European Heart Journal Supplements (2007) 9 (Supplement E), E20–E24doi:10.1093/eurheartj/sum036 Perindopril preserves left ventricular functionin X-linked Duchenne muscular dystrophy Denis Duboc1*, Christophe Meune1, Bertrand Pierre1, Karim Wahbi1,2,Bruno Eymard2, Annick Toutain3, Carole Berard4, Guy Vaksmann5,and Henri-Marc Be 1Department of Cardiology, Cochin Hospital, APHP, Paris V Rene´ Descartes University, 27 rue du Fg St-Jacques,Paris 75014, France2Myology Institute, Pitie´-Salpe´trie`re Hospital, Paris, France3Department of Genetics, Bretonneau University Hospital, Tours, France4Department of Pediatric Rehabilitation, Lyon-Sud Hospital, Lyon, France5Department of Pediatrics, Cardiology Hospital, Lille, France Duchenne muscular dystrophy (DMD), an X-linked disorder due to a lack of dystrophin, is associated with muscle weakness and myocardial dysfunction. DMD children between the ages of 9.5 and 13 years with normal left ventricular ejection fraction were included in this prospective study. They were randomly assigned for 3 years to perindopril 2–4 mg (group 1) or placebo (group 2) in a double-blind protocol, followed by open-label treatment with perindopril for all patients. Left ventricular function was compared between the two groups at 5 years. A total of 28 patients were assigned to group 1 and 29 patients were assigned to group 2. Baseline characteristics weresimilar in both groups. At the end of the 5-year follow-up period, eight patients hadan ejection fraction under 45% in the placebo group vs. one patient in the perindoprilgroup (P , 0.02). All patients were alive in the perindopril group and three had died inthe placebo group (P ¼ 0.07). Early initiation of treatment with perindopril is associ-ated with a preservation of left ventricular function in DMD children and with a trendtowards a lower mortality.
abnormalities, and evolves towards cardiomyopathy withdilatation of the cardiac chambers and depression Duchenne muscular dystrophy (DMD; Figure 1) is an of left ventricular (LV) ejection fraction (EF) due to inherited, X-linked disease characterized by progressive widespread fibrosis; it is responsible for death in approxi- muscle weakness, and it is present in approximately mately 40% of patients aged between 10 and 30 years.6–8 one in 3000 male births.1 The gene, located at Xp21, Angiotensin-converting enzyme (ACE) inhibitors have codes for dystrophin, a sarcolemmal protein that links become first-line drugs in the management of patients the cytoskeleton to the basal lamina via the dystrophin- suffering from congestive heart failure (CHF), since associated glycoprotein complex.2,3 Cardiac involvement they reduce both morbidity and mortality.9,10 On the is inescapable and, with respiratory failure, is the most basis of experimental observation of the salutary effects common cause of fatal outcome.1,4,5 Evidence of myocar- conferred by perindopril in the Syrian hamster, an dial involvement begins with minor electrocardiographic animal model of @ sarcoglycanopathy that is phenotypi-cally similar to DMD,11–13 we examined the preventivemerit of the early administration of perindopril in chil- * Corresponding author. Tel: þ33 1 58 41 16 56; fax: þ33 1 58 41 16 05.
dren with DMD and normal LVEF at inclusion, after & The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org Duchenne muscular dystrophy. Immunohistochemical image of dystrophin in the skeletal muscle. Absence of subsarcolemmal fluoresence in the 5 years of follow-up. Our results on the prevention of LV The prescription of other cardioactive drugs was dysfunction have recently been published.14 allowed during phase II at the discretion of the primarycare physicians.
The protocol of this study has previously been described Data expressed as mean + standard deviation were ana- in detail.14 Briefly, among 80 children screened at 10 lysed according to the intention-to-treat principle, and medical institutions (Appendix), 57 between the ages of LVEF measurements that were available were included 9.5 and 13 years who had genetically confirmed DMD and in the analysis at each time point. Student’s t-tests a LVEF . 55% measured by radionuclide ventriculography, were used for normally distributed continuous variables, were included in a two-phase prospective study. Of the and x2-analysis for differences in frequencies. All remaining patients, 20 had a LVEF that was 55%, and P-values were two-tailed and a P-value of ,0.05 was three patients did not have confirmed DMD. Additional considered statistically significant (Statview software, inclusion criteria included tolerance of a 1-mg test dose of perindopril, and systolic blood pressure that was80 mm Hg in the supine position or .70 mm Hg in thesitting position. Children with contraindications to treat- ment with an ACE inhibitor, those receiving treatmentwith other cardioactive drugs, or who had a blood urea The baseline characteristics of the study groups were nitrogen level of .7 mmol/L, were not included in the similar (Table 1). No pharmaceutical agent other than study. The protocol was approved by the appropriate the study drugs was administered during phase I. During Ethics Review Committees, and informed, written phase II, treatment with perindopril was continued in consent was obtained from the parents or legal the maximum tolerated doses in all patients. In addition, at the beginning of phase II, four patients in group 1(initially allocated to perindopril) and five in group 2 (initially allocated to placebo) were treated withb-adrenergic blockers. All patients were still receiving After their inclusion into the study, the children were treatment with perindopril at the end of phase II. None randomly assigned for 3 years (phase I) in a double-blind of the patients were treated with digoxin, spironolac- fashion to either perindopril 2–4 mg daily as tolerated tone, or steroids during any part of the study; none had (group 1, n ¼ 28), or to placebo (group 2, n ¼ 29). In phase implantable devices, including cardioverter defibrillators II, all patients were followed during open-label treatment or cardiac pacemakers. Compliance to prescription was with perindopril, 2–4 mg daily, for two additional years.
