A single-center randomized controlled trial observing the safety and efficacy of modified step-up graded Valsalva manoeuver in patients with vasovagal syncope
A single-center randomized controlled trial observing the safety and efficacy of modified step-up graded Valsalva manoeuver in patients with vasovagal syncope
Li He 0 1 2
Lan Wang 0 2
Lun Li 0 1 2
Xiaoyan Liu 0 1 2
Yijun Yu 0 1 2
Xiaoyun Zeng 0 2
Huanhuan Li 0 1 2
Ye Gu 0 1 2
0 Science Foundation of Hubei Province, China (Grant No. 2013CFB364) and the Foundation of Wuhan , Hubei Province, China, Grant No. WX15A07
1 Department of Cardiology, Puai Hospital, Huazhong University of Science and Technology , Wuhan, Hubei province, China , 2 Department of Neurology, Puai Hospital, Huazhong University of Science and Technology , Wuhan, Hubei province , China
2 Editor: Moshe Swissa, Kaplan Medical Center , ISRAEL
Non-pharmacological therapies, especially the physical maneuvers, are viewed as important and promising strategies for reducing syncope recurrences in vasovagal syncope (VVS) patients. We observed the efficacy of a modified Valsalva maneuver (MVM) in VVS patients. 72 VVS patients with syncope history and positive head-up tilt table testing (HUTT) results were randomly divided into conventional treatment group (NVM group, n = 36) and conventional treatment plus standard MVM for 30 days group (MVM group, n = 36). Incidence of recurrent syncope after 12 months (6.5% vs. 41.2%, P<0.01) and rate of positive HUTT after 30 days (9.7% vs.79.4%, P<0.01) were significantly lower in MVM group than in NVM group. HRV results showed that low frequency (LF), LF/ high frequency (HF), standard deviation of NN intervals (SDNN) and standard deviation of all 5-min average NN intervals (SDANN) values were significantly lower in the NVM and MVM groups than in the control group at baseline. After 30 days treatment, LF, LF/HF, SDNN, SDANN values were significantly higher compared to baseline in MVM group. Results of Cox proportional hazard model showed that higher SDNN and SDANN values at 30 days after intervention were protective factors, while positive HUTT at 30 days after intervention was risk factor for recurrent syncope. Our results indicate that 30 days MVM intervention could effectively reduce the incidence of recurrent syncope up to 12 months in VVS patients, possibly through improving sympathetic function of VVS patients.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Competing interests: The authors have declared
that no competing interests exist.
Vasovagal syncope (VVS) is a clinical syndrome resulting from systemic hypotension due to
transient global cerebral hypoperfusion, and characterized by rapid onset, short duration and
spontaneous complete recovery [
]. There are three types of VVS: vasodepressor syncope,
cardio-inhibitory syncope and mixed syncope. Although not directly responsible for increased
mortality, VVS could have a tremendous deleterious impact on the daily quality of life of
patients in terms of physical symptoms and injury as well as psychological impact from living
in fear of the next syncopal episode [2±4].
Therapeutic options for VVS remain challenging and far from optimal now [5±7].
