The use of adenosine and adenosine triphosphate

International Journal of Cardiology 183 (2015) 267–273

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

The use of adenosine and adenosine triphosphate testing in the diagnosis, risk stratification and management of patients with syncope: Current evidence and future perspectives Nikolaos Fragakis a,⁎, Antonios P. Antoniadis a, Massimo Saviano b, Vassilios Vassilikos a, Carlo Pappone b a b

3rd Cardiology Department, Hippokration Hospital, Aristotle University Medical School, Thessaloniki, Greece Department of Arrhythmology, Maria Cecilia Hospital, Cotignola, Italy

a r t i c l e

i n f o

Article history: Received 27 May 2014 Received in revised form 8 December 2014 Accepted 3 January 2015 Available online 30 January 2015 Keywords: Adenosine Adenosine triphosphate Syncope

a b s t r a c t Syncope is a significant source of cardiovascular-related morbidity yet the etiology is frequently obscure and the identification of patients at highest risk is challenging. Adenosine (AD) and adenosine triphosphate (ATP) administrations have been suggested as potentially useful non-invasive tools in the diagnostic workup of patients with neurally-mediated or bradycardia-related syncope. It has been postulated that both compounds by modulating the autonomic innervation in the heart and exerting negative chronotropic and dromotropic effects in the conduction system, may unmask the mechanism of syncope. However, the clinical implications derived from the efficacy of both tests in the investigation of syncope remain unclear mainly due to inconclusive and occasionally contradictory results of published studies. This review article summarizes recent and past information in the use of ATP and AD in the investigation of syncope with emphasis on clinical trials. We present the current level of evidence for the use of these agents in clinical practice, identify areas where further research is warranted and highlight the future perspectives of these agents as complements to an accurate risk-stratification of patients with syncope. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Syncope, defined as a temporary, self-limiting loss of consciousness due to transient global cerebral hypoperfusion, constitutes a significant cause of morbidity accounting for many acute visits in the emergency department and frequent hospital admissions [1]. Even in the absence of structural heart disease or life-threatening tachyarrhythmias, syncope can be debilitating and/or relate to critical defects of the cardiac conduction system. Several tests are performed to identify the cause of syncope, in many cases however the etiology remains unknown despite a complete diagnostic investigation. Furthermore, controversy exists as for the appropriate risk-stratification of patients with syncope and the identification of the subset of patients which would benefit more from pacing. Adenosine (AD) and adenosine triphosphate (ATP) administrations have long been proposed as potentially useful non-invasive diagnostic tools in patients with neurally-mediated or bradycardia-related syncope [2]. No consensus however has been reached in their use as study results have been inconclusive [1]. This article summarizes recent and past evidence in the use of both compounds in the diagnostic workup of patients with syncope and highlights the future perspectives of these ⁎ Corresponding author at: Kromnis 42, 55131, Thessaloniki, Greece. E-mail address: [email protected] (N. Fragakis).

http://dx.doi.org/10.1016/j.ijcard.2015.01.089 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

agents in everyday clinical practice. A systematic review of the literature was performed to locate relevant experimental studies as well as clinical studies in humans evaluating the effects of AD and ATP in several patient populations. Clinical studies were identified by interrogating the PubMed online database on the topics of AD, ATP and syncope. Additional keywords included: Neurally mediated syncope, syncope of unknown origin, atrioventricular block, sick sinus syndrome, and tilt table testing. The relevant reports identified ranged from 1985 to 2014 and a structured review of these studies has been developed. We further extended the search to the reference list of the above studies. We limited the search to studies published in English. The search was concluded on 15 May 2014. 2. ATP and adenosine: biochemistry and metabolism ATP is an endogenously occurring nucleoside triphosphate, ubiquitous in all cell types, which is the natural precursor molecule of AD, a purine nucleoside formed by adenine and ribose. ATP has different actions in the intracellular and the extracellular compartment functioning as a coenzyme in many fundamental cellular processes intracellularly and as a molecular mediator between cells extracellularly. Experimental data point towards an increased cellular formation of AD when either the local tissue metabolic demand increases or the regional blood flow and oxygen delivery decreases, especially in tissues which largely rely

