1. Cardiac Arrhythmia in Thalassaemia Limassol, 24 – 26 October 2012 Malcolm Walker University College and the Heart Hospitals, London Clinical Director Hatter Cardiovascular Institute

2. Malcolm Walker TIF 2012 Cardiac Arrhythmias in thalassaemia Plan of talk 1.Historical aspects 2.Relationship to iron overload 3.Clinical Management: Principles & Investigation 4.Specific arrhythmia 5.Technology: Ablation & Devices

3. Malcolm Walker TIF 2012 Cardiac Arrhythmia in thalassaemia 1. Historical aspects

4. Malcolm Walker TIF 2012 History: incidence of arrhythmia & ECG changes thalassaemia, transfused but not chelated AgeNormal ECG %LV hypertrophy % Rhythm abnormality % Heart block % 5-10673366 11-153928446 16-2030405040 21-30126219 TOTAL39402714 Adapted from Ehlers et al 1980

5. Malcolm Walker TIF 2012 Cardiac Arrhythmia in thalassaemia 2. Relationship to iron overload

6. Malcolm Walker TIF 2012 ● 652 patients with  -thalassaemia ● Mean age 27 yr ● Excluded those with heart failure (HF) at first scan Arrhythmia and myocardial iron assessed by cMR T2*

7. Threshold for arrhythmia T2*<20ms Types & frequency: ● AF 78 (12%) ● SVT 14 (2%) ● VT 5 (<1%) ● VF1

8. Malcolm Walker TIF 2012 Adapted from: Marsella et.al. Haematologica 2011; 96: 515 MIOT study group: gender differences

9. Malcolm Walker TIF 2012 Adapted from: Marsella et.al. Haematologica 2011; 96: 515 MIOT study group: T2* and cardiac arrhythmia

10. Conclusions Incidence of arrhythmia very low in this Italian cohort 25 out of 776 patients (3.2%); compared to overall 15% incidence in 1 year (UK cohort; Kirk et al 2009) No statistical relationship with heart iron by T2* in Italian group; clear cut risk associated with T2* in UK cohort (Kirk et al 2009) Arrhythmia and myocardial iron assessed by cMR T2*

11. Reasons for differences between Italian and UK patients? Italian cohort more recent Overall lower T2*; very few patients with T2* < 20 ms More patients on combination Rx (DFO + DFP) Arrhythmia and myocardial iron assessed by cMR T2*

12. Malcolm Walker TIF 2012 AF in thalassaemia major – UCH clinic 80 consecutive clinic attenders 2011-2012  Mean age 38 yr; 51% female  AF current 8.75%  History of AF or pAF 33.7%  DM48.7%  Thyroid22.0%  Hep C (ever)15.0%  Heart failure in last 12 months10.0%

13. Malcolm Walker TIF 2012 AF in thalassaemia – UCH clinic 551110 % incidence Heart iron load by current cMR T2*

14. Reasons for differences between Italian and UK patients? AF in thalassaemia – UCH clinic Relationship between iron load & AF T2* ms Range 5 to 13 yr ago P < 0.05 Walker et al unpublished observations

15. Reasons for differences between Italian and UK patients? Atrial fibrillation (AF) occurs late in life and reflects past history, not current iron status AF in thalassaemia – UCH clinic Relationship between iron load & AF T2* ms Range 5 to 13 yr ago P < 0.05 Walker et al unpublished observations

16. Malcolm Walker TIF 2012 AF in thalassaemia – UCH clinic Risk factors for AF  Diabetes link  71% of those in AF now have DM  69% of those with a history or pAF have DM  LA size (by area by ECHO – cMR volumes awaited)  No clear correlation with AF  Current LV function (systolic, by EF)  No clear correlation with AF  Correlation with previous episode of LV dysfunction

17. Malcolm Walker TIF 2012 Cardiac Arrhythmia in thalassaemia 3. Clinical Management principles & investigation

18. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia Symptoms  Palpitation  Breathlessness  Dizziness or near fainting  Collapse There is a mismatch between symptoms & severity of arrhythmia “Trivial” problems may cause immense anxiety Potentially severe arrhythmia may cause only minor complaints (or no symptoms)

19. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia Symptoms  Palpitation  Breathlessness  Dizziness or near fainting  Collapse  Near fainting, loss of consciousness or collapse Always need to be taken very seriously

20. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia Management requires 1.Diagnosis of the arrhythmia causing the symptoms  ECG  Holter ambulatory monitor – 24 hr or longer Techniques which may be useful  Implantable loop recorder – “Reveal” device  Analysis of repolarisation (QT and JT dispersion)  Electrophysiology study

21. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia – the clinic ECG Atrial Fibrillation AF Supraventricular tachycardia SVT Ventricular ectopic VE

22. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia Management requires 1.Diagnosis of the arrhythmia causing the symptoms  ECG  Holter ambulatory monitor – 24 hr or longer  Event recorders Techniques which may be useful  Implantable loop recorder – “Reveal” device

23. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia – the Holter 24hr ECG Holter 24 hr ECG Patient aged 27 yr Symptom: palpitation + dizziness Shows Ventricular tachycardia VT

24. Malcolm Walker TIF 2012 Holter ambulatory ECG screening Holter screening failed to predict 2 patients From Qureshi et al. Annals NY Acad Sci 2005 Significant arrhythmia detected in 15% patients (n=4) Holter screening failed to predict 2 patients who went on to have significant arrhythmia 30% of the patients with a normal Holter had symptoms CONCLUSION Routine screening of TM population with Holter not sensitive nor specific Need to consider newer technologies – event recorders, ILR

25. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia Management requires 1.Diagnosis of the arrhythmia causing the symptoms  ECG  Holter ambulatory monitor – 24 hr or longer  Event recorders Techniques which may be useful  Implantable loop recorder – “Reveal” device

26. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia Management requires 1.Diagnosis However, making the ECG diagnosis is not enough on its own Importance of the arrhythmia depends critically on knowledge of the underlying cardiac status 1. Ventricular function; structural heart defects 2. Iron burden (cMR T2*) 3. Pro-thrombotic tendency

27. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia Management requires 1.Precise diagnosis 2.Knowledge of underlying cardiac status  Ventricular function & cardiac structure by ECHO  Iron burden (T2*) by cMR An ECHO + cMR are URGENT when 1Ventricular arrhythmia 2Poorly tolerated AF 3Symptoms include loss of consciousness/ collapse/ heart failure

28. Malcolm Walker TIF 2012 Clinical aspects of arrhythmia in thalassaemia - conclusions ECG  Necessary baseline at least every 12/12  At every cardiovascular assessment  It tells us more about the heart than just arrhythmia Holter 24hr ECG  Useful to investigate symptoms  Poor as a screening tool in asymptomatic well chelated TM patients with good LV function

29. Malcolm Walker TIF 2012 Cardiac Arrhythmia in thalassaemia 4. Specific arrhythmia VT AF

30. Malcolm Walker TIF 2012 Specific arrhythmia Tachycardia – ventricular (VT) Ventricular tachycardia (VT) or broad complex tachycardia

31. Malcolm Walker TIF 2012 Specific arrhythmia Tachycardia – ventricular (VT) Ventricular tachycardia (VT) or broad complex tachycardia  This is a medical emergency  Input of emergency physicians/ cardiologists  Immediate cardioversion if in collapse or shock  It always complicates severe iron overload  It may respond to iv chelation with DFO  iv DFO must be started immediately  Combination treatment may be indicated

32. Malcolm Walker TIF 2012 Specific arrhythmia Tachycardia – ventricular (VT) Ventricular tachycardia (VT) or broad complex tachycardia  Once acute event controlled  Consider implantation of ICD  Poor LV function not improving with iv chelation  VT occurs without high iron overload – look for another cause!  ICD must be MRI compatible

33. Malcolm Walker TIF 2012 Specific arrhythmia Atrial Fibrillation AF AF: the commonest arrhythmia  Paroxysmal  Persistent  Permanent

34. Malcolm Walker TIF 2012 Specific arrhythmia: Atrial Fibrillation Risk to patient: Heart Failure 1Cardiac decompensation/ overt heart failure  Most likely when AF first appears - when heart rate is high  Target treatment to: 1.Control rate 2.Restore normal sinus rhythm  Check, urgently if significant heart failure signs: 1.LV function by ECHO 2.Cardiac iron status by cMR T2* 3.Thyroid function etc.