Nowadays, following strategies were attempted to reduce syncope recurrences in VVS patients with
variable efficacies: 1) physical techniques to improve orthostatic tolerance; 2) pharmacologic
interventions to prevent depletion of intravascular volume and/or enhance arterial and venous
tone; 3) cardiac pacing to avert bradycardia [
]; and 4) anatomically guided endocardial
catheter ablation of ganglionated plexi in left atrium . Among above mentioned therapy options,
non-pharmacological therapies, especially the physical maneuvers, are viewed as important and
promising strategies for reducing the syncope recurrences [
]. In a previous study, Krediet and
colleagues demonstrated beneficial effects of leg crossing and muscle tensing in VVS patients
]. Brignole et al. also reported a comparable effect of isometric arm counterpressure
maneuvers to abort impending VVS [
]. In another study, van Dijk et al. showed that physical
counterpressure maneuvers were effective in preventing vasovagal syncope [
Head-up tilt testing (HUTT) is a usual medical procedure to diagnose VVS and to define
potential causes of syncope. Previous report showed that Valsalva maneuver (VM) could
induce syncope in volunteer subjects [
], and the abrupt reduction in mean arterial blood
pressure and subsequent reduction of cerebral perfusion during phase III of VM might be
responsible for VM-induced syncope [
]. Based on these reports, we once asked patients with
suspected syncope to perform the classic VM for several times at the beginning and during
HUTT in an attempt to increase the positive rate of HUTT in these patients. To our surprise,
post VM, the HUTT result became negative in 4 out of 8 patients with previous positive
HUTT results. This finding encouraged us to test if VM could have therapeutic effects in
syncope patients, and two aged (>65 years) hospitalized male patients with recurrent in-hospital
syncope was instructed to perform the classical VM 2 times per day for 5 days under
supervision of medical staffs, no syncope occurred during the subsequent hospital stay and these two
patients were discharged after 1 week and were asked to perform the VM once daily for 30
days at home, syncope did not occur thereafter. In spired by above observations and we started
a literature search to find out if there was a potential link between VM and VVS [
Quantified the individual roles of the cardiovascular system and the autonomic nervous system
(ANS) in the hemodynamic regulations during the VM and found that hemodynamic
responses to the VM were not only determined by the ANS-mediated cardiovascular regulations,
but also significantly affected by the postural-change-induced hemodynamic alterations
preceding the VM. We therefore assumed that the beneficial effects of VM observed in above
circumferences might be related to the modulating role of VM on autonomic nervous function of
VVS patients and we therefore designed present study to test if VM could be an eligible
therapeutic option for VVS patients and observed the autonomic nervous function change post VM
in VVS patients. To reduce the likelihood of inducing syncope by classical VM, a modified
step-up graded VM (MVM) was proposed and patients were trained to perform the MVM in
two phases: accommodation phase ( 10 days) and 30 days standard therapy phase with fixed
time and strength schedule. Incidences of positive HUTT and recurrent syncope were
compared in VVS patients with or without MVM intervention.
Materials and methods
Adult (aged between 18 to 80 years old) patients with recurrent VVS and recognizable
prodromal symptoms were eligible for inclusion in our hospital. The diagnosis of VVS was based on
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the definition of the European Society of Cardiology guidelines [
]. Briefly, the diagnosis was
considered certain with a typical history with episodes triggered by prolonged upright
position, pain, or emotional events and accompanied by lightheadedness, sweating, pallor, and/or
nausea/vomiting. Presyncope was defined as near loss of consciousness. From October 2012
through May 2015, we recruited patients with at least three lifetime syncopal spells associated
with positive HUTT, and 1 syncope recurrence within 2 weeks and follow-up for one year
after 30 days treatment. Patients with other causes of syncope, such as cardiac, cerebral,
pulmonary, and metabolic diseases, were excluded by medical history, 12-lead ECG, skull CT
scanning, chest x-ray, echocardiography and routine laboratory tests. Patients suffered from
serious liver and renal diseases as well as moderate and severe anemia were excluded from this
study (Biochemical parameters were listed in Table 1). Finally, 72 consecutive patients with
recurrent VVS and positive HUTT test were recruited and randomly divided into MVM and
NVM groups by biased coin design randomization method[
] (n = 36 each. We planned to
recruit 30 for each group in our trial protocol. During the trial period, we recruited 36 patients
for each group to ensure the required statistical power in case of loss of patients). (Fig 1).
Conventional therapy included: 1) patient education for the pathophysiology and the benign
nature of VVS and the importance of taking enough dietary salt and fluid in daily life; 2)
avoiding medications which might precede VVS, like diuretics, and vasodilators. Thirty age and
gender matched healthy volunteers were enrolled as normal controls. Twenty-four-hour
Holter monitoring was performed before HUTT test and after 30 days standard MVM or NVM
treatment. All patients gave informed consent for participation in this study, and written
consent was obtained from each participating patient. The study protocol was approved by the
ethical committees of Puai Hospital, Huazhong University of Science and Technology,
Wuhan, China. The study was registered in the Chinese Clinical Trial Register (http://www.
chictr.org.cn, registration number: ChiCTR-TRC-12002514) in September 12, 2012.
