Plasma Neurotransmitter Metabolism In Patients With Coronary Heart Disease Complicated By Atrial Fibrillation With Qi Deficiency And Blood Stasis

Background:With the tremendous changes in society and lifestyle,the incidence and mortality rates of cardiovascular diseases have been constantly increasing,leading to significant social pressure and economic burden in treating these diseases and their complications.Coronary heart disease(CHD)is the most common ischemic heart disease in the world,while atrial fibrillation(AF)is a frequent and serious rapid cardiac arrhythmia,and the two are closely related,often coexisting or causal to each other.Modern research has found that cardiovascular diseases have a mutual interaction with the nervous system,and neurotransmitters can participate in the progression of CHD,AF,and other cardiovascular diseases through various pathways,including autonomic nerves,inflammation,oxidative stress,and other mechanisms,affecting the expression of traditional Chinese medicine(TCM)syndrome.Studies have shown that TCM can treat various cardiovascular diseases by regulating neurotransmitter levels.TCM considers coronary heart disease with atrial fibrillation(CHDAF)as belonging to the category of "chest congestion" and "palpitations," and literature research has shown that the syndrome of Qi deficiency and blood stasis is the important pathogenesis and core syndrome of CHDAF,and the method of nourishing Qi and activating blood circulation is widely used in the treatment of CHD and AF.Therefore,it is of certain significance to conduct in-depth research on the differences in neurotransmitter metabolites of CHDAF patients and CHDAF patients with Qi deficiency and blood stasis syndrome for the assistance of clinical diagnosis and treatment.Objective:This study investigated the differences in plasma neurotransmitter profiles between the CHD group and the healthy group,the CHDAF group and the Coronary heart disease with Sinus rhythm(CHDSR)group,and the CHDAF group with and without Qi deficiency and blood stasis,in order to provide a reference for exploring the biological indicators of Qi deficiency and blood stasis in CHDAF and CHDAF from the perspective of neurotransmitters,and to enrich the ideas of clinical research and diagnosis and treatment.Methods:1 Clinical data collectionOne hundred and twenty CHD patients treated in the Guang’anmen Hospital,China Academy of Chinese Medical Sciences,from June 2022 to December 2022 were collected,and 30 cases of health control during the same period were included.According to the diagnosis criteria for atrial fibrillation,CHD patients were divided into CHDAF)group and CHDSR group,with 90 and 30 cases respectively.The CHDAF group was divided into the CHDAF Qi deficiency and blood stasis group and the non Qi deficiency and blood stasis group according to the "Guidelines for the Treatment of Stable Angina Pectoris in Coronary Heart Disease" and the relevant diagnostic criteria.Their basic data,medical history,auxiliary examinations and other relevant information were collected.2 Determination of plasma neurotransmitter levelsA total of 39 plasma neurotransmitter concentrations and contents of the included subjects were measured by liquid chromatography-tandem mass spectrometry(LCMS/MS).We analyzed the differences in plasma neurotransmitters between the CHD and healthy control groups,the CHDAF and CHDSR groups,and the CHDAF with Qi deficiency and Blood Stasis syndrome and CHDAF without Qi deficiency and Blood Stasis syndrome groups.3 Statistical methodsSPSS 26.0 and GraphPad Prism 8 were used for statistical analysis.Frequency was used to represent count data,and Pearson’s chi-square test was used for comparison between groups.For measurement data with normal distribution,mean±standard deviation(x±s)was used to represent the data.Independent sample t-test was used for comparison of homogeneous variance between two groups,and corrected t-test was used for comparison of heterogeneous variance.For measurement data that did not follow normal distribution,median and quartile range[M(P25,P75)]were used to represent the data,and the Mann-Whitney U test was used for comparison between groups.Pearson or Spearman correlation analysis was used for correlation analysis,and binary logistic