Pathophysiology of atrial fibrillation and associated stroke Module 2 Developed and funded by DBG1780 | June 2013.

Pathophysiology of atrial fibrillationand associated stroke

Module 2

Developed and funded by

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

DBG1780 | June 2013