Twenty-four-hour Holter monitoring and HRV analysis
All recordings were performed with 24-hour Holter monitoring (GE Seer Light recording
box and MARS Software) before HUTT at baseline and after 30 days in all participants. NN
intervals was RR intervals in sinus rhythm and average NN intervals was the mean value of RR
intervals in sinus rhythm. Quantitative heart rate variability (HRV) analysis was performed
according to the guidelines of the European Society of Cardiology and the North American
Society of Pacing and Electrophysiology [
]. HRV parameters were calculated in the time
domain and frequency domain. Time domain related parameters included: standard deviation
of NN intervals (SDNN), standard deviation of all 5-min average NN intervals (SDANN),
square root of mean of the sum of squares of successive NN interval differences (rMSSD),
number of successive NN interval differing by >50ms divided by the total number of
successive NN intervals (pNN50). Frequency domain related parameters included: low frequency
(LF) at frequency between 0.04±0.15 Hz, high frequency (HF) at frequency between 0.15±0.40
Hz, and the low frequency/high frequency ratio (LF/HF) [
Conventional HUTT was performed at baseline and after 30 days in all VVS patients.
Electrocardiogram and systolic and diastolic blood pressure were continuously monitored and
recorded. The patients were placed in the supine position for 10 minutes to obtain baseline
ECG and blood pressure recordings. Patients were tilted to a 70Ê angle for 20 minutes. If
syncope did not occur after 20 minutes, 300 mg nitroglycerin was administered sublingually, and
the test was continued for another 15 minutes. If positive response occurred, HUTT was
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NVM: patients treated with conventional therapy; MVM: patients treated with conventional therapy plus MVM for 30 days group; GPT: glutamate pyruvate
transaminase; GOT: glutamic oxaloacetic transaminase; Cr: creatinine; Glu: glucose; Hb: hemoglobin; CCB: calcium channel blockers; BB: β-blocker; ACEI/ARB:
angiotensin-converting enzyme inhibitors/angiotensin receptor blocker
terminated immediately. HUTT would be deemed to be positive if syncope or presyncope
occurred in association with hypotension (systolic pressure 80 mm Hg, diastolic pressure
50 mm Hg, or mean arterial pressure decrease 25%), and/or cardiac arrhythmia including
sinus bradycardia 40 bpm, repetitive sinoatrial block or sinus pause >3 seconds, or Mobitz
II 2nd or 3rd degree atrioventricular block.
Rational for the modification of the VM and detailed procedures of the MVM.
Previous report indicated that classic VM might induce syncope due to reduced venous return and
decline in systolic blood pressure [
]. To reduce the likelihood of inducing syncope by VM,
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Fig 1. Diagram of patient flow. Consolidated reporting standard for trials diagram of patient flow.
we designed a MVM procedure to increase the toleration of VM without increasing the
potential risk of syncope for VVS patients, VM was graded by expiration strength (mm Hg) and
breath-hold time (second). Expiration strength was divided into 3 grades (Grade A = 20 mm
Hg, Grade B = 30 mm Hg and Grade C = 40 mm Hg) and breath-hold time was divided into 2
lengths (1 = 8 seconds, 2 = 15 seconds) (Fig 2). Expiration strength was controlled by blowing
into a tube connected to sphygmomanometer.
In detail, MVM included three steps: 1. determine the threshold VM level; 2.
accommodation phase: step-up graded VM began with tolerated level of VM till reaching the level C2 (Fig
2); 3. standardized modified VM therapy phase with fixed time and strength schedule (15 VMs
at C2 level/day for 30 days).