regression analysis was used for regression analysis.ROC curve analysis was used for diagnostic value.P<0.05 indicated statistical significance.Results:1 Clinical data comparison between the CHD group and the healthy control groupThere was no significant difference between the CHD group and the healthy group in terms of gender,age,blood pressure and BMI.In terms of clinical indicators,the CHD group showed an increase in urea,creatinine,uric acid(UA)and cholesterol,and a decrease in apolipoprotein B and HDL cholesterol(P<0.05),which were associated with disorders of lipid metabolism and risk factors for disease in the CHD group,while no differences were seen in the rest of the clinical baseline levels.2 Plasma neurotransmitter content comparison between the CHD group and the healthy control groupNo significant differences in cholinergic neurotransmitters were seen between the two groups.The amino acid neurotransmitters showed differences between the two groups,in terms of Tryptophan(Trp)and metabolites,Trp,Indole-3carboxaldehyde(I3A)and Quinolinic acid(QA)levels were reduced in the CHD group,kynure-nic acid(KYNA),3-hydroxyanthranilic acid(3-HAA)acid(3-HAA)were increased(P<0.05).In the CHD group,plasma levels of ornithine,alpha ketoglutaric acid(KGA),aspartate,glutamate and GABA were increased,and levels of arginine(Arg)and succinic acid(SA)were decreased.Among the monoamine neurotransmitters,plasma levels of 5-hydroxyindoleacetic acid(5-HIAA)were increased in the CHD group(P<0.01).Among the catecholamines,norepinephrine,epinephrine(E)and its metabolite vanilloid acid levels were increased(P<0.05).No significant differences were seen in the other monoamine neurotransmitters.3 Clinical data comparison between the CHDAF group and the CHDSR groupThere was no significant difference between the two groups in terms of gender composition,age,BMI,and blood pressure data.Regarding biochemical indices,Urea,homocysteine(HCY),and UA were elevated and prealbumin(PA)was decreased in the CHDAF group,suggesting a relatively significant abnormal metabolic status in the CHDAF group compared with the CHDSR one(P<0.05).In addition,hypersensitive C-reactive protein(hs-CRP)was elevated in the CHDAF group.To some extent,it suggests that the CHDAF group may have a more pronounced hypoinflammatory state.As for coagulation indexes,prothrombin time(PT)and activated partial thromboplastin time(APTT)were higher in the CHDAF group compared with the CHDSR group(P<0.01),indicating that the CHDAF group had a higher risk of bleeding.In terms of cardiac structure and function,the left atrial diameter(LA)and right atrial diameter(RA)were increased in the CHDAF group,and the NT-proBNP level was significantly higher in the CHDAF group(P<0.05),indicating that the CHDAF group showed alterations in cardiac structure and relative deviations in cardiac function.As for the emotion scale,the anxiety and depression self-rating scale scores were higher in the CHDAF patients compared with the CHDSR group,suggesting a higher risk of anxiety and depression(P<0.05).4 Comparison of plasma neurotransmitter levels between the CHDAF group and the CHDSR groupFor choline neurotransmitters,plasma acetylcholine(Ach)levels were significantly lower in the CHDAF group(P<0.01).Among the Trp and metabolites,plasma levels of Trp and I3A were significantly lower in the CHDAF group(P<0.01);plasma levels of KYNA were higher in the CHDAF group(P<0.01).In the other amino acid neurotransmitters,plasma levels of KGA were increased in the CHDAF group(P<0.01).Among the monoamine neurotransmitters,in 5-hydroxytryptamine(5-HT)and its metabolites,5-HT and 5-HIAA plasma levels were increased in the CHDAF group(P<0.01).No significant differences were seen in catecholamines and other monoamine neurotransmitters.Point two column correlation analysis showed that KYNA,5-HIAA,and KGA were positively correlated with CHDAF onset(r:0.337、0.260、0.230,P<0.05)Ach,Trp,and I3A were negatively correlated with CHDAF onset(r:-0.293,-0.397,and-0.461,P<0.05).Differential neurotransmitters showed varying degrees of correlation with differential clinical indicators,showing that Ach was negatively correlated with NTproBNP(r:-0.294,P<0.05);KYNA was positively correlated with APTT and PT(r:0.265,0.238,P<0.05)and negatively correlated