Value of the Electrocardiogram in Determining Cardiac Events and Mortality in Myotonic Dystrophy

Colleran, John A.; Hawley, Rollin J.; Pinnow, Ellen; Kokkinos, Peter; Fletcher, Ross D.

doi:10.1016/s0002-9149(97)00742-x

Cited by 60 publications

(36 citation statements)

References 19 publications

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“…All ECG intervals lengthened with increasing patient age, but the P-R interval in particular had a direct correlation with age. Interestingly, the incidence of cardiac arrhythmic events (including sudden death, complete heart block, atrial fibrillation and syncope) occurred more frequently among patients with a longer baseline P-R interval, and no correlation was seen with any other ECG interval (34). These findings suggest that the P-R interval may be a predictive marker of patients at high risk for future arrhythmic events.…”

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confidence: 87%

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DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

Berul¹,

Maguire²,

Aronovitz³

et al. 1999

J. Clin. Invest.

195

108

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The disorders of skeletal muscle and cardiac function observed in myotonic dystrophy (DM) occur as a consequence of a CTG repeat expansion (1, 2) located in the 3′ untranslated region of a protein kinase, myotonic dystrophy protein kinase (DMPK; 3, 4), on chromosome 19q13.3. The molecular mechanisms by which expanded CTG sequences produce DM pathophysiology remain unresolved, though three models prevail. First, partial loss of DMPK resulting as a consequence of nuclear retention of the mutant DMPK mRNA may contribute to DM (5-8). Second, decreased transcription of a neighboring homeodomain-encoding gene, DMAHP, occurring possibly due to altered chromatin structure near the CTG expansion, may play a role in DM (9, 10). Lastly, transdominant effects associated with expression of expanded CUG repeats and modulation of splicesite recognition may contribute to DM pathology (11-13).The primary clinical cardiac manifestation in DM is the development of conduction disturbances, with progressive atrioventricular (A-V) block and bradycardia. Prolonged A-V conduction (first-degree A-V block) is common, and higher-grade A-V block is a significant cause of death (14-17). The His-Purkinje system may also be affected, with bundle branch block and intraventricular conduction delay (18,19).To test the hypothesis that partial DMPK loss contributes to DM pathology, we developed a mouse strain lacking functional DMPK (DMPK -/-). We have shown that DMPK -/-mice develop late-onset skeletal myopathy as a consequence of abnormal excitation/contraction coupling (20). In this study we demonstrate that DMPK dosage modulates cardiac conduction. On electrocardiogram (ECG), a prolonged P-R interval (first-degree A-V block) was present in adult DMPK -/-mice compared to wild-type controls. Electrophysiological evaluation of DMPK -/-mice demonstrated more serious conduction disturbances including second and third-degree A-V block. Adult DMPK +/-mice also exhibited firstdegree A-V block similar to DMPK -/-mice. Thus, heterozygous animals have a quantifiable cardiac phenotype reminiscent of DM patients. Our results show that DMPK gene disruption causes A-V conduction abnormalities in both homozygous and heterozygous DMPK-deficient mice, and support loss of DMPK as playing a dominant role in the characteristic DM cardiac phenotype. MethodsAnimal care. A total of 27 male and 20 female adult 129/BS strain mice were studied. The mean age was 63.9 ± 21 weeks, with no differences between genotypes. The average weight was 37.7 ± 9 grams. Another 18 young mice were studied to assess age-related alterations in conduction properties. Death occurred in 6 animals due to procedural complications. Mice were housed in a diurnal facility, in compliance with the American Association for the Accreditation of Laboratory Animal Care and each center's Institutional Animal Care and Use Committee. Mice were anesthetized with intraperitoneal ketamine hydrochloride and pentobarbital (0.033 mg/gm each). Myotonic dystrophy (DM) is the most common form of muscular dystrophy...

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confidence: 87%

“…A clinical study demonstrated progressive ECG abnormalities, with 39% of subjects developing firstdegree A-V block and 66% demonstrating intraventricular conduction delays (34). All ECG intervals lengthened with increasing patient age, but the P-R interval in particular had a direct correlation with age.…”

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confidence: 97%

DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

Berul¹,

Maguire²,

Aronovitz³

et al. 1999

J. Clin. Invest.

195

108

View full text Add to dashboard Cite

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“…Many studies have been performed to find variables that could help predict which patients are at increased risk for an adverse cardiac event (15)(16)(17)(18)(19)(20)(21)(22)(23). These studies, using different approaches, usually showed that advancing age and severity of neurological impairment, and a higher degree of conduction disturbance, assessed either by surface electrocardiogram (ECG) or by electrophysiological study, correlate with a worse outcome.…”

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confidence: 99%

Usefulness of clinical and electrocardiographic data for predicting adverse cardiac events in patients with myotonic dystrophy

Breton¹,

Mathieu

2009

Canadian Journal of Cardiology

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“…5 6 Sudden death is rare, and the relative importance of ventricular tachyarrhythmias and bradyarrhythmias remains unclear. [7][8][9][10][11] Prediction of cardiac events has proved diYcult, and several potential risk factors have been evaluated. There is an association between neurological severity and both electrocardiographic conduction system disease and cardiac events.…”

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confidence: 99%

Endomysium in left ventricle

Macchiarelli¹

2001

Heart

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Objective-To assess whether the size of the cytosine-thymine-guanine (CTG) expansion mutation in myotonic dystrophy predicts progression of conduction system disease and cardiac events. Design-Longitudinal study involving ECG and clinical follow up over (mean (SD)) 4.8 (1.8) and 6.2 (1.9) years, respectively, of patients stratified by CTG expansion size (E0 to E4). Patients-73 adult patients under annual review in a regional myotonic dystrophy clinic. Patients were grouped into E0/E1 (n = 25), E2 (n = 34), and E3/E4 (n = 14). Results-The proportion of patients with a QRS complex > 100 ms at baseline increased with the size of the CTG expansion (EO/E1, 4%; E2, 12%; E3/E4, 36%; p = 0.02). This trend was more pronounced at follow up (E0/E1, 4%; E2, 21%; E3/E4, 57%; p = 0.0004). The rate of widening of the QRS complex (ms/year) was similarly related to the size of the mutation (EO/E1, 0.4 (1.3); E2, 1.4 (2.5); E3/E4, 1.5 (1.6); p = 0.04). First degree atrioventricular block was present in 23% of patients at baseline and 34% at follow up, with no significant relation to expansion size. Seven patients suVered a cardiac event during follow up (sudden death in two, permanent pacemaker insertion in three, chronic atrial arrhythmia in two), of whom six were in CTG expansion group E2 or greater. Patients who experienced a cardiac event during follow up had more rapid rates of PR interval increase (9.9 (11.1) v 1.6 (2.9) ms/year; p = 0.008) and a trend to greater QRS complex widening (3.6 (4.5) v 0.9 (1.5) ms/year; p = 0.06) than those who did not. Conclusions-Larger CTG expansions are associated with a higher rate of conduction disease progression and a trend to increased risk of cardiac events in myotonic dystrophy. (Heart 2001;86:411-416)

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Value of the Electrocardiogram in Determining Cardiac Events and Mortality in Myotonic Dystrophy

Cited by 60 publications

References 19 publications

DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

Usefulness of clinical and electrocardiographic data for predicting adverse cardiac events in patients with myotonic dystrophy

Endomysium in left ventricle

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