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Erschienen in: Cardiovascular Drugs and Therapy 5/2022

17.06.2021 | Original Article

Early Myocardial Dysfunction and Benefits of Cardiac Treatment in Young X-Linked Duchenne Muscular Dystrophy Mice

verfasst von: Marie Vincenti, Charlotte Farah, Pascal Amedro, Valerie Scheuermann, Alain Lacampagne, Olivier Cazorla

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 5/2022

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Abstract

Context

Duchenne muscular dystrophy (DMD) is associated with a progressive alteration in cardiac function.

Objective

The aim of this study was to detect early cardiac dysfunction using the high sensitive two-dimensional speckle-tracking echocardiography (2D strain) in mdx mouse model and to investigate the potential preventive effects of the S107 ryanodine receptor (RyR2) stabilizer on early onset of DMD-related cardiomyopathy.

Methods and Results

Conventional echocardiography and global and segmental left ventricle (LV) 2D strains were assessed in male mdx mice and control C57/BL10 mice from 2 to 12 months of age. Up to 12 months of age, mdx mice showed preserved myocardial function as assessed by conventional echocardiography. However, global longitudinal, radial, and circumferential LV 2D strains significantly declined in mdx mice compared to controls from the 9 months of age. Segmental 2D strain analysis found a predominant alteration in posterior, inferior, and lateral LV segments, with a more marked impairment with aging. Then, mdx mice were treated with S107 in the drinking water at a dose of 250 mg/L using two different protocols: earlier therapy from 2 to 6 months of age and later therapy from 6 to 9 months of age. The treatment with S107 was efficient only when administered earlier in very young animals (from 2 to 6 months of age) and prevented the segmental alterations seen in non-treated mdx mice.

Conclusions

This is the first animal study to evaluate the therapeutic effect of a drug targeting early onset of DMD-related cardiomyopathy, using 2D strain echocardiography. Speckle-tracking analyses revealed early alterations of LV posterior segments that could be prevented by 4 months of RyR2 stabilization.

