Presentation on theme: "Cardiomyopathy in DMD Cardiomyopathy in DMD Current state of evidence for heart-specific therapy… Cardiology Department Freeman Hospital & Newcastle University."— Presentation transcript:
Cardiomyopathy in DMD Cardiomyopathy in DMD Current state of evidence for heart-specific therapy… Cardiology Department Freeman Hospital & Newcastle University Newcastle upon Tyne United Kingdom John P. Bourke Consultant Cardiologist & Senior Lecturer Action Duchenne, London – November 2014
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 DMD and Heart Specific Therapies Current focus is on therapies for the whole condition
DMD disease-modifying therapies – Heart Issues(?) Nature of therapyAction Engrafted foetal cardiomyocytes mdx mouse & canine modelsSelective 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 !
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) 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 CMOverall 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-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 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
Steroid effects & the heart in DMD Silversides et al, 2003Markham et al, 2005 Steroid agentDeflazacort vs NeverAny steroid vs Never DesignRetrospective Age of starting Rx8.4 + 2 yrs< 21 yrs Duration of Rx> 3 yrs--- Patient Number33111 Evaluation methodEchocardiogram Results Steroid (+) vs (-) Lost ambulation48% vs 100% Cardio-active Rx LVEF < 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?
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 function Randomised 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 PerindoprilThroughout (n=28)PlaceboInitially (n=29) p Baseline characteristics --- NS Alive at 10 yrs26 (93%)19 (66%)0.02 Kaplan-Meier plot--- 0.013
ACE-inhibitors: Adverse Effects ►Commonhypotension, 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: ◊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 & digoxin 822 (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- prevention in DMD
Aldosterone Antagonists (spironolactone & eplerenone) ►Spironolactone (widespread effects) Gynaecomastia, hyperkalaemia & renal dysfunction Requires 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 failure Addition 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 ClassActionEvidence Glucocorticoid steroids Prednisolone Deflazacort Prolong ambulation / reduce inflammation / maintain cardio- respiratory function Established 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 Established therapy (early deployment better) Beta-blockers Metoprolol Bisoprolol Carvedilol Slow heart / reduce force of LV- contraction Established Established therapy (early deployment probably better) Aldosterone antagonists Spironolactone Eplerenone Reduce / prevent fibrosisTheoretical data & use in other contexts supports use (high K-risk with ACEi) Calcium channel blockers Diltiazem Flunarizine ?? Reduce calcium influx into cellsNo benefit to date Anti-oxidants Q10 Idebenone No benefit to date
How far should we escalate therapies for cardiomyopathy in DMD …?
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 scarred or severely damaged hearts Phase of increasing ‘heart irritability’ (fatal arrhythmias)
Implantable defibrillator therapy for 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?
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 or Steroids + 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) T o 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’ Inclusion Criteria Inclusion Criteria Recruitment ends 31/12/2014 !! ◊ Boys 7 – 12 years old with genetically proven DMD ◊ LVEF > 60% by Simpson’s biplane method ◊ LVEF > 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 assent ◊ No contra-indication to perindopril or bisoprolol
‘DMD Heart-Protection Trial’ Target N = 140 Oct ‘14 24 46 1 5
Final push to maximise recruitment - before 31 st Dec ’14 end
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