The Pathophysiologic Basis Of Collateral-qi Deficiency/Collateral-qi Stagnation And The Effect Of Dredge-Collaterals Herbs Based On Metabonomics

Objective: Under the guidance of"qi-blood correlation"and"Ying-wei-cheng-zhi-tiao-ping"of Vessels-Collateral Theory of Traditional Chinese Medicine(TCM). Based on the results of epidemiological study on 3469 patients with vasculopathy: collateral-qi deficiency and collateral-qi stagnation were the initiating agent, which exists in the whole process of vasculopathy.Metabonomics methods have been applied for the study about the characteristics of metabonomics of the sub-health population without clear western medicine diagnosis, but which was accordance with collateral-qi deficiency and collateral-qi stagnation standard of"vessel collateral-vascular system diseases"criteria for pattern identification. According to syndrome of collateral-qi deficiency and collateral-qi stagnation, the models of rats have been established in these researches. According to the results of clinical population and rats models metabonomics study, the research about metabolic profiling of acylcarnitines,lipids and the effect of dredge-collaterals herbs was to be performed. Based on the potential biomarkers of collateral-qi deficiency and collateral-qi stagnation, to investigate the vascular endothelial function and structure changes, important cytokines and receptors about carnitines, lipids, 5-hydroxytryptamine (5-HT) in aorta, myocardial and cerebral tissues, at the same time the effect and mechanism of dredge-collaterals herbs were about to be explored.Through the clinical population and animals researches mentioned above, to illuminated the characteristics of metabonomics of collateral-qi deficiency and collateral-qi stagnation and its effect on vasculopathy, to reveal the effective mechanism of dredge-collaterals herbs. These researches are important for revealing the initiating effect of excessive fatigue and depression in pathophysiologic and to look for the effective intervention strategies and drugs.Methods:There are three sections in this research:1 The metabonomics research of collateral-qi deficiency and collateral-qi stagnation population Based on the results of epidemiological study about 3469 patients with vasculopathy: collateral-qi deficiency and collateral-qi stagnation were the initiating agent, which existing in the whole process of vasculopathy.The study enrolled sub-health population without clear western medicine diagnostic, in accordance with collateral-qi deficiency and collateral-qi stagnation standard of"vessel collateral-vascular system diseases"criteria for pattern identification.78 subjects included health group(n=28), collateral-qi deficiency group(n=26), collateral-qi stagnation group(n=24).The basic inspections were checked including blood routine ,fasting plasma glucose, blood lipids(TC, TG, HDL, LDL), urine routine, hepatic function (ALT)and renal function(BUN, Cr), chest x-rays, B-ultrasonic of hepatobiliary, electrocardiogram.The plasmas were separated to be detected by UFLC/MS-IT-TOF, the data were filled in SIMCA-P after data transform.The OSC-PLS-DA analysis was applied to distinguish these three groups.2 The acylcarnitines and lipids metabolic profiling researches of collateral-qi deficiency/collateral-qi stagnation in plasma and the effect of dredge-collaterals herbsAccording to the TCM theory"over-strain consuming essence", collateral-qi deficiency model was been established by basic diet combined loaded swimming. According to"depress lead to qi stagnation", collateral-qi stagnation model was been established by constraint.General condition,score of biology,exhausted swimming time, tail swing were detected to evaluate the major syndromes.Based on the results of metabonomics researches of collateral-qi deficiency/collateral-qi stagnation population and rats, selected acylcarnitines and lipids to detect those metabolic profiling. The plasmas were remained from①normal control group,②collateral-qi deficiency group,③ collateral-qi stagnation group,④Ginsenosides group,⑤Allium group.The acylcarnitines metabolic profiling was detected by LC/MS, Dynamic MRM mode was applied in MS. The lipids metabolic profiling was detected by UFLC/IT-TOF MS, ESI+/- mode was applied in MS. The principal components analysis of multivariate and nonparametric test of univariate were