- Email: [email protected]
Letter to the EditorSubclinical cardiac involvement in myotonic dystrophy
Neuromuscular Disorders 14 (2004) 694–698 www.elsevier.com/locate/nmd
Letters to the Editor Letter to the Editor Subclinical cardiac involvement in myotonic dystrophy We read with interest the article by Vinereanu et al. on left ventricular systolic and diastolic function in 14 patients with type 1 myotonic dystrophy (MD1), with no symptoms or clinical signs of heart disease [1]. By using conventional and tissue Doppler echocardiography they found that 29% of the MD1 patients had global diastolic dysfunction and that systolic and diastolic myocardial velocities were lower in MD1 patients than in healthy controls. From these findings they conclude that patients with MD1 had subclinical cardiac impairment. These findings, however, raise several questions. It has been shown that in healthy subjects myocardial velocities are age-dependent with a decline of velocities with age [2]. It would be of interest if in the MD1 patients an age-dependency of the velocities was present. The assumption of an age-dependency of myocardial velocities is substantiated by the findings listed in Table 2, which show that the mean age of the 4 patients with normal tissue Doppler values is 28 years, whereas the mean age of the 10 patients with abnormal tissue Doppler values is 51 years. Additionally, medication may influence myocardial velocities. Thus, it would be interesting to know if any of the patients was on medication. The definition of ‘subclinical’ cardiac involvement is rather arbitrary. It is indicated that the patients had no chest pain or peripheral oedema. It is not stated, however, whether these patients were also free of exertional dyspnoea, palpitations or syncope, symptoms which occur frequently in patients with MD1 and cardiac involvement [3]. From the resting electrocardiogram only PR interval and QRS duration were measured. It is not indicated whether other electrocardiographic abnormalities like ST-abnormalities or QT prolongation were assessed, findings frequently found in patients with MD1 [3]. Overall it is not suitable to assess presence or absence of cardiac involvement only on clinical symptoms because: (1) clinical symptoms as a manifestation of myocardial affection may occur late in the course of the disease long after instrumental investigations had become abnormal already, (2) assessment of clinical symptoms may be impeded by the neurological symptoms and (3) rhythm abnormalities are a major cause of sudden
death in patients with MD1 and to assess cardiac involvement in patients with MD1 it is essential to include electrocardiographic investigations. In how many of the investigated patients would a comprehensive cardiologic investigation [4], including clinical history, symptoms, electrocardiography and conventional Doppler echocardiography have detected signs of cardiac involvement as well? ‘Myotonia of the heart’ is one of the suspected pathomechanisms of cardiac involvement in MD. According to Table 2, 2 patients suffered from severe myotonia and 4 patients from moderate myotonia. Thus, it would be of interest to know whether the 6 patients with severe or moderate myotonia had more diastolic abnormalities than the remaining 8 patients with mild myotonia. Furthermore, do the authors think that the observed myocardial abnormalities are due to pathologies of the cardiac conduction system, which is frequently affected in MD1 [5] or due to myopathic changes of the myocardial cells? The relation of diastolic and systolic dysfunction and electrocardiogram is of interest. By conventional Doppler echocardiography 4 out of 14 patients showed diastolic dysfunction. How many of these 4 patients showed also abnormal systolic or diastolic myocardial velocities on tissue Doppler echocardiography? How many patients showed only abnormal systolic tissue Doppler velocities, only abnormal diastolic tissue Doppler velocities, or a combination of abnormal systolic and diastolic tissue Doppler velocities? Was there an association with diastolic dysfunction as assessed by conventional or tissue Doppler echocardiography and electrocardiographic abnormalities? Which are the 3 patients in Table 2 who had abnormalities on 24-h Holter monitoring? The authors recommend to consider inclusion of tissue Doppler investigations into a screening protocol of patients with MD1 to detect cardiac involvement. Tissue Doppler echocardiography, however, is dependent on the experience of the observer and on the technical equipment and has a considerable inter- and intra-observer variability [2,6]. These factors limit the reliability of tissue Doppler echocardiography. The presented data do not convince us that tissue Doppler echocardiography will yield more information about cardiac involvement in MD1 patients than a comprehensive cardiological investigation.
