Pathophysiology of atrial fibrillation and associated stroke

Module 2

Disruption of heart rhythm in atrial fibrillation

Normal regulation of heart rate and rhythm

Contraction is controlled by the sinoatrial node

Normal heart rhythm is disrupted in AF

AF is characterized by:
Rapid (350600 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 can be:

Irregular and rapid (110180 beats/minute; tachycardia) Irregular and slow (<50 beats/minute; bradycardia)

Cardiac output can be reduced

Goodacre S & Irons R. BMJ 2002;324:5947

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;92:195468

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

Classification of atrial fibrillation

Classification of AF: 2006 joint guidelines of the ACC, AHA and ESC (1)
Classification First detected Recurrent Paroxysmal Persistent Definition First recognized episode of AF 2 episodes of arrhythmia AF that terminates spontaneously AF that persists for >7 days but can be converted with cardioversion AF that cannot be terminated by cardioversion, and long-standing AF (>1 year) where cardioversion not indicated/not attempted

Long-standing persistent

ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology

AHA/ACC/ESC Guidelines. Circulation 2006;114:e257354

Classification of AF: 2006 joint guidelines of the ACC, AHA and ESC (2)
Classification Lone or primary Definition AF without clinical/echo findings of heart disease and age <60 years AF associated with cardiopulmonary disease (e.g. myocardial infarction or pneumonia), cardiac surgery, pericarditis or hyperthyroidism AF that is not associated with damage to the heart valves (e.g. rheumatic mitral valve disease, prosthetic heart valve or mitral valve repair)

Secondary

Non-valvular

ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology; echo = echocardiogram AHA/ACC/ESC Guidelines. Circulation 2006;114:e257354

Classification of 5 types of AF: ESC guidelines 2010

Classification First diagnosed Paroxysmal Persistent Long-standing persistent Permanent AF Definition First recognized episode of AF, irrespective of duration or the presence and severity of AF-related symptoms AF that is self-terminating, usually within 48 hrs AF that persists for >7 days or requires termination by cardioversion AF that has lasted for 1 yr when it is decided to adopt a rhythm control strategy Presence of the arrhythmia is accepted by the patient (and physician)

ESC = European Society of Cardiology

ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369429

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Classification of 5 types of AF: ESC guidelines 2010

First diagnosed episode of atrial fibrillation

(usually 48 hrs)

Paroxysmal

(>7 days or requires CV)

Persistent

persistent (>1 yr)

Long-standing

Permanent
(accepted)

CV = cardioversion ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369429

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Causes of atrial fibrillation

Causes of AF: atrial fibrosis

Fibrotic tissue does not conduct electrical signals efficiently, thereby disrupting the hearts 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 = reninangiotensinaldosterone system 1. Burstein B & Nattel S. J Am Coll Cardiol 2008;51:8029; 2. AHA/ACC/ESC Guidelines. Circulation 2006;114:e257354

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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;92:195468

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Causes of AF: pulmonary veins (PVs)

Oxygenated blood returns to the heart via PVs, which drain into the left atrium 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

Virchows triad

Atrial fibrillation Left ventricular dysfunction Immobility Venous insufficiency/ varicose veins

Atrial fibrillation Trauma/surgery Atherosclerosis Venopuncture Heart valve disease/ replacement Indwelling catheters
HYPERCOAGULABLE STATE

Atrial fibrillation Malignancy Pregnancy Oestrogen therapy Trauma/surgery

Sepsis Thrombophilia Inflammatory bowel disease Nephrotic syndrome

Adapted from Watson T et al. Lancet 2009;373:15566

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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 Virchows triad for thrombogenesis

Watson T et al. Lancet 2009;373:15566

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Components of Virchows triad for thrombogenesis in AF

vWF = Von Willebrand factor Watson T et al. Lancet 2009;373:15566

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Blood stasis in AF
Stasis is the most important cause of thrombosis in AF Erratic heart contraction reduces flow velocity in the atria (stasis), increasing the risk of thromboembolism Predictors of spontaneous echo contrast, a possible marker of stasis in AF, include:
Left atrial enlargement Reduced left atrial appendage flow velocity Left ventricular dysfunction Fibrinogen level

Haematocrit
echo = echocardiogram AHA/ACC/ESC Guidelines. Circulation 2006;114:e257354

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Abnormal changes of the atrial wall in AF

AF causes enlargement of the left atrium and left atrial appendage (LAA) The LAA is the most common site of intra-atrial thrombus formation1 Increased LAA width and length correlates with thromboembolic risk2

1. Blackshear JL & Odell JA. Ann Thorac Surg 1996;61:7559; 2. Stllberger C et al. Ann Intern Med 1998;128:6308

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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 Virchows triad Increased thrombogenesis has been reported in acute-onset or chronic AF13

1. Marin F et al. Heart 2004;90:11626; 2. Roldan V et al. Am Heart J 1998;136:95660; 3. Kahn SR et al. Can Med Assoc J 1997;157:67381

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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 appendage (LAA)
LAA is a small muscular pouch attached to the main atrial chamber In non-valvular AF, ~90% of atrial thrombi occur in the LAA1

Appendage

Appendage Clot Path of dislodged clot

1. Blackshear JL & Odell JA. Ann Thorac Surg 1996;61:7559

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Non-cardioembolic causes of stroke in AF

A proportion (~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:e257354; 2. Bogousslavsky J et al. Neurology 1990;40:104650

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Incidence of ischaemic stroke subtypes (TOAST criteria)

Large artery atherosclerosis Cardioembolism Small artery occlusion
Figure reproduced with permission from the BMJ Publishing Group Ltd. 2008

Other and undetermined causes 15 22 11 26 21 13 24 27

100
80 Incidence (%) 60

40
20 0

33

29 Men (n=150)

41

36

Women (n=182)

Total ischaemic strokes (n=332)

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;79:13448

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Risk factors for atrial fibrillation

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 Female gender

Sawin CT et al. N Engl J Med 1994;331:124952; Kannel WB & Benjamin EJ. Med Clin North Am 2008;92:1740

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Risk factors for AF (2)

Echocardiographic abnormalities:
Left atrial enlargement Increased left ventricular wall thickness

Reduced left ventricular fractional shortening

Thyroid disorders: hyperthyroidism increases the risk of AF 3-fold Inflammation (e.g. myocarditis, pericarditis, systemic inflammation, pneumonia) Sleep apnoea

Sawin CT et al. N Engl J Med 1994;331:124952; Kannel WB & Benjamin EF. Med Clin North Am 2008;92:1740

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Summary

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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