SYSTEMATIC REVIEW

published: 09 April 2018

doi: 10.3389/fphar.2018.00324

Traditional Chinese Medicine for

Bradyarrhythmia: Evidence and
Potential Mechanisms
Shuo Liu 1† , Guihua Tian 1,2† , Jing Chen 3† , Xiaoyu Zhang 1† , Aiming Wu 1 , Min Li 1 , Yang Sun 1 ,
Baoshan Liu 4*, Yanwei Xing 5* and Hongcai Shang 1*
1
Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing
University of Chinese Medicine, Beijing, China, 2 Chinese Cochrane Center, West China Hospital, Sichuan University,
Chengdu, China, 3 Baokang Hospital Affiliated to Tianjin University of Traditional Chinese Medicine, Tianjin, China, 4 Tianjin
Medical University General Hospital, Tianjin, China, 5 Guang’anmen Hospital, Chinese Academy of Chinese Medical
Sciences, Beijing, China

Importance: The incidence of Bradyarrhythmias is high among the population.

However, at early stages of the disease, it cannot always get enough attention
and is lack of safe and effective therapies, until it is serious enough to resort to
pacemaker implantation. Traditional Chinese Medicine (TCM) has a long history of treating
Edited by:
Bradyarrhythmia, with a lot of formulas being widely used in clinical practice. While the
Wei-Dong Zhang,
Second Military Medical University, effectiveness and the underlying mechanisms of these formulas have not yet been clearly
China identified.
Reviewed by:
Yaolong Chen,
Objective: To evaluate the effectiveness of some common TCM formulas in treating
Lanzhou University, China patients with Bradyarrhythmia and to summarize the current evidence as to their
Junjie Xiao, mechanisms.
Shanghai University, China
*Correspondence: Data Sources: Relevant studies were identified by searching for papers published
Baoshan Liu from January 2000 to August 2017 in Pubmed; EMBASE; the Cochrane Library
[email protected]
(Cochrane Central Register of Controlled Trials); the China National Knowledge Internet;
Yanwei Xing
[email protected] and the China biology medicine, Wanfang, and VIP databases. The following medical
Hongcai Shang subject heading (MeSH) terms were included for Pubmed search and adapted for other
[email protected]
databases as needed-“Medicine, Chinese Traditional,” “Bradycardia.”
† Co-first author.
Study Selection: Randomized clinical trials investigating treatment outcomes in
Specialty section: Bradyarrhythmia patients with one of the six TCM formulas (Shenxian-shengmai oral
This article was submitted to liquid, Shensong Yangxin capsule, XinBao pill, Mahuang-Fuzi-Xixin decoction, Zhigancao
Ethnopharmacology,
a section of the journal
decoction and Shengmai injection).
Frontiers in Pharmacology Data Extraction and Synthesis: Two independent reviewers performed the data
Received: 29 December 2017 extraction and assessed study quality. A meta-analysis was performed to calculate risk
Accepted: 20 March 2018
Published: 09 April 2018 ratio (RR) and 95% confidence index (CI) using random-effects and fixed-effects model.
Citation: Results: A total of 121 clinical trials with 11138 patients were included. Of the six TCM
Liu S, Tian G, Chen J, Zhang X, Wu A,
formulas, SXSM (RR:1.33, 95% CI 1.27 to 1.39, P < 0.00001), SSYX (RR:1.52, 95% CI
Li M, Sun Y, Liu B, Xing Y and
Shang H (2018) Traditional Chinese 1.40 to 1.66, P < 0.00001), XB can be more effective than common treatment (RR 1.18,
Medicine for Bradyarrhythmia: 95% CI 1.11 to 1.26, P < 0.00001), as well as placebo (RR 5.33, 95% CI 2.88-9.87,
Evidence and Potential Mechanisms.
Front. Pharmacol. 9:324.
P < 0.00001), but less effective than TCM dialectical therapy (RR:0.75, 95% CI 0.68 to
doi: 10.3389/fphar.2018.00324 0.82, P < 0.00001). Compared to the control group, MFX (RR:1.30, 95%CI 1.23 to 1.37,

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

P < 0.00001), ZGC (RR:1.35, 95%CI 1.23 to 1.48, P < 0.00001), SMI (RR:1.36, 95%CI
1.21 to 1.52, P < 0.00001) can be more effective. The overall quality of the included trials
were relatively low, with the limitations of small sample size, inadequate descriptions in
randomization, allocation concealment and blinding methods.
Conclusions and Relevance: There are evidence that some TCM formulas might help
to relieve Bradyarrhythmias. But with the relatively low quality of the clinical trials and
mechanism studies, we still need more high-quality researches to verify the conclusions.