Letters to the Editor / Neuromuscular Disorders 14 (2004) 694–698
References [1] Vinereanu D, Bajaj BPS, Fenton-May J, Rogers MT, Ma¨dler CF, Fraser AG. Subclinical cardiac involvement in myotonic dystrophy manifesting as decreased myocardial Doppler velocities. Neuromuscul Disord 2004;14:188–94. [2] Nikitin NP, Witte KKA, Thackray SDR, de Silva R, Clark AL, Cleland JGF. Longitudinal ventricular function: normal values of atrioventricular annular and myocardial velocities measured with quantitative two-dimensional color Doppler tissue imaging. J Am Soc Echocardiogr 2003;16:906–21. [3] Finsterer J, Gharebaghi-Schnell E, Sto¨llberger C, Fheodoroff K, Seiser A. Relation of cardiac abnormalities and CTG-repeat size in myotonic dystrophy. Clin Genet 2001;59:350–5. [4] Finsterer J, Sto¨llberger C, Blazek G, Spahits E. Cardiac involvement in myotonic dystrophy, Becker muscular dystrophy and mitochondrial myopathy: a five-year follow-up. Can J Cardiol 2001;17:1061–9. [5] Nguyen HH, Wolfe JT, Holmes DR, Edwards WD. Pathology of the cardiac conduction system in myotonic dystrophy: a study of 12 cases. J Am Coll Cardiol 1988;11:662–71. [6] Vinereanu D, Khokhar A, Fraser AG. Reproducibility of pulsed wave tissue Doppler echocardiography. J Am Soc Echocardiogr 1999;12:492–9.
Claudia Sto¨llbergera,*, Josef Finstererb 2nd Medical Department, University Doz, Steingasse 31/18, A-1030 Wien, Austria b Department of Neurology, Krankenanstalt Rudolfstifung, Juchgasse 25, A-1030 Wien, Austria a
* Corresponding author. Tel./fax: C43-1-713-9870. E-mail address: [email protected] doi:10.1016/j.nmd.2004.05.019
Reply to the Letter to the Editor Reply to Sto¨llberger and Finsterer We thank Drs Sto¨llberger and Finsterer for their comments and careful review of our report. Of course, we agree that very many factors influence myocardial velocities as recorded by tissue Doppler echocardiography. Amongst these, age is indeed one of the most important. As we stated [1], this is true also for patients with myotonic dystrophy—the inverse correlations of longitudinal function with age were K0.65 for mean systolic and K0.80 for mean early diastolic velocities (both, P!0:05). For this reason, we compared patients with MD1 with age-matched controls. Since none of the patients was taking any cardiac medication, we therefore concluded that the observed reductions in myocardial velocities were related to the disease rather than to any other confounding cause. Our conclusions are strongly supported by the recent publication of an almost identical study, which reported very similar findings and conclusions [2]. In our study, it was difficult to assess whether or not patients had exertional dyspnoea because they were limited
695
by their neuromuscular disease. Only two patients had palpitations, related to documented supraventricular tachycardia, and none had syncope. As we reported, seven out of 14 patients had a normal electrocardiogram; in the other seven patients, documented abnormalities included first degree atrioventricular block or bundle branch block. No patient in the series had significant QT prolongation. All patients had a normal cardiovascular examination and a normal cardiothoracic ratio on a routine postero-anterior chest radiograph. All patients had normal conventional echocardiographic studies including left ventricular dimensions, wall thickness and global systolic function. Four patients had global diastolic dysfunction. Thus, in the majority of patients in our study, a comprehensive cardiological assessment using established methods would not have demonstrated any cardiac abnormalities. The major strength of tissue Doppler echocardiography is that it can provide precise quantification of regional myocardial function, with high reproducibility [3]. Studies have now been reported that demonstrate myocardial involvement in several skeletal myopathies, including the dystrophinopathies [4] and Friedreich’s ataxia [5]. These all suggest that tissue Doppler echocardiography may be the most sensitive technique for early diagnosis of cardiac involvement, and the best technique for monitoring treatment [6]. The definition of subclinical disease is often arbitrary, given that there may be a continuous spectrum between normality and abnormality. The number of patients included in our study was too small to allow very detailed subgroup analysis, but the patients with moderate or severe MD1 had lower myocardial systolic velocities than the patients with mild MD1. Since the differences were not statistically significant, they were not reported in detail. As we did report, however, reductions in longitudinal systolic velocity were directly and inversely proportional to prolongation of the QRS complex on the electrocardiogram. Thus, it is possible that intrinsic myocardial function was not significantly abnormal in the patients with MD1, and that lower velocities were observed because of prolonged times to maximal motion of the myocardium. Whether or not patients have abnormal intrinsic contractile function might be answered by studies of regional strain and strain rate, or using the new index of isovolumetric acceleration [7], but these have not yet been performed. In either case, the reported abnormalities remain a marker of cardiac involvement in MD1. We are aware of the hypothesis that patients with MD1 may have myocardial myotonia with delayed relaxation [8], but in our study, longitudinal systolic and diastolic velocities were closely related (rZ0.76; P!0:01). Three quarters of the patients with global diastolic dysfunction also had low longitudinal systolic velocities (!5.4 cm/s). Whether or not isolated myotonia of heart muscle affecting diastolic recovery occurs, could probably be answered best in experimental studies of isolated heart muscle, perhaps using new transgenic models of myotonic dystrophy [9].
