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Isabelle C Van Gelder
University Medical Center Groningen
The Netherlands
My work in atrial fibrillation and stroke
ESC stroke council Prague January 2017
Content
Stroke in rhythm versus rate control studies
Is AF a mechanism or just a marker for stroke
ASSERT
AF is progressive disease and AF progression is
associated with stroke, heart failure and mortality
Hypercoagulability not only mechanism of stroke but
also of AF progression ?
Content
Stroke in rhythm versus rate control studies
New drug targets for AF - Outline
32% rhythm control3% rate control
3% rhythm control4% rate control
28% rhythm control31% rate control
43% rhythm control46% rate control
CV death, stroke, worsening HF
Roy et al. AF-CHF New Engl J Med 2008
Stroke
Kirchhof Am Heart J 2013
Early treatment of AF for Stroke prevention Trial EAST
Content
Stroke in rhythm versus rate control studies
Is AF a mechanism or just a marker for stroke
ASSERT
Risk of ischemic stroke or embolism in SCAF
2580 patients with hypertension, > 65 yrs
no AF, pacemaker or ICD
Follow-up: 2.5 years
Subclinical AF: > 6 min > 190 bpm
Healey New Engl J Med 2012 ASSERT Study
Temporal disconnect
Parekh et al. Circ 2006
VKA therapy
monitoring
Brambatti for the ASSERT Investigators Circulation 2014
stroke
monitoring
VKA therapy
AF: mechanism or marker for stroke ?
SCAF episodes are associated with AF but
only a minority had SCAF in the month
before their stroke
Brambatti for the ASSERT Investigators Circulation 2014
Content
Stroke in rhythm versus rate control studies
Is AF a mechanism or just a marker for stroke
ASSERT
AF is progressive disease and AF progression is
associated with stroke, heart failure and mortality
AF is progressive disease
AF is the most frequent arrhythmia: > 1 million will have AF by 2040
AF is not benign being associated with MACCE
AF is a growing health care problem
Atrial Fibrillation is a progressive disease
… often progresses from self-terminating to non-selfterminating AF
n FU, years AF progression
Euro Heart Survey AF, 2010 1219 1 15%
Record-AF, 2012 2137 1 15%
AF progression is associated with vascular risks
De Vos, Crijns, Euro Heart Survey JACC 2010 AF progression No AF progression p value
CV admissions (%) 71 % 50 % <0.001
Stroke 6 % 2 % 0.003
CV mortality 7 % 3 % 0.005
Risk of ischemic stroke or embolism in SCAF
Healey New Engl J Med 2012 ASSERT Study
Longer subclinical AF: higher risk of stroke
Van Gelder, Healey for the ASSERT Investigators – under review
Years of Follow-up
Cu
mu
lative
even
t ra
tes
0.0
0.0
50
.10
0.1
50
.20
0 0.5 1 1.5 2 2.5 3 3.5
No SCAF>6mins~6hrs>6hrs~24hrs>24hrs
No. at Risk
No SCAF
>6mins~6hrs
>6hrs~24hrs
>24hrs
2455 1926 1708 1528 1251 900 624 390
0 226 302 347 322 281 218 155
0 88 104 103 108 93 80 52
0 91 124 144 140 126 116 85
SCAF > 24 hours
Content
Stroke in rhythm versus rate control studies
Is AF a mechanism or just a marker for stroke
ASSERT
AF is progressive disease and AF progression is
associated with stroke, heart failure and mortality
Hypercoagulability not only mechanism of stroke but
also of AF progression ?
Hypercoagulability and remodeling
RAASCellular Ca2+-
overloadEndothelin-1
Natriuretic
peptides
Heat shock
proteins
Structural Remodeling
Enlarged atria Hypertrophy Fibrosis Dedifferentiation Apoptosis Myolysis
Electrical
Remodeling
Associated
disease
Atrial
Fibrillation
Atrial
Fibrillation
+ + + ++
+ + + - -
Inflammation
oxidative stress
+
+
Focal triggers
of AF
Thrombin
activation
De Jong, Cardiovasc Res, 2011
Hypercoagulability represents a so far unrecognized key
mechanism in atrial remodeling and AF progression
Hypercoagulability and remodeling
Spronk et al. Eur Heart J 2016
Hypercoagulability associated
with atrial remodeling
Spronk et al. Eur Heart J 2016
Hyper-
coagulability
Xa
ThrombinCardiac fibroblast
TGF-β
IL-6
MCP-1
Pro-fibrotic and
inflammatory
cytokines
Dedifferentiation
(Myofibroblasts)
Collagen synthesis
+200% +120%Thrombin (0.01U/ml)
MCP-1
Thrombin + Dabigatran ns ns ns+72%
α-SMA 3H-proline incorporation
Fibroblasts
incubated with
thrombin
Thrombin promotes AF
0
20
40
60
80
Wt TMpro/pro
1/10
6/10
c2 p<0.01
AF inducible
(%)
Wt burst normal sinus rhythm
P
QRS
TMpro/pro atrial fibrillation
QRS
P
burst
0.1
1
10
100
1000
TMpro/pro Wt
AF duration
(s)
0
p<0.01
0.5 s
A
B C TMpro/pro Wt
Ctr Ctr
Ctr
Ctr Ctr
Ctr
Spronk et al. Eur Heart J 2016
TM pro/pro
transgenic mice
with enhanced
thrombin activity
(hypercoagulable
phenotype)
Wildtype mice
Spronk et al. Eur Heart J 2016
Stroke and other MACCE
PAR stimulation
Atrial remodeling *
AF progression
Thrombin activation
TGF-β
* Capillary rarefaction, Inflammation, Myocyte death, Fibroblast proliferation, Fibrosis, Dispersion of conduction & repolarisation
AF Hypertension, heart failure
MCP-1
IL-6
Hypercoagulability and remodeling
Hypercoagulability is the key mechanism in AF
progression
Hypercoagulability varies depending on duration of AF
and severity of the underlying disease
Thrombin inhibitors, Factor Xa inhibitors and vitamin K
antagonists differ with respect to prevention of AF
progression
Hypothesis RACE V
atrialfibrillationresearch.nl
Thank you for your attention