Keywords: Traditional Chinese Medicine, Bradyarrhythmia, evidence-based medicine, mechanisms, systematic

reviews and meta-analyses

INTRODUCTION parasympathetic nervous system, restraining myocardial collagen

hyperplasia and fibrosis, reducing inflammation and increasing
Bradyarrhythmias is a common arrhythmia encountered in antioxidant activity, regulating myocardial energy metabolism
clinical practice. Fatigability, reduced exercise capacity and and ion channels.
symptoms of heart failure (HF) are most familiar signs of the Nowadays, TCM is playing an important role in treating
persistent Bradyarrhythmia, along with some subtle symptoms Bradyarrhythmia. For ease of use, TCM decoction has been
such as irritability, lassitude, inability to concentrate, apathy, developed into a variety of dosage forms, such as capsule,
forgetfulness and dizziness. Dizziness, pre-syncope and syncope dropping pill, oral liquid and injection. What’s more, TCM is
are common symptoms with intermittent severe forms of increasingly welcomed in many developed countries, such as
Bradyarrhythmias and are due to a sudden decrease in cerebral Australia and the United States (Hao et al., 2017). Therefore, to
blood flow (Brignole et al., 2013). According to the survey evaluate the treatment effect and identify potential mechanisms
from Tresch, in the Baltimore Longitudinal Study of Aging, the of TCM formulas for Bradyarrhythmias, we searched six of the
prevalence of unexplained Sinus bradycardia was approximately most often used formulas (SXSM, SSYX, XB, MFX, ZGC, SMI)
4% and was nearly identical in men and women (Tresch and and gave this systematic review.
Fleg, 1986). With the development of technology, pacemaker
implantation is widely used in treating different kinds of
Bradyarrhythmias. In Dublin, the pacemaker implantation rate
was 0.6% (Keaney et al., 2013). However, with the constraints THE SEARCH FOR AND SELECTION OF
of unbalanced economy and technology, the use of pacemaker RCTS
implantation still cannot sufficiently meet the clinical needs
(Baman et al., 2010). As for the patients with abnormal low heart Data Sources and Searches
rate, accompanied with symptoms of palpitation, panting and Relevant studies were identified by searching for papers
fainting, or patients with pacemaker contraindications, there are published from January 2000 to August 2017 in Pubmed;
no safe and effective treatment from modern medicine so far. EMBASE; the Cochrane Library (Cochrane Central Register of
TCM has a long history of treating Bradyarrhythmia, Controlled Trials); the China National Knowledge Internet; and
which may start from as early as the Han Dynasty in the China biology medicine, Wanfang, and VIP databases.
China (about 2,000 years ago). A Chinese physician named The following medical subject heading (MeSH) terms
Zhang Zhongjing first gave the therapies for the symptoms were included for Pubmed search and adapted for other
the same as those of Bradyarrhythmia, which was recorded databases as needed- “Medicine, Chinese Traditional”,
in the TCM classics Treatise on Febrile and Miscellaneous “Bradycardia”; The search algorithm for MEDLINE was as
Diseases (Shang Han Lun in Chinese). Actually, there was no follows: (((((((Traditional Chinese Medicine[Title/Abstract])
specific term for Bradyarrhythmia at that time, the clinicians OR Chinese proprietary medicine[Title/Abstract]))
assigned it as palpitation or slow pulse. For the pathogenesis, OR “Medicine, Chinese Traditional”[Mesh])) OR
TCM physicians take it as stasis of blood because of Qi ((((((((shenxian shengmai[Title/Abstract]) OR ((mahuang fuzi
or Yang deficiency. Accordingly, TCM formulas are aiming xixin[Title/Abstract]) OR zhigancao [Title/Abstract])) OR xin
to reinforcing Qi and warming Yang. Based on modern bao pill[Title/Abstract]) OR shensongyangxin[Title/Abstract])))
pharmacological research, these formulas can be effective AND ((((((((((((Bradycardia[Title/Abstract]) OR Brugada
alleviating Bradyarrhythmia by regulating sympathetic and Syndrome[Title/Abstract]) OR Heart Block[Title/Abstract])
OR Long QT Syndrome[Title/Abstract]))). Similar but adapted
search terms were used for other databases of published reports
Abbreviations: HF, heart failure; HR, heart rate; MFX, Mahuang-Fuzi-Xixin or search engines. The reference lists of all retrieved papers were
decoction; RCT, randomized controlled trial; SMI, Shengmai injection; SB, sinus
bradycardia; SSS, sick sinus syndrome; SXSM, Shenxian-shengmai oral liquid;
checked for other potentially relevant citations, and studies not
SSYX, Shensong Yangxin capsule; TCM, traditional Chinese medicine; XB, XinBao included in the electronic sources mentioned previously were
pill; ZGC, Zhigancao decoction. searched manually.

