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     1 Department of Pediatrics, All India Institute of Medical Sciences,Ansari Nagar, New Delhi-110029, India

    2 Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India

    Sir,

    In response to the letter by Finsterer et al, The authors would like to address the following issues:

    It is known that approximately two-thirds of DMD cases are familial and only one-third are sporadic.[1] DMD, being a lethal X-linked recessive disorder, has a high frequency of isolated cases. One would assume that one-third of the cases result from a denovo mutation.[2] In the current case series family history was positive in only one-third number of cases.[3] Some families deny the presence of positive family history on social grounds. The authors have no registries to confirm such history. Other case series show variable numbers with positive family history. In a recent report, there was family history in five of the 21 patients of Duchenne muscular dystrophy.[4]

    Enlargement of skeletal muscles on history only was noted in 13% of cases as it is mentioned as a symptom not a sign.[3] On examination all had calf hypertrophy. This was in a Table, which was advised to be deleted during peer review. Pseudohypertrophy of other muscles noted include: quadriceps, gluteal, deltoid and infraspinatus.

    Among all patients who were non-ambulatory at the time of enrollment (63.3%), the mean age at loss of ambulation was 8.1 ± 1.2 years. The mean age at the time of the study of all patients: Ambulatory or non-ambulatory was 10.1± 2.3 yrs. Thus there is no discrepancy.[3]

    How to explain that 10% of patients had cardiac symptoms or signs already at onset of DMD ( Mean age at onset: 4.8 yrs), although it is reported that cardiac involvement usually manifests clinically after age 10 yrs or at the onset of wheel chair bound state.[5] This 10% figure is at time of enrollment and not at onset. These 3 children had ages: 9, 10 and fourteen respectively and the latter two were non-ambulatory.

    How to explain that only 10% had symptoms and signs suggestive of cardiac involvement whereas 64% had an EF < 55%. They must be having subclinical cardiac involvement hence it is suggested that cardiac evaluation by echocardiography be carried out periodically. Nigro et al reported that pre-clinical cardiac involvement was found in 25% of patients with DMD under 6 years old increasing to 59% between the ages of 6 and 10 years and then declining in incidence with age. Clinically apparent cardiomyopathy was first evident after 10 years of age and increased in incidence with age, being present in all patients over 18 years of age.[5] The majority of patients with DMD remain free of cardiovascular symptoms until late in the disease course, probably because of their inability to exercise, which may mask cardiac symptoms.[6]

    Eighty percent of patients had a deceleration time of < 150 ms, but all had an E/A ratio> 1 which is compatible with restrictive filling pattern. This could be due to diastolic dysfunction of ventricles possibly due to myocardial fibrosis. The LA size ranged from 17-30mm with a mean of 23.18. Out of those with restrictive filling pattern, the LA size ranged from 19-30 mm with a mean of 23.8 mm. Patients fulfilling the criteria of dilated cardiomyopathy included Incr LV & less EF Pls tell criteria

    Since the age of patients was quite variable, it is desirable to present measurements presented in [Table 2] in relation to body size. This was not possible as majority were nonambulatory with contractures and it was not possible to take their heights and then calculate body surface areas. Left Atrial size has been mentioned now.

    On echocardiography none of the patients showed Left ventricular hypertrabeculation/ noncompaction. Left ventricular hypertrabeculation/ noncompaction (LVHT) is a cardiac abnormality characterized by prominent trabeculations and intertrabecular recesses, and frequently associated with neuromuscular disorders. Although left ventricular hypertrabeculation (LVHT) has been reported in patients with DMD.[7] In patients with Duchenne muscular dystrophy, left ventricular hypertrabeculation/noncompaction (LVHT) represents a compensatory attempt to overcome the failing compacted but dystrophic myocardium.[8] None of the patients who died underwent an autopsy.

