Correspondence
Sudden Death in Myotonic Dystrophy
N Engl J Med 2008; 359:1626-1629October 9, 2008
- Article
To the Editor:
In the study reported by Groh et al. (June 19 issue),1 during long-term follow-up of patients with myotonic dystrophy type 1, 81 of 406 patients died and one third of the deaths were sudden. How many of these deaths were really due to arrhythmia? Arrhythmia was found to be the cause of death in only 9 patients; in the other 18, data on rhythm were not available or were not decisive, and no data from autopsy are provided.
The major cause of death in the population studied is neuromuscular respiratory failure, and weakness of the respiratory muscles may be detected even in patients with minimal signs of muscular disability.2 This raises the question of the clinical relevance of respiratory failure in this population of patients who had different degrees of muscular impairment and died suddenly.
Myotonic dystrophy is a complex, progressive, multisystem disease, and the cause of death may be difficult to establish definitively. Close follow-up, with regular noninvasive and invasive cardiac evaluation and adequate assessment of neuromuscular and respiratory status, is necessary to better understand the true causes of “sudden” deaths.3-5
5 ReferencesAntonio Dello Russo, M.D., Ph.D.
Manuela Pace, M.D.
Fulvio Bellocci, M.D.
Catholic University, 00168 Rome, Italy
adellorusso@tin.it 1
Groh WJ ,Groh MR ,Saha C , et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med 2008;358:2688-2697
Full Text | Web of Science | Medline2
Begin P ,Mathieu J ,Almirall J ,Grassino A . Relationship between chronic hypercapnia and inspiratory-muscle weakness in myotonic dystrophy. Am J Respir Crit Care Med 1997;156:133-139
Web of Science | Medline3
Pelargonio G ,Dello Russo A ,Sanna T ,De Martino G ,Bellocci F . Myotonic dystrophy and the heart. Heart 2002;88:665-670
CrossRef | Web of Science | Medline4
Lazarus A ,Varin J ,Babuty D ,Anselme F ,Coste J ,Duboc D . Long-term follow-up of arrhythmias in patients with myotonic dystrophy treated by pacing: a multicenter diagnostic pacemaker study. J Am Coll Cardiol 2002;40:1645-1652
CrossRef | Web of Science | Medline5
Lazarus A ,Varin J ,Ounnoughene Z , et al. Relationships among electrophysiological findings and clinical status, heart function, and extent of DNA mutation in myotonic dystrophy. Circulation 1999;99:1041-1046
Web of Science | Medline
To the Editor:
Groh et al. report that severe electrocardiographic (ECG) abnormalities are independent risk factors for sudden death in myotonic dystrophy type 1. A substantial number of sudden deaths were caused by ventricular tachyarrhythmias. The authors seem reluctant to explicitly recommend prophylactic therapy with implantable cardioverter–defibrillators (ICDs), since the progression of muscular weakness may limit the prognosis and thus the efficacy of these devices.
We analyzed data from another large cohort.1 In brief, 22.5% of the patients died suddenly (Figure 1AFigure 1
Outcomes in the Study Population and ECG Findings in Patients and Controls.), and the QRS duration was considerably prolonged in patients who died suddenly as compared with controls (Figure 1B). Evidence of a major role of ventricular tachyarrhythmias in the sudden death of patients with myotonic dystrophy type 1 is accumulating.2,3 ECG criteria, particularly the QRS width, may help to identify persons at risk. In our experience, ICD implantation has resulted in appropriate therapy in several such patients. We recommend that patients with myotonic dystrophy type 1 be systematically screened to identify those with the combination of an increased risk of sudden death and a relatively good neuromuscular prognosis. In such patients, the potential value of prophylactic ICD therapy should be considered.Mieke C.E. Hermans, M.D.
Catharina G. Faber, M.D., Ph.D.
University Hospital Maastricht, 6229 HX Maastricht, the Netherlands
m.hermans@mumc. nl Yigal M. Pinto, M.D., Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the NetherlandsThis letter (10.1056/NEJMc081492) was updated on April 7, 2010, at NEJM.org.
