Disclosures. AT owns stock in GE and Medtronic I will be discussing the off label use of gadolinium contrast in children

Transcription

1 Disclosures AT owns stock in GE and Medtronic I will be discussing the off label use of gadolinium contrast in children

2 Myocardial fibrosis burden predicts left ventricular ejection fraction and is modified by age and steroid treatment duration in Duchenne muscular dystrophy Animesh (Aashoo) Tandon, MD, MS*; Chet R. Villa, MD*, Kan N. Hor, MD ; John L. Jefferies, MD, MPH*; Zhiqian Gao, PhD*; Jeffrey A. Towbin*, Brenda L. Wong, MD ; Wojciech Mazur, MD ; Robert J. Fleck, MDǁ; Joshua J. Sticka, MD*; D. Woodrow Benson, MD, PhD ; Michael D. Taylor, MD, PhD* *The Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA The Heart Center, Na onwide Children s Hospital, Columbus, OH, USA Department of Neurology, Cincinna Children s Hospital Medical Center, Cincinna, OH, USA The Heart and Vascular Center at the Christ Hospital, Cincinnati, OH, USA ǁThe Department of Radiology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA Herma Heart Center, Children s Hospital of Wisconsin, Milwaukee, WI, USA Southeast Pediatric Cardiology Society (SPCS) Conference September 5, 2014

3 Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is an X linked genetic neuromuscular disorder caused by mutations in dystrophin Incidence of 1:4000 male births Characterized by muscle weakness

4 Cardiac dysfunction in DMD Is now a leading cause of morbidity and mortality in DMD patients Left ventricular systolic dysfunction often presents in the second decade of life Pathogenesis of dysfunction is not well understood Steroid treatment has been shown to prolong life and delay the onset of cardiac dysfunction Connuck, D. M., L. A. Sleeper, S. D. Colan, G. F. Cox, J. A. Towbin, A. M. Lowe, J. D. Wilkinson, E. J. Orav, L. Cuniberti, B. A. Salbert, S. E. Lipshultz and G. Pediatric Cardiomyopathy Registry Study (2008). "Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry." Am Heart J 155(6): Finsterer, J. and C. Stollberger (2003). "The heart in human dystrophinopathies." Cardiology 99(1): Kirchmann, C., D. Kececioglu, R. Korinthenberg and S. Dittrich (2005). "Echocardiographic and electrocardiographic findings of cardiomyopathy in Duchenne and Becker Kiener muscular dystrophies." Pediatr Cardiol 26(1): Schram, G., A. Fournier, H. Leduc, N. Dahdah, J. Therien, M. Vanasse and P. Khairy (2013). "All cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy." J Am Coll Cardiol 61(9):

5 Myocardial fibrosis Fibrofatty replacement of myocardium Can be due to a variety of causes (necrosis, deposits) and occurs in numerous diseases (sarcoidosis, ischemic CM, hypertrophic CM, dilated CM) In DMD, fibrosis often starts in the free wall of the LV and is usually progressive Hor, K. N., M. D. Taylor, H. R. Al Khalidi, L. H. Cripe, S. V. Raman, J. L. Jefferies, R. O'Donnell, D. W. Benson and W. Mazur (2013). "Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic function." J Cardiovasc Magn Reson 15: 107. Mewton, N., C. Y. Liu, P. Croisille, D. Bluemke and J. A. Lima (2011). "Assessment of myocardial fibrosis with cardiovascular magnetic resonance." J Am Coll Cardiol 57(8):

6 Advanced DMD LGE

7 Specific Aims Longitudinally assess the effect of age and steroid treatment duration on myocardial fibrosis burden Correlate the fibrosis burden with left ventricular ejection fraction (LVEF)

8 Methods All males with DMD n=335 4 CMRs with LGE determined n=99

9 Methods These studies were performed for clinical indications with standard protocols as part of CCHMC s standard of care

10 Patient characteristics Patient Characteristics Age at CMR n=99 (% of all patients) yr (median 12.3, mean 13.0±4.0 yr) Normal LVEF and LGE on all CMR 43 (41.3%) LGE+ on 1 CMR 58 (55.8%) Depressed LVEF on 1 CMR 24 (23.1%) Had both depressed LVEF and LGE on 1 CMR 21 (20.2%) Age of first LGE+ study Age of first CMR with depressed LVEF yr (median 13.5, mean 14.1±3.6 yr) yr (median 14.6, mean 14.6±4.4 yr) Had only LGE 37 (35.6%) Had only depressed LVEF 3 (2.9%)

