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Sincope e adenosina e terapia con teofillina
Dott.ssa Diana Solari
Centro Aritmologico e Syncope Unit Lavagna - Genova
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LOW ADENOSINE SYNCOPE - DEFINITION -
• Syncope without or with very short (≤5 s) prodromes
• Normal heart and normal electrocardiogram
• Idiopathic paroxysmal AV block or sinus bradycardia followed by sinus arrest
• Low baseline values of plasmatic adenosine (APL <0.40 µM) and low expression of A2A adenosine receptors
LOW ADENOSINE SYNCOPE
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IDIOPATIC PAROXYSMAL AV BLOCK
• Paroxysmal third-degree AV block with abrupt onset and absence of other rhythm disturbances before or during the block • High induction rate of transient complete heart block
during exogenous injections of adenosine• No progression to persistent form of AV block• Efficacy of PM implantation
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IDIOPATIC PAROXYSMAL AV BLOCKA)
B)
1 sec
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EFFICACY OF PM IMPLANTATION
www.gimsi.itBrignole et al. Heart Rhythm 2017; 14: 234–239
* Prodromegroup: reflex syncope treatedwith pacemaker (age/sex matchedfrom ISSUE trial)
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LOW PLASMA ADENOSINE
LEVELS
Guieu R et al. JACC 2015; 66: 202-3
LOW EXPRESSION OF ADENOSINE RECEPTORS
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ADENOSINE AND CLINICAL FORMS OF NEURALLY-MEDIATED SYNCOPE
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MECHANISM• Adenosine is suspected to be involved in the mechanism of syncope
through the activation of up-regulated A1 adenosine receptors which are known to be located within the atrioventricular node and the sinus node; their activation causes atrioventricular block and/or sinus bradycardia most often followed by sinus arrest.
• Moreover, In vascular smooth muscles, adenosine binds to type 2A (A2R) receptors and causes relaxation
ADENOSINE SINUS NODE
AV NODEA1-R
A1-R
AV BLOCK
SINUS BRADICARDIA
VESSELSA2-RVASO-
DILATATION
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MECHANISMA1 receptors undergo up- and down-regulation depending on
their chronic exposure to adenosine. In patients with low plasma adenosine values, the subsequent A1 receptor up-regulation
exposes patients to AV block and sinus bradycardiaHigh affinity A1 receptors
saturation curve
Bradycardia zone Hypotension zone
% saturation
Low APL High APL
100%
50%
0.7 (Kd A1)
Mostly free A1 receptors
Saturated A1 receptorsand free A2 receptors
1.8 (Kd A2)APL (µM)
Low affinity A2 receptorssaturation curve
Saturated A2 receptors
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THEOPHYLLINE• Non-selective A1 and A2 adenosine-receptor antagonist• It is able to saturate A1 receptors, thus preventing their
activation in case of an acute increase in endogenous plasma adenosine
• It is also an almost equally potent antagonist of A2 receptors; thus it might have a potential role also counteracting a vasodepressor reflex
• The more adenosine pathways is involved in the mechanism causing syncope (such as in low-adenosine patients), the more theophylline will be effective. Conversely, theophylline should be less effective or ineffective in patients with high adenosine values (such as those with typical vasovagal syncope)
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6 patients with low-adenosine syncope (mean age 50 years; 4 W)
- long history (median 8 years) of recurrent unexplained
syncope without prodrome
- normal heart and normal ECG
- very low baseline values of plasmatic adenosine
- documentation of multiple episodes of paroxysmal AV block
and sinus arrest at the time of syncope
Intra-patient comparison between a period with and a period
without therapy with oral theophylline (within the serum
therapeutic range of 12–18 μg/mL), with the support of
prolonged ECG monitoring
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Case LAV08/13: • 72 yrs, male, 2 syncopes
w/t prodrome• normal heart, normal
ECG, negative EPS• negative tilt testing;
negative ADO test• July 2013: ILR
implantation• August 26, 2013:
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Case LAV08/13: ON THEOPHYLLINE
(Jul 29, 2014)
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Case LAV08/13: OFF THEOPHYLLINE
(Dec 31, 2014)
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Total follow-up on theophylline: 38 months• Asystole 3 sec: #7• Asystole 6 sec: #1• Symptomatic: #0
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Efficacy of theophylline in patients with syncope without prodromes with normal heart and normal ECG
Michele Brignole, Matteo Iori, Diana Solari, Nicola Bottoni, Giulia Rivasi, Andrea Ungar, Jean Claude Deharo, Regis Guieu
• 16 consecutive patients with syncope without prodrome with normal heart and normal ECG
• ECG documentation of syncope with asystolic pause/s by means of prolonged ECG monitoring
• Yearly incidence of syncopal recurrence during a period without and a period with tailored theophylline therapy
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• 16 patients; mean age 47±25 years; 9 female• History of recurrent syncope lasting on average 5 years• ECG: idiopathic AVB in 5 pts; brief progressive SB+ sinus
arrest/s in 11 patients • Median duration of the pauses: 11 s • Median value of plasma adenosine: 0.11 μM/L• Adenosine test positive in 5/7 pts; TTT positive in 3/10 pts
RESULTS
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RESULTS
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• The burden of syncope with theophylline decreased by 80% and 85% compared to no therapy periods
• The burden of asystolic episodes >3 s decreased by 89%.
13 pts with ILR
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RESULTS
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• During theophylline, syncope recurred in 1/5 (20%) pts with AVB vs 9/11 (81%) pts with sinus arrest (p=0.005).
• Among baseline clinical variables, only sinus arrest vs idiopathic AV block was independently predictive of syncope recurrence (p=0.02).
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CONCLUSIONS
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• Theophylline therapy is effective in reducing syncope burden in patients with syncope without prodromes with normal heart and normal ECG
• The efficacy is greater in those with idiopathic AV block• Theophylline therapy is a reasonable alternative to cardiac
pacing, especially in younger patients, and can be used as a “bridge” in order to delay it
• Future trials are needed before such therapy can be recommended in the guidelines
Theophylline in patients with unexplained syncope and low adenosine
(Theo-USA trial)Study verified by ILR, controlled by
propensity-score matching
Theo-USA trial
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GRAZIE PER L’ATTENZIONE
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In patients with chronic low plasma levels of adenosine, a transient release of endogenous adenosine can be sufficient to block conduction in the atrioventricular node and induce prolonged asystole
High affinity A1 receptorssaturation curve
Bradycardia zone Hypotension zone
% saturation
Low APL High APL
100%
50%
0.7 (Kd A1)
Mostly free A1 receptors
Saturated A1 receptorsand free A2 receptors
1.8 (Kd A2)APL (µM)
Low affinity A2 receptorssaturation curve
Saturated A2 receptors
Conversely, when plasma adenosine levels are chronically high, adenosine release is responsible for vasodepression.
