1. Cardiomyopathy in the adult with DMD Best preventative actions in cardiac care Cardiomyopathy in the adult with DMD Cardiology Department Freeman Hospital & Newcastle University Newcastle upon Tyne United Kingdom John P. Bourke Consultant Cardiologist & Senior Lecturer Action Duchenne Meeting – November ‘15

2. International DMD Care Considerations Working Group Bushby K, et al. Lancet Neurol 2010, 9:77-93 & 177-89

3. Heart involvement in DMD..?

4. Natural History of Heart Involvement in DMD A non-invasive longitudinal study without treatments Backman & Nylander Eur Heart J 1992, 13:1239-1244 LV FS% LV EF% Most boys with DMD develop a severe, progressive form of cardiomyopathy

5. Gene-manipulation for DMD Disease modifying interventions (Oligo-medications / Gene therapies / Stem Cells)

6. Cardio-myocyte damage & cell death Ameen V & Robson LG - Open Cardiovascular Medicine Journal 2010, 4:265-77. Heart Failure with Symptoms Inflammatory cascade response initiated Loss of functioning muscle cells Fibro- collagenous scar tissue formation leading to fibrosis Reduced contraction, thinning & stretching of fibrotic regions Dilation of LV chamber DMD dilated cardiomyopathy Let’s start doing something …..

7. Cardio-myocyte damage & cell death Inflammatory cascade response initiated Loss of functioning muscle cells Fibro- collagenous scar tissue formation leading to fibrosis Reduced contraction, thinning & stretching of fibrotic regions DMD dilated cardiomyopathy Dilation of LV chamber Ameen V & Robson LG - Open Cardiovascular Medicine Journal 2010, 4:265-77. Exon skipping, Stem cells & Gene therapies Steroids / ACEi – ARB / Beta- blockers/ Spironolactone / Eplerenone Ivabridine / Sildenefil / Tadanafil Heart Failure with Symptoms

8. Success of an intervention is time dependent..! Smoke Detector / Fire Extinguisher Fire Brigade & Rescue Insurance & Investigation Therapy of DMD-adults cannot compensate for therapies needed in childhood !

9. 0 20 40 60 80 100% 061218243036 LV Function Symptoms Age (years) Normal range Medication & other therapies for Heart Involvement in DMD Disease modifying interventions (Oligo-medications / Gene therapies / Stem cells) Drugs to reduce ‘heart strain’ (ACE-inhibitors / ARBs / Beta-blockers / Sinus node slowing agents; PDE-5 inhibitors) Drugs to reduce symptoms (Milrinone / PDE-5 inhibitors / Diuretics / Digoxin) Drugs to ‘reduce reaction to damage’ (Steroids / Anti-fibrosis agents / ARBs) Changing the natural history of heart involvement in DMD

10. Glucocorticoid steroid therapy in DMD Benefits & Adverse Effects

11. All cause mortality & cardiovascular outcomes with prophylactic steroid therapy in DMD ► Aim: impact of steroid therapy on cardiomyopathy & mortality in DMD Retrospective cohort review of DMD pts on ACEi +/- steroid therapy 86 DMD patients ► 86 DMD patients (9.1 + 3.5 yrs & followed for 11.3 + 4.1 yrs) between 1972-2006 ‘... All received ACEi / ARB therapy but steroids at discretion of caregivers & family..’ ► Deflazacort or prednisolone initiated at 8.6 + 3.5 yrs of age ‘..Pts starting steroids were seen by cardiology & ACEi/ARB started at a younger age..’ ► Serial echos & ECGs every 6-12 months Schram G, et al. J Am Coll Cardiol 2013, 61:948-54

12. Freedom from Cardiomyopathy & Death from Heart Failure Schram G, et al. J Am Coll Cardiol 2013, 61:948-54

13. Development of Cardiomyopathy ► 28% (21/86) developed LV-dysfunction during follow-up 11% (7/63) Steroid (+) vs 61% (14/23) Steroid (-) (p < 0.0001) ► No differences in ECG changes & No arrhythmias in any patient Freedom from new-onset cardiomyopathy (LVEF < 45%) during follow-up: ► Freedom from new-onset cardiomyopathy (LVEF < 45%) during follow-up: ► Rate of decline in LVEF% & FS% lower in steroid treated patients Schram G, et al. J Am Coll Cardiol 2013, 61:948-54 Follow-up (yrs)Steroid (+)Steroid (-) 596.8%95.2% 1094.4%73.9% 1584.1%29.6% Log-rank p < 0.0001