Threshold of tolerated level of VM determination. To determine the tolerated level of
VM of individual patient assigned to MVM group, patients were asked to perform VM in the
order of A1, A2, B1, B2, C1 and C2 level. The VM level, which could be well tolerated without
significant blood pressure and heart rate changes, was defined as threshold VM level for each
a. During the accommodation phase, the maneuvers were performed in 2 sessions every day
(one in the morning and one in the afternoon, morning session consisted 8 VM and
afternoon session consisted 7 VM) under the supervision of research staff, beginning with one
level lower than the previously determined threshold VM level.
b. Patients were asked to perform VM at one level higher in case of tolerating the current level
for two times till reaching the C2 level.
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Fig 2. VM threshold level. Detailed procedures of the MVM for expiration strength grades and breath-hold time.
c. This accommodation period should be finished within 10 days and patients who did not
reach the C2 level within 10 days were excluded from the study.
Standardized MVM therapy phase. This phase is defined as the application of 15 MV at
C2 level daily for 30 days. MVM at this stage could be performed at outpatient department or
at patient's home or office and patients were asked to fill the MVM record sheet.
Follow-up. All Patients were followed up 12 months by phone call or home/clinic visit.
The main endpoint was recurrent syncope.
Continuous variables were presented as mean ± standard deviation (SD). Normal distribution
of continuous variables was performed using Kolmogorov-Smirnov test. The homogeneity of
variance test was performed by Levene test. Continuous data with normal distribution were
assessed by Student's t-test or one-way ANOVA with Post Hoc test (Bonferroni) as indicated.
Non-normal distribution data were tested by two-tailed Mann±Whitney U test or
Kruskal-Wallis non-parametric test as indicated. The Chi-square test was used to compare the ratio or
percentages of categorical variables. The rates of recurrent syncope of NVM and MVM groups
were compared by log rank test of Kaplan-Meier curve. The relationship between HUTT, HRV
and recurrent syncope in VVS patients was assessed by Cox proportional hazards model.
Univariable Cox regression analysis was performed for all clinical parameters and HRV parameters
after 30 days treatments and variables with P values of <0.1 were included in multivariable Cox
regression models. The choice of confounders was based on following considerations: age and
gender belonged to the basic parameters which should be adjusted and HRV could be
significantly affected by beta-blockers. Receiver operating characteristic (ROC) curves of HRV values
were used to predict the recurrent syncope. The cutoff values of HRV were derived from ROC
curve analysis by maximizing the sum of the sensitivity and specificity. All statistical analyses
were performed with SPSS version 22.0. P<0.05 was considered statistically significant.
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Baseline characteristics of the participants
Baseline characteristics of participants are shown in Table 1. Age, gender, heart rate and blood
pressure were similar among three groups. Frequency, duration of syncope, syncope-induced
trauma, syncope type as well as disease history and current medications were also similar
between patients in MVM and NVM groups. Glutamate pyruvate transaminase (GPT),
glutamic oxaloacetic transaminase (GOT), creatinine (Cr), blood glucose (Glu) and hemoglobin
(Hb) levels were similar among three groups.
VM threshold level
After the accommodation phase, 4 patients in MVM group were excluded from the study
since they developed symptoms and signs of syncope at VM level below C2 (1 at B1 level, 2 at
B2 level and 1 at C1 level). One patient in MVM group and 2 patients in NVM group lost to
follow-up and 31 patients in MVM group and 34 patients in NVM group were finally
Positive rate of HUTT after 30 days treatment
HUTT was positive in all VVS patients at baseline. The percentage of positive conventional
HUTT and provocative (nitroglycerin) HUTT was 9.7% and 90.3%, 8.8% and 91.2%
respectively in MVM and NVM group at baseline. After 30 days treatment, the positive rate of
HUTT was 9.7% in MVM group and 79.4% in NVM group (P<0.01, Fig 3A).