    Compared to previous studies,[9] How do you explain the presence of ECG abnormalities in 93% of cases already at a mean age of 10.1 yrs. Though cardiac involvement in DMD increases with age, It is clinically present in all DMD patients not earlier than 18 yrs of age.[5] It has been reported that as a result of evolving cardiomyopathy, 90 percent of patients with DMD exhibit abnormalities in their electrocardiograms (increased R/S amplitude ratio in lead V 1 ; deep q waves in the left precordial leads [V 5 , V 6 ];sinus tachycardia or other sinus arrhythmias.[10],[11] Eighty-four patients with DMD (aged 18.6 +/- 4.8 years) underwent standard and signal-averaged electrocardiography, 24-hour Holter monitoring, and echocardiography. The prevalence of electrocardiographic abnormalities, frequent ventricular premature complexes, LPs, and LV systolic dysfunction was reported 71%, 32%, 28%, and 35%, respectively.[12]

    The pathoanatomic evidence of cardiac involvement in dystrophinopathies is the replacement of myocardium by connective tissue or fat. In DMD, the left ventricular posterobasal and lateral walls are most extensively affected, sparing the right ventricle and the atrium. In DMD, cardiac involvement usually remains subclinical in the early stages of the disease. Typical initial manifestations are sinus tachycardia, tall R1 in V1, prominent Q in I, aVL, V6 or in II, III, and aVF, increased QT dispersion and possibly autonomic dysfunction. Initially, echocardiography is normal or shows regional wall motion abnormalities in areas of fibrosis. With spreading of fibrosis, left ventricular dysfunction and ventricular arrhythmias additionally occur. In the final stages of the disease, systolic function may lead to heart failure and sudden death. Subclinical or clinical CI is present in about 90% of the DMD patients but is the cause of death in only 20% of the DMD patients.[13]

    Origin of rhythm abnormalities in the posterobasal and inferior left ventricular wall: Sanyal et al identified electrocardiographic abnormalities in 63 (84%) of 75 patients with Duchenne's progressive muscular dystrophy. A tall R wave over V1 with an abnormal R/S ratio was seen in 64% of the patients, a deep and narrow Q wave greater than 4 mm over leads I, V5, and V6 in 44%, sinus tachycardia in 32% and right axis deviation in 16%. Ultrastructural characteristics of the heart were determined for two patients with characteristic electrocardiographic abnormalities. These observations support the contention that the distinctive ECG pattern associated with Duchenne's dystrophy results from multifocal degenerative changes involving myocardium, predominantly the posterobasal region of the left ventricle and the posterior papillary muscle.[14] The cardiac involvement in DMD is characterized pathologically by degeneration and fibrosis of the myocardium, centering around the posterolateral wall of the left ventricle.[15] Myocardial fibrosis was observed in most of the patients with DMD in an autopsy study.[16] Autopsy studies have shown that cardiomyopathy of Duchenne's muscular dystrophy (DMD) is characterized by fibrosis of the posterobasal and contiguous lateral wall of the left ventricle.[17]

    Some studies recommend β blockers for sinus tachycardia[18] None of the patients were treated with b blockers instead of digoxin. There was no specific reason for not giving β blockers. In some studies beta-Blockers have been added if echocardiography showed no ventricular remodeling in angiotensin-converting enzyme inhibitor-treated dilated cardiomyopathy patients after 3 months. Early diagnosis and treatment of dilated cardiomyopathy may lead to ventricular remodeling in DMD patients.[19] Due to its protective effect, ACE inhibitors are recommended already at the early stages of the disease. Beta-blockers may be an additional option if indicated.[13] Early treatment with perindopril has been shown to delay the onset and progression of prominent left ventricle dysfunction in children with DMD.[20]

    How to explain the absence of a correlation between clinical parameters, creatine- kinase levels, presence of dystrophin deletions, corticosteroid therapy, and cardiac involvement How to explain the association between deletions and the cardio-thoracic ratio Recently it has been reported that systolic function improves from corticosteroids in addition to skeletal muscle performance.[21] How do you explain that there was no relation between corticosteroid therapy and cardiac involvement There is evidence from randomised controlled studies that glucocorticoid corticosteroid therapy in Duchenne muscular dystrophy improves muscle strength and function in the short-term (six months to two years). The most effective prednisolone regime appears to be 0.75 mg/Kg/day. In the short term, adverse effects were significantly more common but not clinically severe. Long-term benefits and hazards of glucocorticoid treatment cannot be evaluated from the currently published randomised studies. Non-randomised studies support the conclusions of functional benefits but also indicate clinically significant adverse effects of long-term treatment. These benefits and adverse effects have implications for future research studies and clinical practice.[22] Echocardiograms performed from 1997 to 2004 for 111 subjects 21 years of age or younger with Duchenne muscular dystrophy were restrospectively reviewed by Markham et al. Of those treated, 29 received prednisone and 19 received deflazacort. This retrospective study suggests that the progressive decline in cardiac function of patients with Duchenne muscular dystrophy can be altered by steroid treatment. The effect appears to be sustained beyond the duration of treatment and independent of steroid type.[21] Jefferies et al reported that DNA analysis in 47 cases (68%) revealed a significant association between dilated cardiomyopathy and exon 12 and 14 to 17 mutations, possible protection against dilated cardiomyopathy by exon 51 to 52 mutations, and a trend toward significant association between onset of dilated cardiomyopathy and exon 31 to 42 mutations. Statistical significance was based on nominal probability values.[23]

    The number of patients in the current study is too small hence no association was found.[3]

    References

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    2.Haldane JBS. The rate of spontaneous mutation of a human gene. J Genet 1935; 31: 317-326.

