Our work group has constantly focused attention to the myocardial involvement in DMD. A compendium of the results obtained in the field can be found in Engel & Franzini-Armstrong's textbook "Myology" (5
The therapeutic approach of cardiomyopathy has only recently been accepted and is based on the use of ACE inhibitors and beta-blockers to prevent cardiac function deterioration. Digitalis, diuretics and anticoagulants are used in the acute phases, such as congestive heart failure episodes.
We are convinced that the therapeutics are more effective when administered very early in the course of disease – please remember the latin saying "to prevent is better than to cure" – before the fibrosis is established. Dystrophyn plays a critical role in the myocardium by connecting the cytoskeleton to the external membrane, so that its absence causes membrane fragility, loss of transductional force and myocite necrosis, promoted by mechanical stress (33
). The efficacy and the progressive benefit over time of ACEis are consistent with a hemodynamic effect and/or a specific antifibrotic effect of this class of drugs and are concordant with experimental observations made in animal models (35
). Long-term therapy with DFZ is also effective in slowing down the progression of fibrosis in the dystrophin deficient heart.
Our group adopted deflazacort in the treatment of DMD boys since 1990. In 2004 we published (37
) in cooperation with the Toronto group the results of a prolonged observation on 69 DMD patients, treated for at least 4 years by two different treatment protocols (0.6 mg/kg/day, 20 days on/10 days off [N-Protocol] vs. 0.9 mg/kg/day [T-Protocol]) comparing both the long-term benefits and side effects. With respect to the group of 49 untreated DMD boys, the report illustrated the long-term beneficial effects on muscle function and motor performance of deflazacort treatment in both protocols. However the high dose protocol (T-protocol) seemed to be more effective but frequently associated with asymptomatic cataracts.
In the same year we presented at the Mediterranean Society of Myology Congress the results on cardiac function of a long-term period of observation of 60 DMD boys treated with DFZ at the dosage of 0.6 mg/kg/ day for 20 days/month (38
). The mean age at the enrollment was 5.6 years (range 4-11.7); the follow up was 83.7 months on average (range 36-144 months). All the patients had a fourth-month cardiac evaluation by ECG and echocardiography. The following parameters were evaluated: PQ interval, PQ segment, QT interval, QT dispersion, Cardiomyopathic Index (QT/PQ, adjusted for HR), presence of Arrhythmias or Blocks, presence of T wave anomalies, by the ECG; four chambers dimension, wall thicknesses, Ejection Fraction, Fractional Shortening, ultrasonic integrated backscatter (IBS), by the echocardiogram.
At the enrollment, 7 patients had a normal heart, 50 presented a pre-symptomatic stage and 3 were in the arrhytmogenic stage (5
). At the end of the study, no change in electrocardiographic and echocardiographic parameters were observed ( and ). Two patients shifted from a normal heart to the a presymptomatic stage due to a pathological increase in Cardiomyopathic Index, while 2 passed from the presymptomatic stage to the spotty fibrosis stage. None of them presented with overt cardiomyopathy. The data above shown suggest that treatment with deflazacort is able to preserve cardiac function in Duchenne patients.
DFZ treatment. Echocardiographic parameters.
In 2010, on the occasion of the XII ICNMD, we reported the results of a long-term administration (10,8 years on average) of fosinopril and deflazacort in 52 DMD patients aged 18-34,1 years in order to assess whether the early and prolonged administration of both drugs was able to prevent or delay the onset of an overt dystrophinopathic cardiomyopathy (39
). The dosage of fosinopril was 0.3mg/kg b.i.d. continuously. Mean age at the onset of fosinopril administration was 11,4 years (range 6-19). All the patients have been examined at 4-month intervals using a standardised clinical protocol, including clinical examination, standard and dynamic ECG, M-Mode and 2D echocardiography, Echo-color- Doppler-cardiography. We considered as the onset of an overt cardiomyopathy a value of ejection fraction, evaluated in 2D echo-cardiography, ≤ 50%. A historical group of 35 DMD patients – drug naïf – served as control. A LVEF > 50% was observed in 76,9% of DMD treated patients, at a mean age of 23 years, vs 15% of DMD patients of the control group (p < 0,001). On the other hand a LVEF < 50% was observed in 23,1% of DMD treated patients, at a mean age of 19,4 years, vs 85% of the control group, at the same age (p < 0,001). Kaplan-Meyer freedom cardiomyopathy was 70% at the age of 23 years in DMD treated boys vs 15% in the control group.
The effects of steroids and ACEIs on cardiac function in DMD boys have not be recently confirmed (40
). However the study presents several limitations, such as the study design based on physician preference, older boys on combination treatment while younger on steroids alone, too short period of follow up.
In conclusion, we can affirm that:
- Steroids in general and deflazacort in particular, remain the "gold standard" for the treatment of Duchenne muscular dystrophy (41) as they are able to modify the natural history of DMD.
- ACE inhibitors alone and/or in association with deflazacort are effective in slowing down the onset and the progression of dystrophinopathic cardiomyopathy.
- Beta-blockers are useful in DMD cases to reduce heart rate.
- Cardiological treatment should start very early (5 years of age) in the course of the disease, before the fibrosis is established.