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].