Graphical abstract

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Literatur
1.
Zurück zum Zitat Kamdar F, Garry DJ. Dystrophin-deficient cardiomyopathy. J Am Coll Cardiol. 2016;67:2533–46.CrossRef Kamdar F, Garry DJ. Dystrophin-deficient cardiomyopathy. J Am Coll Cardiol. 2016;67:2533–46.CrossRef
2.
Zurück zum Zitat Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK, et al. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 2018;17:445–55.CrossRef Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK, et al. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 2018;17:445–55.CrossRef
3.
Zurück zum Zitat Spurney CF, McCaffrey FM, Cnaan A, Morgenroth LP, Ghelani SJ, Gordish-Dressman H, et al. Feasibility and reproducibility of echocardiographic measures in children with muscular dystrophies. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2015;28:999–1008.CrossRef Spurney CF, McCaffrey FM, Cnaan A, Morgenroth LP, Ghelani SJ, Gordish-Dressman H, et al. Feasibility and reproducibility of echocardiographic measures in children with muscular dystrophies. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2015;28:999–1008.CrossRef
4.
Zurück zum Zitat Taqatqa A, Bokowski J, Al-Kubaisi M, Khalil A, Miranda C, Alaksham H, et al. The use of speckle tracking echocardiography for early detection of myocardial dysfunction in patients with Duchenne muscular dystrophy. Pediatr Cardiol. 2016;37:1422–8.CrossRef Taqatqa A, Bokowski J, Al-Kubaisi M, Khalil A, Miranda C, Alaksham H, et al. The use of speckle tracking echocardiography for early detection of myocardial dysfunction in patients with Duchenne muscular dystrophy. Pediatr Cardiol. 2016;37:1422–8.CrossRef
5.
Zurück zum Zitat Soslow JH, Xu M, Slaughter JC, Stanley M, Crum K, Markham LW, et al. Evaluation of echocardiographic measures of left ventricular function in patients with Duchenne muscular dystrophy: assessment of reproducibility and comparison to cardiac magnetic resonance imaging. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2016;29:983–91.CrossRef Soslow JH, Xu M, Slaughter JC, Stanley M, Crum K, Markham LW, et al. Evaluation of echocardiographic measures of left ventricular function in patients with Duchenne muscular dystrophy: assessment of reproducibility and comparison to cardiac magnetic resonance imaging. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2016;29:983–91.CrossRef
6.
Zurück zum Zitat Mertens L, Ganame J, Claus P, Goemans N, Thijs D, Eyskens B, et al. Early regional myocardial dysfunction in young patients with Duchenne muscular dystrophy. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2008;21:1049–54.CrossRef Mertens L, Ganame J, Claus P, Goemans N, Thijs D, Eyskens B, et al. Early regional myocardial dysfunction in young patients with Duchenne muscular dystrophy. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2008;21:1049–54.CrossRef
7.
Zurück zum Zitat Takano H, Fujii Y, Yugeta N, Takeda S, Wakao Y. Assessment of left ventricular regional function in affected and carrier dogs with Duchenne muscular dystrophy using speckle tracking echocardiography. BMC Cardiovasc Disord. 2011;11:23.CrossRef Takano H, Fujii Y, Yugeta N, Takeda S, Wakao Y. Assessment of left ventricular regional function in affected and carrier dogs with Duchenne muscular dystrophy using speckle tracking echocardiography. BMC Cardiovasc Disord. 2011;11:23.CrossRef
8.
Zurück zum Zitat Li Z, Li Y, Zhang L, Zhang X, Sullivan R, Ai X, et al. Reduced myocardial reserve in young X-linked muscular dystrophy mice diagnosed by two-dimensional strain analysis combined with stress echocardiography. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2017;30:815-827.e9.CrossRef Li Z, Li Y, Zhang L, Zhang X, Sullivan R, Ai X, et al. Reduced myocardial reserve in young X-linked muscular dystrophy mice diagnosed by two-dimensional strain analysis combined with stress echocardiography. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2017;30:815-827.e9.CrossRef
9.
Zurück zum Zitat Amedro P, Vincenti M, De La Villeon G, Lavastre K, Barrea C, Guillaumont S, et al. Speckle-tracking echocardiography in children with Duchenne muscular dystrophy: a prospective multicenter controlled cross-sectional study. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2019;32:412–22.CrossRef Amedro P, Vincenti M, De La Villeon G, Lavastre K, Barrea C, Guillaumont S, et al. Speckle-tracking echocardiography in children with Duchenne muscular dystrophy: a prospective multicenter controlled cross-sectional study. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2019;32:412–22.CrossRef
10.
Zurück zum Zitat McGreevy JW, Hakim CH, McIntosh MA, Duan D. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech. 2015;8:195–213.CrossRef McGreevy JW, Hakim CH, McIntosh MA, Duan D. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech. 2015;8:195–213.CrossRef
