my work in atrial fibrillation and stroke...cv admissions (%) 71 % 50 %
TRANSCRIPT
![Page 1: My work in atrial fibrillation and stroke...CV admissions (%) 71 % 50 %](https://reader035.vdocuments.mx/reader035/viewer/2022071023/5fd870e58ff92930c629081b/html5/thumbnails/1.jpg)
Isabelle C Van Gelder
University Medical Center Groningen
The Netherlands
My work in atrial fibrillation and stroke
ESC stroke council Prague January 2017
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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 ?
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Content
Stroke in rhythm versus rate control studies
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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
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Kirchhof Am Heart J 2013
Early treatment of AF for Stroke prevention Trial EAST
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Content
Stroke in rhythm versus rate control studies
Is AF a mechanism or just a marker for stroke
ASSERT
![Page 7: My work in atrial fibrillation and stroke...CV admissions (%) 71 % 50 %](https://reader035.vdocuments.mx/reader035/viewer/2022071023/5fd870e58ff92930c629081b/html5/thumbnails/7.jpg)
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
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Temporal disconnect
Parekh et al. Circ 2006
VKA therapy
monitoring
Brambatti for the ASSERT Investigators Circulation 2014
stroke
monitoring
VKA therapy
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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
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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
![Page 11: My work in atrial fibrillation and stroke...CV admissions (%) 71 % 50 %](https://reader035.vdocuments.mx/reader035/viewer/2022071023/5fd870e58ff92930c629081b/html5/thumbnails/11.jpg)
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%
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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
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Risk of ischemic stroke or embolism in SCAF
Healey New Engl J Med 2012 ASSERT Study
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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
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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 ?
![Page 16: My work in atrial fibrillation and stroke...CV admissions (%) 71 % 50 %](https://reader035.vdocuments.mx/reader035/viewer/2022071023/5fd870e58ff92930c629081b/html5/thumbnails/16.jpg)
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
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Hypercoagulability represents a so far unrecognized key
mechanism in atrial remodeling and AF progression
Hypercoagulability and remodeling
Spronk et al. Eur Heart J 2016
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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
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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
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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
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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
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atrialfibrillationresearch.nl
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