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Pradeep P.A. Mammen, MD, FACC, FAHAAssociate Professor of Medicine
Co-Director: UTSW Wellstone Muscular Dystrophy CenterMedical Director: Neuromuscular Cardiomyopathy Clinic
Heart Failure, VAD & Heart Transplant ProgramDivision of Cardiology
UT Southwestern Medical Center
Management of DMD-Associated Cardiomyopathy in 2018
2018: End Duchenne TourOctober 13, 2018
Pradeep P.A. Mammen, MD
Faculty Disclosures:American Heart Association: Member of the AHA Career Development
Research Grant CommitteeCalifornia Institute for Regenerative Medicine: Member of the Scientific
& Medical Research Funding Working GroupCareDx Inc.: Consultant and Site PI for the OAR/D-OAR StudyCatabasis Inc.: Consultant & Research GrantHeartWare Inc: ConsultantNational Institute of Health: Research GrantPhaseBio Inc: Member of the Scientific Advisory Committee &
Research Grant
Overview
Introduction: Duchenne muscular dystrophy.
Assessment and management of DMD-associated cardiomyopathy.
Conclusion and key take home message.
Clinical management of cardiomyopathy.
Inherited Myogenic DisordersLocation or Type of
Mutation Examples of
Neuromusclar DisordersCardiac Involvement (Cardiomyopathy or
Arrhythmias)Dystroglycan Complex Duchenne MD, Becker MD, X-
Linked DCMVery common and primary mode of death
Dystroglycan Complex and Cytosolic & SarcomericProteins
Limb-Girdle MD (8 subtypes) Common
Unstable Nucleotide Repeats Myotonic Dystrophy (Type I & II), Facioscapulohumeral MD
Very common
Nuclear Membrane Proteins Emery-Dreifuss MD Very common
Mitochondrial Proteins Mitochondrial Myopathies or Friedreich ataxia
Variable
Glycogen Storage Pompe Disease Very common in infantile but variable in adult onset
Extracellular Matrix Bethlem Myopathy, Congenital MD, Ullrich Congenital MD
Rare
Duchenne Muscular Dystrophy
The Dystrophin-Glycoprotein Complex
MuscleEditors: Hill & Olson
DystrophinopathiesDuchenne muscular dystrophyBecker muscular dystrophyX-Linked dilated cardiomyopathy
>3,000 DMD Mutations
Exon DeletionsPoint MutationsDuplications70%
25%
5%
The Dystrophin Gene
Modified from Eric Olson
Clinical Manifestations of Duchenne Muscular Dystrophy
Typical Progression in DMD
Development of DMD-Associated Cardiomyopathy
Violett al.American J of Cardiology 2012 110:98-102
Life Expectancy in DMD Patients in 2018
Ashwath et al. American J Cardiology 2014 114:284-289
Cardiomyopathy: DMD Carriers
Cardiomyopathy in DMD Carriers
Limited data on the clinical phenotype of DMD carriers.
DMD carriers can develop “silent” heart failure early in life without muscle weakness.
Heart failure in carriers is often unrecognized.
DMD carriers develop symptoms related toheart failure (shortness of breath, fatigue, etc) much later in life.
Cardiomyopathy in Female Carriers of Duchenne & Becker Muscular Dystrophies
DMD(N=152)
BMD(N=45)
Total(N=197)
GeneDeletion
92(61%)
31(69%)
123(62%)
GeneDuplication
9(6%)
3(7%)
12(6%)
GenePoint Mutation
5(3%)
0(0%)
5(3%)
Politano et al. JAMA 1996
Cardiomyopathy in Female Carriers of Duchenne & Becker Muscular Dystrophies
SampleSize
NormalStatus
Pre-clinicalStage
AbnlHrt
with NlLVEF
Dilated CM
Total Cases
of AbnlHrts
DMD/BMD(Age: 5-15 y/o)
33 15(46%)
13(39%)
4(12%)
1(3%)
5 (15%)
DMD/BMD(Age: >15 y/o)
164 16(10%)
75(46%)
50(31%)
18 (11%)
68 (45%)
Politano et al. JAMA 1996
Mechanism for Isolated Cardiomyopathy in DMD Carriers: Skewed X-Inactivation
DMD and DMD Carriers in the United States at Risk of Developing Heart Failure
In 2014, the US population was 320 million people.
• DMD patients in the US: 32k to 46k
• DMD carrier patients in the US: 22k to 30k
Primary Mode of Death in Duchenne Muscular Dystrophy Patients
Healthy Heart
Cardiomyopathy
Arrhythmias
Dilemma in the Management of DMD-Associated Cardiomyopathy
Limited number of well controlled randomized clinical trails to guide management of DMD-associated cardiomyopathy.Limited guidelines for CV care of DMD and DMD carrier patients by the major cardiovascular organizations.
