SINCOPE ED ADENOSINA

Michele Brignole

Centro Aritmologico, Ospedali del Tigullio, Lavagna

Explanatory case 1

• Cinzia, 20 yrs, female

• 50 syncopes/last 2 yrs, no prodromes or very short (<5 sec) blurring of

the vision

• normal heart, normal ECG

• negative tilt testing

Explanatory case 2

• Marcello, 50 yrs,male

• 5 syncopes no prodromes or very short (<5 sec) blurring of the vision;

1 car crash

• normal heart, normal ECG

• positive tilt testing, mixed response (no asystole)

“Low-adenosine syncope” - sincope adenosino-sensibile

Explanatory case 1

• Cinzia, 20 yrs, female

• 50 syncopes/last 2 yrs, no prodromes or very short (<5 sec) blurring of the vision

• normal heart, normal ECG

• negative tilt testing

• Adenosine Plasma Level: 0.09 microM/l (n.v. >0.40)

• June 2013: ILR implantation + theophylline 600 mg/day

Case USA-FU #7 (05/06/2013)

ON theophylline, 30 months (from June 2013 to Nov 2015): no syncope

OFF theophylline, 1 months (from Dec 2015): 2 syncopes

ON theophylline, 6 months (from Jan 2016 to June 2016): no syncope

Explanatory case 2

• Marcello, 50 yrs,male

• 5 syncopes no prodromes or very short (<5 sec) blurring of the vision; 1 car crash

• normal heart, normal ECG

• positive tilt testing, mixed response (no asystole)

• adenosine plasma level: 0.01 microM/l (n.v. >0.40)

• Sept 2015: ILR implantation

• Feb 1, 2016: 2 syncopes

Case USA-FU #18 (22/09/2015)

30 sec asystole

13 sec asystole

• Sept 2016: ON theophylline 600 mg/d ; no symptoms

Explanatory case 3

• Higuchi 51 yrs, female

• 2 syncopes with very short (<5 sec) blurring of the vision, recurrent pre-syncopes

• normal heart, normal ECG

• in-hospital telemetric monitoring (13/02/2003):

Maggi et al. Case III-15. Garcia Civera et al (Ed): Syncope cases. Blackwell Futura 2006: pag 190-1

Explanatory case 3

• Higuchi , 51 yrs, female

• 2 syncopes with very short (<5 sec) blurring of the vision, recurrent pre-syncopes

• normal heart, normal ECG

• EP study (15/02/2003): PA: 60 ms; AH: 70 ms; HV: 35 ms; Wenckebach cycle: 370 ms; SNRT:1190 ms ms

• ATP test:

• Ajmaline test: negative

• Theophylline 240 mg i.v + ATP test:

0

100

50

150

mm Hg

HRA

BP

A

V

A

V

Case III-15. Garcia Civera et al (Ed): Syncope cases. Blackwell Futura 2006: pag 190-1

Explanatory case 3

• Higuchi, now 64 yrs

ON theophylline, 13 year (from 2003 to 2016): no syncopeHolter: nocturnal paroxysmal AV block with max pause of 3.5 sec

Follow-up: May 2016

Explanatory case 4

• Giuliana C, 50 yrs, female

• 20 syncopes during life

• normal heart, normal ECG

• negative CSM, negative HUT, negative EPS

• Holter (1995): paroxysmal AV block, max pause of 4 sec

• ATP test: AV block, max pause 11 sec

Case #1 Heart Rhythm 2016; 13: 1151

ON theophylline, 10 years (from June 1995 to 2005): no syncope

OFF theophylline, 3 years (from 2005 to 2008): 3 syncopes

PM implant, 6 years (from Jan 2008 to 2016): no syncope

AVB with asystole 22+8+4 secAPL=0.12 µM(n.v. 0.40-0.80)

Explanatory case 5

• Michele 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:

P P P P PP

P P P P

APL=0.09 µM(n.v. 0.40-0.80)

PP P P P P

PP

Case #2, M, 72 yrs

B) ON theophylline (Jul 29, 2014)

Case #2, M, 72 yrs

PP

C)

PP P P P P

PP

Case #2, M, 72 yrs

OFF theophylline (Dec 31, 2014)

Extended follow-upNumber of pauses >3 s per month

1

8

0

2

1

0 0 0 0

5

0 0

1 1

0 0 0

2

0 0

1 1

0 0 0 0 0 0 0 0 0 0 0

1

Month 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4

Year 2013 Year 2014 Year 2015 Year 2016

No therapy

Theophylline

Case #2, M, 72 yrs

Heart Rhythm 2015 Dec 9 [Epub ahead of print]

Case #4, F, 71 yrs

OFF theophylline (Oct 22, 2014)

P

P

P P P P PP P

PP

OFF theophylline (Oct 22, 2014)

0

1

2

0

1

4

1

2

6

1

4

5

3

0 0 0 0 0 0 0

Month 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7

Year 2013 Year 2014 Year 2015

Case #4, F, 71 yrs

Number of pauses >3 s per month

No therapy

Theophylline

Heart Rhythm 2015 Dec 9 [Epub ahead of print]

