Pathophysiology of atrial fibrillationand associated stroke
Module 2
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DBG1780 | June 2013
Pathophysiology of atrial fibrillationand associated stroke
Module 2
DBG1780 | June 2013
Disruption of heart rhythmin 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;324:594–7DBG1780 | June 2013
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;92:195468DBG1780 | June 2013
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: 2388-2442DBG1780 | June 2013
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 direct-current 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 DBG1780 | June 2013
Conditions associated with AF include:
• 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 2013DBG1780 | June 2013
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
1. Burstein B, Nattel S. J Am Coll Cardiol 2008;51:802–9;2. AHA/ACC/ESC Guidelines. Circulation 2006;114:e257–354
RAAS = reninangiotensinaldosterone system
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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 self-perpetuating disturbances in electrical signalling (‘electrical remodelling’)1
1. Wijffels MC et al. Circulation 1995;92:1954–68DBG1780 | June 2013
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;339:65966; 2. Schauerte P et al. J Cardiovasc Electrophysiol 2001;12:59299; 3. Zhou S et al. Am J Physiol Heart Circ Physiol 2002;283:H124452; 4. Jais P et al. Circulation 2002;106:247985
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Pathogenesis of clot formation in atrial fibrillation
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Virchow’s triad
HYPERCOAGULABLE STATEEN
DO
TH
ELIA
L DAM
AG
E/
DYSFU
NCTIO
N
CIR
CU
LATO
RY S
TASIS• Atrial fibrillation
• Left ventricular dysfunction• Immobility• Venous insufficiency/ varicose veins
• Atrial fibrillation• Trauma/surgery• Atherosclerosis • Venopuncture• Heart valve disease/ replacement• Indwelling catheters
Adapted from Watson T et al. Lancet 2009;373:155–66
• Atrial fibrillation• Malignancy• Pregnancy• Oestrogen therapy• Trauma/surgery
• 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;373:155–66DBG1780 | June 2013
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 2013DBG1780 | June 2013
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 acute-onset or chronic AF13
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
Clot
Path ofdislodged clot
Appendage
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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)
Bejot Y et al. J Neurol Neurosurg Psychiatry 2008;79:1344–8
Data from prospective population-based study conducted in Dijon, France (152 606 inhabitants); TOAST = Trial of Org 10172 in Acute Stroke Treatment
2941 36
3321 27
22 26 24
15 11 13
0
20
40
60
80
100
Men (n=150) Women (n=182) Total ischaemicstrokes (n=332)
Large artery atherosclerosis Small artery occlusion
Cardioembolism Other and undetermined causes
Inci
dence
(%
)
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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;92:17–40DBG1780 | June 2013
Risk factors for AF (2)
• Echocardiographic abnormalities:– Left atrial enlargement
– Increased left ventricular wall thickness
– Left ventricular fractional shortening
• Thyroid disorders: hyperthyroidism increases the riskof 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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