the effect and mechanism of chinese herbal...

Research ArticleThe Effect and Mechanism of Chinese Herbal Formula Sini Tangin Heart Failure after Myocardial Infarction in Rats

Yuhan Zhu1 Jing Zhao1 Qingqing Han1 ZhenWang1 ZhaoboWang1

Xin Dong1 Jiebai Li1 Lei Liu1 and Xiaoxu Shen 23

1Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine Beijing 100700 China2Cardiology Department Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine Beijing 100700 China3Lab for Research onTheory of Qi-Blood of Integrative Medicine Beijing 100700 China

Correspondence should be addressed to Xiaoxu Shen alienstg163com

Received 9 February 2018 Revised 4 April 2018 Accepted 15 April 2018 Published 27 June 2018

Academic Editor Wen-yi Kang

Copyright copy 2018 Yuhan Zhu et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Objective To investigate the effectiveness andmechanismof theChinese herbal formula Sini Tang (SNT)which consists ofAconitumcarmichaelii (Fuzi) Zingiber officinale (Gan Jiang) and Glycyrrhiza uralensis (Gancao) in heart failure after myocardial infarctionin ratsMethods We established the heart failure after myocardial infarction in model of SD rats by ligating the anterior descendingbranch of left coronary artery Rats were randomly divided into six experimental groups Sham operation group HF groupBenazepril group high dose of SNT group medium dose of SNT group and low dose of SNT group Drugs were administered byoral gavage for eight weeks The detection indexes include left ventricular function by echocardiogram Collagen Volume Fractionby Masson staining level of Plasma Renin Angiotensin II and Aldosterone by radioimmunoassay protein and gene level of ACEand AT1R by western-blot and real-time PCR Results The outcomes of this study indicated that SNT significantly improved theLVEF and LVFS thickened both LVAWd and LVAWs and reduced LVIDs in heart failure after myocardial infarction in rats whencompared with control group (119875 lt 005) Besides SNT significantly reduced the Collagen Volume Fraction (119875 lt 005) The resultsof radioimmunoassay showed that SNT decreased the level of Plasma Renin Angiotensin II and Aldosterone (119875 lt 005) Theoutcomes of western-blot and real-time PCR analysis showed that SNT significantly downregulated the protein and gene level ofACE and AT1R (119875 lt 005) Conclusions The Chinese herbal formula SNT could improve left ventricular systolic function in heartfailure after myocardial infarction in rats and decreased the level of Plasma Renin Angiotensin II and Aldosterone as well asdownregulating the protein and gene level of ACE and AT1R Therefore SNT has potential benefits of improving cardiac functionby inhibiting the excessive activation of Renin-Angiotensin-Aldosterone system in heart failure after myocardial infarction in rats

1 Introduction

HF is a clinical syndrome characterized by typical symptoms(eg breathlessness ankle swelling and fatigue) that may beaccompanied by signs (eg elevated jugular venous pressurepulmonary crackles and peripheral oedema) caused by astructural andor functional cardiac abnormality resulting ina reduced cardiac output andor elevated intracardiac pres-sures at rest or during stress [1] According to the reports ofWorld Health Organization (WHO) in 2010 cardiovasculardisease is the leading cause of death in humans What is

worse nearly 290 million patients suffer from cardiovasculardisease and 45 million patients were diagnosed with heartfailure (HF) in China In Europe about 26 million peoplesuffer from HF [2]

At present coronary heart disease has become the pri-mary cause of heart failure and accounts for more than 50in Europe and North America and 30 to 40 in the EastAsia and Latin America [1] Due to the high morbidity andmortality HF has become the great burden and challengesfor the social economy and healthcare resources Recentlythe treatment of heart failure is mainly based on western

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2018 Article ID 5629342 7 pageshttpsdoiorg10115520185629342

2 Evidence-Based Complementary and Alternative Medicine

medicine in clinical practice [3ndash6] However our traditionalChinese medicine (TCM) also plays an important role in theprevention and treatment of HF [7ndash13]

In the clinical practice blood stasis syndrome and Yangdeficiency syndrome are both the most common manifesta-tions of heart failure However previous studies have focusedon the study of blood stasis syndromeThe studies about Yangdeficiency syndrome are few The treatment based on thetheory ofwarmYang has obtained significant clinical efficacyAs the representative decoction of warm Yang Sini Tang(SNT) which originated from Shang Han Lun is composed ofthree kinds of traditional Chinese herbs namely Aconitumcarmichaelii (Fuzi) Zingiber officinale (Gan Jiang) and Gly-cyrrhiza uralensis (Gancao) The clinical efficacy of SNT hadbeen confirmed by a large number of clinical studies whilethe specific mechanism of its efficacy remains unknownTherefore we conducted this trial to investigate the effectof SNT on cardiac function in heart failure after myocardialinfarction in rats and explore the specific mechanism of SNTin order to provide a scientific basis for the prevention andtreatment of heart failure with SNT

