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Early changes of myocardial deformation properties in patients with dystrophia myotonica type 1: A three-dimensional Speckle Tracking echocardiographic study
International Journal of Cardiology 176 (2014) 1094–1096
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Early changes of myocardial deformation properties in patients with dystrophia myotonica type 1: A three-dimensional Speckle Tracking echocardiographic study Maurizio Galderisi a,⁎, Francesco De Stefano a, Ciro Santoro a, Agostino Buonauro a, Daniela De Palma a, Fiore Manganelli b, Lucia Ruggiero b, Lucio Santoro b, Giovanni de Simone a a b
Hypertension Research Center, Department of Translational Medical Sciences, “Federico II” University Hospital, Naples, Italy Department of Neurosciences, Reproductive and Odontoiatric Sciences, “Federico II” University Hospital, Naples, Italy
a r t i c l e
i n f o
Article history: Received 24 May 2014 Accepted 26 July 2014 Available online 1 August 2014 Keywords: Myotonic dystrophy Cardiomyopathy Real time 3D echocardiography Stroke volume Strain
Dystrophia myotonica type 1 (DM1) is an inherited neuromuscular disorder characterized by progressive myotonia and muscle wasting [1]. Cardiac damage includes abnormalities of conduction system [2] and myocardial fibrosis [3]. The detection of early markers of cardiac involvement could therefore favor identification of patients at risk of developing cardiac complications and, potentially, address to appropriate management. Abnormalities of LV systolic function have never been reported in asymptomatic DM1 using standard echo-Doppler. Among advanced echocardiographic technologies, 2D Speckle Tracking Echocardiography (STE) has demonstrated impaired left ventricular (LV) myocardial deformation in DM1 patients [4,5]. Further technologic advancement of 3D echocardiography has recently developed software which allows us to obtain a homogeneous and simultaneous spatial distribution of all three components of myocardial displacement vector [6]. Accordingly, we attempted to identify early alteration of systolic deformation parameters using 3D STE in DM1 patients free of cardiac symptoms. After obtaining their written informed consent, 28 consecutive DM1 patients (mean age = 34 years, 12 familial and 16 sporadic cases) were eligible for the study and 28 sex and age (± 2 SD) ⁎ Corresponding author at: Echocardiography Laboratory, Department of Translational Medical Science, Edificio 1, Federico II University Hospital of Naples, Via S. Pansini 5, Edificio 1, 80131 Naples, Italy. Tel.: +39 81 7464749; fax: +39 81 5466152. E-mail address: [email protected] (M. Galderisi).
http://dx.doi.org/10.1016/j.ijcard.2014.07.121 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
matched healthy controls, randomly selected, entered the study. Patients with symptoms/signs of heart failure, arrhythmias, coronary artery disease, arterial hypertension, diabetes mellitus, moderate– severe valvular disease, pericardial disease, atrial fibrillation, pacemaker, and undergoing cardiac therapy were excluded. All DM1 patients had genetic confirmation of diagnosis with different number of repeats of triplets CTG in DMPK gene (range = 125–1300). They had signs of neuromuscular involvement (myopathic facies, myotonia and gait abnormalities) but had an independent ambulation and normal physical activity