Failure to include DMD/DMD carrier patients in the majority of the large clinical heart failuretrials.
Clinical Management of Non-Ischemic Cardiomyopathy
Jessup et al. NEJM 2003
LV Remodeling in Human Cardiomyopathy
ACC/AHA Heart Failure StagesStage Definition Examples Treatment
A High risk of developing HF, but no structural heart disease or HF.
HTN, CAD, Diabetes, family history ofcardiomyopathy.
ACEI
B Structural heart disease, but no signs of heart failure (Asymptomatic HF).
Prior MI, LV systolic dysfunction, Valvular disease, RV hypertrophy.
ACEI, Beta-Blockers,and MRA
C Structural heart disease with signs of heart failure(Symptomatic HF).
Dyspnea, fatigue, exercise intolerance, orthopnea, PND.
ACEI, Beta-Blockers,MRA, Diuretics, Digoxin, and other CHF treatment plan
D Refractory HF despite maximal medical therapy.
Marked symptoms at rest despite maximal therapy.
Stage C Treatment LVADHeart TreatmentIV InotropesPalliative Care
Hunt et al. JACC 2001
Heart Failure Management in CHF Patients in 2018
Treatment of heart failure in DMD:* Beta-Blockers (Coreg, Toprol XL, Bisoprolol)* ACEI vs. ARB* Aldosterone Inhibitors (Spironolactone or
Eplerenone)* ARNI (ARB + inhibitor of neprilysin) * Ivabradine* BiDil (or Isordil/Hydralazine)* Diuretics (only if volume overloaded) * Digoxin * AICD vs. BiV/AICD* LVAD and/or Cardiac Transplantation
Trial ACEI Controls RR (95% CI)
CONSENSUS ISOLVD (Treatment)SOLVD (Prevention)
Chronic CHF
Post-MISAVE
TRACEAIRE
39% 54% 0.56 (0.34–0.91)40%35% 0.82 (0.70–0.97)
15% 16% 0.92 (0.79–1.08)
25%20% 0.81 (0.68–0.97)17% 23% 0.73 (0.60–0.89)
Average
0.78 (0.67–0.91)35% 42%
23% 27%
Effect of ACE Inhibitors on Mortality Reduction in Patients With Heart Failure
Mortality
Major Placebo Controlled Trials of b-Blockade in Heart Failure
34% ¯
Cum
ulat
ive
Mor
talit
y (%
)
Days
20
15
5
0
10
P=.0062 (adjusted)
Metoprolol CR/XL(n=1990)
Placebo (n=2001)
US Carvedilol Trials1
Prob
abili
ty o
f Eve
nt-fr
ee S
urvi
val�
Carvedilol (n=696)
Placebo (n=398)
Days
P<.001
0.00 100 200 300 400
65% ¯
1.0
0.8
0.7
0.9
MERIT-HF2
Surv
ival
(% o
f Pat
ient
s) 100
90
80
60
70
06000 400300200100
Days
Carvedilol (n=1156)
Placebo (n=1133)
500
6000 400300200100 500
35% ¯P=.00013
COPERNICUS4
Days
0.0200 400 800
1.0
0.8
0.6
P<.000134% ¯
Bisoprolol (n=1327)
Placebo (n=1320)
CIBIS-II3
0 600
Surv
ival
1Packer M et al. N Engl J Med. 1996;334:1349–1355. 2MERIT-HF Study Group. Lancet. 1999;253:2001–2007. 3CIBIS-II Investigators. Lancet. 1999;353:9–13. 4Packer M et al. N Engl J Med. 2001;344:1651–1658.
Pitt B et al. NEJM 1999
SpironolactonePlacebo
Follow-up (months)
100
80
60
40
20
00 10 20 30 36
RR 0.70 (0.60–0.82)
P<.001
Prob
abili
ty o
f Sur
viva
l (%
)Aldosterone Blockade in Heart Failure
RALES: Randomized Aldactone Evaluation Study
Heart Failure Management: Standard of Care in 2018
ACE-I orARB
BetaBlocker
AldosteroneAntagonist
CRT AICD
ImprovesFunctional Status
ü ü ü
Promotes Changes in LV Structure
ü ü ü
Reduces Hospitalization ü ü ü üDecreases Mortality ü ü ü ü ü
Jessup et al. NEJM 2003
Reverse Cardiac Remodeling in Nonischemic Cardiomyopathy: 33% Rule
33%
33%
33%
Jessup et al. NEJM 2003
Reverse Cardiac Remodeling in DMD-Associated Cardiomyopathy
??