The main end point was the existence of altered LVEF At 36 months, LVEF remained normal in the majority of at 5 years, as assessed by radionuclide ventriculogra- patients, and mean LVEF was similar in both groups. One phy.14 Radionuclide ventriculography was not performed patient did not complete phase I, though had remained in one child at the end of phase I, and in six children at free of cardiovascular events or symptoms at 36 months; LVEF was ,45% in a single patient in each group.
Baseline characteristics of the two study groups Mechanisms of angiotensin-converting enzyme inhibition in the prevention of left ventricular dysfunctionin Duchenne muscular dystrophy Renin–angiotensin–aldosterone system inhibition Blockade of the degradation of bradykinin Prevention of myocyte necrosis and apoptosis Maintaining myocyte regeneration capacities Improvement in diaphragmatic contractility Restoration of neutral nitric oxide synthase activity in the dystrophin-associated glycoprotein complex The gradual onset of the treatment effect and the progressive benefit over time that we observed are consist-ent with an haemodynamic effect and/or a specific antifi- Unless otherwise specified, values given are the mean +SD.
brotic effect of perindopril, and are concordant withexperimental observations made in a model of progressivecardiomyopathy resembling Duchenne myopathy.12,13 Dystrophin in fact plays a critical role in the myocar- After 5 years’ follow-up, perindopril delayed the onset dium by connecting the cytoskeleton to the external and progression of LV dysfunction; in the actively-treated basement membrane. Its absence is responsible for mem- group, only a single patient had a LVEF ,45%, vs. eight brane fragility, loss of transductional force and, ulti- patients in the group assigned to placebo (P ¼ 0.02).14 mately, myocyte necrosis promoted by mechanical None of the patients died in the perindopril group, stress.17,18 Thus, afterload reduction by perindopril may compared with three patients in the placebo group be a key factor in our study, which included children with DMD who were, on an average, less than 11 yearsof age.19 Some of the children were still capable of mus-cular exercise, and there is experimental evidence that the myocardium is vulnerable to pressure overload.20The inhibition of aldosterone synthesis by ACE inhibitors We have previously reported that during the 5-year might also prevent the development of fibrosis,21,22 and follow-up period of our study, perindopril delayed the previous studies have demonstrated a beneficial effect onset and progression of LV dysfunction: in the actively- of such inhibition.23,24 Finally, nitric oxide (NO), a power- treated group, a single patient had an LVEF ,45% at ful antioxidant, might also be involved in the development 5 years, compared with eight patients in the group of cardiac dysfunction in DMD. Mutation of dystrophin is assigned to placebo (P ¼ 0.02).14 We documented a accompanied by loss of dystrophin-associated glyco- benefit on LVEF conferred by the early, instead of protein complex, which includes neural NO synthase.25 delayed, administration of perindopril in DMD children The restoration of neural NO synthase activity in an between the ages of 9.5 and 13 years presenting with animal model was found to result in NO synthesis and limit- normal LVEF at entry into the study. While several other ation of myocardial fibrosis without an increase in the studies have reported a lowering of mortality with ACE expression of membrane-associated cytoskeletal pro- inhibitors in patients suffering from congestive heart teins.26,27 Since ACE inhibitors stimulate the synthesis failure10 or a preventive effect in patients at high risk of NO first by blocking the degradation of bradykinin by of adverse cardiovascular events,15 ours is the first to the direct promotion of the bradykinin type 2 receptor demonstrate a benefit conferred by perindopril on LVEF coupling to NO storage sites28 and second by inhibiting in patients with normal ejection fraction at inclusion aldosterone,29 they may exert part of their beneficial and lacking dystrophin, an orphan disease genetically effects via a NO-related pathway (Table 2).
determined to develop LV dysfunction.