applied to analysis the dataes.3 The changes of vascular endothelial function and the carnitine palmitoyl transferase-Ⅰ(CPT-Ⅰ), phospholipid and 5-HT receptors in aorta, myocardial and cerebral tissues of collateral-qi deficiency/collateral-qi stagnation and the effect of dredge-collaterals herbs105 male Wistar rats were divided randomly into this following 7 groups:①normal control group,②collateral-qi deficiency group,③collateral-qi stagnation group,④collateral-qi deficiency+ ginsenosides group(ginsenosides group),⑤collateral-qi deficiency+Tongxinluo capsule group (CQD+TXL group ) ,⑥collateral-qi stagnation+ allium group (allium group),⑦collateral-qi stagnation+ Tongxinluo capsule group (CQS+TXLgroup).The HE staining ,electron microscope of arota were carried out to observe the endothelial morphological changes. The level of plasma endothelian-1(ET-1) was detected with radioimmunoassay, and serum nitro oxygen(NO) was detected with nitrate reductase.Based on the potential biomarkers in collateral-qi deficiency and collateral-qi stagnation, important cytokines and receptors about carnitines, lipids, 5-HT were studied in aorta, myocardial and cerebral tissues,at the same time the effect and mechanism of dredge-collaterals herbs were reseached. In carnitines research, the energecharge of myocardial tissue was detected by HPLC, CPT-Ⅰ,αsubunit of AMP-activated protein kinase(AMPKα), peroxisome proliferator activated receptorδ(PPARδ)mRNA in aorta and myocardial tissues were detected by real-time reverse transcription PCR(RT-PCR), the CPT-Ⅰ, AMPKα, p-AMPKα, PPARδprotein expressions in aorta and myocardial were detected by the method of Western blot. In phospholipid research, the content of lipoprotein-associated phospho-lipaseA2(Lp-PLA2) in aorta was detected by ELISA. The G protein- coupled receptor4(GPR4) mRNA and protein expressions in aorta was detcted by RT-PCR and Western blot. In 5-HT receptors research, the level of 5-HT in cerebral tissue was detcted by ELISA. The 5-hydroxytryptamine 1D receptor(5-HT1D), The 5-hydroxytryptamine 2A receptor(5-HT2A)mRNA in aorta and 5-HT1D, 5-HT2A, tryptophan hydroxylase(TPH)mRNA in cerebral tissues were detected by RT-PCR. The 5-HT1D and 5-HT2A protein expressions in aorta and cerebral tissues were detected by the method of Western blot.Results:1 The metabonomics research of collateral-qi deficiency and collateral-qi stagnation populationThe basic inspections of enrolled sub-health population were all in normal range. The metabonomics results showed that collateral-qi deficiency/collateral-qi stagnation population were different with health population.Compared with health group, the phenylalanine, tryptophan were slightly increased (P>0.05), lysophosphatidylcholine C17:2 and C18:2(LPC C17:2,LPC C18:2)were decreased(P<0.05 or P<0.01) , LPC C16:1,LPC C16:0,LPC C18:1,LPC C18:0 were slightly decreased(P>0.05) in collateral-qi deficiency group.Compared with health group, phenylalanine, leucine, tryptophan and bilirubin were increased(P<0.05 or P<0.01), acetylcarnitine were slightly increased(P>0.05), LPC C16:0, LPC C16:1,LPC C 17:2,LPC C18:0,LPC C18:1,LPC C18:2 were decreased (P<0.05 or P<0.01) in collateral-qi stagnation group.Based on the OSC-PLS-DA model of metabolite profiling in the three groups, there were differents between them.Compareed with health group, the important metabolites were more ramarkable in collateral-qi stagnation group than collateral-qi deficiency group. phenylalanine, leucine, tryptophan and bilirubin were increased(P<0.05 or P<0.01), LPC C16:0, LPC C18:0,LPC C18:1,LPC C18:2 were decresed (P<0.05 or P<0.01) in collateral-qi stagnation group, but LPC C18:2 was decresed in collateral-qi deficiency group (P<0.05).2 The acylcarnitines and lipids metabolic profiling research of collateral-qi deficiency/collateral-qi stagnation in plasma and the effect of dredge-collaterals herbs2.1 Established the rats models of collateral-qi deficiency/collateral-qi stagnationCompared with normal control group, the rats of collateral-qi deficiency had taken on tired and lazy,activities were sluggish, the rats of collateral-qi stagnation had taken on emotional behavior like fighting, bite, scream, but with the time prolonging, The rats'activities were sluggish.Compared with normal control group, the scores of biology were all increased significantly in model groups(P<0.05 or P<0.01). Compared