Europace Advance Access originally published online on July 19, 2007
Europace 2007 9(8):559-562; doi:10.1093/europace/eum099
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SYNCOPE
The value of adenosine test in the diagnosis of sick sinus syndrome: susceptibility of sinus and atrioventricular node to adenosine in patients with sick sinus syndrome and unexplained syncope
1 2nd Cardiac Department, Kromnis 42, 55131 Thessaloniki, Greece; 2 2nd Cardiac Department, Exochi 57010, Thessaloniki, Greece
Manuscript submitted 6 January 2007. Accepted after revision 23 April 2007.
* Corresponding author. Tel: +30 69442 67643. E-mail address: nfrag{at}panafonet.gr
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Abstract |
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Aims Patients (pts) with sick sinus syndrome (SSS) and unexplained syncope show increased susceptibility of sinus and atrioventricular node (AVN) to intravenous adenosine, respectively. Our aim is to assess the diagnostic value of adenosine test in pts with SSS, as well as to evaluate the response of AVN to adenosine either in pts with unexplained syncope or in pts with syncope and known SSS.
Methods and results The effect of adenosine administration on the sinus and AVN was studied in a population consisted of 19 pts with clinical SSS (group SSS), 7 pts with syncope of unknown origin (group SUO), and 12 control subjects (group C). We calculated the maximum corrected sinus node recovery time (CSNRT), after overdrive pacing of the atrium at cycle lengths of 600, 500, and 400 ms and compared this value with the longest sinus pause, following adenosine administration corrected to the basic cycle length (ADSNRT). The longest R-R interval during atrioventricular block in response to adenosine injection (ADAVB) was also measured. Adenosine was given in a bolus dose of 0.15 mgr/kg through a femoral or large antecubital vein. There was a significant difference in the mean values of CSNRT among the three groups: group SSS (651 ± 228 ms) > group SUO (284 ± 100 ms) = group C (291 ± 117 ms), F(2.35) = 19.078, P = 0.000. A significant difference was also found with ADSNRT: group SSS (5437 ± 6863 ms) > group SUO (122 ± 120 ms) = group C (801 ± 1897 ms), F(2.35) = 4.513, P = 0.018. Using 525 ms as a cutoff value indicating sinus node dysfunction, CSNRT had a sensitivity of 74% and specificity of 100% for diagnosis of SSS while ADSNRT had 94% and 84%, respectively. Higher values of ADAVB in pts with SSS (10659 ± 5872) and SUO (10026 ± 7092) in comparison with controls (3615 ± 5002) were measured, F(2.35) = 5.697, P = 0.007. No difference in the degree of ADAVB was found between the pts with SUO (10026 ± 7092 ms) and syncope in the presence of SSS (12058 ± 6787 ms), F(1.15) = 0.356, P = 0.56.
Conclusion Adenosine test appears to be at least comparable with CSNRT in making the diagnosis of SSS and may be considered as an alternative non-invasive test for confirmation of suspected SSS. No difference in the susceptibility of AVN to adenosine between the pts with syncope in the presence of SSS and those with unexplained syncope was found, suggesting that adenosine test cannot be used to diagnose atrioventricular block as the cause of syncope.