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

Study Selection TCM FOR BRADYARRHYTHMIA EVIDENCE

We included reports of clinical studies with the following AND MECHANISMS
criteria: (1) Randomized clinical trials treating Bradyarrhythmia
using TCM formulas (SXSM, SSYX, XB, MFX, ZGC, SMI), Shenxian-Shengmai Oral Liquid
with no language limitation; (2) Studies reporting efficacy SXSM is prepared from 8 herbs, namely red ginseng, epimedium,
outcomes (healed, markedly effective, effective and ineffective). psoralen, medlar, ephedra, asarum, salvia, and leech (Table 1).
We excluded reports of studies with the following features: (1) It has been listed in the Chinese national directory of health
Two or more TCM formulas vs. conventional therapies; (2) insurance in 2017. Animal experiments showed that SXSM
Studies with flaws such as inappropriate design, incomplete or can increase heart rate by inhibiting heart parasympathetic
wrong results; (3) TCM formulas vs. cardiac pacemaker; (4) transmission based on the decreased CHRNA2 (encodes
Conference paper and academic dissertation; (5) Studies with nicotinic acetylcholine receptor) and increased ACE-1 (encodes
patients less than 20 per group. acetylcholinesterase). SXSM upregulated ATP2A1 and FKBP1B,
therefore, restored Ca2+ stores induced by restored expression of
SERCA2a and FKBP12.6 contributed directly to increased heart
Data Extraction and Quality Assessment rate. In addition, in ventricular myocardium, SXSM increased the
Two authors (SL, JC) reviewed the trials to ensure that they met supply of ATP by enhancing TCA cycle and oxidation-respiratory
inclusion criteria, abstracted the data and this was checked for chain. It also upregulated proteins ranged from enzymes of TCA
accuracy by the other authors. Disagreements were resolved by cycle to subunits of complex I and ATP synthase (Liu et al., 2017).
consensus-based discussion. We performed objective assessment Studies (Liu and Li, 2010; Tang et al., 2010; Guo, 2011; Li
of the trials using the methods specified in the Cochrane G, 2011; Li H, 2011; Ma, 2011; Hu J. et al., 2012; Jiang et al.,
Handbook of Systematic Reviews assessing for risks of bias 2012; Sun et al., 2012; Wang and Liu, 2012; Wu et al., 2012,
(selection bias, performance bias, detection bias, attrition bias, 2015; Yang et al., 2012; Ye, 2012; Hou et al., 2013; Li B, 2013;
reporting bias). Zhuo, 2013; Bai and Hou, 2014; Du, 2014; Ma and Dong, 2014;
The initial search yielded 766 records, 763 in Chinese and 3 in Zhang, 2014; Dong and Ma, 2015; Gao et al., 2015; Jia, 2015; Sun
English. After elimination of duplicate results, 268 articles with and Luo, 2015; Yang and Ren, 2015; Zhou, 2015; He, 2016; Liu
six formulas remained. Finally, 121 articles were reviewed and et al., 2016; Lu et al., 2016; Zhou et al., 2016; Liu H, 2017) of
assessed. There were 32 of SXSM, 36 of SSYX, 21 of XB, 18 of SXSM were included. Courses of the treatment ranged from 1
MFX, 8 of ZGC, 6 of SMI (Figure 1). to 8 weeks. There were 2330 patients involved, including 1,197
in SXSM group (1,091 effective cases) and 1,133 in control group
(780 effective cases). Meta-analyse was performed with a fixed-
Data Synthesis and Analysis effect model as no significant heterogeneity was found (I 2 <
Meta-analysis was performed according to the recommendations
50% , P > 0.1). It showed that SXSM was effective in treating
of Cochrane collaboration and in line with the PRISMA
Bradyarrhythmia (RR: 1.33, 95% CI 1.27 to 1.39, P < 0.00001)
statement (Liberati et al., 2009). To assess effective rate, “cured”
(Figure 3).
and “marked effective” cases are both seen as effective cases.
All these analyses were performed using the Cochrane RevMan
5.3 program. Pooled treatment effects were estimated using Shensong Yangxin Capsule
relative risk (RR) with 95% confidence interval (CI), calculated SSYX is prepared from 12 ingredients such as Panax ginseng,
by random-effects and fixed-effects model. Heterogeneity was dwarf lilyturf tuber, nardostachys root, etc. (Table 1). It was
assessed by chi-square tests and the I 2 statistic-we defined I 2 listed in the Chinese national directory of health insurance
< 50% to be low heterogeneity, referring to the Cochrane in 2009. Mass spectrometric and chromatographic detection
Handbook of Systematic Reviews. Publication bias was estimated identified major constituents including the saponins, phenolic
using funnel plots. acids, tanshinones, lignans, terpenoids, alkaloids, and flavonoids,
according to their chemical structures (Liu et al., 2015). Animal
experiments showed thatmRNA levels of TGF-β1, col-1, col-3,
Study Characteristics MMP-2, MMP-9 and α-SMA were downregulated, whereas
A total of 121 clinical trials with 11,138 patients were included. Smad7 expression was upregulated after treatment with SSYX
2,330 patients were from studies of SXSM, 4660 from SSYX, in rats with cardiac fibrosis (Shen et al., 2014).Meanwhile,
1700 from XB, 1398 from MFX, 651 from ZGC, 399 from SSYX can downregulated the level of ColI and ColIII, restrain
SMI (Table 1) (details of study characteristics were offered as Myocardial collagen proliferation (Dang et al., 2016). After
Supplementary Material). blockage of the autonomic nervous system with metoprolol
Most of the studies only referred randomized allocation and atropin, SSYX had no effect on intrinsic HR (IHR),
without specific randomization method. Only a few studies but decreased corrected sinus node recovery time (CSNRT)
mentioned blinding of participants or outcome assessors. Most and sinus atrium conducting time (SACT). In isolated
studies provided data of diagnostic standards and evaluation guinea pig ventricular myocytes, the most obvious effect
criterion (Figure 2). The time of publication of these 121 studies of SSYX on action potential was a shortening of the action
ranged from 2004 to 2017, 74 of which introduced the occurrence potential duration (APD) without change in shape of action
of side effects. potential.

