An overview of heart rhythm disorders and management in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is the most common adult form of muscular dystrophy, presenting with a constellation of systemic findings secondary to a CTG triplet expansion of the noncoding region of the DMPK gene. Cardiac involvement is frequent, with conduction disease and supraventricular and ventricular arrhythmias being the most prevalent cardiac manifestations, often developing from a young age. The development of cardiac arrhythmias has been linked to increased morbidity and mortality, with sudden cardiac death well described. Strategies to mitigate risk of arrhythmic death have been developed. In this review, we outline the current knowledge on the pathophysiology of rhythm abnormalities in patients with myotonic dystrophy and summarize available knowledge on arrhythmic risk stratification. We also review management strategies from an electrophysiological perspective, attempting to underline the substantial unmet need to address residual arrhythmic risks for this population.

Introduction

Myotonic dystrophy type 1 (DM1; Steinert disease) is the most common form of adult muscular dystrophy, with a prevalence of 1 in 8000 patients. It is characterized by clinical features of striated muscle weakness; early myotonia; ocular, cutaneous, pulmonary, central nervous system, and metabolic abnormalities; and cardiac manifestations (Supplemental Table 1).¹ The genetic basis of DM1 is an unstable CTG triplet repeat expansion in the DMPK gene in the 3ʹ noncoding region located in chromosome 19q13.3. Repeats greater than 39 CTGs are always associated with clinical disease.² Inheritance is autosomal dominant, and genetic anticipation occurs, as with other triplet repeat disorders, associated with worsening phenotypic severity with sequential generations.² The onset of phenotypic expression varies significantly, from a more severe congenital form to mild, late-onset disease. Disease severity and age of onset correlate poorly with expansion size as measured in white blood cells, probably due to somatic mosaicism.³ Myotonic dystrophy type 2 (DM2), which stems from CCTG repeats in the nucleic acid-binding protein (CNBP) gene, is rarer than DM1, with a prevalence that currently is undefined. Both types share similarities in pathophysiology and phenotypical expression. Patients with DM2 develop cardiac abnormalities similar to those of their type 1 counterparts but at an older age. Cardiac management in DM2 patients is largely extrapolated from that of DM1 patients.⁴ Whether this practice is valid in its entirety remains unresolved due to the lack of adequate data. For the purpose of this review, we will focus on data derived from DM1 patients.

Cardiac involvement is a well-recognized driver of mortality in myotonic dystrophy, in some cohorts accounting for up to one-third of events.⁵ It is manifested mainly by conduction disease and the propensity to supraventricular and ventricular arrhythmias (Supplemental Table 2). Younger patients exhibit higher risk for potentially life-threatening cardiac disease than their general population peers, and the risk tends to increase with time due to the progressive nature of the condition.5, 6, 7, 8 A minority of patients may develop systolic dysfunction that is associated with increased risk for life-threatening arrhythmias.⁹ Considering that reduced mobility may conceal heart failure symptoms, supraventricular arrhythmias have the propensity for slower ventricular response rates, and advanced conduction disturbances may be intermittent, the presence of asymptomatic systolic dysfunction and subclinical conduction system involvement may remain undetected. In this setting, the role of cardiology, and particularly electrophysiology, in the management of this population becomes increasingly relevant.