Key Words: Adenosine, Sick sinus syndrome, Corrected sinus node recovery time, Atrioventricular block, Syncope
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Introduction |
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Adenosine is an endogenous nucleoside that decreases spontaneous depolarization in the sinus node and conduction velocity in the atrioventricular node (AVN). These effects are mediated by the adenosine receptor (A1) activating an outward potassium–achetylcholine current, present in the sinus node, atrial tissue, and AVN. Adenosine, by shortening action potential duration and hyperpolarizing the resting membrane potential, makes sinus node cells less excitable, slows their automaticity, and causes atrioventricular nodal slowing or block.1
Sick sinus syndrome (SSS) is one of the commonest indications for permanent pacemaker implantation.2 Although the diagnosis is based mainly on clinical criteria, there are cases where an electrophysiological study (EPS) is required in order to elucidate or confirm the diagnosis. Calculating the sinus node recovery time after overdrive pacing of the atrium, corrected by subtracting the baseline sinus rate (CSNRT), sinus node automaticity and/or sinoatrial conduction is assessed, which is usually abnormal in patients (pts) with SSS.3,4 It has reported a greater sensitivity of sinus node to adenosine administration in pts with SSS, suggesting adenosine bolus injection as a non-invasive investigative test for detecting SSS.5–8 On the Contrary, it is the AVN that showed increased susceptibility to adenosine in pts with unexplained syncope.7
The main objective of the study was to evaluate the diagnostic value of adenosine testing in pts with SSS. Specifically, we would like to examine whether this particular test could identify the pts with SSS even when electrophysiological findings are unremarkable. A secondary aim was to assess whether intrinsic sinus node disease is a necessary pre-condition for adenosine-induced abnormal response of sinus node and whether the response of AVN to adenosine in pts with syncope can predict its underlying mechanism.
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Methods |
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We studied 38 pts (50% men): 19 with clinical SSS based on symptoms and ECG findings (bradycardia, pauses, with or without atrial tachycardias) (group SSS), 7 with syncope of unknown origin (group SUO), and 12 controls (group C). Sick sinus syndrome was considered present or very probable when symptoms (syncope or presyncope) and sinus bradycardia or pauses occurred simultaneously, or when Holter monitoring revealed asymptomatic diurnal sinus bradycardia (<50 bpm) or pauses due to sinus arrest (>2 s) in pts with a history of sudden loss of consciousness independent of posture, followed by rapid recovery.
In SSS group, nine pts had a recent DDD-R pacemaker implantation and the remaining 10 pts underwent an EPS for better evaluation of sinus node function. As syncope of unknown aetiology was defined, the syncope, which remained unexplained, despite a detailed evaluation including complete history, physical examination, neurological evaluation, 12-lead ECG, echocardiography, carotide sinus massage, 24 h ambulatory recording, and tilt testing in those cases with clinical characteristics suggestive of neurally mediated syncope. In working up the pts with syncope of unknown cause, an EPS was also performed. The control group consisted of individuals who underwent EPS for evaluation and subsequently ablation of supraventricular or ventricular tachycardias. None of these pts had clinical evidence of SSS or a history of syncopal or presyncopal attacks. Individuals with suspected orthostatic hypotension or situational syncope (during cough, defecation, micturition) and also with a history of asthma, severe chronic obstructive pulmonary disease, and significant coronary artery disease were excluded from the study. Similarly, pts taking xantines, dipyridamole, and anti-arrhythmic drugs were also.
Electrophysiological study
Patients were studied in the post-absorptive state, after informed consent was obtained. All pts, except those who had already a permanent pacemaker, had an EPS via femoral vein, using three quadripolar catheters placed in the high right atrium, in the region of the bundle of His, and at the right ventricular apex. Additional catheters were placed, as needed, in cases where ablation followed. Atrial stimulation was provided by a Medtronic stimulator at twice diastolic threshold with a rectangular pulse of 2 ms duration. Surface ECG and intracardiac electrograms were recorded using the EPMedSystem (EPMed System, Inc., West Berlin, NJ, USA). The CSNRT was measured with standard technique after the termination of atrial overdrive pacing in trains of 60 s at cycle lengths of 600, 500 and 400 ms. Values 
525 ms were considered as abnormal.4 The longest CSNRT was chosen for comparison with the sinus node response after adenosine administration. In those pts with permanent pacemaker, a similar protocol was followed non-invasively through the permanent atrial lead using the appropriate in every case pacemaker programmer.
