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• W1994668913 abstract "HomeJournal of the American Heart AssociationVol. 4, No. 4Glucocorticoid Therapy for Duchenne Cardiomyopathy: A Hobson's Choice? Open AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessEditorialPDF/EPUBGlucocorticoid Therapy for Duchenne Cardiomyopathy: A Hobson's Choice? Subha V. Raman, MD, MSEE and Linda H. Cripe, MD Subha V. RamanSubha V. Raman Division of Cardiovascular Medicine, Ohio State University, Columbus, OH Search for more papers by this author and Linda H. CripeLinda H. Cripe Nationwide Children's Hospital Heart Center, Coloumbus, OH Search for more papers by this author Originally published26 Mar 2015https://doi.org/10.1161/JAHA.115.001896Journal of the American Heart Association. 2015;4:e001896IntroductionDoubt is not a pleasant condition, but certainty is an absurd one.1As if receiving a diagnosis of Duchenne muscular dystrophy (DMD) were not terrible enough, consider the impact when a parent learns of the disease's progressive and inexorable effects on their son's heart.2 A relentless search for effective therapies against relentless cardiomyopathy ensues. Those with access to well‐informed teams at centers dedicated to interdisciplinary DMD care may get timely and sensitive screening for cardiac involvement, with institution of agents such as angiotensin‐converting enzyme inhibitors and β‐blockers that benefit a broad spectrum of myocardial diseases.3, 4 Those without access to such centers may themselves have to educate less‐experienced clinicians on appropriate diagnostic testing and medical therapy, armed with evidence collected from advocacy organizations or their own web‐based searches. Crucial to decision‐making are published data from high‐quality clinical trials, ideally based on mechanistically insightful preclinical investigations, that provide evidence in favor of or against a particular treatment.In this issue of JAHA, Tandon and colleagues describe their analysis of clinically‐acquired cardiac magnetic resonance scans in conjunction with steroid use recorded from the medical record in a large, single‐center DMD patient cohort.5 Two major findings are reported. First, they confirm prior results showing that increasing age is a risk factor for worsening left ventricular systolic function. As more damaged myocardium is less likely to function properly, increasing late gadolinium enhancement (LGE) abnormality in parallel with declining left ventricular ejection fraction should not come as a surprise. Their second finding describes an association between steroid use and change over time in number of LGE‐positive myocardial segments. When considering the sequelae of chronic corticosteroid therapy, the conclusion that longer steroid treatment duration confers lower age‐related increase in myocardial damage warrants closer examination. In particular, what evidence does the scientific literature offer on glucocorticoid therapy for DMD cardiomyopathy?Randomized controlled trials over the last several decades have established glucocorticoids as the therapy to prolong ambulatory function6; unfortunately, none included any cardiac end points. Evidence from a number of studies associate prednisone and deflazacort use with better cardiac function and outcomes in boys with DMD.7, 8, 9 However, the designs of these retrospective observational studies incur inherent biases that make interpretation of even a large amount of data potentially erroneous.10 Data of similar caliber suggesting that one may retard scoliosis11 and preserve pulmonary function have been used to justify continued prescription of high‐dose glucocorticoids even after loss of ambulation. What is not uncertain are the well‐documented adverse effects of chronic, high‐dose prednisone and, to a lesser extent, deflazacort therapy in DMD: personality changes, weight gain, cataracts, growth hormone and testosterone deficiencies, diabetes, gastrointestinal complications, and bone fractures.12, 13 Notably, glucocorticoid use remains outside of the realm of both pediatric and adult guidelines for heart failure management.14, 15 Even in conditions such as viral myocarditis and cardiac sarcoidosis, the scrutiny of systematic review has exposed the limitations of data generated from observational and retrospective studies, precluding endorsement of efficacy.16, 17Given the authors' implication that longer steroid use is beneficial to the heart in this vulnerable patient population, it is important to carefully consider the limitations of the current study. It is well established that there exists extreme variability in steroid dosing regimens for the treatment of DMD. In addition, many patients elect to be treated with deflazacort, a glucocorticoid not yet available in the United States. Even if we assume similar cardiac effects of prednisone and deflazacort (which may not be the case), the long‐term cardiac impact is likely different for one patient on 15 mg qd for 4 years versus another who receives a weekend pulse regimen of 500 mg for 4 years. The analysis does not distinguish between the 2, yet one