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N. Fragakis et al. / International Journal of Cardiology 183 (2015) 267–273

on oxidative phosphorylation for energy production. AD and ATP exert their physiologic signaling effects via binding two purinergic receptor families in the cell membrane, named adenosine receptor or P1 receptor and ATP receptor or P2 receptor. P1 receptors are G protein-coupled receptors and are further classified into A1R, A2AR, A2BR, and A3R. With regard to P2 receptors two subtypes have been identified: P2X, which are ion channels, and P2Y which are G protein coupled receptors [3]. The half-life of extracellular ATP is extremely short as it is catabolized rapidly to ADP, AMP and AD, the latter in turn being subsequently transported back to the cytoplasm [4]. 3. Electrophysiologic effects and safety profile of ATP and adenosine In the conduction system, ATP and AD exert distinct negative chronotropic and dromotropic effects, by suppressing the sinus nodal automaticity and prolonging the conduction through the atrioventricular node (AVN). Intravenous administration of AD in humans causes sinus bradycardia and sinus arrest [5]. Adenosine can also cause sinoatrial exit block at high concentrations, as well as a relocation of the earliest site of atrial activation from the sinus nodal region to the crista terminalis area [6]. Interestingly, the His-bundle and the Purkinje fibers exhibit even more pronounced decrease in automaticity after AD administration. With regard to the negative dromotropic action of AD it has been shown to increase the A–H interval in a dose-dependent manner mostly due to a suppression of nodal cells action potentials, while it has no effect in the H–V interval [7,8]. At the cellular level, AD induces a hyperpolarization of the resting potential across the membrane, a decrease in the slope of phase 4 depolarization, and a reduction in the action potential duration. During exogenous administration, ATP and/or AD are in general very well tolerated. Either cardiac or extracardiac side effects (i.e. facial flushing, headache, chest discomfort) last for less than 1 min and rarely are of clinical concern. In a few cases, acute exacerbation of asthma lasting for more than 30 min has occurred after AD administration. Atrial fibrillation due to a suppression of the atrial refractoriness can be induced, while the most serious proarrhythmic effect described after AD administration is bradycardia-dependent polymorphic ventricular tachycardia, especially in patients with long QT syndrome [9].

increase of parasympathetic discharges with concomitant sympathetic withdrawal, mediated by specialized cardiopulmonary mechanosensitive and chemosensitive receptors in the left ventricle [12]. This paradoxical reaction stimulates a profound vasodilation and bradycardia which manifest clinically as presyncope and/or syncope. Exogenous administered ATP mimics this mechanism by initially inducing a sympathetic activation through a direct triggering of cardiac excitatory afferent fibers, followed by the activation of vagal sensory nerve terminals that are localized in the left ventricle, which ultimately trigger a cardiocardiac central vagal depressor reflex [13]. AD, as mentioned before, has no vagal activity. Instead, AD causes a continued sympathetic withdrawal that in susceptible individuals results finally in vasovagal syncope (Fig. 1). It has been postulated therefore, that ATP and AD endogenous production may be related to the clinical presentation and their exogenous administration would unmask syncopal symptoms in patients with NMS and SUO. In support of with this concept, patients with positive head-up tilt table testing (HUT) had higher AD plasma concentration and a positive association between the increase in AD levels and the onset of syncope exists [14]. Also, patients with unexplained syncope and positive HUT exhibit an overexpression of the AD receptor A2AR [15]. Representative protocols for AD and ATP administrations are listed in Table 1. 6. The diagnostic role of ATP/adenosine in NMS and SUO Several studies investigated the use of ATP/AD as provocative agents for vasovagal response either during head-up tilt table testing (ATPHUT/ADHUT) or in the supine position (SATP/SAD) in patients with NMS or SUO (Table 2). Shen et al. compared the vasovagal response during ADHUT with a routine HUT in a population of 85 patients investigated for SUO [16]. A similar response was produced by both tests suggesting that ADHUT may be used as an efficient alternative