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

FIGURE 1 | Flowchart of the included studies’ selection process.

Thirty-six studies (Sun and Liu, 2007; Liang, 2009; Ma, 2009; was made according to the types of Bradyarrhythmia. There were
Ge L., 2010; Ge Y., 2010; Jin et al., 2010; Ma and Zhu, 2010; 26 studies of Bradyarrhythmia, 8 studies of Bradyarrhythmia
Zeng et al., 2010; Zhang, 2010, 2016,a,b; Zhang et al., 2010, 2011; accompanied with premature beat, 2 studies of Bradyarrhythmia
Zhao, 2010; Ding et al., 2011; Zhao et al., 2011; Zhu, 2011, 2016; with atrial fibrillation. Subgroup analysis demonstrated that
Jia and Wang, 2012; Pan and Cui, 2012; Xia et al., 2012; Gou, differences between the 3 types of Bradyarrhythmia were not
2013; Li, 2013; Bao and Li, 2014; Liu et al., 2014,a,b; Wang D. obvious (I 2 = 56.3% , P = 0.10). And SSYX is effective in
et al., 2014; Wang W. et al., 2014; Wang X., 2014; Ding, 2016; treating any of the 3 types of Bradyarrhythmia (P < 0.05)
Li et al., 2016; Wang, 2016; Wu, 2016; Wu et al., 2016; Gao, (Figure 4).
2017; Lin, 2017) of SSYX were included. Courses of the treatment
ranged from 2 weeks to 6 months. There were 4,660 patients Xinbao Pill
involved, including 2,371 in SSYX group (2,016 effective cases) XB consists of flos daturae, cornu cervi, ginseng, radix aconiti
and 2,289 in control group (1,264 effective cases). Meta-analyse carmichaeli, etc. (Table 1). There were few basic research on
was performed with a randomized-effect model as heterogeneity this formula as a whole. The main active ingredient of flos
was found (I 2 > 50% , P < 0.10). Pooled result demonstrated daturae is atropine, whichis commonly used as an emergency
that SSYX treatment is more effective than control treatment medicine for improving heart rate (Gao et al., 2005). Cornu
(RR:1.52, 95% CI 1.40 to 1.66, P < 0.00001). Subgroup analysis cervi extract canactivate the pi3k-akt signaling pathway which

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

TABLE 1 | Components of formulas and mechanism of effect.

