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Pathophysiology of atrial fibrillation
and associated stroke
Module 2
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DBG1780 | June 2013
Pathophysiology of atrial fibrillation
and associated stroke
Module 2
DBG1780 | June 2013
Disruption of heart rhythm
in atrial fibrillation
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Normal regulation of heart rate and rhythm
• Contraction is controlled by the sinoatrial node
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Normal heart rhythm is disrupted in AF
• AF is characterized by:
– Rapid (350–600 beats/minute) and irregular atrial activity
– Reduced filling of the left and right ventricles
• Conduction of most impulses from the atria to ventricles
is blocked at the atrioventricular (AV) node
• Ventricular rate is irregular and may be:
– Rapid (100–180 beats/minute; tachycardia)
– Or slow (<50 beats/minute; bradycardia)
• Cardiac output can be reduced
Goodacre S, Irons R. BMJ 2002;324:594–7
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AF begets AF
• AF causes remodelling that contributes to the initiation
and maintenance of AF, including:
– Electrical: shortening of atrial refractory period
– Structural: enlargement of atrial cavities
• Initially, many episodes of AF resolve spontaneously
• Over time, AF tends to become persistent or permanent
due to electrical and structural remodelling
Wijffels MC et al. Circulation 1995;92:195468
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Consequences of AF
• Formation of blood clots (thrombosis) on the atrial walls
that can dislodge (embolize), leading to stroke and
systemic embolism
• Reduction in cardiac output can precipitate heart failure,
leading to distinctive symptoms such as:
– Peripheral oedema
– Dyspnoea
– Pulmonary oedema
– Fatigue
– Chest pain
Dickstein K et al. European Heart Journal 2008; 29: 2388-2442
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Classification of atrial fibrillation
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Types of AF: ESC guidelines
• First diagnosed AF - every patient presenting with AF
for the first time, irrespective of duration of the
arrhythmia or presence or severity of symptoms
• Paroxysmal AF is self-terminating, usually within 48
hours
• Persistent AF is present when an AF episode either lasts
longer than 7 days or requires termination by
cardioversion, either with antiarrhythmic drugs or directcurrent cardioversion
• Long-standing persistent AF has lasted for ≥1 year
and a rhythm control strategy is adopted
• Permanent AF exists when the arrhythmia is accepted
by the patient (and physician) and a rhythm control
strategy is not pursued
ESC Guidelines for the management of atrial fibrillation 2010. Accessed June 2013
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Conditions associated with AF include:
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•
•
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Symptomatic heart failure
Valvular heart disease
Cardiomyopathies
Atrial septal defect
Coronary artery disease
Diabetes mellitus
COPD
Sleep apnoea
Chronic renal disease
ESC Guidelines for the management of atrial fibrillation 2010. Accessed June 2013
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Causes of atrial fibrillation
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Causes of AF: atrial fibrosis
• Fibrotic tissue does not conduct electrical signals
efficiently, thereby disrupting the heart’s rhythm1
• Causes of atrial fibrosis include:2
– Ischaemia
– Atrial dilatation activating signalling pathways including the
RAAS, leading to upregulation of profibrotic factors
(e.g. angiotensin II)
– Genetic factors e.g. mutations of the lamin A/C gene
– Inflammatory conditions e.g. pericarditis, sarcoidosis and
autoimmune disorders
RAAS = reninangiotensinaldosterone system
1. Burstein B, Nattel S. J Am Coll Cardiol 2008;51:802–9;
2. AHA/ACC/ESC Guidelines. Circulation 2006;114:e257–354
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Causes of AF: atrial stretch
• Caused by raised atrial pressure and permanent
stretching
• Conditions that increase intra-cardiac pressure include:
– Hypertension
– Congestive heart failure
– Valvular disease (e.g. mitral stenosis and regurgitation)
– Ischaemia
• AF alters electrophysiological properties, creating selfperpetuating disturbances in electrical signalling
(‘electrical remodelling’)1
1. Wijffels MC et al. Circulation 1995;92:1954–68
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Causes of AF: pulmonary veins (PVs)
• PV electrical activity involved in initiation and
maintenance of AF
– AF can be induced by electrical stimulation or ectopic activity of
PVs1,2
– Spontaneous focal electrical activity in PVs is enhanced by rapid
atrial activity (e.g. AF)3
– Abnormal PV electrical activity in AF patients4
• Shorter refractory period in PVs and delay in electrical conduction
between PVs and atrium vs. control patients
• Underlying mechanisms still need to be elucidated
1. Haissaguerre M et al. N Engl Med 1998;339:65966; 2. Schauerte P et al. J Cardiovasc Electrophysiol
2001;12:59299; 3. Zhou S et al. Am J Physiol Heart Circ Physiol 2002;283:H124452;
4. Jais P et al. Circulation 2002;106:247985
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Pathogenesis of clot formation in atrial