4. Pathophysiogic differences in the effects of ATP versus adenosine Comparing the cardiac effects of ATP versus AD, a clear difference is that the actions of ATP are evidently associated with the vagal tone. ATP elicits a vagal depressor reflex response in the heart by means of upregulating specific receptors in the left ventricle. Maneuvers which enhance the parasympathetic afferent stimuli to the heart, e.g. physostigmine administration and increased plasma calcium levels, trigger an augmented effect of ATP over AD in the cardiac conduction system [10]. On the other hand, data suggest that without the effects of the parasympathetic system, the actions of ATP in the heart are identical to those of AD. Interventions which eliminate the vagal stimulation to the heart, e.g. atropine administration or surgical denervation, practically render the ATP effects similar to those of AD [10]. Furthermore, when the parasympathetic action to the heart is eliminated, the effects of ATP are counteracted by aminophylline, which is a nonselective competitive antagonist of AD receptors, and upregulated by dipyridamole, which acts as an AD reuptake inhibitor [11]. 5. Pathophysiologic basis of the usefulness of adenosine and ATP in the diagnostic investigation of syncopal attacks The cardiac effects of ATP and AD largely account for their value in the diagnostic workup of neurally mediated syncope (NMS) and syncope of unknown origin (SUO). The proposed pathophysiology of NMS postulates that an initial arterial pressure drop elicits an activation of the sympathetic system, which in turn triggers a disproportionate

Fig. 1. Mechanism of action of ATP and AD in NMS. ATP mimics the mechanism of NMS by inducing initially a sympathetic activation followed by the activation of vagal sensory nerve terminals in the left ventricle, which in turn triggers a cardiocardiac central vagal depressor reflex. AD, in contrary to ATP has no vagal activity but causes a persistent downregulation of the sympathetic system which results in negative chronotropic and dromotropic cardiac effects and may precipitate vasovagal syncope.


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Table 1 Protocols for AD and ATP administrations. Test name Patient position Drug administered Dose

Adenosine test Supine Adenosine 0.15 mg/kg followed by a 20 mL saline flush

Adenosine head-up tilt table testing Upright at 60° Adenosine 0.15 mg/kg followed by a 10 mL saline flush

Route of administration Outcome measure

ATP test Supine ATP 20 mg in 10 mL saline followed by a 20 mL saline flush Bolus intravenously via the antecubital vein (within b3 s) Max PP, RR and duration of third-degree AVB

Bolus intravenously via the antecubital vein (within b3 s) ADSNRT

Bolus intravenously via the antecubital vein (within b3 s)

References

[19,20,22,27]

[37–39]

Decrease in sinus heart rate (≥20%) compared with baseline or transient AVB followed by a reflex sinus tachycardia [17,18]

Abbreviations: AD: adenosine. ADSNRT: sinus node recovery time after adenosine administration. ATP: adenosine triphosphate. AVB: atrioventricular block.

diagnostic method in the investigation of patients for NMS [16]. In line with these results, Mittal et al. showed that ADHUT was effective for the induction of vasovagal syncope, with a diagnostic yield comparable to routine HUT [17]. An interesting issue which this study revealed is the clinical discordance between the results of AD and ISO tilt testing. Indeed, patients with negative ADHUT usually required ISO to elicit the positive response during HUT. This study elegantly proved that this discrepancy was probably due to the diverse response of the sympathetic system to each of these agents. Therefore, both tests may have complementary roles in the induction of a positive vagal response. The same group subsequently reported that ADHUT has an excellent specificity (100%) in patients with SUO but a low diagnostic yield, which was also adversely affected by advanced age [18]. On the contrary, Brignole et al. showed that the ATP test does not appear useful in the diagnosis of NMS, using however SATP instead of ADHUT [19]. A following study made a distinction between NMS and the so-called “adenosine-sensitive syncope” thereby justifying why the SATP test should not be used as a substitute for HUT [20]. Indeed, patients with positive SATP were usually older, predominately women, had shorter duration of syncopal episodes, lower prevalence of triggering factors and absence of warning symptoms compared to those with positive HUT. The authors acknowledged however that an important overlap between the two entities exists, possibly due to common pathophysiologic pathways accounting for the positive response to both tests in some patients. Recently, the same group demonstrated that AD plasma levels can distinguish between “adenosine-sensitive syncope” and NMS more efficiently than SATP: patients with “adenosine-sensitive syncope” typically feature low AD plasma levels in contrast with NMS patients which have high levels [21]. Flammang et al. in a series of publications examined not only the value of ATP in the diagnosis of NMS but assessed also its usefulness in therapeutic decision-making [22]. Initially, they tested the hypothesis that the severity of SATP-induced vagal effect may identify a subgroup of patients with NMS at a higher risk of serious cardioinhibitory response and thereby provide an objective basis for pacemaker therapy. In 316 patients with recurrent syncope or presyncope, SATP provoked a cardiac pause in 234 patients (74%). Of these, 130 patients (41%) exhibited a pause N10 s which was considered as an abnormal response since it exceeded the 95th percentile of the normal range of pause values. In a long-term follow-up (49.7 ± 33.5 months), the ones who received a pacemaker had 84% reduction of recurrences compared to patients who were only monitored [22]. Short-pause patients with and without pacemaker had comparable symptom-free survival rates. The authors proposed that SATP through its vagal effect may identify a subgroup of patients at high risk of severe cardioinhibitory response of vagal origin who will probably benefit from pacemaker implantation. It must be noted however that the treatment and control groups were not age-matched, and therefore the effects of age in the study results remain unclear. Furthermore, no confirmation of NMS diagnosis with HUT