Letters to the Editor Letter to the Editor Subclinical cardiac involvement in myotonic dystrophy We read with interest the article by Vinereanu et al. on left ventricular systolic and diastolic function in 14 patients with type 1 myotonic dystrophy (MD1), with no symptoms or clinical signs of heart disease [1]. By using conventional and tissue Doppler echocardiography they found that 29% of the MD1 patients had global diastolic dysfunction and that systolic and diastolic myocardial velocities were lower in MD1 patients than in healthy controls. From these findings they conclude that patients with MD1 had subclinical cardiac impairment. These findings, however, raise several questions. It has been shown that in healthy subjects myocardial velocities are age-dependent with a decline of velocities with age [2]. It would be of interest if in the MD1 patients an age-dependency of the velocities was present. The assumption of an age-dependency of myocardial velocities is substantiated by the findings listed in Table 2, which show that the mean age of the 4 patients with normal tissue Doppler values is 28 years, whereas the mean age of the 10 patients with abnormal tissue Doppler values is 51 years. Additionally, medication may influence myocardial velocities. Thus, it would be interesting to know if any of the patients was on medication. The definition of ‘subclinical’ cardiac involvement is rather arbitrary. It is indicated that the patients had no chest pain or peripheral oedema. It is not stated, however, whether these patients were also free of exertional dyspnoea, palpitations or syncope, symptoms which occur frequently in patients with MD1 and cardiac involvement [3]. From the resting electrocardiogram only PR interval and QRS duration were measured. It is not indicated whether other electrocardiographic abnormalities like ST-abnormalities or QT prolongation were assessed, findings frequently found in patients with MD1 [3]. Overall it is not suitable to assess presence or absence of cardiac involvement only on clinical symptoms because: (1) clinical symptoms as a manifestation of myocardial affection may occur late in the course of the disease long after instrumental investigations had become abnormal already, (2) assessment of clinical symptoms may be impeded by the neurological symptoms and (3) rhythm abnormalities are a major cause of sudden
death in patients with MD1 and to assess cardiac involvement in patients with MD1 it is essential to include electrocardiographic investigations. In how many of the investigated patients would a comprehensive cardiologic investigation [4], including clinical history, symptoms, electrocardiography and conventional Doppler echocardiography have detected signs of cardiac involvement as well? ‘Myotonia of the heart’ is one of the suspected pathomechanisms of cardiac involvement in MD. According to Table 2, 2 patients suffered from severe myotonia and 4 patients from moderate myotonia. Thus, it would be of interest to know whether the 6 patients with severe or moderate myotonia had more diastolic abnormalities than the remaining 8 patients with mild myotonia. Furthermore, do the authors think that the observed myocardial abnormalities are due to pathologies of the cardiac conduction system, which is frequently affected in MD1 [5] or due to myopathic changes of the myocardial cells? The relation of diastolic and systolic dysfunction and electrocardiogram is of interest. By conventional Doppler echocardiography 4 out of 14 patients showed diastolic dysfunction. How many of these 4 patients showed also abnormal systolic or diastolic myocardial velocities on tissue Doppler echocardiography? How many patients showed only abnormal systolic tissue Doppler velocities, only abnormal diastolic tissue Doppler velocities, or a combination of abnormal systolic and diastolic tissue Doppler velocities? Was there an association with diastolic dysfunction as assessed by conventional or tissue Doppler echocardiography and electrocardiographic abnormalities? Which are the 3 patients in Table 2 who had abnormalities on 24-h Holter monitoring? The authors recommend to consider inclusion of tissue Doppler investigations into a screening protocol of patients with MD1 to detect cardiac involvement. Tissue Doppler echocardiography, however, is dependent on the experience of the observer and on the technical equipment and has a considerable inter- and intra-observer variability [2,6]. These factors limit the reliability of tissue Doppler echocardiography. The presented data do not convince us that tissue Doppler echocardiography will yield more information about cardiac involvement in MD1 patients than a comprehensive cardiological investigation.
