Cardiomyopathy in DMDCardiomyopathy in DMD

Current state of evidence for heart-specific therapy…

Cardiology DepartmentFreeman Hospital & Newcastle University

Newcastle upon TyneUnited Kingdom

John P. BourkeJohn P. BourkeConsultant Cardiologist & Senior Lecturer

Action Duchenne, London – November 2014

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

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 & Gene therapies

Steroids / ACEi – ARB / beta-blockers/ spironolactone /

eplerenone

Ivabridine /diuretics Sildenafil

Heart Failure with Symptoms

Therapy aimed at all aspects of DMDand

Heart Specific Therapies

Current focus is on therapies for the whole condition

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

DMD disease-modifying therapies – Heart Issues(?)

Nature of therapy Action

Engrafted foetal cardiomyocytes

mdx mouse & canine models Selective repair seems deleterious to rest of the heart

Cell based therapies - Satellite cells (x)- Mesangioblasts (√)

Multi-potent progenitor cells capable of making any mesodermal tissue (including skeletal or cardiac muscle)

Gene therapy Mini- or micro-dystrophin constructs

Aiming to improve the phenotype (DMD to BMD); Harder to target the heart

Anti-sense oligonucleotides

Exon-skipping[phosphorodiamidate morpholino- oligomers (PMOs)]

Allows production of truncated functional protein (systemic or organ specific delivery)Not all penetrate / benefit the heart

Multiple parallel research programmes in various DMD models ongoing ...

Success of an intervention will be 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)

Drugs to reduce symptoms (Milrinone / Sildenafil / Diuretics / Digoxin)

Drugs to ‘reduce reaction to damage’ (Steroids / Anti-fibrois agents / ARBs)

Mechnaical Pump-support (Pacing / LVAD / Transplant)

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 DMD

► Retrospective cohort review of DMD pts on ACEi +/- steroid therapy

► 86 DMD patients (9.1 + 3.5 yrs & followed for 11.3 + 4.1 yrs) - 1972-2006‘... All received ACEi / ARB therapy but steroids at discretion of caregivers & family ..’

► Serial echos & ECGs every 6-12 months

► 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..’

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

Freedom from cardiomyopathy (LVEF < 45%) & Death from heart failure

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

Freedom from CM Overall Survival

Fewer heart failure related deaths

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

► 20% (17/86) died in 11.3 + 3.6 (steroids) & 11.3 + 5.1 (no steroids) yrs follow-up

11% (7/63) Steroid (+) vs 43% (10/23) Steroid (-) died (p = 0.001)

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 cardiomyopathy 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

Steroid effects & the heart in DMD

Silversides et al , 2003 Markham et al, 2005

Steroid agent Deflazacort vs Never Any steroid vs Never

Design Retrospective Retrospective

Age of starting Rx 8.4 + 2 yrs < 21 yrs

Duration of Rx > 3 yrs ---

Patient Number 33 111

Evaluation method Echocardiogram Echocardiogram

ResultsResults Steroid (+) vs (-)Steroid (+) vs (-) Steroid (+) vs (-)Steroid (+) vs (-)

Lost ambulation 48% vs 100%

Cardio-active RxLVEF < 45%LVFS%LVESD (mm)

10% vs 42%5% vs 58%

33 + 7% vs 21 + 8%30 + 6 vs 37 + 8

Lower if steroid (-)< 10 yrs x 4.4 FS% < 28> 10 yrs x 15

Freedom from cardiomyopathy 93% vs 53%

ACE-inhibitors & Beta-blockers in DMD

Benefits when heart already involved

Jefferies JL, et al. Circulation 2005, 112:2799-2804

Ramaciotti C, et al. Am J Cardiol 2006, 98(6):825-7

A randomised, double-blind trial of lisonopril & losartan in DMD

Allen HD, et al. PLoS Curr 2013, Dec

Beneficial effects of beta-blockers & ACEi in DMD

Ogata H, et al. J Cardiol 2009, 53(1):72-8

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

Can DCM be prevented?Can DCM be prevented?

Effects of perindopril on the onset & progression of LV-systolic dysfunction in DMD

Duboc D, et al, J Am Coll Cardiol 2005, 45(6):855-7.

Perindopril preventive treatment on mortality in DMD: 10-year follow-up

♥♥DMD boys 9.5 to 13 yrs & normal LV functionRandomised to perindopril (2-4 mg) or placebo x 3 yrs Open-label perindopril to all thereafter for < 10 yrs

Duboc et al - Am Heart J, 2007, 154:596-602

PerindoprilPerindopril

ThroughoutThroughout(n=28)

Placebo Placebo

InitiallyInitially(n=29)

p

Baseline characteristics

--- --- NS

Alive at 10 yrs 26 (93%) 19 (66%) 0.02

Kaplan-Meier plot --- --- 0.013

ACE-inhibitors: Adverse Effects

► Common hypotension, cough, hyperkalaemia, headache, dizziness, fatigue, nausea, renal impairment

- Persistent dry cough due to bradykinin increase

- Rash & taste disturbance commoner with captopril

- Particular risk of renal failure if renal impairment , NSAIDs & diuretics / dehydration

- Hyperkalaemia due to suppressed aldosterone levels

particularly if in combination with spironolactone / eplerenone

Other drugs for the heart ...