14. ACE-inhibitors & Beta-blockers in DMD Preventing progressive heart dysfunction

15. ACE-inhibitors + Beta-blockers for DMD Cardiomyopathy

16. ACE-inhibitors + Beta- blockers are of benefit for DMD Cardiomyopathy Therapy should start as soon as LV-dysfunction evident ACEi / ARB + BB seems best Echo suffices in determining the threshold for therapy

17. ACE-inhibitors & Beta-blockers before LV-dysfunction in DMD / BMD Can DCM be prevented?

18. Effects of perindopril on onset & progression of DMD LV-systolic dysfunction Duboc D, et al, JACC 2005, 45(6):855-7 Perindopril preventive treatment on mortality in DMD: 10-year follow-up Duboc et al. Am Heart J, 2007, 154:596-602 DMD boys 9.5 to 13 yrs & normal LV function at baseline RCT perindopril (2-4 mg) vs placebo x 3 yrs; Open-label perindopril to all thereafter for < 10 yrs

19. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial Raman SV, et al. Lancet Neurology 2015, 14:153–161 ■ DMD boys > 7 yrs from 3 USA centres (Jan ‘12-July ‘13) Cardiomyopathy (+) with scars on Late-Gad MRI but normal range LVEF% ■ RCT of eplerenone (25mg/day) vs placebo in addition to ACEi / ARB ■ 1 0 End-point: Change in MRI-measured LV circumferential strain after 12 mths Safety end-point: serial measures of renal function, including serum potassium 188 screened Eplerenone N=20 Placebo N=22 P Median decline in MRI- LV circumferential strain 1.0 (IQR: 0.3-2.2) 2.2 (IQR: 1.3-3.1) 0.02 In boys with DMD and preserved LVEF%, adding eplerenone to ACEI / ARB attenuates the progressive decline in LV systolic function.

20. Treatments already available for Cardiomyopathy in DMD Drug ClassActionEvidence Glucocorticoid steroids Prednisolone Deflazacort Prolong ambulation / reduce inflammation / maintain cardio- respiratory function Established therapy until non-ambulant (adverse effects limit use) ACE-inhibitors / ARBs Perindopril Enalapril Losartan Delay / prevent remodelling of left ventricle / Anti-fibrotic action (angiotensin & TGF- ß 1 blockade) Established therapy (early deployment better) Aldosterone antagonists Spironolactone Eplerenone Reduce / prevent fibrosisEstablished therapy (need for serum K-checks with ACEi) Beta-blockers Metoprolol Bisoprolol Carvedilol Slow heart / reduce force of LV- contraction (Ivabridine, if BB ci or not tolerated) Probably established Theoretical data & use in other contexts Calcium channel blockers Diltiazem Flunarizine ?? Reduce calcium influx into cellsNo benefit to date Anti-oxidants Q10 Idebenone No benefit to date

21. How far should we escalate cardiac therapies for advanced cardiomyopathy in DMD …?

22. 0 20 40 60 80 100% 061218243036 LV Function Symptoms Age (years) Normal range Defibrillator implant to prevent sudden death in DMD..? Risk of sudden death in severely damaged hearts

23. July ’15 – Complete AV Block

24. Mr MA – 21 yrs – DMD LVEF 15-20% - No cardiac symptoms Perindopril, Bisoprolol & Bumetanide Single chamber ICD - Oct ’12 Several shock therapies – May ’13 Complete AV-block – July ‘15 September ‘14

25. 41 seconds from 1 st onset Sept ‘15 (16 months post ICD implant)

26. Finsterer J & Cripe L. Nat Rev Cardiol 2014, doi: 10.1038/nr.cardio.2013.213

27. International DMD Care Considerations Working Group Diagnosis & Management (Parts 1 & 2) Bushby K, et al. Lancet Neurology - 2010, 9:77-93 & - 2010, 9:177-189