Adenosine was administered in a dose of 0.15 mg/kg, very rapidly, through a femoral or a big antecubital vein (in pts who did not undergo EPS), followed by a 20 mL saline flash with the patient in the supine position. A continuous ECG was recorded for 30 s before and 2 min after drug administration where the lengthening of the sinus cycle length from baseline was measured. Corrected sinus node recovery time after adenosine injection (ADSNRT) was calculated by subtracting the basic cycle length from the longest post-adenosine sinus cycle length. The longest R-R interval during AV block in response to adenosine was calculated (ADAVB). A value of 6 s ventricular asystole or 10 s complete AV block even if interrupted by some escape beats is defined as abnormal.9,10
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Data are expressed as mean value ± SD. Continuous variables were compared by one-way analysis of variance (ANOVA). The
2 test was used to compare the nominal parameters between the groups. Pearson correlation coefficient was used to examine the correlation between the CSNRT, ADSNRT, and ADAVB. A value of P < 0.05 was considered significant. |
Results |
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Patients in SSS group were older (69 ± 6 years) compared with those in SUO group (60 ± 8 years) and Control group (47 ± 11 years), P = 0.000. Ten pts (26%) had underlying heart disease, predominantly hypertension (nine pts), and one patient had stable coronary artery disease. The three groups did not differ as far as the presence of the underlying heart disease and the gender was concerned. In SSS group, 10 pts (53%) presented with syncope and nine with presyncope, while in eight pts (42%), there were additionally episodes of paroxysmal atrial fibrillation. All pts who underwent EPS had normal basic intervals at baseline and following stress by incremental atrial pacing. Three pts in SUO group had tilt test, which was negative.
Figure 1A and B shows an example of normal CSNRT with abnormal ADSNRT in a patient with clinical SSS. Taking into account that CSNRT 525 ms indicates sinus node disease, the sensitivity and specificity of CSNRT for the diagnosis of SSS was calculated 74 and 100%, respectively. The positive predictive value (PPV) of the test was found 100% whereas the negative predictive value (NPV) 79%, yielding a predictive accuracy of 87% (2 = 22.167, P = 0.000). Using the same cutoff (525 ms), the ADSNRT had a sensitivity 94% and specificity 84%. The PPV and NPV were 86% and 94%, respectively, with a predictive accuracy of 89% (2 = 25.067, P = 0.000). There was a poor correlation between CSNRT and ADSNRT (r = 0.138, P = 0.573) in SSS group. Higher values of CSNRT and ADSNRT were measured in SSS group compared with SUO and control groups (Figure 2).
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The ADAVB was found significantly higher in groups SSS (10659 ± 5872 ms) and SUO (10026 ± 7092 ms) in relation to control group (3615 ± 5002 ms), F(2.35) = 5.697, P = 0.007.
Examining separately those pts with complete loss of consciousness (syncope), we found a significant difference in CSNRT (659 ± 211 vs. 284 ± 100 ms), F(1.15) = 18.917, P = 0.001, as well as in ADSNRT (5441 ± 5387 vs. 122 ± 120 ms), F(1.15) = 6.688, P = 0.021, between groups SSS and SUO, whereas ADAVB did not differ (12058 ± 6787 vs. 10026 ± 7092 ms), F(1.15) = 0.356, P = 0.560. A significant difference in the degree of ADAVB was found between the pts with syncope (11.221 ± 6770 ms) and controls (3615 ± 5002 ms), F(1.27) = 10.892, P = 0.003.
Using 6000 ms as a cutoff value of ventricular asystole due to complete AV block or 10 000 ms total duration of complete AV block, a weak positive correlation between ADSNRT and ADAVB was found (r = 0.392, P = 0.097).
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Discussion |
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The main finding of this study is that 94% of pts with SSS had abnormal response of sinus node after adenosine injection. This means that intravenous adenosine administration is a useful complementary non-invasive test in establishing the diagnosis of SSS. This study also demonstrates that although the sinus node of pts with SSS is far more sensitive to the effects of adenosine, intrinsic sinus node disease is not a compulsory condition for adenosine-induced abnormal response of sinus node (specificity 84%).
