Relation of CTG expansion and clinical variables to electrocardiogram conduction abnormalities and sudden death in patients with myotonic dystrophy

Abstract

We prospectively followed 63 patients with myotonic dystrophy (DM) after establishing diagnosis of DM for an average 8 years in an attempt to detect conduction disturbances (by electrocardiography and/or Holter monitoring) and sudden cardiac events (sudden death, cardiac syncope) and correlate them to potential predicting factors (CTG repeat expansion in the myotonin protein kinase gene and several clinical variables: clinical type and duration of DM, age and sex). Twenty-six patients developed conduction disturbances, five patients died suddenly, and two patients experienced cardiac syncope necessitating urgent implantation of pacemaker. Analysis showed no significant correlation between conduction disturbances and/or cardiac events and CTG expansion. Furthermore, no correlation was found with type of DM, whereas conduction disturbances and sudden cardiac events correlated with patients' age, duration of disease and male sex. Results on our cohort of DM patients show that CTG expansion has no role in predicting neither conduction abnormalities nor sudden death. It seems that risk of sudden death increases with duration of disease and age, and that risk is higher in male patients.

Introduction

Myotonic dystrophy (DM) is the most common form of muscular dystrophy in adults, characterized by myotonia, muscle weakness and a variety of other symptoms [1]. Cardiac involvement is a frequent manifestation, the most prominent feature being conduction disturbances and arrhythmias, that is one of the leading causes of death in DM patients [2], [3], [4]. It is known that sudden cardiac death is the primary cause of death in up to 30% of patients with DM [5], [6]. The natural history of cardiac involvement in DM is difficult to predict. Furthermore, the determinants and predictors of sudden cardiac death are also not known. Therefore an effective approach to recognizing DM patients at high risk of sudden death remains a challenging issue for physicians taking care for DM patients.

The DM mutation was identified as an unstable cytosine–thymine–guanine (CTG) repeat in the myotonin protein kinase (DMPK) gene [7], [8], [9]. The repeat, which is present 5–37 times in the normal population, was found to be amplified 50 to several thousand times in patients with DM [10], [11]. After the identification of the molecular basis of the DM mutation, a series of publications reported a correlation between the CTG repeat expansion and the severity of the disease; in addition, amplification predicts age at onset of DM [12], [13], [14]. CTG repeat expansion was thought to be a potentially important predictor of cardiac involvement and sudden death in patients with DM. However, different results have been obtained. Whereas some authors found a correlation between CTG repeat expansion and the occurrence of conduction disturbances, others were not able to show such a correlation [13], [14], [15], [16], [17], [18], [19], [20], [21]. Furthermore, no specific data are available on the relation of CTG repeat expansion and sudden death, bearing in mind that results obtained by studying conduction abnormalities could not simply be applied to the problem of sudden death. It is known that ECG conduction abnormalities do not necessarily predict tachyarrhythmia. In this regard it seems useful and appropriate to study these entities (ECG conduction abnormalities and sudden death) both combined and separately. In any case, additional data regarding the association of CTG repeat expansion and both conduction disturbances and sudden death are highly desirable.

In this prospective study, we report a cardiological follow-up of 63 DM patients through an average period of 8 years. We identified patients with conduction abnormalities and explored the possible associations between conduction abnormalities and CTG repeat expansion and several clinical variables (clinical type of DM, duration of disease, sex and age). As mentioned above, patients with sudden cardiac events (sudden cardiac death, cardiac syncope) were handled separately and combined with patients with conduction abnormalities.