has received a cumulative dose nearly 5 times greater than the other. An even more significant limitation of the study is the lack of a formal control group. As only 3 of 98 patients in this cohort were steroid naïve, it is difficult to speculate that the data support a protective effect of glucocorticoid therapy. Some patients were as old as 22.5 years at time of first cardiac magnetic resonance, and some as young as 9.4 years at time of last cardiac magnetic resonance: This implies a wide variation in age span between first and last scans that, in turn, suggests caution in drawing conclusions from data associations in a heterogeneous group of individuals at various stages of cardiac and neuromuscular disease. Finally, the 4% event rate in a multiyear retrospective study of a disease where nearly all patients will die of cardiopulmonary causes suggests that implications regarding prognosis be tempered.LGE positivity is equated with myocardial fibrosis in this article. While this may certainly be valid in more advanced disease, we simply do not have the histopathological corroboration for LGE in early stage Duchenne cardiomyopathy that has been established in other conditions affecting the myocardium. It is likely that some of the LGE positivity represents inflammation as it does in myocarditis, a condition with a nearly identical pattern of epicardial enhancement to that seen in the early myocardial damage of DMD. The label ascribed to LGE has implications beyond nosology: Instead of simply being a marker of disease progression, early LGE positivity may be asking us to more precisely target inflammation with refined therapy.While the authors state that the study was not powered to measure the confounding effect on their findings of angiotensin‐converting enzyme inhibitor, angiotensin receptor blocker, and β‐blocker therapies, it would be useful to know the prevalence of use in this cohort. We recently showed in a randomized, controlled trial that combining eplerenone with background angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker therapy attenuates decline in left ventricular systolic function, noting that evident myocardial damage by late gadolinium enhancement was a requirement for enrollment.18 The present study's finding that LGE‐negative patients did not show a significant ejection fraction decline may be used to justify a strategy of deferring combination therapy if myocardial damage is not evident by LGE. Deferring any cardioprotective treatment based on these results may be ill informed when one recognizes the absence of left ventricular strain data. Hor et al have shown greater sensitivity for early myocardial disease in DMD using tagged cine cardiac magnetic resonance–derived strain, which was abnormal in boys as young as 7 years even in the face of LGE‐negative myocardium with preserved ejection fraction.19This is a medically complex patient population where cardiomyopathy cannot be studied or treated in isolation. A multitude of factors clearly impact the course of both skeletal and cardiac disease from the time of diagnosis. Omission of confounding variables that impact cardiac disease progression, particularly respiratory status and use of ventilatory support devices, clouds data interpretation. Cardiorespiratory interactions are well known to impact both right and left ventricular function. In addition, therapies not infrequently encountered in this patient population include growth hormone, testosterone, vitamin D, as well as a variety of approved and unapproved nutritional supplements—all with the potential to impact myocardial performance and modulate the effects of glucocorticoid therapy.We conclude with 3 observations. First, amidst the daily burden of living with this disease, patients and families searching for useful information may stop with publication titles. Second, some of the variability in glucocorticoid therapy, particularly outside of the United States,20 reflects different perceptions of risk versus benefits by providers and families. And third, retrospective data from a diverse though large cohort must be interpreted with the limitations that such data present. If there is a link between steroid use and preservation of myocardial function in DMD, the truth lies in a carefully controlled prospective clinical trial. We must offer something better than simply “take or leave” glucocorticoids, particularly with increasing longevity for those with DMD. With a number of well‐designed clinical trials under way, better choices for more effective cardioprotection with less attendant morbidity are within reach.Sources of FundingThis study was supported by NIH R01HL116533.DisclosuresNone.Footnotes*Correspondence to: Subha V. Raman, MD, MSEE, Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Ave, Suite 200, Columbus, OH 43210. E‐mail: raman.[email protected]eduThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.References1 Voltaire . Letter to Frederick William, Prince of Prussia (28 November 1770). In: Tallentyre S, ed. Voltaire in His Letters. New York, NY: G.P. Putnam's Sons; 1919.Google Scholar2 Menon SC, Etheridge SP, Liesemer KN, Williams RV, Bardsley T, Heywood MC, Puchalski MD. Predictive value of myocardial delayed enhancement in Duchenne muscular dystrophy. Pediatr Cardiol. 