Skip to main content
SpringerLink
Log in

Left Ventricular Tonic Contraction as a Novel Biomarker of Cardiomyopathy in Duchenne Muscular Dystrophy

  • Original Article
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

Dilated cardiomyopathy (DCM) inevitably afflicts patients with Duchenne muscular dystrophy (DMD) as a consequence of cell death induced by unguarded calcium influx into cardiomyocytes. This mechanism may also inhibit muscle relaxation in early stages of cardiomyopathy. ACE inhibition (ACEi) is known to delay the onset and slow the progression of DCM in DMD. The objective of this study is to use echocardiography to assess for preclinical cardiac changes consistent with intracellular calcium dysregulation before the onset of overt ventricular dysfunction, and to evaluate how prophylactic ACEi may alter these pre-cardiomyopathic changes in the pediatric DMD population. We examined 263 echocardiograms from 70 pediatric patients with DMD. We defined abnormal tonic contraction (TC) as left ventricular internal dimension in diastole (LVIDd) Z-score < −1.5. In our cohort, we found that TC is detectable as early as 8 years of age, and most commonly affects patients between 11 and 15 years. This effect was independent of LV mass and systolic function. Prophylactic ACEi decreased the incidence of TC (p = 0.007) and preserved cardiac function (p < 0.0001). Left ventricular TC often precedes DCM in DMD, most commonly affecting the 11- to 15-year-old age range. TC is not related to ventricular hypertrophy, but rather may be a clinical correlate of the “calcium hypothesis” of DMD pathophysiology. LV TC is thus a promising biomarker for early detection of cardiomyopathy in DMD. ACEi prophylaxis suppresses LV TC and delays the development of DCM in DMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ACEi:

Angiotensin-converting enzyme inhibitor

DCM:

Dilated cardiomyopathy

DMD:

Duchenne muscular dystrophy

FS:

Fractional shortening

LV:

Left ventricle

LVIDd:

Left ventricular internal dimension in diastole

MDA:

Muscular Dystrophy Association

TC:

Tonic contraction

References

  1. Alderton JM, Steinhardt RA (2000) How calcium influx through calcium leak channels is responsible for the elevated levels of calcium-dependent proteolysis in dystrophic myotubes. Trends Cardiovasc Med 10(6):268–272

    Article  CAS  PubMed  Google Scholar 

  2. Ameen V, Robson LG (2010) Experimental models of duchenne muscular dystrophy: relationship with cardiovascular disease. Open Cardiovasc Med J 4:265–277

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bauer R, Straub V, Blain A, Bushby K, MacGowan GA (2009) Contrasting effects of steroids and angiotensin-converting-enzyme inhibitors in a mouse model of dystrophin-deficient cardiomyopathy. Eur J Heart Fail 11(5):463–471

    Article  CAS  PubMed  Google Scholar 

  4. Berchtold MW, Brinkmeier H, Müntener M (2000) Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiol Rev 80(3):1215–1265

    CAS  PubMed  Google Scholar 

  5. Blain A, Greally E, Laval S, Blamire A, Straub V, MacGowan GA (2013) Beta-blockers, left and right ventricular function, and in vivo calcium influx in muscular dystrophy cardiomyopathy. PLoS One 8(2):e57260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Calabrò R, Pisacane C, Pacileo G, Russo MG (1999) Hemodynamic effects of a single oral dose of enalapril among children with asymptomatic chronic mitral regurgitation. Am Heart J 138(5 Pt 1):955–961

    Article  PubMed  Google Scholar 

  7. Carlson CG (1998) The dystrophinopathies: an alternative to the structural hypothesis. Neurobiol Dis 5(1):3–15

    Article  CAS  PubMed  Google Scholar 

  8. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57(6):450–458

    Article  CAS  PubMed  Google Scholar 

  9. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Bécane HM (2005) Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 45(6):855–857

    Article  CAS  PubMed  Google Scholar 

  10. Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A, Berard C, Vaksmann G, Weber S, Bécane HM (2007) Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ follow-up. Am Heart J 154(3):596–602

    Article  CAS  PubMed  Google Scholar 

  11. Goodwin FC, Muntoni F (2005) Cardiac involvement in muscular dystrophies: molecular mechanisms. Muscle Nerve 32(5):577–588

    Article  CAS  PubMed  Google Scholar 

  12. Greally E, Davison BJ, Blain A, Laval S, Blamire A, Straub V, MacGowan GA (2013) Heterogenous abnormalities of in vivo left ventricular calcium influx and function in mouse models of muscular dystrophy cardiomyopathy. J Cardiovasc Magn Reson 15:4