3 References1
de Die-Smulders CE ,Howeler CJ ,Thijs C , et al. Age and causes of death in adult-onset myotonic dystrophy. Brain 1998;121:1557-1563
CrossRef | Web of Science | Medline2
Merino JL ,Carmona JR ,Fernandez-Lozano I ,Peinado R ,Basterra N ,Sobrino JA . Mechanisms of sustained ventricular tachycardia in myotonic dystrophy: implications for catheter ablation. Circulation 1998;98:541-546
Web of Science | Medline3
Merino JL ,Peinado R ,Sobrino JA . Sudden death in myotonic dystrophy: the potential role of bundle-branch reentry. Circulation 2000;101:E73-E73
Web of Science | Medline
To the Editor:
Groh and colleagues showed that patients with myotonic dystrophy type 1 are at high risk for sudden death from cardiac causes. In these patients, the presence of an ECG abnormality (defined by the presence of a rhythm other than sinus rhythm, a PR interval >240 msec, a QRS duration >120 msec, or second- or third-degree atrioventricular block) was an independent predictor of sudden death from cardiac causes, with a sensitivity of 74.1% and a specificity of 61.7%.
Prolongation of the QT interval is a common ECG finding in patients with myotonic dystrophy, with a reported prevalence of up to 33%.1 In these patients, abnormalities of ventricular repolarization appear to be directly associated with the length of CTG trinucleotide repeats.2 Reports also suggest a possible association between QT prolongation and an increased risk of ventricular arrhythmias and sudden death from cardiac causes in patients with myotonic dystrophy.3 Therefore, it would be interesting to investigate whether abnormal prolongation of the QT interval may have an incremental value in predicting sudden death from cardiac causes in this patient population.
3 ReferencesBojan Vrtovec, M.D., Ph.D.
Ljubljana University Medical Center, SI-1000 Ljubljana, Slovenia
bojan.vrtovec@gmail. com Francois Haddad, M.D.
Stanford University School of Medicine, Stanford, CA 943061
Viitasalo MT ,Kala R ,Karli P ,Eisalo A . Ambulatory electrocardiographic recording in mild or moderate myotonic dystrophy and myotonia congenita (Thomsen's disease). J Neurol Sci 1983;62:181-190
CrossRef | Web of Science | Medline2
Melacini P ,Villanova C ,Menegazzo E , et al. Correlation between cardiac involvement and CTG trinucleotide repeat length in myotonic dystrophy. J Am Coll Cardiol 1995;25:239-245
CrossRef | Web of Science | Medline3
Umeda Y ,Ikeda U ,Yamamoto J , et al. Myotonic dystrophy associated with QT prolongation and torsade de pointes. Clin Cardiol 1999;22:136-138
CrossRef | Web of Science | Medline
To the Editor:
The study by Groh et al. correlated severe ECG abnormalities with sudden death in patients with myotonic dystrophy type 1. However, ECG findings had an overall low positive predictive value (12.1%). In addition, the ECG abnormalities were associated with a wide range of relative risks for sudden death (e.g., relative risk associated with atrial tachycardia, 9.34; relative risk associated with first-degree atrioventricular block, 1.50). Therefore, risk stratification in patients with myotonic dystrophy type 1 who have a less severe ECG abnormality, such as first-degree atrioventricular block alone, remains a challenge, and more cost-effective tools for risk stratification are needed.
Fibrosis of cardiac tissue provides a substrate for both conduction block and ectopic activity1 and is one of the main pathophysiological mechanisms of cardiac involvement in myotonic dystrophy type 1.2 Transforming growth factor β1 (TGF-β1) is one of the mediators of myocardial fibrosis, and its level may correlate with the risk of sudden death.3 The serum level of TGF-β1 is increased in patients with cardiomyopathy and correlates with more severe myocardial fibrosis.4 We therefore hypothesize that serum TGF-β1 may serve as a useful noninvasive test for quantification of myocardial fibrosis and further risk stratification of patients with myotonic dystrophy type 1 for sudden death from cardiac causes.
4 ReferencesAli A. Sovari, M.D.
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
asovari@mednet.ucla. edu Samuel C. Dudley, Jr., M.D., Ph.D.
University of Illinois at Chicago, Chicago, IL 606121
Miragoli M ,Salvarani N ,Rohr S . Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res 2007;101:755-758[Erratum, Circ Res 2007;101(10):e114.]
