| Objective: Based on the Chinese medicine theory of "heart domainating blood and vessel",the impact of heart rate circadian rhythm on in-hospital mortality of stroke patients was explored,and the potential targeted Chinese herbs for the treatment of heart and brain was further explored.Methods: The current analysis included stroke patients enrolled in the e ICU Collaborative Research Database between 2014 and 2015.The impact of circadian rhythm on in-hospital mortality was analyzed,in which the cosinor method was used to assess circadian rhythm through three variables: Mesor of heart rate(median circadian rhythm adjustment of heart rate),amplitude of heart rate(half of the distance from the highest to lowest point of circadian rhythm),and peak time of heart rate(the time corresponding to the highest point of circadian rhythm).Logistic regression was used to explore the causal relationship between heart rate circadian rhythm and in-hospital mortality,and covariate balance propensity score was used to correct the bias.The sequence matrix of circadian dysregulation and stroke-related expression data sets was obtained from the GEO database.Weighted gene co-expression network analysis(WGCNA)was used to search for key genes associated with circadian dysregulation and stroke.Single-cell sequencing analysis was used to validate and evaluate the expression of common key genes associated with circadian dysregulation and stroke at the heart and brain cell levels.The CTD database and TCMSP database were used to explore the interaction between gene,chemical substance and Chinese herbs,in order to find Chinese herbs with potential intervention effect on circadian rhythm disorder and stroke.Results: A total of 6,201 eligible patients were included,with 1,002 in-hospital deaths(16.2%).(1)The rank sum test and independent sample t test were used to test the continuous variables and the Chi-square test to test the categorical variables for the intra-group comparison between the survivor group and the non-survivor group.Compare with the survivor group,the non-survivor group was older than the survivor group(P<0.001),the more common complications were diabetes mellitus(P=0.003),chronic obstructive pulmonary disease(P=0.027),heart failure(P<0.001),atrial fibrillation(P=0.033),cirrhosis(P<0.001),cerebral edema(P<0.001),infection(P<0.001)and fever(P<0.001),less use of drugs that interfere with heart rate since the second calendar day(P<0.001)with a higher APACHE Ⅳ score(P<0.001)and a lower Glasgow coma score(P<0.001),shorter hospital stay(P<0.001)and longer ICU stay(P<0.001).(2)After adjusting for confounding factors,logistic regression showed that mesor per 10 beats/min increase was associated with a 1.18-fold(95%CI:1.12,1.25 P<0.001)and amplitude per 5 beats/min was associated with a 1.17-fold(95% CI:1.07,1.27 P<0.001)increase in the risk of in-hospital mortality.The risk of in-hospital mortality was highest in patients who had peak time reached between12:00 and 18:00(1.35,95% CI:1.06,1.72 P=0.015).(3)Of the 12 co-key genes associated with circadian dysregulation and stroke,eight(TMBIM4,ATG12,PHF20L1,ZNFX1,CDS2,HIF1 AN,SORL1 and SRXN1)were significantly expressed in the heart and brain cells.(4)Of the 11 chemicals associated with eight common key genes for circadian dysregulation and stroke,two chemicals(Folic acid and Bisphenol A)interacted with nine Chinese herbs(Mori Follum,Hordei Fructus Germinatus,Capsici Fructus,Hedysarum Multijugum Maxim,Sesami Nigrum Semen,Sojae Semen Nigrum,Chuanxiong Rhizoma,Bombyx Mori L,and Hippophae Fructus).Conclusion:(1)Based on the Chinese medicine theory of "heart domainating blood and vessel",the independent risk effect of heart rate circadian rhythm on in-hospital mortality of stroke patients was clarified.(2)Nine kinds of Chinese herbs(Mori Follum,Hordei Fructus Germinatus,Capsici Fructus,Hedysarum Multijugum Maxim,Sesami Nigrum Semen,Sojae Semen Nigrum,Chuanxiong Rhizoma,Bombyx Mori L,and Hippophae Fructus)are considered as potential intervention drugs for circadian rhythm disorders and stroke,providing a new strategy for the treatment of heart and brain. |