Name of formula Accepted name Main components Mechanism of effect References

Shenxian-shengmai Panax ginseng C.A.Mey. Ginsenosides, Ephedrine Regulate parasympathetic Liu et al., 2017
oral liquid (SXSM) Epimedium brevicornu Maxim. Hydrochloride, Psoralen, psoralen, nervous system
Cullen corylifolium (L.) Medik. icariin, protocatechuic aldehyde
Lycium barbarum L.
Ephedra sinica Stapf
Asarum sieboldii Miq.
Salvia miltiorrhiza Bunge
Whitmania pigra Whitman

Shensong Yangxin Panax ginseng C.A.Mey. saponins, phenolic acids, tanshinones, restrain Myocardial collagen Shen et al., 2014; Liu et al.,
Capsule (SSYX) Ophiopogon japonicus (Thunb.) Ker Gawl. lignans, terpenoids, alkaloids and proliferation and cardiac 2015; Dang et al., 2016
Cornus officinalis Siebold & Zucc. flavonoids, according to their chemical fibrosis
Salvia miltiorrhiza Bunge structures
Ziziphus jujuba Mill.
Taxillus sutchuenensis (Lecomte) Danser
Paeonia anomala subsp. veitchii (Lynch)
D.Y.Hong & K.Y.Pan
Eupolyphagasinensis Walker
Nardostachys jatamansi (D.Don) DC.
Coptis chinensis Franch.
Kadsura longipedunculata Finet &
Gagnep.;
OsDraconis

XinBao pill (XB) Datura metel L. atropine, scopolamine, Ginsenosides, M2 receptor antagonism Shen et al., 2014; Liu et al.,
Cervus nippon Total velvet-antler polypeptide, Aconite 2015; Dang et al., 2016
Panax ginseng C.A.Mey. normal butanol
Aconitum carmichaeli Debeaux
Cinnamomum cassia (L.) J.Presl
Panax notoginseng (Burkill) F.H.Chen
Abelmoschus moschatus Medik.
Venenum Bufonis
DryobalanopsaromaticaGwaertn.f.

Mahuang-Fuzi-Xixin Ephedra sinica Stapf methyl ephedrine, aconine, songrine, reducing inflammation and Tang et al., 2015; Sun et al.,
decoction (MFX) Aconitum carmichaeli Debeaux fuziline, neoline, talatisamine, increasing antioxidant 2016
Asarum sieboldii Miq. chasmanine, benzoylmesaconine, activities
benzoylaconine and benzoylhypaconine

Zhigancao decoction Glycyrrhiza uralensis Fisch. ex DC. uncertain It may be related to the Hai et al., 2017
(ZGC) Zingiber officinale Roscoe content of Ca2+ in muscle
Cinnamomum cassia (L.) J.Presl tissue or excitability of M
Panax ginseng C.A.Mey. receptor
Rehmannia glutinosa (Gaertn.) DC.
Asini Corii Colla
Ophiopogon japonicus (Thunb.) Ker Gawl.
Cannabis sativa L.
Ziziphus jujuba Mill.

Shengmai injection Panax ginseng C.A.Mey. ginsenosides, lignans, steroidal modulate the myocardial Wu et al., 2011; Zhan et al.,
(SMI) Ophiopogon japonicus (Thunb.) Ker Gawl. saponins and homoiso-flavanones energy metabolism 2015
Schisandra chinensis (Turcz.) Baill.

has important effects on the function of the heart (Zálesák may imply the advantage of TCM compatibility (Yang et al.,
et al., 2015; Zhang et al., 2016). As one of the main 2009).
components of ginseng, Ginsenoside Rg5 promotes Angiogenesis Twenty-one studies (Liu et al., 2009, 2014a; Chen et al., 2010,
and Vasorelaxation by Specific Activation of Insulin-like Growth 2016; Di and Zhang, 2010; Zheng, 2011; Li et al., 2012; Zhao,
Factor-1 Receptor. These findings revealed a mechanism for the 2012; Yu, 2013; Zhang, 2013, 2016a,b; Zhu, 2013; Li, 2014, 2016;
positive regulation of vascular function (Cho et al., 2015). What’s Zhu and Zhang, 2014; Siqingqimuge, 2015; Wei et al., 2015;
more, it was noted that Ginsenoside Rg2 can alleviate nervous Xia et al., 2015; Gao et al., 2016; Hu and Zhao, 2016; Zhang
system side effects caused by atropine in flos daturae, which and Li, 2016) of XB were included. Courses of the treatment