2 Materials and Methods

We used 90 male Sprague-Dawley rats (180ndash200 g) providedby the Vital Laboratory Animal Technology Company (Bei-jing China) for this study The experimental protocol andthe use of animals were approved by the Animal Use andManagement Ethics Committee of the Dongzhimen Hospitalaffiliated to Beijing University of Chinese Medicine Theexperimental design and implementation were in accordancewith the ldquoBeijing experimental animal regulationsrdquo and theUnited States National Institutes of Health (NIH) ldquoGuidefor the Care and Use of Laboratory Animalsrdquo Preoperativeand postoperative experimental animals were kept in the KeyLaboratory of Chinese Internal Medicine (Beijing Universityof Chinese Medicine) animal barrier system (temperaturewithin 24ndash26∘C relative humidity 50 to 60) All theanimals were adapted for seven days before the experiment

Rats were randomly divided into six experimental groupsSham operation group (control group with no MI nor HFtreated with deionized water after heart failure 119899 = 15) HFgroup (Heart Failure group treatedwith deionizedwater afterheart failure 119899 = 15) Benazepril group (Benazepril treatedafter heart failure 119899 = 15) high dose of SNT group (high doseof SNT treated after heart failure 119899 = 15) medium dose ofSNT group (medium dose of SNT treated after heart failure119899 = 15) and low dose of SNT group (low dose of SNT treatedafter heart failure 119899 = 15)

21 Preparation for Heart Failure after Myocardial Infarc-tion Model of SD Rats Sprague-Dawley rats were injectedintraperitoneally with pentobarbital sodium (50mgkg) Tra-cheal intubation was connected to an animal ventilator (DH-140 Zhejiang China) After thoracotomy at the third orfourth intercostal space the anterior descending branch ofleft coronary arterywas ligatedOnce the rats have ventricularfibrillation during the operation we injected the rats with 1lidocaine (1mgkg) then closed the thorax and pulled out

of the ventilator after spontaneous respiration was restoredAll rats were intramuscularly injected with penicillin intra-muscularly within three days after surgery One week afterligation Electrocardiogram (ECG) was performed and ratswith pathologic 119876 lt 6 infarct-related ECG leads wereeliminated Four weeks after ligation Echocardiography wasperformed and rats with left ventricular ejection fractionle 45 were diagnosed as having heart failure [14] Duringmodel establishment the general state of the animals includ-ingmental state level of activity body weight food and waterintake urine volume and color stool condition was recordedevery day Heart failure rats with Yang deficiency syndromewere selected according to the manifestation of animals suchas mental sluggishness reduction of physical activity clearurine loose stool and cold limbs

22 Medication Treatment When the animal model of heartfailure was successful at four weeks after ligation accordingto the results of ElectrocardiogramandEchocardiographywescreened the heart failure rats with Yang deficiency syndromeand divided them into six experimental groups randomlySham operation group Heart Failure group Benazeprilgroup high dose of SNT group and medium dose of and lowdose of SNT group Drugs were administered by oral gavagefor eight weeks The SNT was purchased from DongzhimenHospital affiliated to Beijing University of Chinese MedicineThe dosage of the SNT was in accordance with the records ofShang Han Lun by Zhang Zhongjing (Aconitum carmichaelii15 g Zingiber officinale 20 g Glycyrrhiza uralensis 30 g) TheSNT was administered once daily (1114 gkgd in the highdose group of SNT 557 gkgd in the medium dose group ofSNT and 279 gkgd in the low dose group of SNT) to ratsin the SNT group Benazepril was administered once daily(086mgkgd) to rats in the Benazepril group which wassupplied by Beijing Novartis Pharma Ltd (China)

23 Measurement of Left Ventricular Function by Echocar-diogram The Left ventricular ejection fraction (LVEF) Leftventricular fractional shortening (LVFS) Left ventricularinner diameters (LVID) and left ventricular anterior wallthickness (LVAWT) were measured at least three consecutivecardiac cycles by echocardiogram (Vevo 770 VisualSonicsInc USA) The two-dimensional short-axis view of the leftventricular was obtained at the level of the papillary musclealong with the M-mode recordings

24 Measurement of Collagen Volume Fraction by Mas-son Staining of Heart The hearts were fixed in a 4paraformaldehyde solution for 48 hours and then embeddedin paraffin The 5 120583m thick serial sections cut from paraffinblocks were stained withMasson trichrome solutions Imagesof these stained sections were obtained using a light micro-scopeThe Collagen Volume Fraction (CVF) was obtained byusing image analysis software (Image-Pro Plus 60)