with normal control group, the fatigued swimming time was shorted ,the immobility time of the tail swing was prolonged significantly and the struggling frequency was reduced(P<0.01).2.2 The acylcarnitines metabolic profiling research of collateral-qi deficiency/collateral-qi stagnation in plasma and the effect of dredge-collaterals herbsMultivariate analysis: collateral-qi deficiency/collateral-qi could lead to abnormal change acylcarnitines metabolic in plasma. Univariate analysis:①Compared with normal control group, there were 11 acylcarnitines changed in collateral-qi deficiency group, included 4 acylcarnitines increased(C0,Iso-C4,C5:1 and C20:1),7 acylcarnitines decreased (C2,C8:1,C10:2,C4-OH,C5-OH,C14-OH and C16-OH), P<0.05 or P<0.01.②Compared with normal control group, there were 20 acylcarnitines changed in collateral-qi stagnation group, included 19 acylcarnitines increased(C10:1,C12,C14,C14-OH,C14:1,C14:2,C16,C16-OH,C16:1,C16:1-OH,C16:2,C18,C18:1,C18:1-OH,C18:2,C18:2-OH,C20:0,C20:1 and C20:2),1 acylcarnitines decreased(C5-OH), P<0.05 or P<0.01.③Compared with collateral-qi stagnation group,there were 23 acylcarnitines changed in collateral-qi deficiency group, included 2 acylcarnitines increased(C0,C5:1),21acylcarnitines decreased(C4-OH, C5-OH, C8:1,C10:1,C10:2,C12,C14,C14-OH,C14:1,C16,C16-OH,C16:1,C16:1-OH,C16:2,C18,C18:1,C18:1-OH,C18:2,C18:2-OH,C20:0 and C20:2) , P<0.05 or P<0.01.Multivariate analysis:The ginsenosides group gathered with collateral-qi deficiency group,but separated from normal control group,which implied that the acylcarnitines metabolic profiling of ginsenoside group were not recover to the level of normal control group.While the allium group gathered with normal control group,but separated from collateral-qi stagnation group,which implied that the acylcarnitines metabolic profiling of allium group were recover to the level of normal control group.Univariate analysis:①Compared with normal control group,there were 3 acylcarnitines (C0,Iso-C4 and C5:1)recovered the normal level in significant changed acylcarnitines after ginsenoside intervened(P>0.05). Compared with collateral-qi deficiency group,the acylcarnitines has slightly increased and decreased,but there was not significant difference in ginsenoside group (P>0.05).②Compared with normal control group,there were 16 acylcarnitines recovered the level of normal in significant changed acylcarnitines after allium intervened beside 4 acylcarnitines(C18:2,C20:2,C5-OH and C18:2-OH) P>0.05. Compared with collateral-qi stagnation group, 18 acylcarnitines decreased(P<0.05), 2 acylcarnitines(C18 and C5-OH) were not change in allium group(P>0.05). 2.3 The lipids metabolic profiling research of collateral-qi deficiency/collateral-qi stagnation in plasma and the effect of dredge-collaterals herbsMultivariate analysis: collateral-qi deficiency/collateral-qi could lead to abnormal change lipids metabolic in plasma. Univariate analysis:①Compared with normal control group, there were 31 lipids changed in collateral-qi deficiency group, included 2 LPC [LPC(18:1) and LPC (18:2)] increased(P<0.05 or P<0.01), LPC (20:4), lysophosphatidyl ethanolamine [LPE (22:6) ],6 phosphatidyl cholines [PC (32:0),PC (36:4),PC (38:4),PC (38:5),PC (38:6) and PC (40:6)] and 21 triglycerides[TG (50:1),TG (50:2),TG (50:3),TG (52:2),TG (52:4),TG (52:5),TG (54:3),TG (54:4),TG (54:5),TG (54:6),TG (54:7),TG (56:6),TG (56:7),TG (56:8),TG (56:9),TG (58:8),TG (58:9),TG (58:10),TG (58:11),TG (60:12) and TG (60:13)] decreased ( P<0.01).②Compared with normal control group, there were 10 lipids changed in collateral-qi stagnation group, included 3 LPC[LPC (18:1),LPC (18:2) and LPC (O-16:2)] increased(P<0.05 or P<0.01), 5 PC[PC (36:4),PC (38:4),PC (38:5),PC (38:6) and PC (40:6)] and 2 TG[TG (60:12) and TG (62:14)] decreased(P<0.05 or P<0.01).Multivariate analysis:The ginsenosides group gathered with collateral-qi deficiency group,but separated from normal control group,which implied that the lipids metabolic profiling of ginsenoside group were not recover to the level of normal control group.While the allium group gathered with normal control group,but separated from collateral-qi stagnation group,which implied that the lipids metabolic profiling of allium group were recovered to the level of normal control group.Univariate analysis:①Compared with normal control group,there were 4 lipids[PC (38:5),PC (38:6),PC (40:6) and TG (60:12)]recovered to the level of normal in significant changed lipids after ginsenoside intervened(P>0.05). Compared with collateral-qi deficiency group,5 lipids increased[PC(36:4),PC(38:4),PC(38:6),PC(40:6) and TG(58:11)]( P<0.05 or P<0.01), 12 lipids increased [TG(50:1),TG(52:2), TG(52:4), TG(52:5), TG(54:6),TG(54:7),TG(56:7),TG(56:8),TG(56:9),TG(58:9),TG(58:10),TG(60 :13)],but there was not significant differences(P>0.05).