4. Discussion
The
results of this study suggest that a combination of TET and HUTT is more
sensitive for detecting VVS than HUTT alone. Additionally, the
combination of TET and HUTT can help rule out cardiogenic syncope and
exercise-associated serious arrhythmias. Furthermore, patients with a
positive test can recover spontaneously after lying down without
anticholinergic therapy. Thus, the combination TET and HUTT is a
sensitive and safe method for diagnosing VVS, and thus is worthy of
clinical application.
VVS is a common disease of the autonomic nervous system, and can
markedly decrease quality of life. VVS is triggered by increased
adrenergic tone, which can occur due to pain, emotional distress,
urination, and prolonged standing [12]. A loss of balance between
the sympathetic and parasympathetic nerves causes a decrease of
peripheral vascular resistance and inhibition of the heart [13]. The
aim of provocative tests is to reproduce syncope or presyncope through
stimulating the sympathetic nerves. The HUTT is a common test used to
diagnose VVS, and is recommended by guidelines [14]. However,
positive NHUT results range from 51% to 61.8% [15-17].
Exercise-induced VVS has been reported frequently [18]. The
mechanism of exercise-induced VSS includes a parasympathetic reflex to
catecholamine release and hypotension due to post-exercise peripheral
vasodilation and decreased venous return. In one study, 3.1% of all
asymptomatic volunteers were found to be hypotensive after exercise
[19]. In another study, 22% syncope events occurred after exercise
[20]. VVS can be provoked by increased sympathetic nerve
stimulation, such as during strenuous exercise, and TET-induced VVS has
been reported in normal heart patients [21]. The modified treadmill
test has been reported to be a useful tool to diagnosis exercise-related
syncope [22]. Therefore, based on the aforementioned findings we
hypothesized that a combination of the TET and HUTT can improve the
sensitivity of diagnosing VVS.
The results of this study showed that a greater number of younger
patients had positive response to TET combined with HUTT than HUTT
alone. A study showed that the incidence of hypotension after exercise
was 3.1% in healthy subjects < 55 years old, but only 0.3%
in those older than 55 years [19]. In our study, patients with
positive test results had a greater maximal predictive heart rate,
maximal heart rate, and percent of maximal predictive heart rate as
compared to those with negative results. This suggests that greater
excitability of the sympathetic nervous system is associated with a
higher rate of VSS.
In current study, we used the treadmill test to stress the
cardiovascular system to a maximal age-predicted heart rate in order to
increase the sensitivity of diagnosing syncope. The mean exercise
tolerance is 13.15 ± 1.66 metabolic equivalents (METS). Reasons to stop
the TET are fatigue or reaching the maximal predicted heart rate. Then
test is then stopped when the goal is reached. The combination of TET
with HUTT had a markedly high sensitivity of 94.7% for diagnosing VVS.
On the other hand, the TET can detect coronary artery disease and
arrhythmias, and thus exclude cardiogenic syncope. Doi et al. raised the
concept that the TET is a useful diagnostic tool to detect
exercise-related VVS, but is not useful for exercise-unrelated VVS
[22]. The sensitivity and specificity for detecting exercise-related
VVS are 78% and 95%, respectively. However, the sensitivity for
detecting exercise-unrelated VVS is only 19%. The sensitivity of HUTT
is 84%m so we combined TET with HUTT to resolve the problem of the low
sensitivity for diagnosing exercise-unrelated VVS. In our study, only 3
patients developed syncope during the BHUT. Sublingual nitroglycerin was
administered for the NHUT, as described by Raviels et al. [16], and
sublingual nitroglycerin is more convenient and practical than
isoproterenol. Nitroglycerin enhances venous pooling and stimulates
adrenalin secretion, and thus results in a higher positive provocation
rate [23]. The sensitivity of HUTT, including BHUT and NHUT, was
46.5%. Combined with TET, however, the sensitivity was increased to
94.7%. Taken together, these results indicate that TET combined with
HUTT is a safe and simple way to diagnose VVS, and is well-tolerated by
patients.
Both the HUTT and the TET are imperfect tools with no gold-standard.
Based on the European Society of Cardiology guidelines for the use of
diagnostic questionnaires for diagnosing syncope, we used the Calgary
syncope symptom score as the reference standard in this study. The
sensitivity and specificity of the Calgary score are good for diagnosis,
but the specificity is lower when the history is undefined.
An important part of the TET is that patients must cease to exercise
when they reach their maximal predicted heart rate or fatigue occurs. We
monitored blood pressure and ECG results during the exercise and
recovery periods, and our data showed that all of the patients
demonstrated presyncope or syncope during the first 0-3 min of the
recovery period, but not during the exercise period. To our best
knowledge, this is the first study to examine using the TET combined
with the HUTT for diagnosing VVS. The combined testing should be
administered by a doctor and a nurse who were capable of managing
syncope and complications, and cardiopulmonary resuscitation equipment
should be immediately available [21].