25 Measurement of Plasma Renin Angiotensin II and Aldos-terone by Radioimmunoassay The blood was collected fromaorta abdominalis The Plasma Renin Angiotensin II andAldosterone levels weremeasured by radioimmunoassayThe

Evidence-Based Complementary and Alternative Medicine 3

test kits were purchased from Beijing Sino-UK institute ofBiological Technology (China)

26 Western-Blot Analysis Fifty micrograms of cell lysatesandmyocardial tissue were separated on 10 sodiumdodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gelsand then transferred onto nitrocellulose membranes Anti-Angiotensin converting enzyme 1 antibody (ACE) (ab216476)and anti-Angiotensin II type 1 receptor antibody (AT1R)(ab18801) were purchased from Abcam Cambridge UKHRP conjugated immunoglobulin was used as a secondaryantibody (Jackson ImmunoResearch Laboratories) WestPico Chemiluminescent (Pierce) was used as the substrateto visualize protein bands and quantified using densitometryimage analysis software (Image Master VDS PharmaciaBiotech)

27 Real-Time PCR Analysis Total RNA was extracted fromthe myocardial infarcted marginal area of rats using TRI-zol regent (Invitrogen) DNase-treated RNA was used forfirst strand cDNA synthesis using M-MLV reverse tran-scriptase (Promega) and oligo (dT) according to the man-ufacturersquos protocols and 1 120583L cDNA samples were usedfor conventional PCR amplifications Real-time quantitativePCR analysis was performed in a real-time PCR system(StepOne Applied Biosystems) and the expression levels ofACE and AT1R were normalized to GAPDH determinedby a SYBR Green-based comparative cycle threshold CTmethod Real-time PCR primers sequences are as followsACE-F 51015840-GCCATGAAGTTGGGCTACAG-31015840 ACE-R 51015840-TCTGTGACGAGCCATTCAGT-31015840 AT1R-F 51015840-TACGCC-AGTGTGTTCCTTCT-31015840 AT1R-R 51015840-ATGATGCAGGTG-ACTTTGGC-31015840 GAPDH-F 51015840-CAACTCCCTCAAGAT-TGTCAGCAA-31015840 GAPDH-R 51015840-GGCATGGACTGTGGT-CATGA-31015840

28 Statistical Methods We used the software program SPSS200 to conduct the statistical analysis All results wereexpressed as mean plusmn SD For multiple comparisons eachvalue was compared by one way ANOVA following Dunnetttest when each datum conformed to normal distributionwhile the non-normally distributed continuous data werecompared by using nonparametric tests A value of 119875 lt 005was considered statistically significant

3 Results

Five of 15 animals in the HF group 1 of 15 in the Benazeprilgroup 2 of 15 in the high dose of SNT group 2 of 15 in themedium dose of SNT group and 3 of 15 in the low dose ofSNT group died within the eight-week period after coronaryartery ligation

31 Changes in Left Ventricular Function by Echocardiogram

LVEF Compared with Sham operation group LVEF wassignificantly reduced in the HF group Compared with theHF group LVEF in Benazepril group the high dose of SNTgroup medium dose of SNT group and low dose of SNT

group were significantly increased There was no significantdifference in LVEF among high dose of SNT group mediumdose group of SNT and low dose of SNT group

LVFS Compared with Sham operation group LVFS wasdecreased significantly in HF group Compared with HFgroup LVFS in Benazepril group high dose of SNT groupand middle dose of SNT group were significantly increasedLVFS had no significant difference between HF group andlow dose of SNT groupThere was no significant difference inLVFS among high dose of SNT group medium dose of SNTgroup and low dose of SNT group

LVAWT LVAWT includes left ventricular end-diastolic ante-rior wall thickness (LVAWd) and left ventricular end-systolicanterior wall thickness (LVAWs) Comparedwith Shamoper-ation group LVAWd and LVAWswere significantly decreasedin HF group Compared with HF group LVAWd and LVAWswere significantly increased in Benazepril group high dose ofSNT groupmediumdose of SNT group and low dose of SNTgroup There was no significant difference in LVEF amongthose three kinds of SNT group

LVID LVID include left ventricular end-diastolic inner diam-eter (LVIDd) and left ventricular end-systolic inner diameter(LVIDs) Compared with Sham operation group LVIDs inHF group was increased significantly Compared with HFgroup LVIDs in Benazepril group high dose of SNT groupand middle dose of SNT group were significantly decreasedLVIDs had no significant difference between HF group andlow dose of SNT groupThere was no significant difference inLVIDd among Sham operation group HF group Benazeprilgroup and the three kinds of SNT groups (Table 1 andFigure 1)