◊ Anti-fibrosis agents (spironolactone / eplerenone)

◊ Ivabradine (sinus node slowing agent)

◊ Growth Hormone (LV- hypertrophy effect)

In heart failure:In heart failure:

◊ Diuretics (furosemide / bendroflumethiazide)

◊ Nitrates (venodilators)

◊ Phosphodiesterase-5 inhibitors (Sildenafil)

► Double-blind study of adding spironolactone to existing therapy in severe heart failure

► N = 1663 - LVEF < 35%ACEi, loop diuretic & digoxin822 (spiro 25mg) & 842 (placebo)

End-Pt: Death from all causes

N Engl J Med 1999, 341(10):709-717

Spironolactone reduced risk of death by 30%

??? ??? Special role in fibrosis-Special role in fibrosis-

prevention in DMD prevention in DMD

Aldosterone Antagonists (spironolactone & eplerenone)

► Spironolactone (widespread effects)

Gynaecomastia, hyperkalaemia & renal dysfunctionRequires careful monitoring of urea, creatinine & electrolytes

Spironolactone dosage should be no < 25-50 mg/day

Contraindicated, if serum potassium > 5 mmol/l

or serum creatinine > 220micromoles/l

► Eplerenone (~ 1000 times more cardio-specific ....)

Less gynaecomastia but otherwise as for spironolactone

Ivabradine & outcomes in chronic heart failureAddition of ivabradine (a pure sinus node slowing agent)

to optimum medical therapy

SHIFT - Swedberg K, et al. Lancet 2010, 376:875-885

Benefit due to reduced hospital admissions for CCF

Treatments already available for Cardiomyopathy in DMD

Drug Class Action Evidence

Glucocorticoid steroids PrednisoloneDeflazacort

Prolong ambulation / reduce inflammation / maintain cardio-respiratory function

EstablishedEstablished 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)

EstablishedEstablished therapy (early deployment better)

Beta-blockers MetoprololBisoprololCarvedilol

Slow heart / reduce force of LV-contraction

EstablishedEstablished therapy(early deployment probably better)

Aldosterone antagonists SpironolactoneEplerenone

Reduce / prevent fibrosis Theoretical data & use in other contexts supports use(high K-risk with ACEi)

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 therapies for cardiomyopathy in DMD …?

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Defibrillator implant to prevent sudden death in DMD ..?

Risk of sudden death in scarred or severely damaged hearts

Phase of increasing ‘heart

irritability’(fatal arrhythmias)

Implantable defibrillator

therapyfor patients

with DMD ??

Chaotic rhythm

Shock delivered automatically

Normal rhythm

Impact of ICD therapy on QoL in DMD?

A registry of DMD-patient experiences & outcomes of ICD therapy, if deployed?

Implantable LV-Assist DeviceImplantable LV-Assist Device

A less invasive approach to cardiac-assist device therapy

► Extra-aortic counter-pulsation device for long-term treatment

► NYHA class III & ambulatory class IV heart failure patients

► ECG gated inflation/deflation; Polyurethane balloon cuff;

► Pneumatically driven; Up to 26cc (depending on aortic size)

► Full or mini-sternotomy implanted;

► EF increased over time by up to 30% !!

Davies et al. Heart Lung & Circulation 2005, 14:178-86

C-Pulse System (Sunshine Heart)

Significant progress but much uncertainty ...

► Stick with what we know is beneficial or begin to combine therapies?

Steroids alone until LV-impaired orSteroids + ACEi + BB + spironolactone from early years

► Content to keep patients asymptomatic alone or push for longer survival?Add ICD therapy to protect against SCD

► Add LV-assist devices when heart failure symptoms intervene despite drugs or time for palliative care pathways?

LVAD or Counter-pulsation devices

How far is it ethical / justified to escalate therapy?

The BHF-funded ‘DMD Heart-Protection Trial’ (Ongoing)

To determine in a major clinical trial whether starting:

◊ combination therapy with ACE-inhibitor & beta-blocker

◊ before the onset of echo-detectable LV dysfunction

◊ delays onset or slows progression rate of cardiomyopathy

◊ five-UK-centre, double-blind, randomised, placebo-controlled trial

◊ over 5 years (2 years recruitment / 3-5 years follow up)

The BHF-funded ‘DMD Heart-Protection Trial’The BHF-funded ‘DMD Heart-Protection Trial’

Inclusion Criteria Inclusion Criteria Recruitment ends 31/12/2014 !!

◊◊ Boys 7 – 12 years old with genetically proven DMDBoys 7 – 12 years old with genetically proven DMD

◊◊ LVEF LVEF >> 60% by Simpson’s biplane method 60% by Simpson’s biplane method (normal range = 63 + 5%)

◊◊ No global or regional wall motion abnormalities No global or regional wall motion abnormalities (echocardiogram)

◊◊ Informed consent from parents / guardians & child’s assentInformed consent from parents / guardians & child’s assent

◊◊ No contra-indication to perindopril or bisoprololNo contra-indication to perindopril or bisoprolol

‘‘DMD Heart-Protection Trial’DMD Heart-Protection Trial’

Target N = 140

Oct ‘1424

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Final push to maximise recruitment - before 31st Dec ’14 end