cardiomyopathy in the adult with dmd best preventative actions in cardiac care cardiomyopathy in the...

Best preventative actions in cardiac care

Cardiomyopathy in the adult with DMDCardiomyopathy in the adult with DMD

Cardiology DepartmentFreeman Hospital & Newcastle University

Newcastle upon TyneUnited Kingdom

John P. BourkeJohn P. BourkeConsultant Cardiologist & Senior Lecturer

Action Duchenne Meeting – November ‘15

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

Heart involvement in DMD..?

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

Gene-manipulation for DMD

Disease modifying interventions (Oligo-medications / Gene therapies / Stem Cells)

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 …..

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

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 !

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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

Glucocorticoid steroid therapy in DMD

Benefits & Adverse Effects

All cause mortality & cardiovascular outcomes with prophylactic steroid therapy in DMD

► Aim: impact of steroid therapy on cardiomyopathy & mortality in DMDRetrospective 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

Freedom from Cardiomyopathy & Death from Heart Failure

Schram G, et al. J Am Coll Cardiol 2013, 61:948-54

Development of Cardiomyopathy

► 28% (21/86) developed LV-dysfunction during follow-up11% (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 cardiomyopathyFreedom from new-onset cardiomyopathy (LVEF < 45%) (LVEF < 45%) during follow-up: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 (-)

5 96.8% 95.2%

10 94.4% 73.9%

15 84.1% 29.6%Log-rank p < 0.0001

ACE-inhibitors & Beta-blockers in DMD

Preventing progressive heart dysfunction

ACE-inhibitors + Beta-blockers for DMD Cardiomyopathy

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

ACE-inhibitors & Beta-blockers before LV-dysfunction in DMD / BMD

Can DCM be prevented?Can DCM be prevented?

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 baselineRCT perindopril (2-4 mg) vs placebo x 3 yrs; Open-label perindopril to all thereafter for < 10 yrs

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

■ 10 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 EplerenoneN=20

PlaceboN=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.

Treatments already available for Cardiomyopathy in DMD

Drug Class Action Evidence

Glucocorticoid steroids PrednisoloneDeflazacort

Prolong ambulation / reduce inflammation / maintain cardio-respiratory function

Established therapy until non-ambulant(adverse effects limit use)

ACE-inhibitors / ARBs PerindoprilEnalaprilLosartan

Delay / prevent remodelling of left ventricle / Anti-fibrotic action (angiotensin & TGF-ß1 blockade)

Established therapy (early deployment better)

Aldosterone antagonists SpironolactoneEplerenone

Reduce / prevent fibrosis Established therapy(need for serum K-checks with ACEi)

Beta-blockers MetoprololBisoprololCarvedilol

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 DiltiazemFlunarizine

?? Reduce calcium influx into cells No benefit to date

Anti-oxidants Q10 Idebenone

No benefit to date

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

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Defibrillator implant to prevent sudden death in DMD ..?

Risk of sudden death in severely damaged hearts

July ’15 – Complete AV Block

Mr MA – 21 yrs – DMD

LVEF 15-20% - No cardiac symptomsPerindopril, Bisoprolol & Bumetanide

Single chamber ICD - Oct ’12

Several shock therapies – May ’13

Complete AV-block – July ‘15

September ‘14

41 seconds from 1st onsetSept ‘15 (16 months post ICD implant)

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

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