2014; 35:1279–1285.CrossrefMedlineGoogle Scholar3 Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A, Berard C, Vaksmann G, Weber S, Bécane H. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years' follow‐up. Am Heart J. 2007; 154:596–602.CrossrefMedlineGoogle Scholar4 Rhodes J, Margossian R, Darras BT, Colan SD, Jenkins KJ, Geva T, Powell AJ. Safety and efficacy of carvedilol therapy for patients with dilated cardiomyopathy secondary to muscular dystrophy. Pediatr Cardiol. 2008; 29:343–351.CrossrefMedlineGoogle Scholar5 Tandon A, Villa CR, Hor KN, Jefferies JL, Gao Z, Towbin JA, Wong BL, Mazur W, Fleck RJ, Sticka JJ, Benson DW, Taylor MD. 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 doi: 10.1161/JAHA.114.001338.LinkGoogle Scholar6 Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; Group DMDCCW . Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010; 9:77–93.CrossrefMedlineGoogle Scholar7 Silversides CK, Webb GD, Harris VA, Biggar DW. Effects of deflazacort on left ventricular function in patients with Duchenne muscular dystrophy. Am J Cardiol. 2003; 91:769–772.CrossrefMedlineGoogle Scholar8 Markham LW, Spicer RL, Khoury PR, Wong BL, Mathews KD, Cripe LH. Steroid therapy and cardiac function in Duchenne muscular dystrophy. Pediatr Cardiol. 2005; 26:768–771.CrossrefMedlineGoogle Scholar9 Schram G, Fournier A, Leduc H, Dahdah N, Therien J, Vanasse M, Khairy P. All‐cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy. J Am Coll Cardiol. 2013; 61:948–954.CrossrefMedlineGoogle Scholar10 Barrett‐Connor E, Grady D, Stefanick ML. The rise and fall of menopausal hormone therapy. Annu Rev Public Health. 2005; 26:115–140.CrossrefMedlineGoogle Scholar11 Harvey A, Baker L, Williams K. Non‐surgical prevention and management of scoliosis for children with Duchenne muscular dystrophy: what is the evidence?J Paediatr Child Health. 2014; 50:E3–E9.CrossrefMedlineGoogle Scholar12 Angelini C. The role of corticosteroids in muscular dystrophy: a critical appraisal. Muscle Nerve. 2007; 36:424–435.CrossrefMedlineGoogle Scholar13 Ricotti V, Ridout DA, Scott E, Quinlivan R, Robb SA, Manzur AY, Muntoni F. Long‐term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy. J Neurol Neurosurg Psychiatry. 2013; 84:698–705.CrossrefMedlineGoogle Scholar14 Kantor PF, Lougheed J, Dancea A, McGillion M, Barbosa N, Chan C, Dillenburg R, Atallah J, Buchholz H, Chant‐Gambacort C, Conway J, Gardin L, George K, Greenway S, Human DG, Jeewa A, Price JF, Ross RD, Roche SL, Ryerson L, Soni R, Wilson J, Wong K; Children's Heart Failure Study G . Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines. Can J Cardiol. 2013; 29:1535–1552.CrossrefMedlineGoogle Scholar15 Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation/American Heart Association Task Force on Practice G . 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013; 128:e240–e327.LinkGoogle Scholar16 Sadek MM, Yung D, Birnie DH, Beanlands RS, Nery PB. Corticosteroid therapy for cardiac sarcoidosis: a systematic review. Can J Cardiol. 2013; 29:1034–1041.CrossrefMedlineGoogle Scholar17 Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev. 2013; 10:CD004471.Google Scholar18 Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, McCarthy B, Taylor MD, Jefferies JL, Rafael‐Fortney JA, Lowe J, Roble SL, Cripe LH. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double‐blind, placebo‐controlled trial. Lancet Neurol. 2015; 14:153–161.CrossrefMedlineGoogle Scholar19 Hor KN, Wansapura J, Markham LW, Mazur W, Cripe LH, Fleck R, Benson DW, Gottliebson WM. Circumferential strain analysis identifies strata of cardiomyopathy in Duchenne muscular dystrophy: a cardiac magnetic resonance tagging study. J Am Coll Cardiol. 2009; 53:1204–1210.CrossrefMedlineGoogle Scholar20 Griggs RC, Herr BE, Reha A, Elfring G, Atkinson L, Cwik V, McColl E, Tawil R, Pandya S, McDermott MP, Bushby K. Corticosteroids in Duchenne muscular dystrophy: major variations in practice. Muscle Nerve. 2013; 48:27–31.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Law M, Cohen H, Martin A, Angulski A and Metzger J (2020) Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies, Journal of Clinical Medicine, 10.3390/jcm9020520, 9:2, (520) Meyers T and Townsend D (2019) Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy, International Journal of Molecular Sciences, 10.3390/ijms20174098, 20:17, (4098) April 22, 2015Vol 4, Issue 4Article InformationMetrics © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.https://doi.org/10.1161/JAHA.115.001896PMID: 25814623 Originally publishedMarch 26, 2015 KeywordsEditorialsGlucocorticoidDuchenne muscular dystrophy cardiomyopathycardiac magnetic resonance imagingPDF download SubjectsComputerized Tomography (CT)Heart Failure" @default.
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• W1994668913 title "Glucocorticoid Therapy for Duchenne Cardiomyopathy: A Hobson's Choice?" @default.
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