    3.Gulati S, Saxena A, Kumar V, Kalra V. Duchenne muscular dystrophy: prevalence and patterns of cardiac involvement. : Indian J Pediatr 2005 May; 72(5) : 389-393.

    4.Thong MK, Bazlin RI, Wong KT. Diagnosis and management of Duchenne muscular dystrophy in a developing country over a 10-year period. Dev Med Child Neurol 2005 Jul; 47(7) : 474-477.

    5.Nigro G, Comi LI, Politano L, Bain RJ. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol 1990 Mar; 26(3) : 271-277.

    6.Engel AG, Franzini-Armstrong C. Myology. 2nd ed. New York, McGraw-Hill, 1994

    7.Finsterer J, Gelpi E, Stollberger C. Left ventricular hypertrabeculation/noncompaction as a cardiac manifestation of Duchenne muscular dystrophy under non-invasive positive-pressure ventilation. Acta Cardiol 2005 Aug; 60(4) : 445-448.

    8.Finsterer J, Stollberger C, Feichtinger H. Noncompaction in duchenne muscular dystrophy: frustrated attempt to create a compensatory left ventricle Cardiology 2006; 105(4) : 223-225. Epub 2006 Feb 27.

    9.Sanyal SK, Johnson WW. Cardiac conduction abnormalities in children with Duchenne's progressive muscular dystrophy: electrocardiographic features and morphologic correlates. Circulation 1982 Oct;66(4):853-63.

    10.Griggs RC, Reeves W, moxely RT. The heart in Duchenne muscular dystrophy . In Rowland LP ed. Pathogenesis of human muscular dystrophies. Amsterdam, Excerpta Medica, 1977, 661.

    11.Farah MG, Evans EB, Vignos PJ Jr. Echocardiographic evaluation of left ventricular function in Duchenne's muscular dystrophy. Int J Cardiol 1990; 26 : 271-277.

    12.Corrado G, Lissoni A, Beretta S, Terenghi L, Tadeo G, Foglia-Manzillo G, Tagliagambe LM, Spata M, Santarone M. Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy. Am J Cardiol 2002 Apr 1; 89(7) : 838-841.

    13.Finsterer J, Stollberger C. The heart in human dystrophinopathies. Cardiology 2003; 99(1) : 1-19.

    14.Sanyal SK, Johnson WW, Thapar MK, Pitner SE. An ultrastructural basis for electrocardiographic alterations associated with Duchenne's progressive muscular dystrophy. Circulation 1978 Jun; 57(6) : 1122-1129.

    15.Ishikawa K. Cardiac involvement in progressive muscular dystrophy of the Duchenne type. Jpn Heart J 1997 Mar; 38(2) : 163-180.

    16.Moriuchi T, Kagawa N, Mukoyama M, Hizawa K. Autopsy analyses of the muscular dystrophies. Tokushima J Exp Med 1993 Jun; 40(1-2) : 83-93.

    17.Angermann C, Spes C, Pongratz D. Cardiac manifestation of progressive muscular dystrophy of the Duchenne type Z Kardiol 1986 Sep; 75(9) : 542-551.

    18.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 Feb; 13(2) : 166-172.

    19.Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM, Fernbach SD, Neish SR, Smith EO, Towbin JA. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 2005 Nov 1; 112(18) : 2756-2758.

    20.Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Becane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 2005 Mar 15; 45(6) : 855-857.

    21.Markham LW, Spicer RL, Khoury PR, Wong BL, Mathews KD, Cripe LH. Steroid therapy and cardiac function in duchenne muscular dystrophy. Pediatr Cardiol 2005 Nov-Dec; 26(6) : 768-771.

    22.Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2004; (2) : CD003725.

    23.Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM, Fernbach SD, Neish SR, Smith EO, Towbin JA. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 2005 Nov 1; 112(18) : 2756-2758.(Gulati Sheffali, Saxena Anita, Kalra Vee)