was required in this study [23]. In a following non-randomized study, the same authors aiming to more effectively elucidate the mechanism of NMS for a tailored therapy, performed both SATP and HUT in 72 patients hospitalized for presyncope or SUO. SATP test, that was considered per se as specific to identify subjects at high risk of severe cardioinhibitory reflex, was found positive in eight (11%) patients while only three patients were positive on both tests. The authors concluded that HUT and SATP test individually and jointly determine the mechanism of vasovagal symptoms in most patients and could play a synergistic role in the selection of the optimal therapeutic strategy (pharmaceutical treatment or pacing). Another important observation was that age increases the probability of a positive SATP test, emphasizing on the importance of having an age-matched control group in ATP studies. The observation by Brignole et al. [20] and Flammang et al. [23], that positive SATP/SAD tests indicate a distinct group of patients with syncope were also confirmed by Perennes at al. showing that older patients and women with SUO more frequently had a positive SATP test [24], More recently, Deharo et al. demonstrated that HUT and ATP may identify different subsets of patients with NMS due to their different purinergic profiles. Positive HUT identifies those with high adenosine plasma level and high expression of A2AR receptors while positive SATP those with low adenosine plasma level and low A2AR [15]. Another critical question is whether a positive SATP test can predict the clinical outcome and the mechanism of spontaneous syncope in patients with NMS. As previously mentioned, in the study by Flammang et al. the patients with long pause after SATP who received a pacemaker did better compared to those who were only monitored; however, there a placebo control arm was not included [22]. This fundamental issue was subsequently tested by Brignole et al. who enrolled patients with multiple attacks of suspected NMS and severe clinical presentation [25]. In this prospective study, 164 out of 392 patients (48%) had positive HUT, while 53 out of 180 (29%) showed positive SATP test (i.e. complete AV block or sinus pause with a ventricular pause ≥ 6.0 s). The correlation between syncope and cardiac rhythm disturbances was documented by an implantable loop recorder (ILR). Syncope was documented by ILR in 106 (26%) patients after a median follow-up of 3 months. The results of the study were rather disappointing in the context that the mechanism of spontaneous syncope was not predicted either by the ATP test or the HUT and therefore these tests had little or no value for guiding specific therapy. The same results were confirmed in another study of identical methodology but with much smaller number of patients [26]. Finally, the important issue of SATP reproducibility in the short and the long term was tested only in one study demonstrating a high reproducibility of symptoms and electrocardiographic abnormalities [27]. 7. ATP/adenosine and AV block Although the mechanisms of ATP and AD actions on AVN are not identical, both agents exert a pronounced negative dromotropic effect

270

Table 2 Studies using adenosine triphosphate (ATP) or adenosine (AD) as provocative agents for vasovagal response in patients with NMS or SUO. Study

Diagnosis Patients (No./age in years)

Shen et al. [16]

NMS

85/61 ± 17

Gender (F/M)

