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Journal of Cardiovascular Magnetic Resonance

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Open Access 01-12-2016 | Research

Myocardial late gadolinium enhancement is associated with clinical presentation in Duchenne muscular dystrophy carriers

Authors: Paul Wexberg, Marion Avanzini, Julia Mascherbauer, Stefan Pfaffenberger, Birgit Freudenthaler, Reginald Bittner, Günther Bernert, Franz Weidinger

Published in: Journal of Cardiovascular Magnetic Resonance | Issue 1/2017

Abstract

Background

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that occurs in males leading to immobility and death in early adulthood. Female carriers of DMD are generally asymptomatic, yet frequently develop dilated cardiomyopathy. This study aims to detect early cardiac manifestation in DMD using cardiovascular magnetic resonance (CMR) and to evaluate its association with clinical symptoms.

Methods

Clinical assessment of DMD carriers included six minutes walk tests (6MWT), blood analysis, electrocardiography, echocardiography, and CMR using FLASH sequences to detect late gadolinium enhancement (LGE). T1-mapping using the Modified Look-Locker Inversion recovery (MOLLI) sequence was performed quantify extracellular volume (ECV).

Results

Of 20 carriers (age 39.47 ± 12.96 years) 17 (89.5 %) were clinically asymptomatic. ECV was mildly elevated (29.79 ± 2.92 %) and LGE was detected in nine cases (45 %). LGE positive carriers had lower left ventricular ejection fraction in CMR (64.36 ± 5.78 vs. 56.67 ± 6.89 %, p = 0.014), higher bothCK (629.89 ± 317.48 vs. 256.18 ± 109.10 U/l, p = 0.002) and CK-MB (22.13 ± 5.25 vs. 12.11 ± 2.21 U/l, p = 0.001), as well as shorter walking distances during the 6MWT (432.44 ± 96.72 vs. 514.91 ± 66.80 m, p = 0.037). 90.9 % of subjects without LGE had normal pro-BNP, whereas in 66.7 % of those presenting LGE pro-BNP was elevated (p = 0.027). All individuals without LGE were in the NYHA class I, whereas all those in NYHA classes II and III showed positive for LGE (p = 0.066).

Conclusions

Myocardial involvement shown as LGE in CMR occurs in a substantial number of DMD carriers; it is associated with clinical and morphometric signs of incipient heart failure. LGE is thus a sensitive parameter for the early diagnosis of cardiomyopathy in DMD carriers.

Trial registration

Clinicaltrials.gov, NCT01712152 Trial registration: October 19, 2012.

First patient enrolled: September 27, 2012 (retrospectively registered).

Bushby KM. The muscular dystrophies. Baillieres Clin Neurol. 1994;3:407–30.PubMed

Morrison LA. Dystrophinopathies. Handb Clin Neurol. 2011;101:11–39.CrossRefPubMed

Angelini C. The role of corticosteroids in muscular dystrophy: a critical appraisal. Muscle Nerve. 2007;36:424–35.CrossRefPubMed

Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the Netherlands. Neuromuscul Disord. 2003;13:166–72.CrossRefPubMed

American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics. 2005;116:1569–73.CrossRef

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016. doi:10.1093/eurheartj/ehw128.

Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A, et al. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ follow-up. Am Heart J. 2007;154:596–602.CrossRefPubMed

Raman SV, Hor KN, Mazur W, Halnon NJ, Kissle JT, He X, et al. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14:153–61.CrossRefPubMed

McNally EM, Kaltman JR, Benson DW, Canter CE, Cripe LH, Duan D, et al. Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, Lung, and Blood Institute in collaboration with Parent Project Muscular Dystrophy. Circulation. 2015;131:1590–8.CrossRefPubMedPubMedCentral

10.

Muzzarelli S, Ordovas K, Higgins CB. Cardiovascular MRI for the assessment of heart failure: focus on clinical management and prognosis. J Magn Reson Imaging. 2011;33:275–86.CrossRefPubMed

11.

Yilmaz A, Gdynia HJ, Baccouche H, Mahrholdt H, Meinhardt G, Basso C, et al. Cardiac involvement in patients with Becker muscular dystrophy: new diagnostic and pathophysiological insights by a CMR approach. J Cardiovasc Magn Reson. 2008;10:50.CrossRefPubMedPubMedCentral

12.

Yilmaz A, Gdynia HJ, Mahrholdt H, Sechtem U. Cardiovascular magnetic resonance reveals similar damage to the heart of patients with Becker and limb-girdle muscular dystrophy but no cardiac symptoms. J Magn Reson Imaging. 2009;30:876–7.CrossRefPubMed

13.

Puchalski MD, Williams RV, Askovich B, Sower CT, Hor KH, Su JT, et al. Late gadolinium enhancement: precursor to cardiomyopathy in Duchenne muscular dystrophy? Int J Cardiovasc Imaging. 2009;25:57–63.CrossRefPubMed

14.

Walcher T, Kunze M, Steinbach P, Sperfeld AD, Burgstahler C, Hombach V, et al. Cardiac involvement in a female carrier of Duchenne muscular dystrophy. Int J Cardiol. 2010;138:302–5.CrossRefPubMed

15.

Walcher T, Steinbach P, Spiess J, Kunze M, Gradinger R, Walcher D, et al. Detection of long-term progression of myocardial fibrosis in Duchenne muscular dystrophy in an affected family: a cardiovascular magnetic resonance study. Eur J Radiol. 2011;80:115–9.CrossRefPubMed

16.

Finsterer J, Stollberger C, Avanzini M, Bastovansky A, Wexberg P. Late gadolinium enhancement as subclinical myocardial involvement in a manifesting Duchenne carrier. Int J Cardiol. 2011;146:231–2.CrossRefPubMed

17.