There were 2 patients with recurrent syncope in MVM group and 14 patients with recurrent
syncope in NVM group during 12 months follow-up. There were only 2 vasodepressor
syncope patients with recurrent syncope, and no cardio-inhibitory and mixed syncope patient
with recurrent syncope in MVM group. There were 5 vasodepressor syncope patients and 9
mixed syncope patients with recurrent syncope, and no cardio-inhibitory syncope with
recurrent syncope in NVM group during 12 months follow-up. Recurrent syncope of vasodepressor
syncope was similar between MVM and NVM groups. Recurrent syncope of mix syncope was
significantly reduced in MVM group compared to NVM group. During the follow-up period
after therapy, syncope recurrence rate was 0% and 5.9% in the MVM and NVM group at one
month, 0% and 23.6% at 3 months, 3.2% and 29.5% at 6 months and 6.5% and 41.2% at the 12
months. Kaplan-Meier curves suggested that the incidence of rate of recurrent syncope was
Fig 3. Positive rate of HUTT and the incidence of recurrent syncope in NVM and MVM group. (A) positive rate of HUTT at
baseline and after 30 days treatment in NMV and MVM groups, (B) The Kaplan-Meier curves for recurrent syncope rates during
12 months follow-up in NMV and MVM groups. P<0.01.
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significantly lower in the MVM group than in the NVM group (log rank test, P = 0.001, Fig
Relationship between HUTT at 30 days after intervention and incidence of recurrent
syncope. All VVS patients were divided into HUTT negative group and HUTT positive
group according to the HUTT results at 30 days post NVM and MVM intervention. There
were 35 patients in HUTT negative group and 1 patient developed recurrent syncope during
12 months follow-up, and 30 patients in HUTT positive group and 15 patient developed
recurrent syncope during 12 months follow-up. Kaplan-Meier curves suggested that the incidence
of rate of recurrent syncope was significantly higher in the HUTT positive group than in the
negative HUTT group (log rank test, P = 0.000, Fig 4). Results of Cox proportional Hazard
model showed that positive HUTT at 30 days after intervention was a significant risk factor for
recurrent syncope (HR = 22.38, 95%CI 2.95±169.85, P = 0.003, and the adjusted HR = 24.01,
95%CI 3.09±186.59, P = 0.002 after adjustment with gender, age and beta-blockers Table 2).
Relationship between HRV at 30 days after intervention and incidence of recurrent
syncope. LF, LF/HF, SDNN and SDANN values were significantly lower in the NVM and MVM
groups than in the control group at baseline. Average NN intervals, HF, rMSSD and pNN50
values were similar among the three groups at baseline and after 30 days treatment. LF and LF/
HF values were significantly higher in MVM group than in NVM group after 30 days
treatment. LF and LF/HF values were similar between MVM group and CON group after 30 days
treatment. LF, LF/HF, SDNN and SDANN values were significantly higher compared to
baseline in MVM group (Fig 5).
Results of Cox proportional hazard model showed that higher SDNN and SDANN values,
but not LF/HF ratio at 30 days after intervention, before and after adjusting for gender, age
and beta-blockers, were protective factors for syncope recurrence (SDNN: HR = 0.974, 95%CI
0.951±0.997, P = 0.029; SDANN: HR = 0.966, 95%CI 0.939±0.993, P = 0.014; SDNN: adjusted
HR = 0.966, 95%CI 0.937±0.996, P = 0.025; SDANN: adjusted HR = 0.950, 95%CI 0.915±0.986,
P = 0.007, Table 2). The ROC curve analysis showed that the sensitivity and specificity for
predicting no recurrent syncope were 53.1% and 81.2%, respectively, with a SDNN cutoff value
129 at 30 days after intervention, and the area under the curve was 0.690 (95%CI 0.549±
0.831, P = 0.023 Fig 6A), and the sensitivity and specificity were 65.3% and 68.7%, respectively,
with a SDANN cutoff value 103.5, and the area under the curve was 0.709 (95%CI 0.561±
0.856, P = 0.013 Fig 6B)
Fig 4. HUTT and the incidence of recurrent syncope in all VVS patients. The Kaplan-Meier curves for recurrent
syncope rates during 12 months follow-up of patients from HUTT positive and HUTT negative groups.