11 Patient characteristics Patient Characteristics Age at CMR n=99 (% of all patients) yr (median 12.3, mean 13.0±4.0 yr) Normal LVEF and LGE on all CMR 43 (41.3%) LGE+ on 1 CMR 58 (55.8%) Depressed LVEF on 1 CMR 24 (23.1%) Had both depressed LVEF and LGE on 1 CMR 21 (20.2%) Age of first LGE+ study Age of first CMR with depressed LVEF yr (median 13.5, mean 14.1±3.6 yr) yr (median 14.6, mean 14.6±4.4 yr) Had only LGE 37 (35.6%) Had only depressed LVEF 3 (2.9%)

12 Patient characteristics Patient Characteristics n=99 (% of all patients) Treated with deflazacort 51 (51.5%) Treated with prednisone 12 (12.1%) Treated with both deflazacort and prednisone 33 (33.3%) No steroid treatment 3 (3.0%) Age at initiation of steroids yr (median 6.8, mean 7.0±2.5 yr) Duration of steroid treatment yr (median 7.2, mean 7.6±3.4 yr)

13 Patient characteristics Patient Characteristics n=99 (% of all patients) Treated with deflazacort 51 (51.5%) Treated with prednisone 12 (12.1%) Treated with both deflazacort and prednisone 33 (33.3%) No steroid treatment 3 (3.0%) Age at initiation of steroids yr (median 6.8, mean 7.0±2.5 yr) Duration of steroid treatment yr (median 7.2, mean 7.6±3.4 yr)

14 Study characteristics 469 total CMR studies 146 studies (31.1%) were LGE positive 59 studies (12.6%) demonstrated depressed LVEF (LVEF<55%)

15 Risk of dysfunction A patient s relative risk of having depressed LVEF on any study if he was LGE positive on any study was 5.2 ( , p=0.0007).

16 LVEF vs. age

17 LGE negative LGE posi ve All males with DMD n=335 4 CMRs with LGE determined n=99 LGE negative LGE positive n=52

18 t LGE We defined t LGE as the estimated age at which a given patient developed LGE t LGE was set at the date midway between the last LGE negative study and the first LGE positive study

19 LVEF vs. time after t LGE

20 LGE burden We quantitated the number of LV segments positive for LGE Cerqueira, M. D., N. J. Weissman, V. Dilsizian, A. K. Jacobs, S. Kaul, W. K. Laskey, D. J. Pennell, J. A. Rumberger, T. Ryan, M. S. Verani and A. H. A. W. G. o. M. S. a. R. f. C. Imaging (2002). "Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association." Circulation 105(4):

21 LGE burden over time

22 LVEF vs. LGE burden

23 Modifiers of the fibrosis burden A multivariate model of the number of LGE+ LV segments was constructed Significant age steroid treatment duration interaction Interaction term β= 0.01±0.005 (95% CI , p=0.01)

24 Summary Patients who had LGE were much more likely to have depressed LVEF When a patient did not have LGE, LVEF did not change significantly over time When a patient developed LGE, LVEF declined about 2%/year Fibrosis burden was the best correlate of LVEF The development of fibrosis played a role in the decline of LVEF Steroids potentially work through modulation of the fibrosis burden

25 Limitations Retrospective data collection Survival bias We did not account for potential differences in patients medication regimens

26 Why does it matter? Potentially, we should develop therapies that target the development of fibrosis In animal models of heart failure, aldosterone antagonism has been shown to prevent the development of myocardial fibrosis Brilla, C. G. (2000). "Aldosterone and myocardial fibrosis in heart failure." Herz 25(3):

27 Potential DMD cardiac therapies DMD mouse models: ACE inhibitors, aldosterone antagonists, and angiotensinreceptor blockers decrease fibrosis and improve LV function DMD human males: steroids and ACEinhibitors have shown a protective effect on cardiac function (Bish et al., 2011; Rafael Fortney et al., 2011; Spurney et al., 2011); (Duboc et al., 2007; Hor et al., 2011; Jefferies et al., 2005; Kwon et al., 2012; Markham et al., 2008; Mavrogeni et al., 2009; Politano and Nigro, 2012; Ramaciotti et al., 2006; Schram et al., 2013; Silversides et al., 2003)

28 Conclusions Progressive fibrofatty myocardial replacement is likely a substrate for myocardial dysfunction in DMD cardiomyopathy Development of LGE is a strong marker for the acceleration of LV systolic dysfunction in DMD patients Steroids may modulate fibrosis burden

29 Acknowledgements Dr. Michael Taylor Dr. Lynn Jefferies Dr. Jeffrey Towbin The Heart Institute, HIRC, and the Division of Neurology at CCHMC All or portions of this manuscript were or will be submitted as a thesis in partial fulfillment of requirements for a Master of Science degree. This publication was supported by an Institutional Clinical and Translational Science Award, NIH/NCRR 5UL1RR Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