32 Changes in Collagen Volume Fraction by Masson StainingCompared with Sham operation group the Collagen VolumeFraction (CVF) significantly increased in HF group Com-pared with the HF group CVF was significantly decreased inBenazepril group high dose of SNT group andmedium doseof SNT group CVF had no significant difference between lowdose of SNT group and HF group There was no significantdifference among high dose of SNT group medium dosegroup of SNT and low dose of SNT group (Figure 2)

33 Changes in Plasma Renin Angiotensin II and Aldos-terone by Radioimmunoassay Compared with Sham opera-tion group the level of Plasma Renin Angiotensin II andAldosterone was significantly increased in the HF groupCompared with the HF group the level of Plasma ReninAngiotensin II and Aldosterone was significantly decreasedin Benazepril group themedium dose of SNT group and lowdose of SNT groupThe high dose of SNT group significantlyreduced the level of Angiotensin II and AldosteroneThe lowdose of SNT group only significantly reduced the level ofAngiotensin II There was no significant difference amonghigh dose of SNT group medium dose group of SNT and lowdose of SNT group (Figures 3ndash5)


Table 1 LV function in rats eight weeks post-HF

Group 119899 LVEF LVFS LVAWd LVAWs LVIDd LVIDsSham operation 10 7297 plusmn 677 4417 plusmn 635 080 plusmn 013 098 plusmn 012 847 plusmn 123 477 plusmn 105Heart Failure 10 2938 plusmn 512lowast 1457 plusmn 271lowast 061 plusmn 010lowast 072 plusmn 012lowast 958 plusmn 144 820 plusmn 134lowast

Benazepril 10 5246 plusmn 1059lowast 2865 plusmn 711lowast 079 plusmn 011 097 plusmn 012 917 plusmn 156 663 plusmn 162lowast

High dose of SNT 10 5522 plusmn 867lowast 2994 plusmn 539lowast 085 plusmn 010 094 plusmn 012 754 plusmn 203 536 plusmn 182

Medium dose of SNT 10 5303 plusmn 275lowast 2877 plusmn 180lowast 085 plusmn 013 109 plusmn 017 959 plusmn 150 683 plusmn 113lowast

Low dose of SNT 10 4380 plusmn 565lowast 2309 plusmn 348lowast 084 plusmn 006 106 plusmn 009 1062 plusmn 138lowast 816 plusmn 113lowast

LVEF left ventricular ejection fraction LVFS left ventricular fractional shortening LVAWd left ventricular end-diastolic anterior wall thickness LVAWs leftventricular end-systolic anterior wall thickness LVIDd left ventricular end-diastolic inner diameter LVIDs left ventricular end-systolic inner diameter lowast119875 lt005 versus Sham operation group 119875 lt 005 versus Heart Failure group

Figure 1 Representative tracing of echocardiography LV function

34 Changes in Protein Expression Level of ACE and ATIRby Western-Blot Analysis When compared with Sham oper-ation group HF group had significantly upregulated proteinexpression level of ACE and ATIR Compared with the HFgroup the Benazepril group high dose of SNT group andlow dose of SNT group had significantly downregulatedexpression level of ACE and ATIR protein The mediumdose of SNT group only significantly downregulated theexpression level of ACE protein There was no significantdifference among high dose of SNT group medium dose ofSNT group and low dose of SNT group (Figures 6 and 7)

35 Changes in Gene Expression Level of ACE mRNA andATIR mRNA by Real-Time PCR Analysis When comparedwith Sham operation group HF group had significantlyupregulated gene expression level of ACE mRNA and ATIRmRNA Compared with the HF group the Benazepril grouphigh dose of SNT group and low dose of SNT group hadsignificantly downregulated gene expression level of ACEmRNA and ATIR mRNA The gene expression level ofACE mRNA and ATIR mRNA had no significant difference

between medium dose of SNT group and HF group Therewas no significant difference among high dose of SNT groupmedium dose group of SNT and low dose of SNT group(Figures 6 and 7)

4 Discussion

In our study all the animals were adapted for seven daysbefore the experiment One week after ligation Electrocar-diogram (ECG) was performed Four weeks after ligationEchocardiography was performed When the animal modelof heart failure was successful at four weeks after ligationaccording to the results of Electrocardiogram and Echocar-diography we screened the model rats and divided them intosix experimental groups randomly Drugs of each group wereadministered by oral gavage for eight weeks Eight weeks aftertreatment Electrocardiogram and Echocardiography wereperformed once again in order to evaluate the effectivenessof Sini decoction The blood and heart tissue of all ratswere collected on the same day after Electrocardiogram andEchocardiography

