My work in atrial fibrillation and stroke...CV admissions (%) 71 % 50 %

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


New drug targets for AF - Outline

32% rhythm control3% 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



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



ASSERT



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



ASSERT



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


Spronk et al. Eur Heart J 2016

Hypercoagulability associated

with atrial remodeling


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


TM pro/pro

transgenic mice

with enhanced

thrombin activity

(hypercoagulable

phenotype)

Wildtype mice


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 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

My work in atrial fibrillation and stroke...CV admissions (%) 71 % 50 %

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