11.
Zurück zum Zitat Stedman HH, Sweeney HL, Shrager JB, Maguire HC, Panettieri RA, Petrof B, et al. The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature. 1991;352:536–9.CrossRef Stedman HH, Sweeney HL, Shrager JB, Maguire HC, Panettieri RA, Petrof B, et al. The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature. 1991;352:536–9.CrossRef
12.
Zurück zum Zitat Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, et al. Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A. 2010;107:1559–64.CrossRef Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, et al. Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A. 2010;107:1559–64.CrossRef
13.
Zurück zum Zitat Nakamura A, Yoshida K, Takeda S, Dohi N, Ikeda S. Progression of dystrophic features and activation of mitogen-activated protein kinases and calcineurin by physical exercise, in hearts of mdx mice. FEBS Lett. 2002;520:18–24.CrossRef Nakamura A, Yoshida K, Takeda S, Dohi N, Ikeda S. Progression of dystrophic features and activation of mitogen-activated protein kinases and calcineurin by physical exercise, in hearts of mdx mice. FEBS Lett. 2002;520:18–24.CrossRef
14.
Zurück zum Zitat Chakouri N, Farah C, Matecki S, Amedro P, Vincenti M, Saumet L, et al. Screening for in-vivo regional contractile defaults to predict the delayed doxorubicin cardiotoxicity in juvenile rat. Theranostics. 2020;10:8130–42.CrossRef Chakouri N, Farah C, Matecki S, Amedro P, Vincenti M, Saumet L, et al. Screening for in-vivo regional contractile defaults to predict the delayed doxorubicin cardiotoxicity in juvenile rat. Theranostics. 2020;10:8130–42.CrossRef
15.
Zurück zum Zitat Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A. 1993;90:3710–4.CrossRef Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A. 1993;90:3710–4.CrossRef
16.
Zurück zum Zitat Johnstone VPA, Viola HM, Hool LC. Dystrophic cardiomyopathy—potential role of calcium in pathogenesis, treatment and novel therapies. Genes. 2017;8. Johnstone VPA, Viola HM, Hool LC. Dystrophic cardiomyopathy—potential role of calcium in pathogenesis, treatment and novel therapies. Genes. 2017;8.
17.
Zurück zum Zitat Andre L, Fauconnier J, Reboul C, Feillet-Coudray C, Meschin P, Farah C, et al. Subendocardial increase in reactive oxygen species production affects regional contractile function in ischemic heart failure. Antioxid Redox Signal. 2013;18:1009–20.CrossRef Andre L, Fauconnier J, Reboul C, Feillet-Coudray C, Meschin P, Farah C, et al. Subendocardial increase in reactive oxygen species production affects regional contractile function in ischemic heart failure. Antioxid Redox Signal. 2013;18:1009–20.CrossRef
18.
Zurück zum Zitat Spurney C, Yu Q, Nagaraju K. Speckle tracking analysis of the left ventricular anterior wall shows significantly decreased relative radial strain patterns in dystrophin deficient mice after 9 months of age. PLoS Curr. 2011;3:RRN1273.CrossRef Spurney C, Yu Q, Nagaraju K. Speckle tracking analysis of the left ventricular anterior wall shows significantly decreased relative radial strain patterns in dystrophin deficient mice after 9 months of age. PLoS Curr. 2011;3:RRN1273.CrossRef
19.
Zurück zum Zitat Li W, Liu W, Zhong J, Yu X. Early manifestation of alteration in cardiac function in dystrophin deficient mdx mouse using 3D CMR tagging. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson. 2009;11:40. Li W, Liu W, Zhong J, Yu X. Early manifestation of alteration in cardiac function in dystrophin deficient mdx mouse using 3D CMR tagging. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson. 2009;11:40.
20.
Zurück zum Zitat Mori K, Hayabuchi Y, Inoue M, Suzuki M, Sakata M, Nakagawa R, et al. Myocardial strain imaging for early detection of cardiac involvement in patients with Duchenne’s progressive muscular dystrophy. Echocardiogr Mt Kisco N. 2007;24:598–608.CrossRef Mori K, Hayabuchi Y, Inoue M, Suzuki M, Sakata M, Nakagawa R, et al. Myocardial strain imaging for early detection of cardiac involvement in patients with Duchenne’s progressive muscular dystrophy. Echocardiogr Mt Kisco N. 2007;24:598–608.CrossRef
21.
Zurück zum Zitat Ogata H, Nakatani S, Ishikawa Y, Negishi A, Kobayashi M, Ishikawa Y, et al. Myocardial strain changes in Duchenne muscular dystrophy without overt cardiomyopathy. Int J Cardiol. 2007;115:190–5.CrossRef Ogata H, Nakatani S, Ishikawa Y, Negishi A, Kobayashi M, Ishikawa Y, et al. Myocardial strain changes in Duchenne muscular dystrophy without overt cardiomyopathy. Int J Cardiol. 2007;115:190–5.CrossRef
22.
Zurück zum Zitat Ait Mou Y, Lacampagne A, Irving T, Scheuermann V, Blot S, Ghaleh B, et al. Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy. J Mol Cell Cardiol. 2018;114:345–53.CrossRef Ait Mou Y, Lacampagne A, Irving T, Scheuermann V, Blot S, Ghaleh B, et al. Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy. J Mol Cell Cardiol. 2018;114:345–53.CrossRef