35. Malcolm Walker TIF 2012 Specific arrhythmia: Atrial Fibrillation Risk to patient: Stroke 2Stroke risk depends critically on:  Prothrombotic status  Structural heart disease  Impaired LV  Higher risk if AF is persistent or permanent or frequent paroxysms of more than 12 hr duration 1.Restore normal sinus rhythm where possible 2.Anti-coagulation with warfarin (INR 2.5) or new agents  Check 1.Cardiac ECHO for LA size, LV function, valve disease

36. Malcolm Walker TIF 2012 Specific arrhythmia AF – special circumstances 1.Complicating cardiac failure 2.Precipitating cardiac failure 3.In iron loaded TM with good LV function 4.In non iron loaded TM with good function

37. Malcolm Walker TIF 2012 Specific arrhythmia AF – special circumstances 1.Complicating cardiac failure 2.Precipitating cardiac failure These are urgent situations requiring admission 1.Consider TOE guided DC Cardioversion 2.Itensify Rx: iv DFO: 24r x 7 days plus DFP (?) 3.Conventional long term management: aim to prevent further attacks 1. Betablockers 2. Amiodarone (short to medium term) 3. Anticoagulation

38. Malcolm Walker TIF 2012 Specific arrhythmia AF – special circumstances 3.In iron loaded TM with good LV function 4.In non iron loaded TM with good function These are non-urgent situations requiring 1.Consider TOE guided DC Cardioversion after 4 weeks anticoagulation 2.Itensify chelation Rx: if iron overloaded 3.Conventional rate & rhythm control 1. Betablockers 2. Rate lowering calcium channel blockers 4.Anticoagulation with warfarin or new agents

39. Malcolm Walker TIF 2012 Specific arrhythmia AF – long term prevention strategy Long term prevention strategies of AF  Medication: generally poor at long term prevention  Effective drugs potentially too toxic (Amiodarone)  Less toxic drugs often less effective (Beta-block, Flecainide) Thalassaemia population may have an advantage, if AF complicates iron overload. Removing iron may effectively prevent AF for many years (?)  Consider ablation and other therapies

40. Catheter based ablation for AF Cardiac catheter based techniques Complex & time consuming (2 to 4hr) Often GA required Specialist EP cardiologists & service Success rates 70 to 80% Recurrence rates approx 15% at 1 year Risk of Stroke, cardiac perforation 1% to 2% Complications and success rates may be different for thalassaemia population

41. Malcolm Walker TIF 2012 Catheter based ablation for AF

42. Malcolm Walker TIF 2012 Catheter based ablation for AF

43. Malcolm Walker TIF 2012 Catheter based ablation for AF Rhythm control by ablation  General success rates 70% to 80% “cure”  15% need second ablation In TM population  Experience is young  Anecdotal evidence of much higher recurrence rates

44. Malcolm Walker TIF 2012 AF: Interventional techniques to reduce stroke risk Left atrial appendage occluder  Catheter based technique  Reduces risk of stroke Structural defect closure  Patent foramen ovale (PFO) closure  If patient has strong pro-thrombotic tendency

45. Malcolm Walker TIF 2012 Bradycardia & heart block in thalassaemia Complete heart block common in the past is rare today

46. Malcolm Walker TIF 2012 Bradycardia & heart block in thalassaemia Complete heart block is rare Mandates the use of a pacemaker  Historically this would prevent the use of cMR forever!

47. Malcolm Walker TIF 2012 “Patients and the implanting community deserve nothing less than devices that are safe by design and not by chance.” – J. Rod Gimbel, MD, FACC Emanuel Kanal, MD, FACR For more information visit: http://www.medtronic.com/mrisurescan/

48. Malcolm Walker TIF 2012 4 chambers LA LV Lead Signal alteration RA RV

49. Malcolm Walker TIF 2012 cMR safe pacemakers

50. Malcolm Walker TIF 2012 Arrhythmia and thalassaemia Conclusions Complex pathophysiology, which may be changing as TM population ages Practical management issues largely revolve around intensified chelation, as this may control problem Role of EP techniques needs to be fully defined Devices need to be cMR compatible