patients with hypertension,higher plasma aldosterone concentration was independently correlated with the risk of WMLs.Furthermore,plasma aldosterone concentration was positively correlated with the white matter lesion load,while blood pressure level only mediated slight effects,suggesting that there was a pathway independent of blood pressure in the relationship between aldosterone and WMLs.(2)Spironolactone treatment could significantly reduce the progression of white matter lesion load in patients with hypertension,and its effect was more obvious with the increase of oral daily dose and the duration of oral time.This effect was independent of the protective effect brought by lowering blood pressure.Mineralocorticoid receptor antagonists might have a somewhat delaying effect on the progression of white matter lesion load in patients with hypertension.(3)There were characteristic expressed proteomes in the hypertensive patients with WMLs,among which APP may be the key differential protein in the occurrence of WMLs.Calcium-mediated signaling in synaptic vesicle cycle might be involved in the occurrence and development of WMLs and related adverse outcomes in such patients.In addition,animal models have further confirmed that APP may mediate the pathogenesis of aldosterone-related WMLs. |
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