fibrillation
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Virchow’s triad
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Atrial fibrillation
Left ventricular dysfunction
Immobility
Venous insufficiency/
varicose veins
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Atrial fibrillation
Trauma/surgery
Atherosclerosis
Venopuncture
Heart valve disease/
replacement
• Indwelling catheters
HYPERCOAGULABLE STATE
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Atrial fibrillation
Malignancy
Pregnancy
Oestrogen therapy
Trauma/surgery
Adapted from Watson T et al. Lancet 2009;373:155–66
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Sepsis
Thrombophilia
Inflammatory bowel disease
Nephrotic syndrome
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Thrombogenic tendency in AF
• The pathogenesis of thromboembolism in AF is complex
and multifactorial
• Extensive abnormal changes of the atrial wall, blood
stasis and blood constituents are clearly evident in
patients with AF
• Thus, AF could drive a prothrombotic or hypercoagulable
state by virtue of its fulfilment of Virchow’s triad for
thrombogenesis
Watson T et al. Lancet 2009;373:155–66
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Thromboembolism in AF
• Risk of stroke and systemic embolism is linked to such
factors as:
– Stasis in left atrium (LA)
– Reduced flow velocity in the left atrial appendage (LAA)
– Endocardial abnormalities (progressive atrial dilatation,
endocardial denudation)
ESC Guidelines for the management of atrial fibrillation 2010. Accessed June 2013
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Hypercoagulable state in AF
• In AF, abnormal changes are evident in:
– Platelets and proteins of the coagulation cascade
– Inflammatory cytokines and growth factors
• Presence of a prothrombotic or hypercoagulable state in
AF completes Virchow’s triad
• Increased thrombogenesis has been reported in acuteonset or chronic AF13
1. Marin F et al. Heart 2004;90:1162–6; 2. Roldan V et al. Am Heart J 1998;136:956–60;
3. Kahn SR et al. CMAJ 1997;157:673–81
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Abnormal changes of the atrial wall in AF
• AF causes enlargement of the left atrium and left atrial
appendage (LAA), a small muscular pouch attached to
the main atrial chamber
• The LAA is the dominant source of embolism (~90%) in
non-valvular AF1,2
• Increased LAA width and length correlates with
thromboembolic risk3
1. Blackshear JL, Odell JA. Ann Thorac Surg 1996;61:755–9;
2. Watson T et al. Lancet 2009;373:155―66;
3. Stöllberger C et al. Ann Intern Med 1998;128:630–8
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Left atrial appendage and thrombus formation in AF
• Atria do not contract properly leading to stasis in the
left atrium and left atrial appendage (LAA)
Appendage
Appendage
Clot
Path of
dislodged clot
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Non-cardioembolic causes of stroke in AF
• A proportion (up to 25%) of strokes in AF occur from
causes other than thromboembolism:1,2
– Thromboembolism from heart chambers other than the left
atrium
– Atherosclerotic plaques in vessels (e.g. proximal aorta)
– Underlying cerebrovascular disease
1. AHA/ACC/ESC Guidelines. Circulation 2006;114:e257–354;
2. Bogousslavsky J et al. Neurology 1990;40:1046–50
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Incidence of ischaemic stroke subtypes (TOAST criteria)
100
Incidence (%)
80
Large artery atherosclerosis
Small artery occlusion
Cardioembolism
Other and undetermined causes
15
11
13
22
26
24
21
27
41
36
Women (n=182)
Total ischaemic
strokes (n=332)
60
40
20
33
29
0
Men (n=150)
Data from prospective population-based study conducted in Dijon, France (152 606 inhabitants);
TOAST = Trial of Org 10172 in Acute Stroke Treatment
Bejot Y et al. J Neurol Neurosurg Psychiatry 2008;79:1344–8
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Risk factors for atrial fibrillation
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Risk factors for AF (1)
• Advancing age
• Cardiovascular diseases:
– Hypertension
– Diabetes mellitus, insulin resistance and the metabolic syndrome
– Myocardial infarction
– Congestive heart failure
– Valvular disease and heart surgery
• Excessive alcohol intake
• Family history of AF
• Male gender
Kannel WB & Benjamin EJ. Med Clin North Am 2008;92:17–40
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Risk factors for AF (2)
• Echocardiographic abnormalities:
– Left atrial enlargement
– Increased left ventricular wall thickness
– Left ventricular fractional shortening
• Thyroid disorders: hyperthyroidism increases the risk
of AF three-fold
• Inflammation (e.g. myocarditis, pericarditis, systemic
inflammation, pneumonia)
• Sleep apnoea
Sawin CT et al. N Engl J Med 1994;331:1249–52; Kannel WB, Benjamin EF. Med Clin North Am
2008;92:17–40
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Summary
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Summary
• AF is characterized by an irregularly irregular heart rate
• Classification:
– Paroxysmal
– Persistent
– Permanent
• Causes:
– Atrial fibrosis
– Atrial stretch
– Pulmonary veins
• Thrombi can form on the atrial walls and then dislodge,
leading to stroke and systemic embolization
• Pathogenesis of thromboembolism is complex and
multifactorial
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