??
??
Medical Management ofDMD-Associated Cardiomyopathy
UTSW Neuromuscular Cardiomyopathy Clinic: Initial CV Assessment of DMD Patients
Clinical & Molecular Phenotyping
Assessment &Management of CV Status in DMD Patients
Cardiac Electrical Assessment: EKG & Holter
Cardiac Imaging: Cardiac MRI
UTSW Neuromuscular Cardiomyopathy Clinic: Initial CV Assessment of DMD Patients
Biochemical Phenotyping
Genetic Phenotyping
Electrical Phenotyping
Structural Phenotypingwith Cardiac
Imaging
FunctionalStatus
(DMD Carriers)
Laboratory data to calculate the Seattle Heart Failure Score (CBC with diff, comprehensive metabolic panel, lipid profile, and uric acid level)
Genetic sequencing of the dystrophin gene.
12-Lead EKG Cardiac MRI 6-Minute Walk Test
TSH/FT4 24-Hour Holter Cardiac CT Scan Cardiopulmonary Stress Test
HgA1C Loop recorder vs Medtronic Reveal LINQ
ECHO
Cardiac Biomarkers (total CK, CK-MB, TnI/TnT, Pro-BNP, and hs-CRP)
MUGA
2018 Heart Failure Management of DMD-Associated cardiomyopathy
Treatment of heart failure in DMD:* Beta-Blockers (Coreg, Toprol XL, Bisoprolol)* ACEI vs. ARB* Aldosterone Inhibitors (Spironolactone or
Eplerenone)* Steriods * ARNI (ARB + inhibitor of neprilysin) ??* Ivabradine ??* BiDil (or Isordil/Hydralazine) ??* Diuretics (only if volume overloaded) * Digoxin ??* AICD vs. BiV/AICD* LVAD and/or Cardiac Transplantation
Role of Perindopril in Preventing LV Dysfunction
DMD-Associated Cardiomyopathy
Duboc et al.JACC 2004 45:855-857
Role of Eplerenone and ACEI inDMD-Associated Cardiomyopathy
Raman et al.Lancet Neurology 2015 14:153-161
Role of Steroids inDMD-Associated Cardiomyopathy
Schram et al.JACC 2013 61:948-954
Role of Steroids inDMD-Associated Cardiomyopathy
Schram et al.JACC 2013 61:948-954
Superior images, especially assessment of the RV.
Identification of myocardial fibrosis by presenceof delayed enhancement.
More accurate assessment of the RVEF (normal mean: 63%, range: 53-67%) and LVEF (normal mean: 67%, range: 62-72%).
Cardiac MRI vs ECHO in Duchenne Muscular Dystrophy Patients
UTSW Clinical Algorithm to TreatingDMD-Associated Cardiomyopathy
Cardiac MRI: Preferred imaging tool to assesscardiac structure and function
Normal LVEF(-) DE
Normal LVEF(+) DE
Abnormal LVEF(-) DE
Abnormal LVEF(+) DE
ACEI(or ARB)
ACEI (or ARB)+ Aldosterone
Receptor Antagonist
Beta-Blocker+ ACEI (or ARB)
Beta-Blocker+ ACEI (or ARB)+Aldosterone
Receptor Antagonist
Use of Guideline Directed Heart Failure Medications in DMD
Medications Initial(n=43)
End(n=43)
Beta-Blockers (%) 37 74
ACE-I or ARB (%)86 98
Mineralocorticoid Receptor Antagonist (%) 7 47
Cheeran & Khan et al. J of American Heart Association 2017
UTSW Experience: Reverse Cardiac Remodeling in DMD Cardiomyopathy
2/65
19/65
30/65
11/65 patients expired in 7 years
3/65
Role of LVADs in DMD-Associated Cardiomyopathy
Three Models of Mechanical VADs
Baughman et al. NEJM 2007
HeartMate I
HeartMate II
HeartWareHeartMate III
Use of LVADs in Advanced Cardiomyopathy Patients
HeartMate I
HeartMate II
HeartWare
HeartMate III
Immediate stabilization of hemodynamics.
Reduces wall stress.Improves overall cardiomyocyte function.
Favorable alterations in cellular/organ geometry.
Purpose of VADsBridge to recovery.Bridge to transplantation.Destination therapy (permanent device).Bridge to decision.
Mechanical VAD Support for Patients with Advanced Heart Failure
Infection.