Evidence-Based Complementary and Alternative Medicine 5(

)

60

50

40

30

20

10

0

Collagen Volume Fraction

lowast

lowast

lowast

lowast

lowast

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

Figure 2 Changes in Collagen Volume Fraction SNT Sini Tanglowast119875 lt 005 versus Sham operation group

119875 lt 005 versus HeartFailure group

(pg

ml)

5

4

3

2

1

0

Renin

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowastlowast

lowast

Figure 3 Changes in Plasma Renin by radioimmunoassay SNTSini Tang lowast119875 lt 005 versus Sham operation group 119875 lt 005 versusHeart Failure group

Previous studies revealed that SNT has the potentialto improve early ventricular remodeling after myocardialinfarction [15] and a benefit of anti-inflammatory effects inMI rats [16] The study by Zhou et al [17] revealed that SNTcould protect myocardium in isoproterenol- (ISO-) inducedmyocardial injury Liao et al [18] found that SNT couldeffectively inhibit ISO-induced myocardial fibrosis The trialby Zhao et al found that SNT could provide protection

Angiotensin II150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowastlowast

(pg

ml)

Figure 4 Changes in plasma Angiotensin II by radioimmunoassaySNT Sini Tang lowast119875 lt 005 versus Sham operation group 119875 lt 005versus Heart Failure group

120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowast

(pg

ml)

Aldosterone

Figure 5 Changes in plasma Aldosterone by radioimmunoassaySNT Sini Tang lowast119875 lt 005 versus Sham operation group 119875 lt 005versus Heart Failure group

by inhibiting cardiomyocyte apoptosis Besides SNT couldease the oxidative stress in Adriamycin- (ADR-) inducedheart failure rats [19] These previous studies confirmed theprotection function of SNT in heart failure rats A formerstudy which was conducted by Liu et al [15] reported thatChinese medicine formula SNT has the potential to improveearly ventricular remodeling and cardiac function after MI


Figure 6 Changes inACEmRNAandACEprotein SNT Sini Tanglowast119875 lt 005 versus Sham operation group


Figure 7 Changes in AT1R mRNA and ATIR protein SNT SiniTang lowast119875 lt 005 versus Sham operation group

119875 lt 005 versusHeart Failure group

The mechanism may be related to the reduction of thelevels of Toll-like receptors (TLR-2 and TLR-4) collagenscontent and the transformation of growth factor-120573 1 (TGF-120573 1) in myocardial tissue Moreover a lot of studies havedemonstrated that myocardial remodeling and abnormalactivation of RAAS are closely correlated However the effectof SNT in Renin-Angiotensin-Aldosterone system (RAAS)of heart failure after myocardial infarction in rats remainsuncertain

In this study SNT has significantly improved the cardiacfunction in heart failure after myocardial infarction in ratsSNT significantly improved the LVEF and LVFS thickenedboth LVAWd and LVAWs and decreased LVIDs in heartfailure after myocardial infarction in rats when compared

with control group The result of Masson scanning showedthat SNT significantly reduced the Collagen Volume Fractionwhich alleviated the condition of collagen deposition Theresults of radioimmunoassay indicated that SNT decreasedthe level of Plasma Renin Angiotensin II and AldosteroneThe outcomes of western-blot and real-time PCR analysisshowed that SNT significantly downregulated the protein andgene level of ACE and AT1R

Previous studies had confirmed the clinical efficacy ofSNT and the results of our study revealed that SNT improvedthe cardiac function in heart failure after myocardial infarc-tion in rats by inhibiting the activation of RAAS RAASwas considered to be a simple neurohumoral regulationmechanism at first while after the research of RAAS blockersuch as Renin inhibitors and Angiotensin converting enzymeinhibitors (ACEI) the role of RAAS system has been gradu-ally paid attention to In the cardiovascular field pathologicalactivatedRAAS can lead to excessive vasoconstriction hyper-plasia of vascular smooth muscle and myocardial hypertro-phy and fibrosis Inhibiting the RAAS had benefits amongpatients with hypertension acute myocardial infarction andheart failure [20ndash23]Therefore inhibiting excessive activatedRAAS system has become an important target for clinicalprevention and treatment of heart failure

5 Conclusions

The Chinese herbal formula SNT could improve left ven-tricular systolic function in heart failure after myocardialinfarction in rats and decreased the level of Plasma ReninAngiotensin II and Aldosterone as well as downregulatingthe protein and gene level of ACE and AT1R ThereforeSNT has potential benefits of improving cardiac functionby inhibiting the excessive activation of Renin-Angiotensin-Aldosterone system in heart failure after myocardial infarc-tion in rats