34/51

Drug

14/38 ±

54%

60%

Definition of positivity

HUT/ISO or GLYC

Positivity/sensitivity/specificity

Concordant positive response (%)

ADHUT VVS

Y/Y

55%

ADHUT VVS

Y/Y

Sensitivity: 67% ADHUT 88% HUT Sensitivity: ADHUT 10% vs HUT/ISO 8% (ns) ADHUT 19% vs HUT 22% (ns) Positivity: ADHUT 18% Specificity: 100%

10 Mittal et al. [17] NMS

Mittal et al. [18] SUO Brignole et al. [19]

NMS

Brignole et al. [20]

SUO

Flammang et al. SUO [22]

201/55 ± 20

129/54 ± 19 26/64 ± 11 121 (HUT + 45 ± 20) (ATP + 68 ± 10) (Both + 58 ± 18) 316 (121 with presyncope)/74 ± 0.6

120/81

None

77/52

30/30 ±

71%

ADHUT VVS

8/18

10 31/62 ±

4.8 ± 5.5

SATP

SA N 2 s, AVB

Y/N

SATP non-diagnostic

33%

Median HUT + 3 SATP + 2 Both + 4 4.4 ± 0.6

SATP

Pause N 6 s

Y/Y

21%

SATP

Pause N 10 s

N/N

Sensitivity: 15% SATP 64% HUT Sensitivity: SATP 41% Specificity: 94%

NS

SATP

Pause N 10 s

N/N

NA

NA

43%

SATP

Pause N 10 s

Y/Y

6%

Median 6

SATP

Pause ≥ 6 s

Y/Y

6.9 ± 4.6/year

SATP

Pause ≥ 6 s

Y/Y

Positivity: SATP 8% Positivity: HUT 57% Sensitivity compared to ILR documented syncope: SATP 30% HUT 45% No correlation between ILR documented syncope and HUT or SATP response

69/52

16 None

162/154 51/56 ±

Flammang et al. SUO [27] Flammang et al. [23] Brignole et al. NMS [25]

80/72 ± 12

36/44

2 None

72/(16 with presyncope)/65 ± 2 392/66 ± 14

29/43

None

Deharo et al. [26]

25/60 ± 17

NMS

215/177 None

14/11

Abbreviations: ADHUT: head-up tilt table testing with adenosine administration. AVB: atrioventricular block. GLYC: oral glyceryl trinitrate. HUT: head-up tilt table testing. NA: non-applicable. ISO: isoproterenol. ILR: implantable loop recorder. NMS: neurally-mediated syncope. NS: not stated. SA: sinus arrest. SATP: adenosine triphosphate administration in the supine position. SUO: syncope of unknown origin. VVS: vasovagal syncope.

None

N/N

59% 33% NA

NA

NS

NS


Controls Syncope recurrence (No./age) (% or mean/median no. of episodes)


on AVN conduction [28–30]. It is reasonable therefore to postulate that individuals with an increased susceptibility of the AVN to these two compounds may develop paroxysmal AV block associated with a prolonged ventricular pause which can ultimately lead to a syncopal attack. This rationale framed the concept of testing the AV node response to exogenous AD or ATP in patients with SUO. Brignole et al. validated SATP in 24 patients who serendipitously had an ECG recording of spontaneous syncope [31]. AVB was the cause of the asystolic pause in 15 and sinus arrest in 9 patients. In a control group of 90 subjects, the upper 95th percentile for the maximal R–R interval during SATP-induced AVB was 6000 ms. Prolonged AVB with an asystolic pause of ≥6000 ms was induced in 53% of the patients with documented AVB but in none of those with sinus arrest. The main conclusion derived from this study was that SATP by inducing prolonged AVB was able to reproduce the mechanism of syncope in patients with spontaneous paroxysmal AVB. Similar to other studies, the authors confirmed that compared to their ATP-negative counterparts, the ATP-positive patients were older, more frequently females and were more likely to manifest sudden syncopal attacks. However, these results were not confirmed in a following study by the same group: in 36 patients with positive SATP, half of them had syncope recurrence and just 3 (19%) had ILR-documented AV block [32].