Letters to the Editor / Neuromuscular Disorders 14 (2004) 694–698
References [1] Vinereanu D, Bajaj BPS, Fenton-May J, Rogers MT, Ma¨dler CF, Fraser AG. Subclinical cardiac involvement in myotonic dystrophy manifesting as decreased myocardial Doppler velocities. Neuromuscul Disord 2004;14:188–94. [2] Nikitin NP, Witte KKA, Thackray SDR, de Silva R, Clark AL, Cleland JGF. Longitudinal ventricular function: normal values of atrioventricular annular and myocardial velocities measured with quantitative two-dimensional color Doppler tissue imaging. J Am Soc Echocardiogr 2003;16:906–21. [3] Finsterer J, Gharebaghi-Schnell E, Sto¨llberger C, Fheodoroff K, Seiser A. Relation of cardiac abnormalities and CTG-repeat size in myotonic dystrophy. Clin Genet 2001;59:350–5. [4] Finsterer J, Sto¨llberger C, Blazek G, Spahits E. Cardiac involvement in myotonic dystrophy, Becker muscular dystrophy and mitochondrial myopathy: a five-year follow-up. Can J Cardiol 2001;17:1061–9. [5] Nguyen HH, Wolfe JT, Holmes DR, Edwards WD. Pathology of the cardiac conduction system in myotonic dystrophy: a study of 12 cases. J Am Coll Cardiol 1988;11:662–71. [6] Vinereanu D, Khokhar A, Fraser AG. Reproducibility of pulsed wave tissue Doppler echocardiography. J Am Soc Echocardiogr 1999;12:492–9.
Claudia Sto¨llbergera,*, Josef Finstererb 2nd Medical Department, University Doz, Steingasse 31/18, A-1030 Wien, Austria b Department of Neurology, Krankenanstalt Rudolfstifung, Juchgasse 25, A-1030 Wien, Austria a
* Corresponding author. Tel./fax: C43-1-713-9870. E-mail address: [email protected] doi:10.1016/j.nmd.2004.05.019
Reply to the Letter to the Editor Reply to Sto¨llberger and Finsterer We thank Drs Sto¨llberger and Finsterer for their comments and careful review of our report. Of course, we agree that very many factors influence myocardial velocities as recorded by tissue Doppler echocardiography. Amongst these, age is indeed one of the most important. As we stated [1], this is true also for patients with myotonic dystrophy—the inverse correlations of longitudinal function with age were K0.65 for mean systolic and K0.80 for mean early diastolic velocities (both, P!0:05). For this reason, we compared patients with MD1 with age-matched controls. Since none of the patients was taking any cardiac medication, we therefore concluded that the observed reductions in myocardial velocities were related to the disease rather than to any other confounding cause. Our conclusions are strongly supported by the recent publication of an almost identical study, which reported very similar findings and conclusions [2]. In our study, it was difficult to assess whether or not patients had exertional dyspnoea because they were limited
695
by their neuromuscular disease. Only two patients had palpitations, related to documented supraventricular tachycardia, and none had syncope. As we reported, seven out of 14 patients had a normal electrocardiogram; in the other seven patients, documented abnormalities included first degree atrioventricular block or bundle branch block. No patient in the series had significant QT prolongation. All patients had a normal cardiovascular examination and a normal cardiothoracic ratio on a routine postero-anterior chest radiograph. All patients had normal conventional echocardiographic studies including left ventricular dimensions, wall thickness and global systolic function. Four patients had global diastolic dysfunction. Thus, in the majority of patients in our study, a comprehensive cardiological assessment using established methods would not have demonstrated any cardiac abnormalities. The major strength of tissue Doppler echocardiography is that it can provide precise quantification of regional myocardial function, with high reproducibility [3]. Studies have now been reported that demonstrate myocardial involvement in several skeletal myopathies, including the dystrophinopathies [4] and Friedreich’s ataxia [5]. These all suggest that tissue Doppler echocardiography may be the most sensitive technique for early diagnosis of cardiac involvement, and the best technique for monitoring treatment [6]. The definition of subclinical disease is often arbitrary, given that there may be a continuous spectrum between normality and abnormality. The number of patients included in our study was too small to allow very detailed subgroup analysis, but the patients with moderate or severe MD1 had lower myocardial systolic velocities than the patients with mild MD1. Since the differences were not statistically significant, they were not reported in detail. As we did report, however, reductions in longitudinal systolic velocity were directly and inversely proportional to prolongation of the QRS complex on the electrocardiogram. Thus, it is possible that intrinsic myocardial function was not significantly abnormal in the patients with MD1, and that lower velocities were observed because of prolonged times to maximal motion of the myocardium. Whether or not patients have abnormal intrinsic contractile function might be answered by studies of regional strain and strain rate, or using the new index of isovolumetric acceleration [7], but these have not yet been performed. In either case, the reported abnormalities remain a marker of cardiac involvement in MD1. We are aware of the hypothesis that patients with MD1 may have myocardial myotonia with delayed relaxation [8], but in our study, longitudinal systolic and diastolic velocities were closely related (rZ0.76; P!0:01). Three quarters of the patients with global diastolic dysfunction also had low longitudinal systolic velocities (!5.4 cm/s). Whether or not isolated myotonia of heart muscle affecting diastolic recovery occurs, could probably be answered best in experimental studies of isolated heart muscle, perhaps using new transgenic models of myotonic dystrophy [9].