    Article  PubMed  PubMed Central  Google Scholar 

  13. Head SI, Williams DA, Stephenson DG (1992) Abnormalities in structure and function of limb skeletal muscle fibres of dystrophic mdx mice. Proc Biol Sci 248(1322):163–169

    Article  CAS  PubMed  Google Scholar 

  14. Hor KN, Kissoon N, Mazur W, Gupta R, Ittenbach RF, Al-Khalidi HR, Cripe LH, Raman SV, Puchalski MD, Gottliebson WM, Benson DW (2015) Regional circumferential strain is a biomarker for disease severity in Duchenne muscular dystrophy heart disease: a cross-sectional study. Pediatr Cardiol 36(1):111–119

    Article  PubMed  Google Scholar 

  15. Markham LW, Michelfelder EC, Border WL, Khoury PR, Spicer RL, Wong BL, Benson DW, Cripe LH (2006) Abnormalities of diastolic function precede dilated cardiomyopathy associated with Duchenne muscular dystrophy. J Am Soc Echocardiogr 19(7):865–871

    Article  PubMed  Google Scholar 

  16. Møller JE, Dahlström U, Gøtzsche O, Lahiri A, Skagen K, Andersen GS, Egstrup K, OPTIMAAL Study Group (2004) Effects of losartan and captopril on left ventricular systolic and diastolic function after acute myocardial infarction: results of the optimal trial in myocardial infarction with angiotensin II antagonist losartan (OPTIMAAL) echocardiographic substudy. Am Heart J 147(3):494–501

    Article  PubMed  Google Scholar 

  17. Raczek KK, Dorey F, Wong PC, Szmuszkovicz JR, Menteer J (2010) Relative versus absolute values: using patient and population norms for echocardiography in pediatric cardiac transplant recipients. Pediatr Transplant 14(2):182–187

    Article  PubMed  Google Scholar 

  18. Ramaciotti C, Heistein LC, Coursey M, Lemler MS, Eapen RS, Iannaccone ST, Scott WA (2006) Left ventricular function and response to enalapril in patients with duchenne muscular dystrophy during the second decade of life. Am J Cardiol 98(6):825–827

    Article  CAS  PubMed  Google Scholar 

  19. Schram G, Fournier A, Leduc H, Dahdah N, Therien J, Vanasse M, Khairy P (2013) All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy. J Am Coll Cardiol 61(9):948–954

    Article  PubMed  Google Scholar 

  20. Townsend D, Yasuda S, McNally E, Metzger JM (2011) Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex. FASEB J 25(9):3106–3114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wagner S, Knipp S, Weber C, Hein S, Schinkel S, Walther A, Bekeredjian R, Müller OJ, Friedrich O (2012) The heart in Duchenne muscular dystrophy: early detection of contractile performance alteration. J Cell Mol Med 16(12):3028–3036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Williams IA, Allen DG (2007) Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol 292:H846–H855

    Article  CAS  PubMed  Google Scholar 

  23. Woolf PJ, Lu S, Cornford-Nairn R, Watson M, Xiao XH, Holroyd SM, Brown L, Hoey A (2006) Alterations in dihydropyridine receptors in dystrophin-deficient cardiac muscle. Am J Physiol Heart Circ Physiol 290:H2439–H2445

    Article  CAS  PubMed  Google Scholar 

  24. Yasuda S, Townsend D, Michele DE, Favre EG, Day SM, Metzger JM (2005) Dystrophic heart failure blocked by membrane sealant poloxamer. Nature 436(7053):1025–1029

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology at Children’s Hospital of Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Jennifer A. Su & JonDavid Menteer

  2. Children’s Hospital of Los Angeles, 4650 W. Sunset Blvd, Mailstop #34, Los Angeles, CA, 90027, USA

    Jennifer A. Su, Leigh Ramos-Platt & JonDavid Menteer

  3. Division of Neurology at Children’s Hospital of Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Leigh Ramos-Platt

Authors
  1. Jennifer A. Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leigh Ramos-Platt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. JonDavid Menteer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer A. Su.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed Consent

For this type of retrospective study formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, J.A., Ramos-Platt, L. & Menteer, J. Left Ventricular Tonic Contraction as a Novel Biomarker of Cardiomyopathy in Duchenne Muscular Dystrophy. Pediatr Cardiol 37, 678–685 (2016). https://doi.org/10.1007/s00246-015-1331-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-015-1331-1

Keywords

Search

Navigation