8. ATP sensitive paroxysmal AV block ATP sensitive paroxysmal AV block features recurrent episodes of sudden onset syncope due to long pauses caused by paroxysmal of AV block. Interestingly, this entity does not resemble either intrinsic AV block due to AV conduction disease or extrinsic vagal AV block. It is distinguished by the lack of progression to persistent forms of AV block, while the patients (predominately older women) appear to have normal ECG, absence of structural heart disease and good response to pacemaker therapy [21,33,34]. A low baseline adenosine plasma level (as opposed to patients with NMS) and an increased susceptibility to exogenous AD are also typical in these patients [34]. Brignole et al. showed a high (83%) positive response after SAD or SATP in a group of 18 patients with paroxysmal AV block reproducing the clinical AV block. In the same group, HUT induced a vasovagal syncope in 7 (41%) of cases, but never reproduced AV block [34]. In a recent report Blanc et al. confirmed the high sensitivity of this group in ATP administration [33]. Even

271

though these results were disputed by Deharo et al. who showed that SATP/SAD testing was also frequently positive in patients with NMS [21], the existing data rather converge in the usefulness of SATP/SAD test in this group of syncope patients.

9. ATP/adenosine and sick sinus syndrome (SSS) The hypothesis that SSS is an adenosine-mediated disease was set first by Watt almost three decades ago [35]. Since then, few studies have investigated whether patients with SSS may have an abnormal response to SATP/SAD test, and also whether it can be used as a tool to diagnose SSS (Table 3). Benedini et al. first published an investigation on the value of ATP in assessing SN function in man [36]. In this study, a significant lengthening of sinus cycle length in response to striadyne (a purinic compound similar to ATP) in patients with SSS but not in controls was shown, proving thus that this test can unveil SN dysfunction with high sensitivity and specificity. Brignole et al. also tested clinically the effect of exogenous ATP in a group of patients with SSS or combined SSS and NMS [19]. This study showed that in about half of patients, an abnormal response to SATP was observed, while no such response was detected in the control group [19]. Resh et al. were the first among other investigators who compared the effect of AD on the lengthening of sinus cycle length (ADSNRT) to corrected sinus node recovery time (CSNRT) showing that it has a comparable value in confirming the diagnosis of SSS [37]. A similar specificity (97% vs 95%) but superior sensitivity (80% vs 70%) between ADSNRT and CSNRT was found by Burnett D et al. [38] who suggested that ADSNRT can be used as an alternative to invasive testing in patients with suspected SSS. To assess the hypothesis that intrinsic SN disease is a prerequisite for adenosine-induced abnormal response of SN, our group compared the ADSNRT and CSNRT in 19 patients with clinical SSS, 7 with SUO and 12 controls. Even though we confirmed the high sensitivity of ADSNRT in patients with SSS (94%), a rather low specificity (84%) was detected, revealing that SN disease is not a sine qua non for an abnormal response of SN to AD [39]. In a successive publication, we demonstrated that the SN response to AD relates to the severity of SN dysfunction. Indeed, ADSNRT was more prolonged in SSS patients with syncope or presyncope as compared to those without. A cut-off value of ADSNRT N 1029 ms proved appropriate to distinguish between mild and severe forms of SND [40]. Finally, Parry et al. using the ESC

Table 3 Studies using adenosine triphosphate (ATP) or adenosine (AD) as a diagnostic tool to detect sinus node dysfunction. Diagnosis Benedini et al. [36] SSS

Patients Gender Controls (No./age in years) (F/M) (No./age in years)

Drug Definition of positivity

26/65 ± 14

SATP N2071 ms

19/7

Brignole et al. [19] SSS & SSS + NMS 53/75 ± 8

24/29

Resh et al. [37] SSS Burnett et al. [38] SSS Fragakis et al. [39] SSS

11/70 ± 6 10/71 ± 10 19/69 ± 6

1/10 6/4 10/9

Parry et al. [41] SND Fragakis et al. [40] SSS

4/76 ± 6 33/70 ± 9

3/1 28/18

Abbreviations: ADSNRT: sinus node recovery time after adenosine administration. AVB: atrioventricular block. NMS: neurally-mediated syncope. SAD: adenosine administration in the supine position. SATP: adenosine triphosphate administration in the supine position. SSS: sick sinus syndrome. SUO: syncope of unknown origin. VA: ventricular asystole.

