Prolonged Corrected QT Interval in Patients with Myotonic Dystrophy Type 1

Abstract

Background and PurposezzSudden cardiac death is one of the leading causes of death in patients with myotonic dystrophy type 1 (DM1). It has been proposed that a prolonged QT interval is associated with sudden cardiac death in several neurological diseases, including multiple system atrophy, idiopathic Parkinson's disease, and diabetic autonomic neuropathy. However, analyses of the corrected QT (QTc) interval in DM1 patients are rare in the literature. The purposes of this study were to determine the association between the QT interval and DM1, and the affecting factors.MethodszzThirty-nine patients diagnosed with DM1 through genetic testing were enrolled. The QTc interval (calculated using Bazett's formula: QTc=QT/√RR) was compared between these patients and 39 normal healthy controls. The clinical and laboratory factors affecting QTc interval in the patient group were investigated.ResultszzThe QTc interval was significantly longer in the DM1 group (411.2±44.7 msec, mean± SD) than in the normal control group (355.6±20.6 msec). Intragroup analysis revealed that a prolonged QTc interval in DM1 patients was associated with being female and older, having a longer disease duration, and exhibiting abnormal electrocardiography findings.ConclusionszzThe higher incidence of sudden cardiac death in the DM1 population is associated with the observed prolonged QTc interval in those patients.

Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

“…Concurrently Mbnl1 depletion results in the enhanced expression of embryonic splice isoforms of RNAs regulating sodium and calcium currents ( Scn5a, Asph, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2 ), intra and inter cellular transport ( Clta, Stx2 and Tjp1/Zo-1 ), compliance of the myocardium ( Myom1 ), cell survival ( Capn3, Sirt2, Csda ) cytoskeleton and sarcomere assembly and function ( Trim55 , Mapt , Pdlim3 , Pdlim5 , Sorbs1 , Sorbs2 , Fhod1 and Spag9 ) and encoding sarcomere structural proteins ( Tnnt2, Ldb3 ). As several of these features are observed in DM112345678910111232344973, this study supports a key role for Mbnl1 depletion in the initiation of DM1 cardiac pathology.…”

“…Interestingly, as with DM1, where functional and structural involvement is associated with age and the male gender1015, significant cardiac hypertrophy manifested at 6 months of age in male Mbnl1 ΔE2/ΔE2 mice, with females showing a trend towards hypertrophy. In contrast, QTc widening in DM1 is associated with being female and older5. Reminiscent of this feature, QTc widening was more prominent at 6 months of age in female Mbnl1 ΔE2/ΔE2 mice when compared to males.…”

Biophysical mechanisms for QRS- and QTc-interval prolongation in mice with cardiac expression of expanded CUG-repeat RNA

“…DM1 patients often exhibit a variety of different ECG abnormalities, including AV block (PR-interval prolongation), slowed propagation of ventricular depolarization (QRS-interval prolongation), and delayed ventricular repolarization (QT-interval prolongation; Phillips and Harper, 1997; Groh et al, 2008; Wahbi et al, 2012; Park et al, 2013). Since these ECG defects result in a heightened risk of SCD, it is important to establish animal models that reproduce DM1-like ECG defects in order to elucidate the underlying biophysical mechanisms and to develop effective interventions.…”

“…In fact, DMPK expression is highest in the heart (Maeda et al, 1995; Sarkar et al, 2004). As a consequence, ≥65% of DM1 patients develop cardiac conduction abnormalities, including PR-interval and QRS-interval prolongation, as well as QT-interval prolongation as observed on surface electrocardiograms (ECGs; Phillips and Harper, 1997; Groh et al, 2008; Wahbi et al, 2012; Park et al, 2013). Clinical studies have correlated age, larger CTG expansion size, and degrees of PR- and QRS-interval prolongation with risk of developing high-grade atrioventricular (AV) block, bradycardia, and asystole.…”

Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction

“…First, we observed a reduction in the median survival in model flies, which correlates with reports for affected humans ( Petri et al, 2012 ). Cardiac mortality in individuals with DM1 usually occurs because of progressive left ventricular dysfunction, ischemic heart disease, pulmonary embolism, or as a result of unexpected sudden death (SD) associated with the corrected prolonged QT interval (period including electrical depolarization and repolarization of the ventricles) ( Park et al, 2013 ). Second, heart conduction abnormalities are common in individuals with DM1 ( Groh et al, 2008 ; McNally and Sparano, 2011 ).…”