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request

Disclosure

Yuhan Zhu is the first author Jing Zhao Qingqing Han andJiebai LI are co-first authors

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

References

[1] P Ponikowski A A Voors S D Anker et al ldquoESC Guidelinesfor the diagnosis and treatment of acute and chronic heartfailurerdquo European Heart Journal vol 18 no 8 p ehw128 2016


[2] Lopez-Sendon ldquoThe heart failure epidemicrdquo Medicographiavol 33 pp 363ndash369 2011

[3] L Shen P S JhundM C Petrie et al ldquoDeclining risk of suddendeath in heart failurerdquoTheNewEngland Journal ofMedicine vol377 no 1 pp 41ndash51 2017

[4] V S Tan D M Nash E McArthur et al ldquoImpact of InjectableFurosemide Hospital Shortage on Congestive Heart FailureOutcomes A Time Series Analysisrdquo Canadian Journal of Car-diology vol 33 no 11 pp 1498ndash1504 2017

[5] W Yao NWang J Qian et al ldquoRenal sympathetic denervationimproves myocardial apoptosis in rats with isoproterenol-induced heart failure by downregulation of tumor necrosisfactor-120572 and nuclear factor-120581Brdquo Experimental and TherapeuticMedicine vol 14 no 5 pp 4101ndash4110 2017

[6] A C Pandey J J Lancaster D T Harris S Goldman and EJuneman ldquoCellular Therapeutics for Heart Failure Focus onMesenchymal StemCellsrdquo StemCells International vol 2017 pp1ndash12 2017

[7] K Wang J Wu D Zhang X Duan and M Ni ldquoComparativeefficacy of Chinese herbal injections for treating chronic heartfailure a network meta-analysisrdquo BMC Complementary andAlternative Medicine vol 18 no 1 2018

[8] L Chen Y Cao H Zhang et al ldquoNetwork pharmacology-basedstrategy for predicting active ingredients and potential targetsof Yangxinshi tablet for treating heart failurerdquo Journal ofEthnopharmacology vol 219 pp 359ndash368 2018

[9] K Gao H Zhao and J Gao Mechanism of Chinese MedicineHerbs Effects on Chronic Heart Failure Based on MetabolicProfiling Front Pharmacol 8 64 2017

[10] M Tsai W Hu J Chiang et al ldquoImproved medical expen-diture and survival with integration of traditional Chinesemedicine treatment in patients with heart failure A nationwidepopulation-based cohort studyrdquoOncotarget vol 8 no 52 2017

[11] D Fan J Qi and M Zhang ldquoInsights of Chinese medicine onventricular remodeling Multiple-targets individualized-treatmentrdquoChinese Journal of IntegrativeMedicine vol 23 no 9pp 643ndash647 2017

[12] A Riba L Deres B Sumegi K Toth E Szabados and R Hal-mosi ldquoCardioprotective effect of resveratrol in a postinfarctionheart failure modelrdquoOxidativeMedicine and Cellular Longevityvol 2017 Article ID 6819281 2017

[13] K Wang J Wu X Duan et al ldquoHuangqi injection in thetreatment of chronic heart failurerdquo Medicine vol 96 no 39 pe8167 2017

[14] J Ni Y Shi L Li et al ldquo Cardioprotection against Heart Failureby Shenfu Injection via TGF- rdquo Evidence-Based Complementaryand Alternative Medicine vol 2017 pp 1ndash16 2017

[15] J Liu K Peter D Shi et al ldquoTraditional formula modernapplication Chinesemedicine formula Sini tang improves earlyventricular remodeling and cardiac function after myocardialinfarction in ratsrdquo Evidence-Based Complementary and Alterna-tive Medicine vol 2014 Article ID 141938 10 pages 2014

[16] J Liu K Peter D Shi et al ldquoAnti-inflammatory effects of thechinese herbal formula sini tang in myocardial infarction ratsrdquoEvidence-Based Complementary and Alternative Medicine vol2014 Article ID 309378 10 pages 2014

[17] J Zhou X Ma M Shi et al ldquoSerum metabolomics analysisreveals that obvious cardioprotective effects of low dose Sinidecoction against isoproterenol-induced myocardial injury inratsrdquo Phytomedicine vol 31 pp 18ndash31 2017

[18] H-C Liao Y Liu and B Zhou ldquoEffects of Sini decoction onthe expressions of Smad2 and Smad7 in isoproterenol inducedmyocardial fibrosis ratsrdquo Zhongguo Zhong Xi Yi Jie He Za ZhiZhongguoZhongxiyi Jiehe Zazhi vol 32 no 7 pp 934ndash938 2012