Controls: 21/56 ± 18 Vasovagal: 8/59 ± 10 Controls: 31/62 ± 16 NMS: 26/64 ± 11 Controls: 12/60 ± 16 67/59 ± 18 Controls: 12/47 ± 11 SUO: 7/60 ± 8 21/∼37 ± 13 Controls: 30 (12 with SUO)/55 ± 13

SATP N2000 ms SAD SAD SAD

≥550 ms ADSNRT N 550 ms ADSNRT ≥ 525 ms

SAD SAD

VA N 6 s and/or 2nd/3rd degree AVB N 10 s ADSNRT ≥ 1029 ms

Sensitivity/specificity 93%/100% ∼50%/99% 64%/87% 80%/97% 94%/84% 100%/NA 57%/97%

272


guideline values as cut-off for positive SAD, (i.e. ventricular asystole N 6 s and/or 2nd/3rd degree AV block N 10 s) [1] reported a 100% sensitivity of SAD in the detection of severe SSS in a small group of patients referred for pacemaker implantation [41].

10. Cardiac pacing guided by ATP/adenosine response The proof of concept that patients with SUO may benefit from permanent cardiac pacing on the basis of a positive ATP test has been tested in a non-randomized and blinded fashion in the past with rather positive results [22]. Recently, a patient-blinded, multicenter, randomized superiority trial recruited 80 consecutive patients with SUO and positive SATP, defined as AV or sinoatrial block lasting N 10 s [42]. The patients were randomized in 2 groups (DDD pacing at 70 bpm and AAI at 30 bpm) and were followed-up for a mean of 16 months. An impressive 75% reduction of syncope recurrence was observed in the DDD pacing group. Nevertheless, a 23% of the population still had episodes of syncope despite the introduction of DDD pacing and this was attributed to different coexisting mechanisms potentially accountable for syncope. As previously mentioned, patients (mainly older women) with unexplained syncope, a “normal” ECG, paroxysmal AV block and prolonged AV block during ATP injection show also favorable response to pacing therapy [21,33,34]. Nevertheless, the ATP/AD test cannot thus far be recommended as a diagnostic test to select patients for cardiac pacing mainly due to its low predictive value and lack of correlation with spontaneous syncope (class III, level B, according to the current guidelines) [1]. 11. Conclusions and future perspectives The role of ATP/AD test in elucidating the pathophysiological mechanism behind syncope remains controversial. Most of the published studies are of small caliber, feature diverse research methodology and lack well-matched control groups in terms of age. The same limitations were pointed out by Parry et al. in a very comprehensive review, almost a decade ago [43] and are still timely at present [44]. Although several studies investigated the effect of ATP/AD on the autonomic nervous system and the cardiac conduction system of patients suffering from syncope, the results remain obscure. In NMS, the test seems to have a rather limited diagnostic value even though it adequately replicated the pathophysiological mechanism implicated in this condition. The existence of different subsets of patients with NMS with diverse purinergic profiles exhibiting variable sensitivity to ATP/AD test may account for this discrepancy. The role of the ATP/AD test to unveil paroxysmal episodes of AV block as the underlying cause of SUO is also controversial mainly due to the relatively poor correlation between ATP-induced AV block and ECG recordings during spontaneous syncope. Nevertheless, the diagnostic yield appears higher in specific subgroups as those with ATP-sensitive paroxysmal AV block. In patients with SN dysfunction, AD test has an at least comparable to CSNRT diagnostic value, suggesting that it could be used as a complementary non-invasive test to confirm the diagnosis in patients with suspected SSS. In view of these uncertainties, the institution of cardiac pacing on the basis of a positive ATP/AD test becomes even more dubious although recent data are very promising. Clearly, much further work is warranted before the ATP/AD test is widely adopted as a diagnostic modality in the unexplained syncope workup. The introduction of appropriate criteria for the proper selection of patients who are likely sensitive to this test may increase its diagnostic yield and help identifying the patients at highest risk which could benefit from cardiac pacing. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. All authors report no conflicts of interest.

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