Using a cutoff value of 525 ms, which is the generally accepted value of CSNRT indicating sinus node dysfunction,4,11 the ADSNRT appears to be a remarkably sensitive test (94%) in expense, however, of specificity, which is lower compared with CSNRT (84 vs. 100%). This high sensitivity of adenosine test indicates that it can be used instead of EPS in pts with symptoms and ECG findings suggestive of SSS in order to confirm the diagnosis. The high negative predictive value (NPV) (94%) of this test means also that it can be used as a useful complementary test in working up the pts with syncope of unknown aetiology. The relatively low specificity (84%) of adenosine test makes, however, mandatory the EPS in patients without clinical evidence of SSS.
Resh et al.6 using a similar cutoff value (550 ms) reported a comparable specificity for the adenosine test (87%) with a lower however sensitivity (64%). The route of drug administration may account for this difference as the majority (72%) of patients with SSS received adenosine through a peripheral vein, but only in 47% of our population. In another study, Burnett et al.8 re-evaluated the use of adenosine test in 10 pts with suspected SSS including also 67 controls, 41 of whom had an EPS for syncope of unknown cause. The authors reported a lower sensitivity (80%) with higher specificity (97%) compared with our study, which again could be attributed to the route of drug administration that was exclusively through a peripheral vein. A different population selection may also account for this variation, since a higher percentage of pts with SUO were included in this study.
The higher percentage of AVN abnormal response after adenosine administration in pts with syncope or presyncope indicates a higher sensitivity of AVN to adenosine in this group of pts. This is in accordance with previous studies, which showed that pts with unexplained syncope show greater susceptibility of AVN to adenosine or adenosine triphosphate (ATP) than those without syncope.9,10 We did not, however, find difference in AVN response between pts with syncope due to SSS or SUO, indicating that adenosine test is not a useful test to distinguish the underlying mechanism of syncope. The weak positive correlation between ADAVB and ADSNRT indicates also that sinus node does not show analogous to AVN susceptibility to adenosine in the presence of syncope or near-syncope. This is in keeping with a previous study where ATP injection reproduced AV block with a pause >6 s in 53% of the pts with documented spontaneous AV block but in none of those with sinus arrest.9
The dose of adenosine used in this study is similar to those used in previous studies.6,8 The commonest symptoms were transient flushing, breathlessness, chest pressure, and nausea without haemodynamic compromise. There were, however, few cases with long asystolic pauses (up to 23 s) requiring emergency pacing for few seconds, indicating that if adenosine intravenously is used, particularly in pts with suspected abnormalities of sinus node and/or AV node, back up transvenous or transthoracic pacing capabilities seem to be helpful.
Study limitations
The results of this study are dependent on the characteristics of our population. Our pts had no evidence of structural heart disease, whereas all pts in SSS group had episodes of syncope or presyncope.
Patients in group SSS had a mean age significantly older than those of group SUO and group C. A number of studies documented elevated vascular and interstitial adenosine levels in aged hearts.12,13 Increased endogenous adenosine levels might artificially enhance the sensitivity of sinus node to infused adenosine. Hinschen et al.14 showed also that the myocardium is sensitized to direct chronotropic action of adenosine, as it grows older due to substantial increase in functional A1 adenosine receptor sensitivity. This may also contribute to the abnormal sinus node response to administered adenosine in SSS group. This is an important limitation that may have affected our conclusions concerning the sensitivity and specificity of the adenosine test for the diagnosis of SSS.
Although, in pts with SSS, the duration of AV block was always longer than sinus arrest, allowing therefore the evaluation of adenosine effect on the AV node, we cannot exclude a different response of AV node in case of normal sinus node function.
Due to the lack of implantable loop recorder, it remains unclear whether the mechanism of syncope in our pts coincides with the degree of sinus or AVN abnormalities revealed by adenosine administration. Donateo et al.15 showed in a small prospective study that the mechanism of syncope was heterogeneous and ATP-induced AV block predicted AV block as the mechanism of spontaneous syncope only in a few pts.
