Evaluation and Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy
Hugh D. Allen MD Jerry R. Mendell MD Kevin M. Flanigan MD (Nothing to disclose)
What are the fundamental questions to be addressed? • What happens to the heart in DMD? When? • How should the heart be evaluated? • Should DMD boys be treated? • What with? When?
Spherical Shape Less Efficient for Contraction
Cardiac Abnormalities in Duchenne Muscular Dystrophy • Progressive scarring • Not related to rate of skeletal muscle changes • Process starts in LV posterior wall– Thins and weakens, can’t contract normally • Progresses to Apex, ultimate LV dysfunction with decreasing shortening fraction, ejection fraction, rounding • Develop increased average heart rate (automaticity) independent of cardiomyopathy
Normal LV Shape
Systolic Functional Measurements by Echo • Left Ventricular End Diastolic Dimension • Shortening Fraction • Ejection Fraction • Wall Stress Analysis
Ejection Fraction • Amount of blood ejected divided by initial volume of ventricle • Trace 2-d image of ventricle, extrapolate volume by Simpson’s formula • Has been validated by angiography, casts • Present ‘gold standard’ of systolic function
MRI
Analysis of Cardiac Relaxation Lusitropic State • Diastolic function – Fibrosis leads to stiffness – Stiff myocardium moves poorly (thus not all dilate) – Decreased compliance; loses elasticity
• Tissue Doppler • Speckle Analysis
• Pulsed wave Doppler spectral display of lateral mitral valve annular velocities. In addition to the systolic myocardial Sa wave, the peak velocities of the early diastolic Ea wave and late diastolic Aa wave are measured
Strain Rate Analysis • • • •
Several segments of LV wall sampled One spot selected and movement analyzed Function curves generated over cardiac cycle Shows segments that move poorly vs normal segments • Mainly used in adult ischemic disease • Technique in its infancy in pediatrics • Has been used in Duchenne (2 studies)-positive results
The Curves
Control
DCM
Cardiomyopathy Treatment • Digoxin Generally Out • ACE-I vs ACE-B (Lisinopril vs Losartan) • B-Blockers • Diuretics • Aldactone • Milrinone
ACE-I (Inhibitor)
(Captopril, Enalapril, Perindopril, Lisinopril) • Derived from venom of Jararaca-Brazilian pit viper • Nobel laureate Sir John Vane; postdoc Sergio Ferreira • Blocks production of Angiotensin II, a vasoconstrictor • Effect is vascular relaxation • Lessens cardiac work • Effective in adult CAD w CHF • Lisinopril can be given once daily
Jaracara-Brazilian Pit Viper
ACR-B (Blocker) • Template = Losartan (Cozaar) • Given once daily • Angiotensin blocker, thus vessel does not constrict under Angiotensin II influence • TGF-B inhibitor – Used in Marfan to delay or lessen aortic dilation-smooth muscle may even regenerate – In MDX mouse, skeletal muscle regeneration
Database • All Echo-Doppler studies on MD Patients since 2003 • Now have total 907 studies in database • Demographic and Functional Information • Total DMD = 148 • Total cardiomyopathy = 59
EF before and after Lisinopril Initiation (Viollet, Thrush, Allen, Mendell; in Preparation)
• 25 DMD patients with DCM followed for more than 12 months (up to 40 months) after Lisinopril initiation • (Updated study now 59 boys)
Natural History Decrease in EF
y = -0.006 + 0.46 R2 = 0.33
Stable 8 patients (Age = 15.8 ± 5.7; EF = 47 ± 8%)
y = -10-4 + 0.47 R2 = 0.00016
Improvement 15 patients (Age = 14.9 Âą 4.1; EF = 40 Âą 9%)
y = 0.0006 + 0.47 R2 = 0.0022
MDA Multicenter Study Sites Boston Children’s
St. Louis Children’s
Nationwide Children’s
U. Of Minnesota Children’s
U.C. Davis
MDA Study Major Components • Natural History Study – Boys over 8yo with EF>55 – Boys already on treatment – Serial Echo-Doppler functional studies – Will provide large data base – Will allow insight into progression of cardiomyopathy, effects of treatment, genotypic/phenotypic comparisons
Questions Addressed in MDA Multicenter Protocol • • • • • • •
How Valid Are the Echo Measurements? What Is the Natural History of CM vs Genotype? Does Muscle Function Correlate with CM? How Useful Is Lusitropic Evaluation? When Does Automaticity Develop? Is Lisinopril More Effective than Losartan in CM? Effect of Lisinopril vs Losartan on Muscle Function?
Was Steinbeck Prophetic?
Overview of Protocol • Technicians on site, inter and intra-observor validation study-done, close correlation • Natural History – Serial Echo information, Holter and EKG along with genotype and muscle testing in DMD boys
• DCM-arbitrarily defined as EF <55% – Blinded ACEi or ACRb treatment, standardized – 4 mos interval echo testing, muscle testing – 1 year study
Lisinopril vs. Losartan • Boys who have not been treated (75 each group) • EF <55% • Given capsule containing either lisinopril or losartan at standard doses • Echo-Doppler and skeletal muscle evaluations every 4 months x 1 year (covered by grant) • Safety parameters regarding any deterioration (>5% decline, double Rx, >10%, go off protocol) • Will allow comparison of drugs, see is one is superior • Probably only study that will ever potentially answer this
Conclusions and Questions • If one is superior, it can be recommended • If lisinopril and losartan show similar results, it is a draw • If Losartan =/> Lisinopril and slows or improves skeletal muscle changes, it is preferable • Will the study be long enough to provide meaningful data? • Information may provide basis for further study into question of prophylactic vs therapeutic Rx