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

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

3. Disruption of heart rhythm in atrial fibrillation DBG1780 | June 2013

4. Normal regulation of heart rate and rhythm Contraction is controlled by the sinoatrial node DBG1780 | June 2013

5. 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 DBG1780 | June 2013

6. 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 DBG1780 | June 2013

7. 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 DBG1780 | June 2013

8. Classification of atrial fibrillation DBG1780 | June 2013

9. 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

10. 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 2013 DBG1780 | June 2013

11. Causes of atrial fibrillation DBG1780 | June 2013

12. Causes of AF: atrial fibrosis Fibrotic tissue does not conduct electrical signals efficiently, thereby disrupting the heart’s rhythm 1 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 = renin  angiotensin  aldosterone system DBG1780 | June 2013

13. 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;92:1954–68 DBG1780 | June 2013

14. 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 PVs 1,2 –Spontaneous focal electrical activity in PVs is enhanced by rapid atrial activity (e.g. AF) 3 –Abnormal PV electrical activity in AF patients 4 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 DBG1780 | June 2013

15. Pathogenesis of clot formation in atrial fibrillation DBG1780 | June 2013

16. Virchow’s triad HYPERCOAGULABLE STATE ENDOTHELIAL DAMAGE/ DYSFUNCTION CIRCULATORY STASIS 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 DBG1780 | June 2013

17. 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 DBG1780 | June 2013

18. 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 DBG1780 | June 2013

19. 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 AF 1  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 DBG1780 | June 2013

20. 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 AF 1,2 Increased LAA width and length correlates with thromboembolic risk 3 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 DBG1780 | June 2013

21. 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 of dislodged clot Appendage DBG1780 | June 2013

22. 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 DBG1780 | June 2013

23. 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 29 41 36 33 21 27 22 26 24 15 11 13 0 20 40 60 80 100 Men (n=150)Women (n=182)Total ischaemic strokes (n=332) Large artery atherosclerosis Small artery occlusion CardioembolismOther and undetermined causes Incidence (%) DBG1780 | June 2013

24. Risk factors for atrial fibrillation DBG1780 | June 2013

25. 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 DBG1780 | June 2013

26. 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 DBG1780 | June 2013

27. Summary DBG1780 | June 2013

28. 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