Iles L, Pfluger H, Phrommintikul A, Cherayath J, Aksit P, Gupta SN, et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol. 2008;52:1574–80.CrossRefPubMed

18.

Jellis C, Wright J, Kennedy D, Sacre J, Jenkins C, Haluska B, et al. Association of imaging markers of myocardial fibrosis with metabolic and functional disturbances in early diabetic cardiomyopathy. Circ Cardiovasc Imaging. 2011;4:693–702.CrossRefPubMed

19.

Messroghli DR, Walters K, Plein S, Sparrow P, Friedrich MG, Ridgway JP, et al. Myocardial T1 mapping: application to patients with acute and chronic myocardial infarction. Magn Reson Med. 2007;58:34–40.CrossRefPubMed

20.

Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Asscotiation of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;29:277–314.CrossRef

21.

Kellman P, Wilson JR, Xue H, Ugander M, Arai AE. Extracellular volume fraction mapping in the myocardium, part 1: evaluation of an automated method. J Cardiovasc Magn Reso: Off J Soc Cardiovasc Magn Reson. 2012;14:63.CrossRef

22.

Wong TC, Piehler K, Meier CG, Testa SM, Klock AM, Aneizi AA, et al. Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality. Circulation. 2012;126:1206–16.CrossRefPubMedPubMedCentral

23.

Lesca G, Demarquay G, Llense S, Streichenberger N, Petiot P, Michel-Calemard L, et al. Symptomatic carriers of dystrophinopathy with chromosome X inactivation bias. Rev Neurol (Paris). 2003;159:775–80.

24.

Azofeifa J, Voit T, Huebner C, Cremer M. X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum Genet. 1995;96:167–76.CrossRefPubMed

25.

Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, Leschot NJ, et al. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study. Lancet. 1999;353:2116–9.CrossRefPubMed

26.

Engel A, Yamamoto M, Fischbeck K. Dystrophinopathies. In: Engel A, Franzini-Armstrong C, editors. Myology. 3rd ed. New York: McGraw-Hill; 2004. p. 1133–87.

27.

Alderton J, Steinhardt R. How calcium influx through calcium leak channels is responsible for the elevated levels of calcium-dependent protelysis in dystrophic myotubes. Trends Cardiovasc Med. 2000;10:268–72.CrossRefPubMed

28.

McCarter G, Steinhardt R. Increased activity of calcium leak channels caused by proteolysis near sarcolemmal ruptures. J Membr Biol. 2000;176:169–74.CrossRefPubMed

29.

Carlson C. The dystrophinopathies: an alternative to the structural hypothesis. Neurobiol Dis. 1998;5:3–15.CrossRefPubMed

30.

Constantin B, Sebille S, Cognard C. New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD. J Muscle Res Cell Motil. 2006;27:357–86.CrossRef

31.

Arahata K, Ishiura S, Ishiguro T, Tsukahara T, Suhara Y, Eguchi C, et al. Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy peptide. Nature. 1988;333:861–3.CrossRefPubMed

32.

Hoffman EP. Clinical and histopathological features of abnormalities of the dystrophin-based membrane cytoskeleton. Brain Pathol. 1996;6:49–61.CrossRefPubMed

33.

Mavrogeni S, Markousis-Mavrogenis G, Papavasiliou A, Kolovou G. Cardiac involvement in Duchenne and Becker muscular dystrophy. World J Cardiol. 2015;7:410–4.CrossRefPubMedPubMedCentral

34.

Florian A, Roesch S, Bietenbeck M, Engelen M, Stypmann J, Waltenberger J, et al. A. Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study. Eur Heart J Cardiovasc Imaging. 2016;17:326-33. http://dx.doi.org/10.1093/ehjci/jev161.

35.

Giglio V, Puddu P, Camastra G, Sbarbari S, Della Sala S, Ferlini A, et al. Patterns of late gadolinium enhancement in Duchenne muscular dystrophy carriers. J Cardiovasc Magn Reson. 2014;16:45. doi:10.1186/1532-429X-16-45.CrossRefPubMedPubMedCentral

36.

Lang S, Shugh S, Mazur W, Sticka J, Rattan M, Jefferies J, et al. Myocardial fibrosis and left ventricular dysfunction in Duchenne muscular dystrophy carriers using cardiac magnetic resonance imaging. Pediatr Cardiol. 2015;36:1495–501.CrossRefPubMed

37.

Tandon A, Villa C, Hor K, Jefferies J, Gao Z, Towbin J, et al. Myocardial fibrosis burden predicts left ventricular ejection fraction and is associated with age and steroid treatment duration in Duchenne muscular dystrophy. J Am Heart Assoc. 2015;4:e001338.CrossRefPubMedPubMedCentral

38.

Kammerlander A, Marzluf B, Zotter-Tufaro C, Aschauer S, Duca F, Bachmann A, et al. T1-mapping by cardiac magnetic resonance imaging: from histological validation to clinical implication. J Am Coll Cardiol Img. 2016;9:14–23.CrossRef

Title: Myocardial late gadolinium enhancement is associated with clinical presentation in Duchenne muscular dystrophy carriers
Authors: Paul Wexberg
Marion Avanzini
Julia Mascherbauer
Stefan Pfaffenberger
Birgit Freudenthaler
Reginald Bittner
Günther Bernert
Franz Weidinger
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Cardiovascular Magnetic Resonance / Issue 1/2017
Electronic ISSN: 1532-429X
DOI: https://doi.org/10.1186/s12968-016-0281-y

At a glance: The STEP trials

Springer Medicine

Myocardial late gadolinium enhancement is associated with clinical presentation in Duchenne muscular dystrophy carriers

Abstract

Background

Methods

Results

Conclusions

Trial registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

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