levels. Echocardiography was performed using a Vivid E9 ultrasound machine (GE Healthcare, Horten, Norway), equipped with both a 2.5 MHz transducer with harmonic capability and a 3D volumetric transducer. Standard echo-Doppler examination was performed according to the standards of our laboratory. Real-time 3D echocardiography was performed and analyzed according to previously described procedures [7]. Data sets were stored digitally in raw data and exported to a workstation (Echopac PC, 110.1.1, GE Healthcare) equipped with commercially available software (4D Auto LVQ software, GE Healthcare) for off-line 3D analysis. By using this software 3D volumetric parameters, LV mass and regional directional strains (longitudinal, circumferential, radial) as well as area strain were generated and presented as strain curves and a colorcoded 17-segments bull's eye plot. Global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS) and global radial strain (GRS) were calculated as weighted averages of the regional values from the 17 myocardial segments. Body mass index, heart rate, blood pressure were comparable between the two groups. Number of CTG-repeats in DM1 patients was 495.5 ± 299.2 (range = 84–1300). First degree atrio-ventricular block was the most represented ECG abnormality. Table 1 summarizes standard echo-Doppler and 3D results. In the pooled population, GAS was related to SV and LV mass index (Fig. 1). The associations of GAS with both 3D LV mass index (β = 0.41) (p b 0.001) and SV (β = 0.33) (p b 0.01) remained significant after adjusting for heart rate and sphericity index by a multiple linear regression analysis (cumulative R2 = 0.29, SEE = 3.3%, p b 0.001). Our study is the first to identify changes of 3D echocardiographic volumetric and 3D STE parameters in patients with DM1 free of heart failure. We found a reduction of LV chamber size and LV mass
M. Galderisi et al. / International Journal of Cardiology 176 (2014) 1094–1096 Table 1 Standard echo-Doppler and 3D echocardiographic analysis of the left ventricle. Variable Standard echo Doppler LVM (g) LVM/Ht (g/m2.7) RDWT EDV (mL) ESV (mL) SV (mL) EF (%) E/A ratio E velocity DT (msec) E/e′ ratio 3D echocardiography 3D EDV (mL) 3D ESV (mL) 3D SV (mL) 3D EF (%) Sphericity index 3D LVM (g) 3D LVM/Ht (g/m2.7) GLS (%) GCS (%) GAS (%) GRS (%)
Healthy controls
DM1 patients
p
140.1 30.9 0.32 100.1 39.0 61.1 62.4 1.45 187.9 6.31
± ± ± ± ± ± ± ± ± ±
36.3 5.9 0.05 27.7 12.1 17.9 5.4 0.53 53.1 1.56
110.8 26.8 0.32 75.5 27.8 47.7 63.2 1.64 195.8 6.37
± ± ± ± ± ± ± ± ± ±
34.0 7.3 0.06 19.9 10.4 11.4 6.5 0.67 45.6 1.55
=0.003 =0.03 0.927 b0.0001 b0.0001 b0.001 0.600 0.257 0.552 0.902
119.9 49.0 72.2 60.5 0.37 140.2 31.6 −16.1 −16.2 −28.3 41.4
± ± ± ± ± ± ± ± ± ± ±
31.2 17.6 15.6 6.4 0.09 12.8 4.3 1.7 2.6 3.4 7.3
90.2 36.0 54.4 60.9 0.31 117.1 28.6 −15.1 −14.2 −24.7 36.0
± ± ± ± ± ± ± ± ± ± ±
23.8 13.6 13.9 7.7 0.09 13.3 3.2 2.7 1.7 4.0 7.8
b0.0001 =0.003 b0.0001 0.849 b0.01 b0.0001 =0.004 =0.09 b0.001 b0.001 b0.01
LVM = left ventricular mass, LVM/Ht = left ventricular mass indexed for height, RDWT = relative diastolic wall thickness, EDV = end-diastolic volume, ESV = endsystolic volume, SV = stroke volume, EF = ejection fraction, DT = deceleration time, e ′ = early diastolic velocity of mitral annulus, GLS = global circumferential strain, GCS = global circumferential strain, GAS = global area strain, and GRS = global radial strain.