23.
Zurück zum Zitat Su JB, Cazorla O, Blot S, Blanchard-Gutton N, Ait Mou Y, Barthélémy I, et al. Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy. Cardiovasc Res. 2012;95:86–96.CrossRef Su JB, Cazorla O, Blot S, Blanchard-Gutton N, Ait Mou Y, Barthélémy I, et al. Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy. Cardiovasc Res. 2012;95:86–96.CrossRef
24.
Zurück zum Zitat Modesto K, Sengupta PP. Myocardial mechanics in cardiomyopathies. Prog Cardiovasc Dis. 2014;57:111–24.CrossRef Modesto K, Sengupta PP. Myocardial mechanics in cardiomyopathies. Prog Cardiovasc Dis. 2014;57:111–24.CrossRef
25.
Zurück zum Zitat Williams IA, Allen DG. Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol. 2007;292:H846-855.CrossRef Williams IA, Allen DG. Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol. 2007;292:H846-855.CrossRef
26.
Zurück zum Zitat Leone M, Magadum A, Engel FB. Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations. Am J Physiol Heart Circ Physiol. 2015;309:H1237-1250.CrossRef Leone M, Magadum A, Engel FB. Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations. Am J Physiol Heart Circ Physiol. 2015;309:H1237-1250.CrossRef
27.
Zurück zum Zitat Van Erp C, Loch D, Laws N, Trebbin A, Hoey AJ. Timeline of cardiac dystrophy in 3–18-month-old MDX mice. Muscle Nerve. 2010;42:504–13.CrossRef Van Erp C, Loch D, Laws N, Trebbin A, Hoey AJ. Timeline of cardiac dystrophy in 3–18-month-old MDX mice. Muscle Nerve. 2010;42:504–13.CrossRef
28.
Zurück zum Zitat Blain A, Greally E, Laval SH, Blamire AM, MacGowan GA, Straub VW. Absence of cardiac benefit with early combination ACE inhibitor and beta blocker treatment in mdx mice. J Cardiovasc Transl Res. 2015;8:198–207.CrossRef Blain A, Greally E, Laval SH, Blamire AM, MacGowan GA, Straub VW. Absence of cardiac benefit with early combination ACE inhibitor and beta blocker treatment in mdx mice. J Cardiovasc Transl Res. 2015;8:198–207.CrossRef
29.
Zurück zum Zitat Spurney CF, Sali A, Guerron AD, Iantorno M, Yu Q, Gordish-Dressman H, et al. Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx mice. J Cardiovasc Pharmacol Ther. 2011;16:87–95.CrossRef Spurney CF, Sali A, Guerron AD, Iantorno M, Yu Q, Gordish-Dressman H, et al. Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx mice. J Cardiovasc Pharmacol Ther. 2011;16:87–95.CrossRef
30.
Zurück zum Zitat Li Y, Zhang S, Zhang X, Li J, Ai X, Zhang L, et al. Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy. Cardiovasc Res. 2014;103:60–71.CrossRef Li Y, Zhang S, Zhang X, Li J, Ai X, Zhang L, et al. Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy. Cardiovasc Res. 2014;103:60–71.CrossRef
31.
Zurück zum Zitat Kleopa KA, Drousiotou A, Mavrikiou E, Ormiston A, Kyriakides T. Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy. Hum Mol Genet. 2006;15:1623–8.CrossRef Kleopa KA, Drousiotou A, Mavrikiou E, Ormiston A, Kyriakides T. Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy. Hum Mol Genet. 2006;15:1623–8.CrossRef
32.
Zurück zum Zitat Coley WD, Bogdanik L, Vila MC, Yu Q, Van Der Meulen JH, Rayavarapu S, et al. Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet. 2016;25:130–45.CrossRef Coley WD, Bogdanik L, Vila MC, Yu Q, Van Der Meulen JH, Rayavarapu S, et al. Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet. 2016;25:130–45.CrossRef
33.
Zurück zum Zitat van Putten M, Putker K, Overzier M, Adamzek WA, Pasteuning-Vuhman S, Plomp JJ, et al. Natural disease history of the D2-mdx mouse model for Duchenne muscular dystrophy. FASEB J Off Publ Fed Am Soc Exp Biol. 2019;33:8110–24. van Putten M, Putker K, Overzier M, Adamzek WA, Pasteuning-Vuhman S, Plomp JJ, et al. Natural disease history of the D2-mdx mouse model for Duchenne muscular dystrophy. FASEB J Off Publ Fed Am Soc Exp Biol. 2019;33:8110–24.
34.
Zurück zum Zitat Pons F, Robert A, Fabbrizio E, Hugon G, Califano JC, Fehrentz JA, et al. Utrophin localization in normal and dystrophin-deficient heart. Circulation. 1994;90:369–74.CrossRef Pons F, Robert A, Fabbrizio E, Hugon G, Califano JC, Fehrentz JA, et al. Utrophin localization in normal and dystrophin-deficient heart. Circulation. 1994;90:369–74.CrossRef
Metadaten
Titel
Early Myocardial Dysfunction and Benefits of Cardiac Treatment in Young X-Linked Duchenne Muscular Dystrophy Mice
verfasst von
Marie Vincenti
Charlotte Farah
Pascal Amedro
Valerie Scheuermann
Alain Lacampagne
Olivier Cazorla
Publikationsdatum
17.06.2021
Verlag
Springer US
Erschienen in
Cardiovascular Drugs and Therapy / Ausgabe 5/2022
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07218-7

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