management of dmd-associated cardiomyopathy in 2018 · heart failure, vad & heart transplant...

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


Reverse Cardiac Remodeling in Nonischemic Cardiomyopathy: 33% Rule

33%

33%

33%


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

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



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


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

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

management of dmd-associated cardiomyopathy in 2018 · heart failure, vad & heart transplant...

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