②Compared with normal control group, there were 9 lipids changed in collateral-qi stagnation group recovered to the level of normal in significant changed lipids after allium intervened beside PC(38:6), P>0.05. Compared with collateral-qi stagnation group, 5 lipids[PC(36:4), PC(38:4), PC(38:5), PC(38:6) and PC(40:6)] increased(P<0.05 or P<0.01), LPC18:1 decreased (P<0.05).3 The changes of vascular endothelial function and carnitines, phospholipid and 5-HT receptors in aorta, myocardial and cerebral tissues of collateral-qi deficiency/collateral-qi stagnation and the effect of dredge-collaterals herbs3.1 The changes of vascular endothelial function the effect of dredge-collaterals herbsUnder the light microscope of HE staining, the aortic endothelial cells of model groups were swelling and endomembrane became into thickening and abound with inflammatory cell infiltration under that.Under the scanning electron microscope, most of endomenmbrane of mitochondria in endothelial cells were fusion or disappeared.Under the transmission electron microscope,the crack were swelling, organelles disappeared, vacuole appeared, karyotheca became indistinct.Compared with normal control group, the level of ET-1 were increased and the level of NO were decreased in collateral-qi deficiency/collateral-qi stagnation( P<0.05 or P<0.01).Compared with model groups, general condition had become better in ginsenosides, allium and Tongxinluo groups, the score of biology were decreased significantly in dredge-collaterals herbs groups(P<0.05 or P<0.01). Compared with collateral-qi deficiency group in 14-day fatigued swimming, ginsenosides and Tongxinluo could prolong the time(P<0.05). Compared with collateral-qi stagnation group,the immobility time decreased, the struggling frequence increased in allium and Tongxinluo groups(P<0.05 or P<0.01). The vascular endothelial structure in aorta became better under the light microscope and electron microscope, Tongxinluo was better than ginsenosides and allium. Compared with collateral-qi deficiency/collateral-qi stagnation group, the level of ET-1 were decreased and the level of NO were increased(P<0.05 or P<0.01).3.2The changes of CPT-Ⅰin aorta and myocardial tissues of collateral-qi deficiency/collateral-qi stagnation and the effect of dredge-collaterals herbsCompared with normal control group, the energecharge of myocardial tissue was slightly increased in collateral-qi deficiency group, but there was not significant difference(P>0.05).Compared with normal control group and collateral-qi stagnation group, the expressions of CPT-Ⅰ, AMPKα, PPARδmRNA were decreased ( P<0.01) and the proteins expression of CPT-Ⅰ,AMPKα, pAMPKa,PPARδwere also decreased in aorta and myocardial tissue. Compared with normal control group, the above indexes were not significant difference in collateral-qi stagnation group.Compared with collateral-qi deficiency group, the energecharge of myocardial tissue was increased in ginsenoside and Tongxinluo groups(P<0.01), the expressions of CPT-Ⅰ, AMPKα, PPARδmRNA were increased in aorta and myocardial tissue (P<0.05 or P<0.01), the proteins expression of CPT-Ⅰ,AMPKα, pAMPKa were increased in ginsenoside groups, the proteins expression of CPT-Ⅰ,AMPKα, pAMPKa, PPARδwere also increased in Tongxinluo groups in aorta and myocardial tissue. 3.3The change of cytokines about phospholipid in aorta of collateral-qi deficiency/collateral-qi stagnation and the effect of dredge-collaterals herbsCompared with normal control group, the content of Lp-PLA2 in aorta of collateral-qi deficiency/collateral-qi stagnation group increased(P<0.01). Compared with normal control group, the expressions of GPR4mRNA in aorta of collateral-qi deficiency group were increased(P<0.01), the expressions of GPR4 in aort were also increased,but there was not significant difference in collateral-qi stagnation group (P>0.05).Compared with collateral-qi deficiency group, the content of Lp-PLA2 in aorta was decreased in ginsenoside and Tongxinluo groups, while compared with collateral-qi stagnation group, the content also reduced(P<0.01). Compared with collateral-qi deficiency group, the expressions of GPR4mRNA in aorta of collateral-qi deficiency group were decreased(P<0.01), the expressions of GPR4 protein were also decreased. 