Web of Science | Medline2
Nguyen HH ,Wolfe JT III ,Holmes DR Jr ,Edwards WD . Pathology of the cardiac conduction system in myotonic dystrophy: a study of 12 cases. J Am Coll Cardiol 1988;11:662-671
CrossRef | Web of Science | Medline3
Sovari AA ,Morita N ,Weiss JN ,Karagueuzian HS . Serum transforming growth factor-beta1 as a risk stratifier of sudden cardiac death. Med Hypotheses 2008;71:262-265
CrossRef | Web of Science | Medline4
Sanderson JE ,Lai KB ,Shum IO ,Wei S ,Chow LT . Transforming growth factor-beta(1) expression in dilated cardiomyopathy. Heart 2001;86:701-708
CrossRef | Web of Science | Medline
Author/Editor Response
As Dello Russo and colleagues suggest, it is impossible to know with certainty that arrhythmias were the cause of death in our patients with myotonic dystrophy type 1 who died suddenly. We used the accepted World Health Organization definition of sudden unexpected death and detected postcollapse rhythms in 17 of the 27 patients (not 9 of 27, as Dello Russo et al. suggest). Ventricular fibrillation was the most common postcollapse rhythm. The study findings, taken in conjunction with the known myocardial abnormalities of fibrosis and conduction-system degeneration, make it probable that acute unstable arrhythmias were responsible for the majority of sudden deaths. The study was a multicenter investigation, and the ability to request autopsies was limited.
We agree that progressive skeletal-muscle weakness leading to respiratory failure is a significant issue in the care of patients with myotonic dystrophy. Respiratory failure was the most common cause of death in our study. Whether respiratory status had a role in the initiation of the event leading to sudden death is not clear. As detailed in our article, the presence of severe muscular weakness did affect the patients' and caregivers' decisions regarding the treatment of unstable arrhythmias. On the basis of our study findings, we agree that a yearly noninvasive evaluation, including assessment for atrial tachyarrhythmias and severe conduction abnormalities on the ECG, will aid in determining the risk of sudden death. We do not agree that nonmortality outcomes from nonrandomized observations in a referred population have proved the diagnostic usefulness of invasive electrophysiological studies or the therapeutic benefit of prophylactic pacemakers in the management of sudden death in patients with myotonic dystrophy.1-3
The cohort analysis by Hermans and colleagues provides support for our finding that sudden death is a common cause of death among patients with myotonic dystrophy type 1 and that pacemakers may not prevent sudden death. We understand the rationale behind their recommendation for prophylactic ICDs. However, we believe that the population of patients with myotonic dystrophy type 1 is of sufficient size and clinical complexity that a prospective mortality assessment of the benefit of ICDs is indicated. With the worldwide interest in evaluating methods to prevent sudden death in patients with myotonic dystrophy type 1, a multinational trial would be optimal. We encourage investigators providing care for patients with myotonic dystrophy type 1 to design and implement such a necessary trial.
Vrtovec and Haddad question whether QT prolongation detected on ECG predicts sudden death in patients with myotonic dystrophy type 1. We found no independent association between markers of prolonged repolarization and sudden death.
Sovari and Dudley hypothesize that TGF-β1 could serve as a biomarker for sudden death in patients with myotonic dystrophy type 1. We did not evaluate TGF-β1 and have seen no published data.
3 ReferencesWilliam J. Groh, M.D., M.P.H.
Deepak Bhakta, M.D.
Robert M. Pascuzzi, M.D.
Indiana University, Indianapolis, IN 46202
wgroh@iupui.edu 1
Lazarus A ,Varin J ,Ounnoughene Z , et al. Relationships among electrophysiological findings and clinical status, heart function, and extent of DNA mutation in myotonic dystrophy. Circulation 1999;99:1041-1046
Web of Science | Medline2
Lazarus A ,Varin J ,Babuty D ,Anselme F ,Coste J ,Duboc D . Long-term follow-up of arrhythmias in patients with myotonic dystrophy treated by pacing: a multicenter diagnostic pacemaker study. J Am Coll Cardiol 2002;40:1645-1652
CrossRef | Web of Science | Medline3
Pelargonio G ,Dello Russo A ,Sanna T ,De Martino G ,Bellocci F . Myotonic dystrophy and the heart. Heart 2002;88:665-670
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
M.C.E. Hermans, Y.M. Pinto, I.S.J. Merkies, C.E.M. de Die-Smulders, H.J.G.M. Crijns, C.G. Faber. (2010) Hereditary muscular dystrophies and the heart. Neuromuscular Disorders 20:8, 479-492
CrossRef