30 Acknowledgements Dr. Tim Slesnick Dr. Will Border Dr. Bill Mahle Sibley Heart Center Cardiology/CHOA/Emory

31 Questions?

32 References Birnkrant, D.J., Ashwath, M.L., Noritz, G.H., Merrill, M.C., Shah, T.A., Crowe, C.A., and Bahler, R.C. (2010). Cardiac and pulmonary function variability in Duchenne/Becker muscular dystrophy: an initial report. J Child Neurol 25, Bushby, K., Finkel, R., Birnkrant, D.J., Case, L.E., Clemens, P.R., Cripe, L., Kaul, A., Kinnett, K., McDonald, C., Pandya, S., et al. (2010). Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 9, Connuck, D.M., Sleeper, L.A., Colan, S.D., Cox, G.F., Towbin, J.A., Lowe, A.M., Wilkinson, J.D., Orav, E.J., Cuniberti, L., Salbert, B.A., et al. (2008). Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry. Am Heart J 155, Eagle, M., Baudouin, S.V., Chandler, C., Giddings, D.R., Bullock, R., and Bushby, K. (2002). Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 12, Fairclough, R.J., Wood, M.J., and Davies, K.E. (2013). Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nat. Rev. Genet. 14, Fayssoil, A., Nardi, O., Orlikowski, D., and Annane, D. (2010). Cardiomyopathy in Duchenne muscular dystrophy: pathogenesis and therapeutics. Heart Fail Rev 15, Feng, J., Yan, J., Buzin, C.H., Towbin, J.A., and Sommer, S.S. (2002). Mutations in the dystrophin gene are associated with sporadic dilated cardiomyopathy. Mol Genet Metab 77, Finsterer, J., and Stollberger, C. (2003). The heart in human dystrophinopathies. Cardiology 99, 1 19.

33 References Flanigan, K.M., Dunn, D.M., von Niederhausern, A., Soltanzadeh, P., Gappmaier, E., Howard, M.T., Sampson, J.B., Mendell, J.R., Wall, C., King, W.M., et al. (2009). Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat 30, Foster, H., Popplewell, L., and Dickson, G. (2012). Genetic therapeutic approaches for Duchenne muscular dystrophy. Hum. Gene Ther. 23, Frankel, K.A., and Rosser, R.J. (1976). The pathology of the heart in progressive muscular dystrophy: epimyocardial fibrosis. Hum Pathol 7, Goyenvalle, A., Seto, J.T., Davies, K.E., and Chamberlain, J. (2011). Therapeutic approaches to muscular dystrophy. Hum Mol Genet 20, R Hoffman, E.P., Brown, R.H., and Kunkel, L.M. (1987). Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, Hoogerwaard, E.M., Ginjaar, I.B., Bakker, E., and de Visser, M. (2005). Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy. Neurology 65, Hor, K.N., Taylor, M.D., Al Khalidi, H.R., Cripe, L.H., Raman, S.V., Jefferies, J.L., O Donnell, R., Benson, D.W., and Mazur, W. (2013). Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic function. J Cardiovasc Magn Reson 15, 107. Jefferies, J.L., Eidem, B.W., Belmont, J.W., Craigen, W.J., Ware, S.M., Fernbach, S.D., Neish, S.R., Smith, E.O., and Towbin, J.A. (2005). Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 112,

34 References Kaspar, R.W., Allen, H.D., Ray, W.C., Alvarez, C.E., Kissel, J.T., Pestronk, A., Weiss, R.B., Flanigan, K.M., Mendell, J.R., and Montanaro, F. (2009). Analysis of dystrophin deletion mutations predicts age of cardiomyopathy onset in becker muscular dystrophy. Circ Cardiovasc Genet 2, Kirchmann, C., Kececioglu, D., Korinthenberg, R., and Dittrich, S. (2005). Echocardiographic and electrocardiographic findings of cardiomyopathy in Duchenne and Becker Kiener muscular dystrophies. Pediatr Cardiol 26, McNally, E.M. (2008). Duchenne muscular dystrophy: how bad is the heart? Heart 94, Mewton, N., Liu, C.Y., Croisille, P., Bluemke, D., and Lima, J.A. (2011). Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 57, Monaco, A.P., Bertelson, C.J., Liechti Gallati, S., Moser, H., and Kunkel, L.M. (1988). An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2, Muntoni, F., Torelli, S., and Ferlini, A. (2003). Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol 2, Towbin, J.A., and Bowles, N.E. (2002). The failing heart. Nature 415, Tuffery Giraud, S., Beroud, C., Leturcq, F., Yaou, R.B., Hamroun, D., Michel Calemard, L., Moizard, M.P., Bernard, R., Cossee, M., Boisseau, P., et al. (2009). Genotype phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD DMD database: a model of nationwide knowledgebase. Hum Mutat 30,