3.4 The changes of 5-HT receptors in aorta and cerebral tissue of collateral-qi deficiency/collateral-qi stagnation and the effect of dredge-collaterals herbs①Compared with normal control group, the level of 5-HT in cerebral tissue were increased in collateral-qi deficiency group(P<0.01), however, which were slightly decreased in collateral-qi stagnation group(P>0.05).②Compared with normal control group, the expressions of 5-HT1DmRNA were decreased and 5-HT2A mRNA were increased in aorta of collateral-qi deficiency group and collateral-qi stagnation group (P<0.01).③Compared with normal control group, the expressions of 5-HT1D, 5-HT2A, TPHmRNA were not significant change(P>0.05).Compared with normal control group, the expressions of 5-HT1D and TPHmRNA were decreased, but 5-HT2AmRNA was increased (P<0.01) .④Compared with normal control group, the protein expressions of 5-HT1D were decreased , 5-HT2A were increased in aorta of collateral-qi deficiency group and collateral-qi stagnation group.⑤Compared with normal control group, the protein expressions of 5-HT1D were slightly increased in cerebral tissue of collateral-qi deficiency group, the protein expressions of 5-HT2A were increased in cerebral tissue of collateral-qi stagnation group.①The level of 5-HT in cerebral tissue were decreased in collateral-qi deficiency group and increased in collateral-qi stagnation group ,but there was not significant change(P>0.05).②Compared with collateral-qi deficiency group, the expressions of 5-HT1DmRNA were increased and 5-HT2A mRNA were decreased in aorta of collateral-qi deficiency group and collateral-qi stagnation group (P<0.05 or P<0.01).③Compared with collateral-qi stagnation group, the mRNA expressions of 5-HT1D were increased,5-HT2A mRNA was decreased in allium and Tongxinluo groups (P<0.05 or P<0.01).④Compared with model groups, the protein expressions of 5-HT1D were increased , 5-HT2A was decreased in aorta of dredge-collaterals herbs groups.⑤Compared with collateral-qi deficiency group, the protein expressions of 5-HT1D were increased in cerebral tissue of ginsenoside group and Tongxinluo group , as compared with collateral-qi stagnation group, the protein expressions of 5-HT2A were decreased of Tongxinluo group.Conclusion:1Under the guidance of Vessels-Collateral Theory, metabonomics methods have been applied firstly for pathophysiological basis study of the sub-health population in accordance with collateral-qi deficiency and collateral-qi stagnation and rat models, which have provided new research idea for revealing the initiating effect of excessive fatigue and depression in pathophysiological behaviorsUnder the guidance of"qi-blood correlation"and"Ying-wei-cheng-zhi-tiao-ping"of Vessels-Collateral Theory, based on the results of epidemiological study on 3469 patients with vasculopathy: collateral-qi deficiency and collateral-qi stagnation are the initiating agents, which exist in the whole process of vasculopathy. Metabonomics methods have been applied for pathophysiologic basis study in sub-health population without clear western medicine diagnosis, however which is in accordance with collateral-qi deficiency and collateral-qi stagnation standard and the rat models, which have provided new research idea of revealing the initiating effect of excessive fatigue and depression in pathophysiologic. 2 Through the analysis for the metabonomics and metabolic profiling, the characteristics of metabonomics of collateral-qi deficiency and collateral-qi stagnation of populations and rat models about acylcarnitines and lipids have been reveled preliminary,which probabily has provid metabonomics basis for screening in sub-health population due to social and psychological behavior factors.The metabonomics results showed that collateral-qi deficiency/ collateral-qi stagnation populations were different from health population, which has suggested that there exists material basis in collateral-qi deficiency and collateral-qi stagnation syndromes. At the same