(detectable by both 2D and 3D imaging) paralleling reduction of SV and substantial impairment of 3D strain components, without alteration of ejection fraction (EF). The impairment of 3D strain involved mainly GCS and GAS, and to a lesser extent GRS. GLS was relatively preserved. The reduced GAS, a comprehensive parameter of myocardial deformation, was associated with reduced LV mass index and reduced stroke volume (SV), i.e., an indicator of LV pump performance. LV geometric abnormalities observed in DM1 patients are consistent with pathological abnormalities seen in striated muscles including myocardium [8]. These alterations could be responsible of lower
1095
LV mass. The assessment of myocardial deformation in DM1 was performed only in two previous studies which used 2D STE [4,5]. Both studies showed a reduction of GLS. In particular, the second one [5] found a reduction of GLS in 21.7% of 129 unselected DM1 patients (mean age = 44 years) including 43 referring cardiac symptoms. The reduction of GLS was accompanied with EF ≤ 50% in 26 DM1 patients. In the present study, 3D STE allowed a simultaneous assessment of all strain components in 28 DM1 patients who had normal EF (with 2D and 3D echocardiography), were younger and all free of cardiac symptoms by selection. Conversely, the reduction of strain components involved mainly GCS and GAS whereas GRS was marginally lower and GLS not significantly different in comparison with the controls. GCS is expression of the contraction of the midwall layer of cardiomyocytes. This reduction is in agreement with cardiac magnetic resonance imaging studies, showing a peculiar pattern of interstitial fibrosis of midwall septum at the early phases of the disease [9]. High levels of TGF-β1, a sensitive biomarker of fibrosis, have been also observed in DM1 patients at risk for arrhythmias and sudden cardiac death [10]. The reduction of GAS in our patients was positively related with both LV mass index and SV, even after adjusting for heart rate and sphericity index as a parameter of LV cavity geometry. The direct association of GAS with LV mass recalls the impact of the loss of myocardial tissue and subsequent replacement by myocardial fibrosis [8] on the myocardial deformation. The association of GAS and SV can be interpreted as an expression of the possible impact of this comprehensive myocardial deformation parameter on LV pump performance. Our findings allow us to indirectly recognize that, even in the early phases of the disease, DM1 might induce a loss of contractile fibers which primarily involves midwall myocardium. Threedimensional echocardiography can detect alterations of LV myocardial function and systolic performance that cannot be observed by standard 2D echocardiography. These abnormalities seem to appear early, longer before the onset of overt heart failure in this clinical setting.
Conflict of interest No conflict of interest.
Fig. 1. In the left part, scatterplot and regression lines of individual values of LV mass index (x line) and global area strain (y-line) in healthy controls and MD patients*. In the right part, scatterplot and regression lines of individual values of stroke volume (x-line) and global area strain (y-line) in healthy controls and MD patients*. LV = left ventricular. *Values of global area strain considered as “positive” (sign +) to build the univariate relations in order to homogenize the results of analyses and strengthen their clinical meaning: the higher values the better strain deformation independent on the plus/minus sign.
1096
M. Galderisi et al. / International Journal of Cardiology 176 (2014) 1094–1096