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Present study showed that the MVM intervention for 30 days is safe, feasible and effective to
treat patients with VVS and MVM significantly reduced the positive rate of HUTT and
Fig 5. HRV analysis. HRV analysis of CON, NVM and MVM groups at baseline and after 30 days treatment. P<0.05;
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Fig 6. ROC curve of SDNN and SDANN. (A) ROC curve of SDNN after 30 days treatment, (B) ROC curve of SDANN after 30 days treatment.
recurrence rate of syncope. Moreover, LF, LF/HF, SDNN and SDANN values were all reduced
in syncope patients compared to control subjects at baseline. HRV analysis showed that LF,
LF/HF, SDNN and SDANN were significantly increased in patients allocated to MVM
compared to baseline. Results of Cox proportional hazard model showed that higher SDNN and
SDANN values at 30 days post intervention were protective factors, while positive HUTT was
a risk factor for recurrent syncope. Autonomic nervous function is assumed to be normal
during the non-syncope period of VVS patients [
]. However, our study results indicated that
there was an abnormally increased sympathetic activity during the non-syncopal period of
VVS patients. MVM could improve sympathetic function, which might be one potential
mechanism responsible for the beneficial effects of MVM in VVS patients, especially for mix
syncope patients. To our best knowledge, this is the first report on the efficacy and potential
mechanism of MVM in VVS patients.
Effects and compliance of modified VM in VVS patients
Till now, the therapy option for VVS is far away from optimal. Recently, several studies
demonstrated satisfactory therapeutic results of physical training in VVS patients [10±12]. In our
study, patients with recurrent VVS and positive HUTT test were recruited and randomly
divided into MVM and NVM groups (Fig 1). Present study reported exciting short-term and
long-term effectiveness of the MVM for VVS patients to reduce the positive rate of HUTT and
recurrence rate of syncope. (Fig 3). Although repeated HUTT was not recommended to assess
the therapeutic effects of various strategies in VVS patients [
], our results suggested positive
HUTT was related significantly higher risk for recurrent syncope, indicating the value of
repeated HUTT for predicting therapy efficacy in selected patients (Fig 4). Our study also
demonstrated that recurrent syncope of mix syncope was significantly reduced in MVM group
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compared to NVM group during 12 months follow-up, which implied that mix syncope would
benefit most from MVM treatment. Our results showed that MVM practiced in this study
setting was safe, inexpensive and easy to perform, well tolerated and associated with good
compliance (except one patient lost to follow up in MVM group, none of the rest patients in
MVM group discontinued the MVM and none of the VVS patients in MVM group
experienced syncope during the 30 days standard MVM intervention), therefore, MVM might serve
as a feasible and effective therapeutic alternative option for VVS patients. Moreover, after the
accommodation phase, which was performed under the supervision of medical staffs, this
MVM was safely practiced by patients themselves at outpatient clinics, home or office during
the standardized MVM phase. Above points might be responsible for the good compliance of
MVM observed in this VVS patient cohort.
Methodological viewpoint of the MVM
In our experience, the step-up procedure, in that the classic VM was divided into A1 to C2
levels (6 sub-levels, Fig 2), and patients were trained to increase the expiration strength and length
of VM from A1 to C2 under the supervision of medical staffs during the around 10 days
accommodation phase, then perform 15 MVM daily for another 30 days at C2 level, serves as
the key points responsible for the satisfactory compliance and safety of MVM in this VVS
patient cohort. In fact, except the unknown situation of the one lost to follow up patient, no
patient experienced syncope during the MVM procedure. It is known that classical VM might
ªproceedº rather than treat VVS. In fact, the ªbegin low and go slowº principle applied in the
present MVM works well in studied VVS patients, the gradually increased expiration strength
and length of VM might therefore be crucial to avoid the unwanted impact of classical VM on
hemodynamic and ANS in VVS patients.