The route of adenosine administration was not the same in all pts, so we cannot exclude a different response according to the route of injection.
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Conclusions |
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This study shows that adenosine-mediated abnormal response of sinus node is a test with high sensitivity in pts with clinical evidence of SSS, pointing out that it can be used as a useful complementary test to confirm the diagnosis in this group of pts. The present study shows also that sinus node disease is not a necessary pre-condition for adenosine-induced abnormal response of sinus node, indicating that this test can be used cautiously in order to exclude the diagnosis of SSS in pts with syncope of unknown cause. The relatively low specificity of the test does not make it also a particularly useful test to pick up from asymptomatic population individuals with probable sinus node disease. Finally, the adenosine-mediated abnormal response of AVN appears to depend on symptoms (syncope or not) and not on the assumed underlying mechanism of syncope.
Conflict of interest: none declared.
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References |
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[1] Shen WK, Kurachi Y. Mechanisms of adenosine-mediated actions on cellular and clinical cardiac electrophysiology. Mayo Clin Proc (1995) 70:274–91.[Abstract]
[2] Kusumoto FM, Goldshlager N. Cardiac pacing. N Engl J Med (1996) 334:89–97.
[3] Narula OS, Samet P, Javier R. Significance of the sinus node recovery time. Circulation (1972) 45:140–58.
[4] Benditt DG, Gornick C, Dunbar D, Almquist A, Pool-Scheider S. Indications for electrophysiological testing in diagnosis and assessment of sinus node dysfunction. Circulation (1987) 75:93–9.
[5] Benedini G, Cuccia C, Bolognesi R, Affatato A, Gallo G, Renaldini E, et al. Value of purinic compounds in assessing sinus node dysfunction in man: a new diagnostic method. Eur Heart J (1984) 5:394–403.
[6] Resh W, Feuer J, Wesley RC. Intravenous adenosine. A non-invasive diagnostic test for sick sinus syndrome. PACE (1992) 15:2068–73.[Medline]
[7] Brignole M, Menozzi C, Alboni P, Oddone D, Gianfranchi L, Gaggioli G, et al. The effect of exogenous adenosine in patients with neutrally mediated syncope and sick sinus syndrome. PACE (1994) 17:2211–16.[Medline]
[8] Burnett D, Abi-Samra F, Vacek JL. Use of intravenous adenosine as a non-invasive diagnostic test for sick sinus syndrome. Am Heart J (1999) 137:435–8.[CrossRef][Web of Science][Medline]
[9] Brignole M, Gaggioli G, Menozzi C, Gianfranchi L, Bartoletti A, Bottoni N, et al. Adenosine-induced atrioventricular block in patients with unexplained syncope. Circulation (1997) 96:3921–7.
[10] Flammang D, Church T, Waynberger M, Chassing A, Antiel M. Can adenosine 5'-triphosphate be used to select treatment in severe vasovagal syndrome? Circulation (1997) 96:1201–12.
[11] Gann D, Tolentino A, Samet P. Electrophysiologic evaluation of elderly patients with sinus bradycardia. A long term follow-up study. Ann Intern Med (1979) 90:24–9.
[12] Dobson JG Jr, Fenton RA, Romano FD. Increased myocardial adenosine production and reduction of b-adrenergic contractile response in aged hearts. Circ Res (1990) 66:1381–90.
[13] Headrick JP. Impact of aging on adenosine levels, A1/A2 responses, arrhythiogenesis, and energy metabolism in rat heart. Am J Physiol Heart Circ Physiol (1996) 270:H897–906.
[14] Hinschen AK, Rosemeyer RB, Headrick JP. Age-related changes in A1-adenosine receptor-mediated bradycardia. Am J Physiol Heart Circ Physiol (2000) 278:H789–95.
[15] Donateo P, Brignole M, Menozzi C, Bottoni N, Alboni P, Dinelli M, et al. Mechanism of syncope in patients with positive adenosine triphosphate test. J Am Coll Cardiol (2003) 41:93–8.
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