References [1] Harper PS myotonic dystrophy. 3rd ed. London: Saunders; 2001. [2] Petri H, Vissing J, Witting N, Bundgaard H, Kober L. Cardiac manifestations of myotonic dystrophy type 1. Int J Cardiol 2012;160:82–8. [3] Schneider-Gold C, Beer M, Köstler H, et al. Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): a quantitative 31P-MRS and MRI study. Nerve Muscle 2004;30:636–44. [4] Wahbi K, Ederhy S, Bécane HM, et al. Impaired myocardial deformation detected by speckle-tracking echocardiography in patients with myotonic dystrophy type 1. Int J Cardiol 2011;152:375–6. [5] Petri H, Witting N, Ersboll MK, et al. High prevalence of cardiac involvement in patients with myotonic dystrophy type 1: a cross-sectional study. Int J Cardiol 2014; 174:31–6. [6] Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus
[7]
[8] [9]
[10]
statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr 2011;12:167–205. Galderisi M, Esposito R, Schiano-Lomoriello V, et al. Correlates of global area strain in native hypertensive patients: a three-dimensional speckle-tracking echocardiography study. Eur Heart J Cardiovasc Imaging 2012;13:730–8. Motta J. Cardiac abnormalities in myotonic dystrophy. Electrophysiologic and histopathologic studies. Am J Med 1978;67:467–73. Verhaert D, Richards K, Rafael-Fortney JA, Subha R. Cardiac involvement in patients with muscular dystrophies: magnetic resonance imaging phenotype and genotypic considerations. Circ Cardiovasc Imaging 2011;4:67–76. Turillazzi E, Neri M, Riezzo I, Di Palo M, Evangelisti L, Fineschi V. Cardiac fibrosis, arrhythmia and sudden death in myotonic dystrophy type 1: could TGF-β1 improve the predictive accuracy of patients at risk, opening new therapeutic challenges? Int J Cardiol 2013;168:4976–8.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Early changes of myocardial deformation properties in patients with dystrophia myotonica type 1: A three-dimensional Speckle Tracking echocardiographic study Maurizio Galderisi a,⁎, Francesco De Stefano a, Ciro Santoro a, Agostino Buonauro a, Daniela De Palma a, Fiore Manganelli b, Lucia Ruggiero b, Lucio Santoro b, Giovanni de Simone a a b
Hypertension Research Center, Department of Translational Medical Sciences, “Federico II” University Hospital, Naples, Italy Department of Neurosciences, Reproductive and Odontoiatric Sciences, “Federico II” University Hospital, Naples, Italy
a r t i c l e
i n f o
Article history: Received 24 May 2014 Accepted 26 July 2014 Available online 1 August 2014 Keywords: Myotonic dystrophy Cardiomyopathy Real time 3D echocardiography Stroke volume Strain
Dystrophia myotonica type 1 (DM1) is an inherited neuromuscular disorder characterized by progressive myotonia and muscle wasting [1]. Cardiac damage includes abnormalities of conduction system [2] and myocardial fibrosis [3]. The detection of early markers of cardiac involvement could therefore favor identification of patients at risk of developing cardiac complications and, potentially, address to appropriate management. Abnormalities of LV systolic function have never been reported in asymptomatic DM1 using standard echo-Doppler. Among advanced echocardiographic technologies, 2D Speckle Tracking Echocardiography (STE) has demonstrated impaired left ventricular (LV) myocardial deformation in DM1 patients [4,5]. Further technologic advancement of 3D echocardiography has recently developed software which allows us to obtain a homogeneous and simultaneous spatial distribution of all three components of myocardial displacement vector [6]. Accordingly, we attempted to identify early alteration of systolic deformation parameters using 3D STE in DM1 patients free of cardiac symptoms. After obtaining their written informed consent, 28 consecutive DM1 patients (mean age = 34 years, 12 familial and 16 sporadic cases) were eligible for the study and 28 sex and age (± 2 SD) ⁎ Corresponding author at: Echocardiography Laboratory, Department of Translational Medical Science, Edificio 1, Federico II University Hospital of Naples, Via S. Pansini 5, Edificio 1, 80131 Naples, Italy. Tel.: +39 81 7464749; fax: +39 81 5466152. E-mail address: [email protected] (M. Galderisi).
http://dx.doi.org/10.1016/j.ijcard.2014.07.121 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
