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Methods
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Discussion
Conclusions
Author contributions
Disclosures and funding sources
Conflicts of interest
Introduction Head-up tilt (HUT) testing has become a widely accepted diagnostic tool for the evaluation of neurally mediated syncope (NMS), which is a major cause of unexplained syncope [1–4]. However, a drug-free HUT test has a low diagnostic yield. HUT testing using isoproterenol (ISP) and isosorbide dinitrate (ISDN) has higher diagnostic yields than drug-free HUT testing but requires more time. ISP HUT testing requires continuous infusion of ISP and titration to heart rate before HUT testing. However, this protocol is hampered by suboptimal specificity [5]. In addition, ISDN has been the most popular provocation agent for HUT testing. A common protocol of ISDN HUT testing consists of a 15-min HUT test after administration of ISDN. However, there is some discrepancy within the literature regarding the specificity of the ISDN HUT test [6–12]. The administration of exogenous adenosine triphosphate has various effects such as a vasodilatory effect, a depressive effect of resazurin activity, and a sympathoexcitatory effect via baroreflex and peripheral chemoreceptor activation. Adenosine has been proposed to be an endogenous modulator of NMS [13]. Recently, it has been reported that adenosine is useful in eliciting NMS [13,14]. The purpose of this study was to investigate the clinical usefulness of adenosine compared to ISP and ISDN during HUT testing in a Japanese population.
Materials and methods
Results
Discussion The principal finding of this study is that adenosine is a safe and effective pharmacological agent for the provocation of unexplained syncope in patients with NMS. The diagnostic yield of adenosine HUT testing (18.2%) was higher than that of ISP HUT testing (6.1%; p=N.S.), but not significantly so. Therefore, the adenosine HUT test is as useful as the ISP HUT test for inducing NMS. A previous report had suggested that drug-free tilt tests may be misleading in 20–40% of patients owing to a high false-negative rate [15]. Therefore, current guidelines for tilt testing recommend a 2-stage tilt testing protocol that has a drug-free tilt testing and tilt testing given with pharmacological provocation [1,3,19]. However, patients often cannot stand continuously in HUT testing with pharmacological provocation because of the longer time requirement (more than 15min). The adenosine HUT takes only a short time (5min) and can be easily performed just after a drug-free tilt testing. The yield of the adenosine HUT test in the patients younger than 40 years was significantly higher than that in the patients older than 40 years, but this was not true for the diagnostic yields of the ISP HUT test. It is therefore particularly worthwhile to perform adenosine HUT testing in patients younger than 40 years. The pharmacological effects of adenosine are mediated via various effectors. In addition to its cardiac effects mediated by the A1 receptor, binding of adenosine to the A2 receptor results in coronary and systemic vasodilatation [16,17]. In contrast, adenosine infusion in patients results in sympathetic activation, characterized by an increase in systolic blood pressure, heart rate, and ventilation, effects mediated by baroreflex and chemoreceptor activation. In a recent study, bolus doses of adenosine were associated with a triphasic response. The first phase was a hypertensive response. The second phase was hypotension related to vasodilatation. The third phase was sinus tachycardia caused by baroreceptor unloading. Vasovagal syncope occurs after the third phase [13]. Mittal et al. reported that adenosine tilt testing in patients younger than 40 years had a higher diagnostic yield than that in patients older than 40 years [18]. Our study in Japanese patients showed the same results. In the case of unknown syncope involving young patients who have no heart disease and no cerebral disease, pharmacological induction may be performed if the drug-free tilt test result is negative. An additional result is that adenosine HUT testing, which takes only 5min, has the possibility of decreasing false results in young patients with NMS. The results of adenosine and ISP tilt testing were discordant in a previous study [18]. Our study yielded more concordant results in Japanese patients. We believe that this discrepancy may reflect different patient sensitivities related to the mechanism of sympathetic activation by adenosine (chromoreceptor activation and unloading of baroreceptors) and isoproterenol (direct adrenergic stimulation and unloading of baroreceptors).