[19] M Q Zhao W K Wu D Y Zhao et al ldquoProtective effectsof sini decoction on adriamycin- induced heart failure and itsmechanismrdquo Zhong Yao Cai vol 32 no 12 pp 1860ndash1863 2009

[20] L Te Riet J H M van Esch A J M Roks A H van denMeiracker and A H J Danser ldquoHypertension renin-angi-otensin-aldosterone system alterationsrdquo Circulation Researchvol 116 no 6 pp 960ndash975 2015

[21] A Mascolo M Sessa C Scavone et al ldquoNew and old roles ofthe peripheral and brain reninndashangiotensinndashaldosterone system(RAAS) Focus on cardiovascular and neurological diseasesrdquoInternational Journal of Cardiology vol 227 pp 734ndash742 2017

[22] S Y Choi B G Choi S Rha et al ldquoAngiotensin-convertingenzyme inhibitors versus angiotensin II receptor blockers inacute ST-segment elevation myocardial infarction patients withdiabetes mellitus undergoing percutaneous coronary interven-tionrdquo International Journal of Cardiology vol 249 pp 48ndash542017

[23] C Tai T Gan L Zou et al ldquoEffect of angiotensin-convertingenzyme inhibitors and angiotensin II receptor blockers oncardiovascular events in patients with heart failure a meta-analysis of randomized controlled trialsrdquo BMC CardiovascularDisorders vol 17 no 1 2017

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Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

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medicine in clinical practice [3ndash6] However our traditionalChinese medicine (TCM) also plays an important role in theprevention and treatment of HF [7ndash13]

In the clinical practice blood stasis syndrome and Yangdeficiency syndrome are both the most common manifesta-tions of heart failure However previous studies have focusedon the study of blood stasis syndromeThe studies about Yangdeficiency syndrome are few The treatment based on thetheory ofwarmYang has obtained significant clinical efficacyAs the representative decoction of warm Yang Sini Tang(SNT) which originated from Shang Han Lun is composed ofthree kinds of traditional Chinese herbs namely Aconitumcarmichaelii (Fuzi) Zingiber officinale (Gan Jiang) and Gly-cyrrhiza uralensis (Gancao) The clinical efficacy of SNT hadbeen confirmed by a large number of clinical studies whilethe specific mechanism of its efficacy remains unknownTherefore we conducted this trial to investigate the effectof SNT on cardiac function in heart failure after myocardialinfarction in rats and explore the specific mechanism of SNTin order to provide a scientific basis for the prevention andtreatment of heart failure with SNT

2 Materials and Methods

We used 90 male Sprague-Dawley rats (180ndash200 g) providedby the Vital Laboratory Animal Technology Company (Bei-jing China) for this study The experimental protocol andthe use of animals were approved by the Animal Use andManagement Ethics Committee of the Dongzhimen Hospitalaffiliated to Beijing University of Chinese Medicine Theexperimental design and implementation were in accordancewith the ldquoBeijing experimental animal regulationsrdquo and theUnited States National Institutes of Health (NIH) ldquoGuidefor the Care and Use of Laboratory Animalsrdquo Preoperativeand postoperative experimental animals were kept in the KeyLaboratory of Chinese Internal Medicine (Beijing Universityof Chinese Medicine) animal barrier system (temperaturewithin 24ndash26∘C relative humidity 50 to 60) All theanimals were adapted for seven days before the experiment

Rats were randomly divided into six experimental groupsSham operation group (control group with no MI nor HFtreated with deionized water after heart failure 119899 = 15) HFgroup (Heart Failure group treatedwith deionizedwater afterheart failure 119899 = 15) Benazepril group (Benazepril treatedafter heart failure 119899 = 15) high dose of SNT group (high doseof SNT treated after heart failure 119899 = 15) medium dose ofSNT group (medium dose of SNT treated after heart failure119899 = 15) and low dose of SNT group (low dose of SNT treatedafter heart failure 119899 = 15)

21 Preparation for Heart Failure after Myocardial Infarc-tion Model of SD Rats Sprague-Dawley rats were injectedintraperitoneally with pentobarbital sodium (50mgkg) Tra-cheal intubation was connected to an animal ventilator (DH-140 Zhejiang China) After thoracotomy at the third orfourth intercostal space the anterior descending branch ofleft coronary arterywas ligatedOnce the rats have ventricularfibrillation during the operation we injected the rats with 1lidocaine (1mgkg) then closed the thorax and pulled out

of the ventilator after spontaneous respiration was restoredAll rats were intramuscularly injected with penicillin intra-muscularly within three days after surgery One week afterligation Electrocardiogram (ECG) was performed and ratswith pathologic 119876 lt 6 infarct-related ECG leads wereeliminated Four weeks after ligation Echocardiography wasperformed and rats with left ventricular ejection fractionle 45 were diagnosed as having heart failure [14] Duringmodel establishment the general state of the animals includ-ingmental state level of activity body weight food and waterintake urine volume and color stool condition was recordedevery day Heart failure rats with Yang deficiency syndromewere selected according to the manifestation of animals suchas mental sluggishness reduction of physical activity clearurine loose stool and cold limbs

