1. Adenosine testing in syncope Dr Steve W Parry Falls and Syncope Service Royal Victoria Infirmary and Institute for Ageing and Health, Newcastle University

2. Outline What is it? What does an adenosine test diagnose? What do the guidelines tell us about adenosine testing? How do you do it? Where are we now?

3. Adenosine triphosphate (ATP) Ubiquitous purinergic amine Rapid catabolism to adenosine (ATP: some vagal effects) Profound negatively chronotropic and dromotropic effects on AV node High degree AV block, asystole

4. ATP and syncope investigation Confusion re diagnostic criteria and underlying pathophysiology –VVS –Sinus node disease –High degree AV block –“Adenosine-sensitive syncope” –“Brady-pacing indications”

5. ATP and vasovagal syncope Supine ATP in Dx of neurally mediated syncope and SND (Brignole PACE 1994) –20mg iv ATP, 79 older patients (71 years) v 31 controls (62 years) –Similar ATP test positivity in both groups, all diagnoses –More recent results in 175 patients “ATP no substitute for HUT” (Brignole et al Heart 2000)

6. Adenosine and vasovagal syncope

7. ATP and syncope investigation: Vasovagal syncope “Fainting rats” (Waxman et al Circulation 1998) –VVS rats: isoproterenol and IVC clamp –Dipyridamole (adenosine inhibitor) caused paradoxic bradycardia at lower iso doses –? Adenosine augments sympathoinhibition during vasovagal response Humans: higher plasma adenosine levels during positive HUT in patients with VVS (Saadjian, Circulation 2002)

8. ATP and vasovagal syncope Adenosine IV as provocateur during head up tilt table test –Adenosine tilt less sensitive than isoproterenol tilt (Shen et al JACC 1996, Perez-Paredes et al Rev Espanol Cardiol 1998)

9. ATP and vasovagal syncope Flammang et al (Circulation 1997) ATP 20mg –10 sec duration of AVB for diagnosis –Initial studies “cardio-inhibitory VVS” No proof, diagnostic criteria –316 patients with VVS, 51 younger controls –130 (41%) patients pauses >10 sec (84% AVB) v only 3 controls –Increasing positivity with advancing age –Further studies establishing reproducibility (J Cardiovasc Elect 1998) and response to pacing (Circulation 1999) –Account for around half of all patients reported

10. The Flammang experience..... Flammang et al (Heart Rhythm, 2006 abstr) –Multicentre “placebo-controlled” RCT DDD v AAI @ 30bpm –Patients with SUO, “mostly vasovagal” No HUT, no data on why VVS –77 patients age 78 years

11. Rhythm 2006 Europace 1999 Circulation 1997 Retrospective study (n=316) Prospective study (n=20) Multicenter study (n=77) The Flammang experience.....

12. Adenosine and sinus node dysfunction

13. ATP and sinus node dysfunction Brignole et al 1994: ATP unhelpful in SND diagnosis, though SND needed for ATP-related sinus arrest Burnett et al Am Heart J 1999 –10 patients with SND v 67 age matched controls –80% sensitivity, 97% specificity Fragakis et al Europace 2007 –Similar results Editorials: “promising but more work needed”

14. Adenosine and atrioventricular block

15. ATP and high degree AVB Brignole et al (Circulation 1997) –60 patients (57+/-19 y) v 90 controls –15 with AVB and 9 with sinus arrest –Upper 95 th percentile in controls 6000ms –ATP >6 sec in 53% AVB patients, none of SA –? Higher susceptibility of pts with AVB to ATP

16. Newcastle pilot study (Parry et al QJM 2009) Adenosine 20mg iv bolus (Negative HUT, CSM, EP diagnosis excluding alternative diagnoses) Paced groups –CSS –SND –AVB VVS “Clean” EP controls ATP and “brady-pacing indications”

17. DiagnosisN=Mean age (sd)Adenosine positive (>6 sec asystole) Sensitivity (%) SSS AVB CSS VVS EPC 5 (4 F) 7 (1F) 7 (4F) 10(8F) 8 (7F) 77 (5.7) 69 (15.0) 75 (4.9) 57 (19.0) 37 (14.6) 5765157651 100 85.7 50 163 screened, 37 enrolled (!): 50% unsuitable (contraindications, AF) 40% refusal of CSM, 10% refusal of adenosine

18. ATP and ILRs

19. Donateo et al (JACC 2003) –36 ATP positive patients with ILR, 69 yr –22 had syncope 11 (69%) had bradycardia 50% had long ventricular pause Deharo et al (JACC 2006) –25 patients with tilt +ve VVS, 8 CI, mean 60 yr, all ILR –No relation between adenosine and CI response during tilt

20. ATP and ILRs ISSUE 2 Brignole et al Eur Heart J 2006 –392 patients, 343 tilted, 164 (48%) +ve –180 ATP, 53 (29%) positive –Syncope with ILR in 106 (26%) at 3/12 –No relationship between ATP positivity and HUT results

21. What do the guidelines say? ACC/AHA/HRS and ESC pacing guidelines –Adenosine testing not mentioned ESC syncope guidelines 2009 –“Cannot be recommended”; Class III

22. If you must..... Usual cautions/contraindications Counsel your patient.... Continuous ECG/BP monitoring 20 mg IV adenosine with rapid flush > 6 sec asystole or > 10 sec high degree AVB abnormal No adverse events to date in >1500 patients and control subjects

23. Where are we with ATP? Contradictory evidence base –Some indications of unmasking of conducting tissue disease –Predominantly older patients in non-VVS literature –Increasing positivity with advancing age –ILR studies show little or no correlation between ATP positivity and real-time ECG/tilt diagnosis Difficult patient groups – confusion re underlying diagnoses, many with VVS –Good evidence from pacing intervention studies of efficacy in ATP positive patients

24. Where are we with ATP? ATP or Adenosine, –Contradictory evidence –Both used in the literature –ATP metabolism to adenosine very fast –Pelleg, Flammang “vagal effect vital” Dog studies, not replicated in guinea pig or cat 6 sec or 10 sec asystole –6 sec based on Brignole’s work, 95 th centile in 175 controls –10 sec based on Flammang’s work, ditto!