35 Comparison to overall cohort 335 DMD patients Similar overall age of the cohort Similar distribution of LGE 23.9% LGE positive 5.7% LGE indeterminate 70.4% LGE negative Similar rate of depressed LVEF: 11.7%

36 Patient characteristics Patient Characteristics Age at CMR n=99 (% of all patients) yr (median 12.3, mean 13.0±4.0 yr) Normal LVEF and LGE on all CMR 43 (41.3%) LGE+ on 1 CMR 58 (55.8%) Depressed LVEF on 1 CMR 24 (23.1%) Had both depressed LVEF and LGE on 1 CMR 21 (20.2%) Age of first LGE+ study Age of first CMR with depressed LVEF yr (median 13.5, mean 14.1±3.6 yr) yr (median 14.6, mean 14.6±4.4 yr) Had only LGE 37 (35.6%) Had only depressed LVEF 3 (2.9%) Treated with deflazacort 51 (51.5%) Treated with prednisone 12 (12.1%) Treated with both deflazacort and prednisone 33 (33.3%) No steroid treatment 3 (3.0%) Age at initiation of steroids Duration of steroid treatment yr (median 6.8, mean 7.0±2.5 yr) yr (median 7.2, mean 7.6±3.4 yr)

37 Characteristics of study cohort Patient age at the time of CMR ranged from 6.6 to 29.4 years (median 12.3, mean 13.1±4.1 years), which was similar to the overall cohort There were 45 patients (45.5%) who developed LGE before depressed LVEF; 12 (12.1%) patients developed depressed LVEF before LGE; and 3 patients (3.0%) developed both on the same study

38 Prevalence of and age of onset of LGE and depressed LVEF There were 146 (31.1%) LGE positive studies and 59 (12.6%) studies that demonstrated depressed LVEF; these were similar to the cross section of the entire DMD cohort (23.9% LGE positive, 5.7% LGE indeterminate, and 70.4% LGE negative; 11.7% with depressed LVEF)

39 Effect of age and time since development of LGE on LVEF An age only model for the entire cohort demonstrated that LVEF declined 0.58±0.10%/year (mean±standard error, p<0.0001, r2=0.067) (Figure 1) LGE /+ group: LVEF did not decline significantly before the development of LGE (0.26±0.22%/year, p=0.23, Figure 2), but was significant after the development of LGE (2.2±0.31%/year, p<0.0001) The rate of LVEF decline accelerated by 1.9±0.45%/year (p<0.0001) at tlge

40 Determinants of LVEF in DMD patients Univariate analyses showed that LVEF declined with increased steroid treatment duration by 0.43±0.10% (p<0.0001, r2=0.028) LVEF was lower when LGE was positive ( 3.9±0.57%, p<0.0001, r2=0.092) LVEF decreased with increased number of LGE+ LV segments by 0.93±0.09% (p<0.0001, r2=0.171) Multivariate analyses showed that only the number of LGE+ LV segments was a significant predictor of LVEF (β= 0.82±0.11, p<0.0001).

41 Modifiers of the myocardial fibrosis burden Once LGE developed, the number of LGE+ LV segments increased with age by 1.2 segments/year (95% confidence interval , Figure 3) A multivariate model of the number of LGE+ LV segments was constructed for the entire cohort using a lognormal distribution with age, duration of steroid treatment, and their interaction as predictors There was a significant age steroid treatment duration interaction, suggesting that a longer steroid duration attenuated the age related increase in number of LGE+ LV segments, though the effect was small (interaction term β= 0.01±0.005, , p=0.010).

42 Cardiac outcomes Of the 99 total patients in the cohort, 4 died during the study period; of these 4 patients, 3 were LGE positive on their last CMR and 3 had LVEF<55 (mean 48.0±15%) No patients in this cohort had undergone heart transplant or LVAD implantation Given the low rate of these events, statistical testing could not be performed At least one Holter study was performed on 76 of the 99 patients Non sustained ventricular tachycardia (1 patient) Atrial fibrillation (1 patient) Non sustained atrial tachycardia (8 patients) were infrequently observed. There was no statistically significant difference in risk of arrhythmias based on having 1 CMR with LGE, nor was there a relationship to LVEF.

43 Comparison to previous studies Our study is the largest longitudinal examination of CMR in the DMD population to date, but direct comparison with other studies is challenging due to variations in age range and disease severity Our cohort demonstrated similar proportions of patients with normal LVEF (76%) compared to other studies (70%,2 76%,5 88%9). Previous studies have reported a broad range of LGE positivity in DMD patients (from 32%9 to 70%10); comparing the 58% we observed is difficult given that the other studies had patients of different age ranges and provided limited data regarding steroid duration, which our study suggests may modulate the development of LGE Our data also corroborate previous reports that LGE in general appears to develop before depressed LVEF,10, 11 but extends this observation to show that once LGE has developed, there is on average a decline in LVEF.