J Am Coll Cardiol 2013;62:1075–80

APL (µM)

APL µM (median) 0.33 µM 0.25 µM 0.85 µM 0.49 µM

J Am Coll Cardiol 2013;62:1075–80

“Low adenosine” syncope:

syncope w/t prodrome, normal heart & normal ECG

High affinity A1 receptors saturation curve

AV block zone Sinus arrest/bradycardiazone

% saturation

Low APL High APL

100%

50%

0.7 (Kd)

Mostly freereceptors

Mostly saturatedreceptors

0.10.01 2 10

APL (M)J Am Coll Cardiol 2011; 58: 167–73

Pathophysiological observations

ß1 R A1 R M2 R

Catecholamines Adenosine Ach

+ -cAMP level

Ica currents

+ -+Ik ado/Ach

Direct effects

Indirect effects

Pathophysiological observations

J Am Coll Cardiol 2011; 58: 167–73

Cellmembrane

Syncopal faint

Cardiac intrinsic

cause

Neurally-mediated

(reflex) cause

Low

Adenosine

(asystole)

Normal

Adenosine

High

Adenosine

(hypotension)

Adenosine phenotypes

and neurally-mediated syncope

“Low adenosine” syncopes

Idiopathic AV block

& Syncope w/t prodromes

Vasovagal syncope

Clinical features

Prodromes Absent or very short (<5 s) Always present

Structural heart dis. Absent Absent

Age of presentation Any age, but most >40 yrs Any age, but most <40 yrs

History of syncope Short (avg 1 year) Long (avg 10 years)

Laboratory findings

Plasmatic adenosine Very low Very high

Adenosine/ATP test Mostly positive (asystolic 3°

degree AV block)

May be positive

Tilt Table Test Mostly negative Mostly positive

66%5%

31%No or mild

rhythm variations

Asystole

(avg 11±5 s)Tachycardia

2-year diagnostic yield of

Implantable Loop Recorder (ILR)

in 58 patients with

unexplained syncope,

no prodrome and normal heart

NND=number needed for diagnosis

32%

54%

NND = 1.8NND = 3.1

Mechanism of syncope

The mechanism of syncope without prodromes with normal heart and normal electrocardiogramMichele Brignole, Regis Guieu, Marco Tomaino, Matteo Iori, Andrea Ungar, Cristina Bertolone, Matthias Unterhuber,

Nicola Bottoni, Francesca Tesi, Jean Claude Deharo. Heart Rhythm 2016

Pt

no.

Age Gender Adenosine

plasma level

(μmol/L)

End-point event

(diagnosis)

Max pause

duration, s

Mechanism-

specific therapy

Recurrence of

syncope on

therapy

1 72 M 0.09 Sudden AVB 6.1 Theophylline No

2 78 F hemolysis Sudden AVB 20 Pm Pre-syncope

3 77 F 0.15 Sudden AVB 10 Pm No

4 71 F 0.37 Sudden AVB 3.5+2.5+2.5 Pm No

5 80 F hemolysis Sudden AVB 13 Theophylline No

6 78 F 0.60 Sudden AVB 22 Theophylline No

7 71 F 0.10 Sudden AVB 7 Theophylline No

8 71 F 0.14 Sudden AVB 10 Pm No

9 73 F 0.40 Sudden AVB 10 Pm No

10 38 M 0.12 Sudden SA 16 Pm No

11 20 F 0.09 Progressive SB + SA 14 Theophylline No

12 71 F 0.15 Progressive SB + SA 6.5 Pm No

13 50 M <0.01 Progressive SB + SA 14 Theophylline No

14 58 M 0.15 Progressive SB + SA 4+2+2 Theophylline Syncope

15 41 M 0.18 Progressive SB + SA 6 Theophylline No

16 76 F 0.7 Progressive SB + SA 12 Pm No

17 72 F 0.50 Progressive SB + SA 8 Pm No

The mechanism of syncope without prodromes with normal heart and normal electrocardiogramMichele Brignole, Regis Guieu, Marco Tomaino, Matteo Iori, Andrea Ungar, Cristina Bertolone, Matthias Unterhuber,

Nicola Bottoni, Francesca Tesi, Jean Claude Deharo. Heart Rhythm 2016

Prodrome (*)

No prodrome

* Prodrome group: reflex syncope treated with pacemaker (age/sex matched from ISSUE trial)

7%

25%

Brignole et al. Heart Rhythm 2016

ATP test positivity rate (max RR ≥6 s)

Subjects w/t syncope (controls) 5%

Unexplained syncope (Tilt- and CSM -) 28%

Unexplained syncope, no prodrome,normal ECG

60%

Idiopathic AV block 66%

Source

Circulation 1997;96:3921-3927 J Am Coll Cardiol 2011; 58: 167–73 J Am Coll Cardiol 2013;62:1075–80

Adenosine phenotypes

and neurally-mediated syncope

Adenosine phenotypes

and neurally-mediated syncope

24%35%

73%

Low adenosine(No prodr + CSS)

Normal adenosine(Situational)

High adenosine(VVS)

Tilt test positivity rate

Guieu et al. JACC 2015: 66: 204