matched healthy controls, randomly selected, entered the study. Patients with symptoms/signs of heart failure, arrhythmias, coronary artery disease, arterial hypertension, diabetes mellitus, moderate– severe valvular disease, pericardial disease, atrial fibrillation, pacemaker, and undergoing cardiac therapy were excluded. All DM1 patients had genetic confirmation of diagnosis with different number of repeats of triplets CTG in DMPK gene (range = 125–1300). They had signs of neuromuscular involvement (myopathic facies, myotonia and gait abnormalities) but had an independent ambulation and normal physical activity levels. Echocardiography was performed using a Vivid E9 ultrasound machine (GE Healthcare, Horten, Norway), equipped with both a 2.5 MHz transducer with harmonic capability and a 3D volumetric transducer. Standard echo-Doppler examination was performed according to the standards of our laboratory. Real-time 3D echocardiography was performed and analyzed according to previously described procedures [7]. Data sets were stored digitally in raw data and exported to a workstation (Echopac PC, 110.1.1, GE Healthcare) equipped with commercially available software (4D Auto LVQ software, GE Healthcare) for off-line 3D analysis. By using this software 3D volumetric parameters, LV mass and regional directional strains (longitudinal, circumferential, radial) as well as area strain were generated and presented as strain curves and a colorcoded 17-segments bull's eye plot. Global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS) and global radial strain (GRS) were calculated as weighted averages of the regional values from the 17 myocardial segments. Body mass index, heart rate, blood pressure were comparable between the two groups. Number of CTG-repeats in DM1 patients was 495.5 ± 299.2 (range = 84–1300). First degree atrio-ventricular block was the most represented ECG abnormality. Table 1 summarizes standard echo-Doppler and 3D results. In the pooled population, GAS was related to SV and LV mass index (Fig. 1). The associations of GAS with both 3D LV mass index (β = 0.41) (p b 0.001) and SV (β = 0.33) (p b 0.01) remained significant after adjusting for heart rate and sphericity index by a multiple linear regression analysis (cumulative R2 = 0.29, SEE = 3.3%, p b 0.001). Our study is the first to identify changes of 3D echocardiographic volumetric and 3D STE parameters in patients with DM1 free of heart failure. We found a reduction of LV chamber size and LV mass
M. Galderisi et al. / International Journal of Cardiology 176 (2014) 1094–1096 Table 1 Standard echo-Doppler and 3D echocardiographic analysis of the left ventricle. Variable Standard echo Doppler LVM (g) LVM/Ht (g/m2.7) RDWT EDV (mL) ESV (mL) SV (mL) EF (%) E/A ratio E velocity DT (msec) E/e′ ratio 3D echocardiography 3D EDV (mL) 3D ESV (mL) 3D SV (mL) 3D EF (%) Sphericity index 3D LVM (g) 3D LVM/Ht (g/m2.7) GLS (%) GCS (%) GAS (%) GRS (%)
Healthy controls
DM1 patients
p
140.1 30.9 0.32 100.1 39.0 61.1 62.4 1.45 187.9 6.31
± ± ± ± ± ± ± ± ± ±
36.3 5.9 0.05 27.7 12.1 17.9 5.4 0.53 53.1 1.56
110.8 26.8 0.32 75.5 27.8 47.7 63.2 1.64 195.8 6.37
± ± ± ± ± ± ± ± ± ±
34.0 7.3 0.06 19.9 10.4 11.4 6.5 0.67 45.6 1.55
=0.003 =0.03 0.927 b0.0001 b0.0001 b0.001 0.600 0.257 0.552 0.902
119.9 49.0 72.2 60.5 0.37 140.2 31.6 −16.1 −16.2 −28.3 41.4
± ± ± ± ± ± ± ± ± ± ±
31.2 17.6 15.6 6.4 0.09 12.8 4.3 1.7 2.6 3.4 7.3
90.2 36.0 54.4 60.9 0.31 117.1 28.6 −15.1 −14.2 −24.7 36.0
± ± ± ± ± ± ± ± ± ± ±
23.8 13.6 13.9 7.7 0.09 13.3 3.2 2.7 1.7 4.0 7.8
b0.0001 =0.003 b0.0001 0.849 b0.01 b0.0001 =0.004 =0.09 b0.001 b0.001 b0.01
LVM = left ventricular mass, LVM/Ht = left ventricular mass indexed for height, RDWT = relative diastolic wall thickness, EDV = end-diastolic volume, ESV = endsystolic volume, SV = stroke volume, EF = ejection fraction, DT = deceleration time, e ′ = early diastolic velocity of mitral annulus, GLS = global circumferential strain, GCS = global circumferential strain, GAS = global area strain, and GRS = global radial strain.