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

FIGURE 2 | Risk of bias graph (A) SXSM, (B) SSYX, (C) XB, (D) MFX, (E) ZGC, (F) SMI.

ranged from 1 weeks to 3 months. There were 1,700 patients and Asari Radix et Rhizoma (Asarum) (Table 1). Mass
involved, including 797 in XB group (644 effective cases) and spectrometric and chromatographic detection identified
903 in control group (699 effective cases). Subgroup analysis was 52 compounds, including alkaloids, amino acids and
performed as substantial heterogeneity was found (I 2 > 50% , P organic acids. The main constituents are methyl ephedrine,
< 0.10). It is divided into three subgroup based on the different aconine, songrine, fuziline, neoline, alatisamine, chasmanine,
treatments in control group. There were 12 studies comparing benzoylmesaconine, benzoylaconine, and benzoylhypaconine
XB with common treatment, 7 studies comparing XB with TCM (Sun et al., 2016). Experiments showed that MFX decoction
dialectical therapy, 2 studies comparing XB with placebo. The significantly depressed the expression of IL-6, MCP-1 and
results showed that differences between the 3 subgroups were TNF-α, and markedly increased expression of IL-10 in serum,
obvious (I 2 = 97.9% , P < 0.05) , indicating the source of indicating the effect of reducing inflammation and increasing
heterogeneity. While minimal or no heterogeneity was observed antioxidant activities (Tang et al., 2015; Rong et al., 2016). That
within three subgroups (Figure 5). implied how MFX decoction may affect Bradyarrhythmiaas
As a result, XB can be more effective than common treatment inflammation is related to myocardial injury which is one
(RR 1.18, 95% CI 1.11-1.26, P < 0.00001), as well as placebo (RR of the pathological basis of Bradyarrhythmia (Larsen et al.,
5.33, 95% CI 2.88-9.87, P < 0.00001), but less effective than TCM 2013).
dialectical therapy (RR:0.75, 95% CI 0.68-0.82, P < 0.00001) Studies (Ning, 2004; Fan and Yang, 2005; Geng et al., 2010;
(Figure 5). Zhang L, 2011; Bao, 2012; Cheng, 2012; Wei and Liu, 2012;
Deng et al., 2014; Fang et al., 2014; Wang Z, 2014; Xu and
Mahuang-Fuzi-Xixin Decoction Long, 2014; Ji and Zhang, 2015; Du, 2016; Hu and Huang, 2016;
MFX, a classical formula from Treatise on Febrile Diseases Huang and Zhang, 2016; Yu, 2016; Yuan, 2016; Li, 2017) of MFX
(Shang Han Lun in Chinese), is comprised of Ephedrae Herba were included. Courses of the treatment ranged from 2 weeks
(Ephedra), Aconiti Lateralis Radix Praeparata (Aconitum) to 3 months. There were 1398 patients involved, including 722

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

FIGURE 3 | SXSM for Bradyarrhythmia efficacy by meta-analysis.

in MFX group (656 effective cases) and 676 in control group which is a disease of opposite pathogenesis compared with
(472 effective cases). Meta-analyse was performed with a fixed- Bradyarrhythmia. There may exist a two-way regulation effect
effect model as no significant heterogeneity was found (I 2 < that requires further study.
50% , P > 0.10). It showed that MFX was effective in treating Eight studies (Hu, 2012; Qiu, 2012; Gao and Chen, 2014;
Bradyarrhythmia (RR:1.30, 95% CI 1.23 to 1.37, P < 0.00001) Cheng, 2016; Kong, 2016; Long, 2016; Wang X., 2016; Zhou and
(Figure 6). Yang, 2016) of ZGC were included. Courses of the treatment
ranged from 1 to 3 months. There were 651 patients involved,
Zhigancao Decoction including 326 in ZGC group (279 effective cases) and 325 in
ZGC also comes from Treatise on Febrile Diseases (Shang Han control group (206 effective cases). Meta-analyse was performed
Lun in Chinese). It is used as a representative formula to with a fixed-effect model as no significant heterogeneity was
treat almost any kind of arrhythmia containing nine commonly found (I 2 < 50% , P > 0.10). It showed that ZGC was effective
used herbs (Radix glycyrrhizae preparata, Ginger, Cassia in treating Bradyarrhythmia (RR:1.35, 95% CI 1.23 to 1.48, P <
Twig, Ginseng, dried rehmannia, Donkey-hide gelatin, Radix 0.00001) (Figure 7).
Ophiopogonis, Fructus Cannabis, Fructus Ziziphi Jujubae).
Recent studies showed that ZGC can effect the Ca2+ content Shengmai Injection
in muscle tissue and the excitability of M receptors (Hai et al., SMI was developed from a classic TCM formula, which
2017). It was reported that ZGC can also treat atrial fibrillation, is a combination of Panax ginseng, Ophiopogon japonicas