22 Medication Treatment When the animal model of heartfailure was successful at four weeks after ligation accordingto the results of ElectrocardiogramandEchocardiographywescreened the heart failure rats with Yang deficiency syndromeand divided them into six experimental groups randomlySham operation group Heart Failure group Benazeprilgroup high dose of SNT group and medium dose of and lowdose of SNT group Drugs were administered by oral gavagefor eight weeks The SNT was purchased from DongzhimenHospital affiliated to Beijing University of Chinese MedicineThe dosage of the SNT was in accordance with the records ofShang Han Lun by Zhang Zhongjing (Aconitum carmichaelii15 g Zingiber officinale 20 g Glycyrrhiza uralensis 30 g) TheSNT was administered once daily (1114 gkgd in the highdose group of SNT 557 gkgd in the medium dose group ofSNT and 279 gkgd in the low dose group of SNT) to ratsin the SNT group Benazepril was administered once daily(086mgkgd) to rats in the Benazepril group which wassupplied by Beijing Novartis Pharma Ltd (China)

23 Measurement of Left Ventricular Function by Echocar-diogram The Left ventricular ejection fraction (LVEF) Leftventricular fractional shortening (LVFS) Left ventricularinner diameters (LVID) and left ventricular anterior wallthickness (LVAWT) were measured at least three consecutivecardiac cycles by echocardiogram (Vevo 770 VisualSonicsInc USA) The two-dimensional short-axis view of the leftventricular was obtained at the level of the papillary musclealong with the M-mode recordings

24 Measurement of Collagen Volume Fraction by Mas-son Staining of Heart The hearts were fixed in a 4paraformaldehyde solution for 48 hours and then embeddedin paraffin The 5 120583m thick serial sections cut from paraffinblocks were stained withMasson trichrome solutions Imagesof these stained sections were obtained using a light micro-scopeThe Collagen Volume Fraction (CVF) was obtained byusing image analysis software (Image-Pro Plus 60)

25 Measurement of Plasma Renin Angiotensin II and Aldos-terone by Radioimmunoassay The blood was collected fromaorta abdominalis The Plasma Renin Angiotensin II andAldosterone levels weremeasured by radioimmunoassayThe






3 Results






















4 Discussion



)

60

50

40

30

20

10

0


lowast

lowast

lowast

lowast

lowast

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT



(pg

ml)

5

4

3

2

1

0

Renin

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowastlowast

lowast



Angiotensin II150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowastlowast

(pg

ml)


120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowast

(pg

ml)

Aldosterone












5 Conclusions


Data Availability


Disclosure




References





























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
























3 Results






















4 Discussion



)

60

50

40

30

20

10

0


lowast

lowast

lowast

lowast

lowast

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT



(pg

ml)

5

4

3

2

1

0

Renin

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowastlowast

lowast



Angiotensin II150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowastlowast

(pg

ml)


120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowast

(pg

ml)

Aldosterone












5 Conclusions


Data Availability


Disclosure




References





























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of































4 Discussion



)

60

50

40

30

20

10

0


lowast

lowast

lowast

lowast

lowast

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT



(pg

ml)

5

4

3

2

1

0

Renin

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowastlowast

lowast



Angiotensin II150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowastlowast

(pg

ml)


120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowast

(pg

ml)

Aldosterone












5 Conclusions


Data Availability


Disclosure




References





























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















)

60

50

40

30

20

10

0


lowast

lowast

lowast

lowast

lowast

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT



(pg

ml)

5

4

3

2

1

0

Renin

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowastlowast

lowast



Angiotensin II150

140

130

120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowastlowast

(pg

ml)


120

110

100

90

80

70

60

50

40

30

20

10

0

Sham

ope

ratio

n

Hea

rt F

ailu

re

Bena

zepr

il

Hig

h do

se o

f SN

T

Med

ium

dos

e of S

NT

Low

dos

e of S

NT

lowast

lowast

(pg

ml)

Aldosterone












5 Conclusions


Data Availability


Disclosure




References





























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




























5 Conclusions


Data Availability


Disclosure




References





























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of














































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















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