cardiomyopathy in the adult with dmd best preventative actions in cardiac care cardiomyopathy in the...
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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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Age Age (years)(years)
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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