time, there were different between collateral-qi deficiency and collateral-qi stagnation, the amino acids and lipids metabolisms were disordered in collateral-qi deficiency syndrome, however the amino acids ,lipids , energy metabolisms were disordered in collateral-qi stagnation syndrome, which has testified the scientific value of syndrome differentiation based on Vessels-Collateral Theory. The results suggested that tryptophan ,phenylalanine maybe the important metabolic markers to predict hypertension, LPC maybe the important metabolic markers for predicting hyperlipemia, atherosclerosis and vascular endothelial dysfunction.The metabolic profiling results show that collateral-qi deficiency/collateral-qi stagnation populations were different from normal control group. The levels of acylcarnitines and lipids were decreased in collateral-qi deficiency, which may be related with CPT-Ⅰand lipids mobilization.The levels of acylcarnitines and lipids were increased in collateral-qi stagnation, which maybe related to acylcarnitines overstock and vascular endothelial dysfunction based on LPC increased. In addtion PC(36:4),PC (38:6),PC (40:6) may be the important metabolic markers to predict hyperlipemia.3 The study shows that the collateral-qi deficiency/collateral-qi stagnation symptomss can result in vascular endothelial function injury,and can cause the abnormal regulation of myocardial energy metabolism,5-HT and its receptors in cerebral tissueAccording to the results of metabonomics, the effect of collateral-qi deficiency/collateral-qi stagnation syndromes in aorta, myocardial and cerebral tissue on cytokines and receptors about energy, phospholipids and tryptophan have been investigated.In this study , collateral-qi deficiency/collateral-qi stagnation syndromes can induce vascular endothelial dysfunction, the mechanism may be related to the decrease of the expressions of CPT-I mRNA and protein, the increase of the levels of LP-PLA2 and the disorder of 5-HT1D/5-HT2A. These syndromes can induce dysfunction in energy metabolisms, and its mechanism may be related to CPT-I mRNA and protein decreased via AMPKαand PPARδpathway. The nergecharge of myocardial tissue was slightly increased, which may be the specific performance of"Zhi". In addition, the level of 5-HT in cerebral tissue diorder, which may be the important pathogenic of hypertension, central fatigue and depression.4 The dredge-collaterals herbs can adjust the metabolite profiling and pathological changes in aortic myocardial and cerebral tissue, which reflected the scientific content of relationship between"Bing-zheng-fa-yao"and the systematic effect of compound dredge-collaterals herbs, from"Tiao"to"Ping"recovered homeostasisIn this study , ginsenosides, allium and Tongxinluo capsule were applied. Ginsenosides and allium could adjust the disorder of acylcarnitines and lipids metabolite profiling. The dredge-collaterals herbs can improve vascular endothelial function and energy metabolisms through increasing energecharge of myocardial tissue, increasing the expression of CPT-I, activing AMPK and PPARδpathway. The dredge-collaterals herbs can decreas the levels of Lp- PLA2 and the expressions of GPR4mRNA and protein in aortic, which can inhibit vascular endothelial dysfunction induced by LPC. The herbs also can adjust the expressiones of 5-HT1D and 5-HT2A in aortic and cerebral tissue , and can adjust the levels of 5-HT in cerebral tissue. 5 Based on the metabonomics results of population and rats, we have proposed intervention strategies for treating vasculopathy that"the ahead intervention, syndrome differentiation and adjustmentThrough the clinical population and animals researches in our study, which has illuminated the characteristics metabonomics of collateral-qi deficiency and collateral-qi stagnation and its effect on aorta ,myocardial ,cerebral tissue, which has also revealed the initiating effect of excessive fatigue and depression.The therapeutic effects included regulat ting mood and relaxing stress, at the same time syndrome differentiation and adjustment should be applied on sub-health population.The CTP-I,LPC,PC,5-HT and its receptors ,which about energy , phospholipids and tryptophan metabolisms,should be adjusted. The precursors of vasculopathy should be improved, and the vasculopathy caused by hypertension and hyperlipidemia should be prevented early.