Muscular dystrophies are responsible for major deteriorations at the levels of both skeletal and cardiac muscle. Cardiac modifications can be observed at the level of the electrical activity (excitability or conduction abnormalities) as well as at the level of haemodynamics (heart failure). As the incidence of heart muscle damage is very high, early detection of heart damage during a myopathy should therefore systematically be part of the check-up process of the disease, so that symptomatic treatment of the cardiac disease can be initiated as early as possible. Unfortunately, at the time of writing, no really curative treatment is yet available.
Our research efforts to define an effective therapeutic strategy were first of all based on the pathophysiology of the cardiac damage. The myopathic CHF147 hamster is deficient in delta-sarcoglycan and represents a valuable animal model, as it develops a cardiomyopathy which rapidly evolves into heart failure. After a certain degree of extension of any damage to the cardiac muscle, the clinical syndrome known as heart failure sets in. This worsens autonomously and inevitably towards terminal heart failure. The syndrome of heart failure can be defined from a haemodynamic point of view as the incapacity of the heart to ensure a rate of perfusion sufficient to cover the needs of the organism. At this stage of disease advancement, it can be considered that a second pathology sets in, independent of the initial genetic origin.

 

Cardiac tissue presents certain specificities at the cell level, in particular the absence of satellite cells is paralleled with the weak regenerating capacity of the myocardium. Thus, the death of cardiac muscle cells leads to a non-contractile fibrous scar, all the more reducing the contractile capacity of the myocardium. A therapeutic trial of myoblast transfer in the hearts of CHF147 hamsters which had reached a stage of dilated cardiopathy without decompensation of their heart failure was carried out in collaboration with J. Pouly and JT Vilquin (197). The therapeutic benefit was limited by the low survival rate of the muscle cells and above all, by the lack of integration of these cells in the myocardial tissue. Other therapeutic approaches were evaluated in parallel.

 

The introduction of the normal gene at an early stage of the disease remains an important research path in order to prevent the appearance of cardiac muscle lesions. At a more advanced stage, simply treating the original genetic cause will no longer be sufficient, and heart failure management will be necessary. A therapeutic trial on CHF147 hamsters with heart failure was attempted in order to induce a hypertrophic compensation aimed to retard the loss of cardiocytes and the thinning of the ventricular cavity walls, and thus slow the progression towards dilated cardiopathy. For this, we considered the systematic administration of low doses of IGF-1 growth factor (257). This treatment allowed the partial preservation of the myocardium in the absence of correction of the initial genetic defect, and in particular, a lower degree of fibrosis was observed (Fig. 1).

Moreover, we have been able to highlight the preservation of a large part of the contractile capacities of the cardiac muscle. The systematic administration of a growth factor by systemic route can cause extra-cardiac side-effects. This has led us to envisage a therapeutic trial based on the transfer of the IGF-1 intracardiac gene. Our results have shown that it is possible to obtain comparable beneficial effects using this approach (Fig. 2).

This shows the feasibility of a therapeutic approach by gene transfer in the framework of cardiomyopathies, and thus opens the possibility of specifically limiting IGF-1 effects in the cardiac muscle.