Strokes.Device Malfunction
Mechanical pump failure.LVAD Thrombosis.Fractures in drive line.
Bleeding.
Complications Related to Mechanical VAD Support
Hemodynamic Stabilization of a DMD Patient with Advanced Heart Failure
History of Present Illness - 18 year old male with DMD presenting with worsening heart failure and recurrent admissions to the hospital for heart failure.
Stoller et al.ESC-Heart Failure 2017 4:397-383
Hemodynamic Stabilization of a DMD Patient with Advanced Heart Failure
Stoller et al.ESC-Heart Failure 2017 4:397-383
Hemodynamic Stabilization of a DMD Patient with Advanced Heart Failure
Stoller et al.ESC-Heart Failure 2017 4:397-383
Laboratory Data Pre-LVAD Post-LVAD(5 Years)
Na (mmol/L) 136 140
BUN/Cr (mg/dL) 22/0.44 14/0.15
Hgb (g/dL) 9.3 14.6
AST (Units/dL) 522 37
ALT (Units/dL) 1135 38
Total Bili (mg/dL) 2.9 0.9
Total CK (Units/L) 608 488
Troponin (ng/mL) 0.14 0.02
NT-proBNP (pg/mL) 10,408 924
Hemodynamic Stabilization of a DMD Patient with Advanced Heart Failure
ECHO Parameters
Post-LVAD(1 week)
Post-LVAD(5 Years)
IVSD (cm) 0.70 0.86
LVPD (cm) 0.70 0.96
LVEDD (cm) 7.10 6.50
LVESD (cm) 6.40 6.00
RVEF (%) 20 30-40
LVEF (%) 15 17
Hemodynamic Stabilization of a DMD Patient with Advanced Heart Failure
Conclusions
Key Points: Take Home Messages
All DMD patients require a full cardiac and pulmonary assessment.
Cardiovascular complications in DMD and DMD-Carrier patients are common.
* Cardiomyopathy: Leading cause of death in DMD patients in 2018.
* Arrhythmias??
Cardiac MRI is the preferred imaging tool toaccurately assess the cardiac structure of theDMD patients.
Key Points: Take Home MessagesConsider all adult DMD patients as ACC/AHA Stage B patients. In addition, DMD Carriers should be viewed as ACC/AHA Stage A patients.
Beta-blockers appear to improve cardiac function in DMD-associated cardiomyopathy.
Initiate ACEI early in DMD patients irrespective of LV function.
Benefits of implantation of BiV/AICDs or AICDs remain unclear.
Initiate aldosterone inhibitors esp. if the cardiac MRI reveals early delayed enhancement.
UTSW Transplant SurgeonsPietro Bajona, MD
Lynn (Chip) Huffman, MDMichael E. Jessen, MD
Matthias Peltz, MDW. Steve W. Ring, MDMichael A. Wait, MD
Sarah Talbott, RN: Pre-Transplant CoordinatorsScott Schexnayder, BSN, RN: Lead Transplant Coordinator
Kelly Johnson, RN, PhD, Dagny Teiber, RN, and Kathy Weber, RN: Transplant Coordinators
Carol Bjorkman, RN, ACNP: Transplant Nurse PractitionerCatherine Fitzsimmons, MSN, NP-C: Transplant/VAD Nurse Practitioner
Lelia Nichols, RN, ACNP: Transplant/VAD Nurse PractitionerMary E. Hightower, RN, BSN: Transplant/VAD Nurse
Brenda Thompson, RN, MS, CCRN, CNS: CHF Nurse PractitionerTerri Nabozny, RN, MSN, FNP : CHF Nurse Practitioner
Lea Helms: CHF NurseKathleen H. Toto, RN, MSN, ACNP: CHF Nurse Practitioner
PA: CHF Physician Assistant
UTSW Transplant CardiologistsAlpesh Amin, MD
Faris Araj, MDMark H. Drazner, MD, MSc
Sonia Garg, MD, MEngJustin Grodin, MD, MPH
Pradeep P.A. Mammen, MDRobert Morlend, MD
Jenny Thibodeau, MD, MSc
Acknowledgements
UTSW MDA ClinicJeffrey Elliott Lauren PhillipsMeredith Bryarly Jaya TrivediShaida Khan Steven VerninoSharon Nations Lan Zhou
UTSW Wellstone Center:Eric N. Olson Rhonda Bassel-Duby Susan IannacconeJay W. Schneider Beverly A. RothermelJaya Trivedi
CMC MDA ClinicSusan IannacconeDiana CastroCMC CHF ClinicWilliam ScottClaudio Ramaciotti