Cardiac Pathology in Myotonic Dystrophy Type 1

Abstract

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.

Keywords: RNA foci; RNA splicing; RNA toxicity; antisense oligonucleotides; cardiac conduction; cardiac pathology; fatty infiltration; fibrosis; myotonic dystrophy; sudden death; triplet repeat mutation.

Figure 1

Cardiac Pathology in DM1. DM1-A (subendocardium) and DM1-B (myocardium) are autopsy specimens with evidence of typical cardiac pathology in DM1 showing interstitial fibrosis and fatty infiltration. H&E staining shows interstitial fibrosis (light pink regions) between cardiomyocytes as well as fatty infiltration (clear circumscribed areas in the middle of the tissue indicative of fat droplets). Gamori-trichrome staining highlights collagen (blue). Oil Red O staining detects lipids (red). Perilipin immunofluorescence (Perilipin-IF) (green) detects perilipin, a surface marker on fat droplets. Scale bar is 200 µm for above row and 100 µm for bottom row.

Figure 2

RNA Foci in DM1 Cardiomyocytes. RNA-FISH (RNA fluorescence in-situ hybridization) with a CY3 labeled (CAG)₁₀ probe detects nuclear foci of mutant DMPK mRNA (red dots). Immunofluorescence microscopy for MBNL1 (MBNL1-IF) shows sequestration of MBNL1 (green dots). Merged image shows co-localization of RNA foci with MBNL1. Nuclei are stained blue with DAPI. Scale bar is 10 µm.