Potential mechanism of MVM on VVS
Although we observed satisfactory effects of MVM in studied VVS patients, the underlying
mechanisms is not fully clear now and could not be proved with certain by present study,
as fairly pointed out by Coffin et al [
]. VVS is now recognized as a disease related with
autonomous neural disorder [
], and HRV is a commonly used method to evaluate the
autonomic nervous function nowadays [
]. The mechanisms of VVS episode is characterized by
increased cardiovagal tone and reduced peripheral sympathetic activity [
nervous function is assumed to be normal during the non-syncope period of VVS patients [
Present results (Fig 5) found that HF, rMSSD and pNN50 (parameters reflecting the
parasympathetic activities) were similar among control and syncope patients, suggesting the
parasympathetic function was normal during the non-syncopal period of VVS patients. However,
SDNN (reflecting total sympathetic and parasympathetic activity), LF (reflecting combined
action of sympathetic and parasympathetic activity), LF/HF (reflecting the balance of
sympathetic and parasympathetic function) and SDANN (reflecting sympathetic function) were all
reduced in syncope patients compared to control subjects, indicating abnormally increased
sympathetic activity in VVS patients during the non-syncopal period. LF and LF/HF values
were similar between MVM group and CON group after 30 days treatment, indicating
sympathetic activity returned to normal after 30 days MVM therapy. Previous studies showed that
HRV results could be significantly affected by beta-blockers [
], our results showed that
SDNN and SDANN values at 30 days post intervention were increased in VVS patients
allocated to MVM group and results of Cox proportional hazard model indicated that higher
SDNN and SDANN values at 30 days post intervention are protective factors for recurrent
syncope, before and after adjusting for gender, age and beta-blockers use. Therefore, the
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difference in SDNN and SDANN values between VVS patients with NVM and MVM groups
were unlikely induced by beta-blockers. SDNN 129 at 30 days post intervention was related
to less syncope up to 12 months (Fig 6). Thus, our results might hint, to some extent, that the
observed efficacy of MVM might at least partly be associated with the impact of MVM on
autonomous nervous tone, in favor of improved sympathetic function, in VVS patients.
Clearly, future studies comparing the effects of previously reported physical training [10±12]
and present MVM in VVS patients and studies aiming to exploring the underlying working
mechanisms of MVM are warranted.
Firstly, this is a single-center study with a small patient cohort. Studies with larger patient
cohort are needed to validate the results of present study. Secondly, Holter monitoring and
HRV analysis were not performed at 12 months after treatment to observe autonomic nervous
function in VVS patients. Thirdly, the underlying working mechanisms of MVM in VVS
remain largely unknown now and need to be explored in future studies.
Our study results suggest that MVM therapy strategy is safe and associated with satisfactory
short- and long-term effects in this VVS patient cohort. Our results further hint a role of
improved sympathetic function in VVS post MVM. Future multi-center studies are warranted
to validate results shown in the present study.
S1 CONSORT Checklist. CONSORT checklist.
S1 Table. Raw data of baseline characteristics. Raw data of all baseline characteristics for
each patient in three groups.
S2 Table. Raw data of HUTT. The raw data of HUTT for each patient in NVM and MVM
groups at baseline and after 30 days treatment.
S3 Table. Raw data of recurrent syncope incidence. The raw data of recurrent syncope
incidence for each patient in NVM and MVM groups during 12 months follow-up.
S4 Table. Raw data of HRV. HRV raw data of each patient in three groups at baseline and
after 30 days treatment.
S1 Clinical Trial Protocol. Clinical trial protocol in Chinese.
S2 Clinical Trial Protocol. Clinical trial protocol in English.
S1 Ethics Committee Approval Document. Ethics committee approval document in
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S2 Ethics Committee Approval Document. Ethics committee approval document in
No other persons have made substantial contributions to the manuscript.
Data curation: Li He.
Formal analysis: Lan Wang.
Investigation: Lun Li, Xiaoyun Zeng.
Project administration: Ye Gu.
Resources: Xiaoyan Liu.
Software: Yijun Yu.
Writing ± original draft: Huanhuan Li.
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