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

FIGURE 4 | SSYX for Bradyarrhythmia efficacy by meta-analysis.

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

FIGURE 5 | XB for Bradyarrhythmia efficacy by meta-analysis.

and Schisandra chinensis (Table 1). The constituents included accepted. In this article, we evaluated the effect of six of the
ginsenosides, lignans, steroidal saponins and homoisoflavanones most often reported TCM formulas for Bradyarrhythmia with
(Wu et al., 2011). Proteomics study found that SMI can systematic review method, and reviewed their different potential
up-regulate glucose oxidation, TCA cycle and ATP synthesis mechanisms as well as therapeutic features (Table 1).
related proteins, down-regulate proteins catalyzing fatty acid We also assessed the equality of the Chinese patent medicine
β-oxidation, implying the inhibition of this pathway to avoid used in studies. Thirty-two RCTs evaluated the effect of SXSM.
high oxygen consumption and modulate the myocardial energy As a listed Chinese patent drug with the China’s National
metabolism (Zhan et al., 2015). Registrated No. Z20080183 and detailed drug instruction
Six studies (Fang, 2005; Zhao and Wang, 2007; Li et al., 2008; (containing components, description, dosage, indications etc.
Wang et al., 2012; Zheng and Zhao, 2015; Wu, 2017) of SMI Figure 9A), SXSM is manufactured by a single company
were included. Courses of the treatment ranged from 14 to 20 (Buchang Pharmaceutical Corporation, Heze, China). Thirty-
days. There were 399 patients involved, including SMI in SMI six RCTs evaluated the effect of SSYX, (Shijiazhuang Yiling
group (176 effective cases) and 199 in control group (129 effective Pharmaceutical Co., Ltd.) produced the drug. SSYX is a listed
cases). Meta-analyse was performed with a fixed-effect model as Chinese patent drug with the China’s National Registrated No.
no significant heterogeneity was found (I 2 < 50% , P > 0.10). Z20103032 and detailed drug instruction (Figure 9B). XB was
It showed that SMI was effective in treating Bradyarrhythmia evaluated in 21 RCTs, 6 of which didn’t specify any information
(RR:1.36, 95%CI 1.21 to 1.52, P < 0.00001 (Figure 8). of manufacturer and product batch number (Di and Zhang,
Traditional Chinese medicine has a long history of treating 2010; Zhang, 2013; Zhu and Zhang, 2014; Wei et al., 2015; Hu
arrhythmia using different kinds of therapies. There are some and Zhao, 2016; Zhang and Li, 2016). Ten studies used XB
classic TCM formulas with constant compositions are widely produced by Guangdong Xinbao pharma-tech company (Liu

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

FIGURE 6 | MFX for Bradyarrhythmia efficacy by meta-analysis.

FIGURE 7 | ZGC for Bradyarrhythmia efficacy by meta-analysis.