with PA(r:-0.247,P<0.05);Trp was positively correlated with PA(r:0.162,P<0.05)and negatively correlated with NTproBNP,LA,APTT,PT,hs-CRP,and HCY(r:-0.258,-0.353,-0.307,-0.269,0.214,-0.332,P<0.05);5 HIAA was positively correlated with LA,APTT,PT,hsCRP,HCY,and UA(r:0.189,0.313,0.375,0.279,0.286,0.265,P<0.05).i3A was negatively correlated with SAS,APTT,PT,and hs-CRP(r:-0.205,-0.328,-0.284,0.252,P<0.05)and positively correlated with PA(r:0.315,P<0.05).kGA positively correlated with SAS,NTproBNP,RA,LA,PT,and hs-CRP(r:0.262,0.269,0.309,0.296,0.255,P<0.05).Binary logistic regression analysis of differential neurotransmitters revealed that Ach,KYNA,5-HIAA,KGA,and I3A were the influencing factors for CHDAF.The AUC were 0.689,0.752,0.706,0.683,0.771 and 0.924 when the influential factors Ach,KYNA,5-HIAA,KGA,I3A and the combined model of influential factors were included in the ROC model prediction,respectively.5 Clinical Data Comparison between Qi Deficiency and Blood Stasis Group and NonQi Deficiency and Blood Stasis Group of CHDAFThere were no significant differences between the two groups in terms of gender composition,age,blood pressure and BMI.In terms of medical history,the probability of stroke was higher in the Qi deficiency and blood-stasis group,and in terms of clinical indicators,the LA and CHA2DS2-VASC score levels appeared to be elevated in the Qi deficiency and blood-stasis group.6 Plasma neurotransmitter levels in the Qi deficiency and blood stasis group and the non Qi deficiency and blood stasis group in atrial fibrillation in coronary artery diseaseNo significant differences were seen between the two groups for cholinergic neurotransmitters.In terms of Trp and metabolites,the plasma levels of KYNA and Tryptophol(TOL)were increased in the Qi deficiency and blood stasis group(P<0.05);the plasma levels of I3A,Trp and QA were decreased(P<0.05);in terms of other amino acid neurotransmitters,the plasma levels of Arg,Glutamine(Gln)and SA were decreased in the Qi deficiency and blood stasis group(P<0.05).Glutamine(Gln)and SA plasma levels were reduced in the Qi deficiency and blood stasis group(P<0.05).Among the monoamine neurotransmitters,the plasma levels of Melatonine(MT)and N-Acetylserotonin(NAS)were increased in the Qi deficiency and blood stasis group in terms of 5-HT and metabolites(P<0.05).For catecholamines and metabolites,E and metanephrine(ME)were elevated in the Qi deficiency and blood stasis group compared to the non-Qi deficiency and blood stasis group,with a statistically significant difference(P<0.05).No significant differences were seen for the remaining monoamine neurotransmitters.The degree of correlation was determined using the point two-column correlation coefficient(r).The results showed that E,KYNA,MT,NAS,ME and TOL were positively correlated with the onset of Qi deficiency and blood stasis evidence in CHDAF patients(r:0.222,0.279,0.281,0.249,0.276 and 0.235,respectively,P<0.05);I3A,Arg,QA,Gln and Trp were negatively correlated with the onset of Qi deficiency and blood stasis evidence in CHDAF patients(r:-0.261,-0.314,-0.213,0.320,-0.243,-0.293,P<0.05).The results of the binary logistic regression analysis showed that E,KYNA and NAS were the influencing factors for the evidence of Qi deficiency and blood stasis in CHDAF.The AUC were 0.642,0.636,0.657 and 0.882 when the influencing factors E,KYNA,NAS and the combined model of influencing factors were incorporated into the ROC model prediction,respectively.Conclusion:1 Patients with coronary atrial fibrillation have altered plasma neurotransmitter profiles,with differences focusing on acetylcholine,tryptophan metabolic processes,and 5-hydroxytryptamine metabolic processes,which may be related to mechanisms such as autonomic regulation,immune inflammatory response and energy metabolism during atrial fibrillation.2 The plasma neurotransmitter metabolism spectrum of patients of coronary heart disease and atrial fibrillation with Qi deficiency and blood stasis syndrome has changed.The differences were mainly in the metabolic processes of tryptophan,melatonin and catecholamines,which may be related to sympathetic activation,impaired energy metabolism,altered circadian rhythm and imbalance of intestinal homeostasis in patients with Qi deficiency and blood stasis.