Beyond cardiac involvement, DMD is also characterized In addition to a preservation of LVEF, we also report a by a progressive deficit of intercostal muscles and dia- trend towards a lower mortality in the perindopril phragmatic function, leading to severe chronic respiratory group; this result is in accordance with the recent Cande- insufficiency. Furthermore, previous experimental studies sartan in Heart Failure Reduction in Mortality (CHARM) have observed a beneficial effect of ACE inhibition on dia- study conducted in the adult population with heart phragmatic contractility.30 More recently, using the Mdx failure, which used the same cut-off of 45% for LVEF mouse — an animal model lacking dystrophin — it has and demonstrated that patients with an LVEF ,45% had been demonstrated that blocking the renin angiotensin an increased mortality during follow-up.16 pathway very early before the beginning of the fibrosis process preserves the muscle function of these mice by maintaining stem cell myoblast regeneration.31 Althoughthe beneficial effects that we observed on heart function The following French investigators and institutions participated may not be attributed to myocyte regeneration capacity, in this study: Brigitte Fetizon, MD, St-Joseph Hospital, Paris; our overall results suggest a global favourable effect on Marie-Paule Scemmama, MD, Armand Trousseau Hospital, Paris; Alain Carpentier, MD, Marc Sautelet Institute, VilleneuveD’Asque; Guy Vaksmann, MD, Charles Francart, MD, CardiologyHospital, Lille; Louis Vallee, MD, General Hospital B, Lille;Carole Berard, MD, Lyon-Sud Hospital, Lyon; Colette Age, MD, Brigitte de Breyne, MD, Louis Pradel Hospital, Lyon; AlainChenard, MD, Jean-Michel de Kermadec, MD; Fabienne Tertrain, Our study may have important implications in the man- MD, Martine Legrand, MD, General Hospital, Meaux; Miche agement of patients with DMD. We and others had Mayer, MD, St-Vincent de Paul Hospital, Paris; Annick Toutain, reported the preventive effect of ACE inhibition MD, Bretonneau Hospital, Tours; Alain Chantepie, MD, PhD, against LV contractility deterioration.14,32,33 However, there is still ongoing controversy as to whether DMD Jean-Yves Devaux, MD, PhD, Denis Duboc, MD, PhD, Cochin patients should be treated early (preventively) with ACE inhibitors.34–36 Since we limited the study entry topatients between the ages of 9.5 and 13 years, theoptimal age for initiation of therapy remains to bedetermined.14 The recent documentation of reduced myocardial strain by magnetic resonance imaging in 13 1. Emery AEH. Duchenne muscular dystrophy. 2nd ed. Oxford, UK: children with DMD whose mean age was the same as Oxford University Press; 1993. p1–392.
that of our patients,37 supports the earlier introduction 2. Ray PN, Belfall B, Duff C, Logan C, Kean V, Thompson MW, of ACE inhibitor treatment, a hypothesis that warrants Sylvester JE, Gorski JL, Schmickel RD, Worton RG. Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscu-lar dystrophy. Nature 1985;318:672–675.
3. Ervasti JM, Campbell KP. Membrane organisation of the dystrophin- glycoprotein complex. Cell 1991;66:1121–1131.
4. Gilroy J, Cahalan JL, Berman R et al. Cardiac and pulmonary compli- cations in Duchenne’s progressive muscular dystrophy. Circulation1963;27:484–493.
The randomized, double-blind phase of our protocol was 5. Melacini P, Vianello A, Villanova C, Fanin M, Miorin M, Angelini C, limited to 3 years, after which perindopril was dispensed Dalla Volta S. Cardiac and respiratory involvement in advanced in an open-label fashion. Although this could be highly stage Duchenne muscular dystrophy. Neuromuscul Disord 1996;6: criticized, our approach might be considered as valid in this particular setting of a rare disease. Moreover, the 6. Nigro G, Comi LI, Politano L, Bain RJ. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol 1990; inclusion of all patients throughout a prolonged follow-up period and the continuation of perindopril in all patients during the open-label period, associated with adequate lence of left ventricular systolic dysfunction in Duchenne muscular compliance, were strengths of the study.
dystrophy: an echocardiographic study. Am Heart J 1994;127:618–623.
Although this study is one of the largest studies of 8. Mukoyama M, Kondo K, Hizawa K, Nishitani H. Life spans of Duchenne DMD, it was not powered to analyse mortality, and the muscular dystrophy patients in the hospital care program in Japan.
trend towards lower mortality must be interpreted with 9. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293–302.
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13. Haleen SJ, Weishaar RE, Overhiser RW, Bousley RF, Keiser JA, The authors are indebted to Dr Guy Lerebours (Servier Labora- Rapundalo SR, Taylor DG. Effects of quinapril, a new angiotensin con- tories) and Rodolphe Ruffy for their assistance during the study verting enzyme inhibitor, on left ventricular failure and survival in and the preparation of the manuscript.
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This study was supported by a grant from the French Associ- 14. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Be ation against Myopathies (AFM) and Servier Laboratories.
Effect of perindopril on the onset and progression of left ventriculardysfunction in Duchenne Muscular disease. J Am Coll Cardiol 2005; Conflict of interest: none declared.
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