et al., 2009; Chen et al., 2010; Li et al., 2012; Zhu, 2013; Li, company (Fang, 2005). The ingredients are basically the same in
2014, 2016; Siqingqimuge, 2015; Xia et al., 2015; Gao et al., 2016; both SMIs, but the dosages of injection are different (Figure 9D).
Zhang, 2016,a,b). Five studies used XB produced by Guangdong None of the studies described the details about drug chemical
Taiantang Pharmaceutical company (Zheng, 2011; Zhao, 2012; profile or preparation methods.
Yu, 2013; Liu et al., 2014,a,b; Chen et al., 2016). The ingredients
and dosage are basically the same in both XBs (Figure 9C). CONCLUSION
SMI was evaluated in 6 RCTs. Three studies didn’t provide
information of manufacturer and product batch number (Wang In conclusion, TCM formulas showed treatment effect on
et al., 2012; Zheng and Zhao, 2015; Wu, 2017). Two studies used Bradyarrhythmia while most of the included studies were in
SMI produced by Suzhong Yaoye group pharmaceutical limited low quality. There were a number of clinical trials, but most
company (Zhao and Wang, 2007; Li et al., 2008). One study of them had limitations on small sample size and inadequate
used SMI produced by China resources sanjiu pharmaceutical descriptions in randomization methods, allocation concealment

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

FIGURE 8 | SMI for Bradyarrhythmia efficacy by meta-analysis.

FIGURE 9 | Four included Chinese patent medicine and their drug instructions (A) SXSM. (B) SSYX. (C) XB. (D) SMI.

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Liu et al. Traditional Chinese Medicine for Bradyarrhythmia

and blinding methods. Among the six included TCM formulas, are still needed to evaluate the effectiveness and safety of TCM
SXSM, SSYX, XB, SMI were patent medicine which were formulas and innovative researches of mechanism are required
authenticated and standardized on marker compounds according as well.
to the Chinese Pharmacopeia. But the chemical compounds
of the same Chinese patent medicine may not be consistent AUTHOR CONTRIBUTIONS
when produced by different companies and in different batches.
XB and SMI were produced by more than one manufacturer, HS and SL defined the research theme. SL, GT, and JC designed
and some of the studies included didn’t specify information of the methods and analyzed the data. JC interpreted the results. SL,
manufacturer or product batch number. For herbal compound YX, and XZ wrote the manuscript, and contributed equally to this
decoctions like ZGC and MFX, the components among work. All authors discussed the results and commented on the
different studies were hard to keep consistent, which made it manuscript.
more important to report full information of the ingredients.
Apparently, the importance of components consistency was ACKNOWLEDGMENTS
ignored in most of the current clinical studies. It is highly
recommended to give full consideration of it and introduce This study was supported by grants from the Basic Research
the source of the species, origin, and concocted methods Foundation of Beijing University of Chinese Medicine (no.2016-
for each component. Moreover, high performance liquid JYB-JSMS-026) and the National Natural Science Foundation of
chromatography, high performance capillary electrophoresis, China (No. 81430098).
and gas chromatography should be applied to quantitate the
components. It would be helpful for further research and SUPPLEMENTARY MATERIAL
evaluation. On mechanism research, high quality literatures were
rare. A lot of efforts had been wasted on repetitious researches The Supplementary Material for this article can be found
of low level which cannot reveal the mechanism of TCM online at: https://www.frontiersin.org/articles/10.3389/fphar.
formulas. Therefore, high-quality clinical research and evidence 2018.00324/full#supplementary-material

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AN15103
Zhang, P., Li, D., and Wang, X. (2010). Analysis of the curative effect of Shen Conflict of Interest Statement: The authors declare that the research was
Song Yangxin Capsule in the treatment of sinus Bradycardia and ventricular conducted in the absence of any commercial or financial relationships that could
premature beat [in Chinese]. Chin. J. Misdiagn. 10, 6576–6577. be construed as a potential conflict of interest.
Zhang, Y. (2013). Clinical analysis of patients with chronic arrhythmia. Guide
China Med. 11, 214–215. doi: 10.3969/j.issn.1671-8194.2013.18.154 Copyright © 2018 Liu, Tian, Chen, Zhang, Wu, Li, Sun, Liu, Xing and Shang.
Zhang, Y. (2014). Clinical observation of Shen Xian Shengmai oral liquid in the This is an open-access article distributed under the terms of the Creative Commons
treatment of hypothyroid sinus Bradycardia [in Chinese]. Mod. Diagn. Treat. Attribution License (CC BY). The use, distribution or reproduction in other forums
25, 3732–3733. is permitted, provided the original author(s) and the copyright owner are credited
Zhang, Y. (2016a). Clinical observation of Xinbao Pill combined with and that the original publication in this journal is cited, in accordance with accepted
trimetazidine in treatment of chronic heart failure Induced by Coronary Heart academic practice. No use, distribution or reproduction is permitted which does not
Disease [in Chinese]. Hubei J. Tradit. Chin. Med. 38, 3–5. comply with these terms.

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