(detectable by both 2D and 3D imaging) paralleling reduction of SV and substantial impairment of 3D strain components, without alteration of ejection fraction (EF). The impairment of 3D strain involved mainly GCS and GAS, and to a lesser extent GRS. GLS was relatively preserved. The reduced GAS, a comprehensive parameter of myocardial deformation, was associated with reduced LV mass index and reduced stroke volume (SV), i.e., an indicator of LV pump performance. LV geometric abnormalities observed in DM1 patients are consistent with pathological abnormalities seen in striated muscles including myocardium [8]. These alterations could be responsible of lower
1095
LV mass. The assessment of myocardial deformation in DM1 was performed only in two previous studies which used 2D STE [4,5]. Both studies showed a reduction of GLS. In particular, the second one [5] found a reduction of GLS in 21.7% of 129 unselected DM1 patients (mean age = 44 years) including 43 referring cardiac symptoms. The reduction of GLS was accompanied with EF ≤ 50% in 26 DM1 patients. In the present study, 3D STE allowed a simultaneous assessment of all strain components in 28 DM1 patients who had normal EF (with 2D and 3D echocardiography), were younger and all free of cardiac symptoms by selection. Conversely, the reduction of strain components involved mainly GCS and GAS whereas GRS was marginally lower and GLS not significantly different in comparison with the controls. GCS is expression of the contraction of the midwall layer of cardiomyocytes. This reduction is in agreement with cardiac magnetic resonance imaging studies, showing a peculiar pattern of interstitial fibrosis of midwall septum at the early phases of the disease [9]. High levels of TGF-β1, a sensitive biomarker of fibrosis, have been also observed in DM1 patients at risk for arrhythmias and sudden cardiac death [10]. The reduction of GAS in our patients was positively related with both LV mass index and SV, even after adjusting for heart rate and sphericity index as a parameter of LV cavity geometry. The direct association of GAS with LV mass recalls the impact of the loss of myocardial tissue and subsequent replacement by myocardial fibrosis [8] on the myocardial deformation. The association of GAS and SV can be interpreted as an expression of the possible impact of this comprehensive myocardial deformation parameter on LV pump performance. Our findings allow us to indirectly recognize that, even in the early phases of the disease, DM1 might induce a loss of contractile fibers which primarily involves midwall myocardium. Threedimensional echocardiography can detect alterations of LV myocardial function and systolic performance that cannot be observed by standard 2D echocardiography. These abnormalities seem to appear early, longer before the onset of overt heart failure in this clinical setting.
Conflict of interest No conflict of interest.
Fig. 1. In the left part, scatterplot and regression lines of individual values of LV mass index (x line) and global area strain (y-line) in healthy controls and MD patients*. In the right part, scatterplot and regression lines of individual values of stroke volume (x-line) and global area strain (y-line) in healthy controls and MD patients*. LV = left ventricular. *Values of global area strain considered as “positive” (sign +) to build the univariate relations in order to homogenize the results of analyses and strengthen their clinical meaning: the higher values the better strain deformation independent on the plus/minus sign.
1096
M. Galderisi et al. / International Journal of Cardiology 176 (2014) 1094–1096
References [1] Harper PS myotonic dystrophy. 3rd ed. London: Saunders; 2001. [2] Petri H, Vissing J, Witting N, Bundgaard H, Kober L. Cardiac manifestations of myotonic dystrophy type 1. Int J Cardiol 2012;160:82–8. [3] Schneider-Gold C, Beer M, Köstler H, et al. Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): a quantitative 31P-MRS and MRI study. Nerve Muscle 2004;30:636–44. [4] Wahbi K, Ederhy S, Bécane HM, et al. Impaired myocardial deformation detected by speckle-tracking echocardiography in patients with myotonic dystrophy type 1. Int J Cardiol 2011;152:375–6. [5] Petri H, Witting N, Ersboll MK, et al. High prevalence of cardiac involvement in patients with myotonic dystrophy type 1: a cross-sectional study. Int J Cardiol 2014; 174:31–6. [6] Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus
[7]
[8] [9]
[10]
statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr 2011;12:167–205. Galderisi M, Esposito R, Schiano-Lomoriello V, et al. Correlates of global area strain in native hypertensive patients: a three-dimensional speckle-tracking echocardiography study. Eur Heart J Cardiovasc Imaging 2012;13:730–8. Motta J. Cardiac abnormalities in myotonic dystrophy. Electrophysiologic and histopathologic studies. Am J Med 1978;67:467–73. Verhaert D, Richards K, Rafael-Fortney JA, Subha R. Cardiac involvement in patients with muscular dystrophies: magnetic resonance imaging phenotype and genotypic considerations. Circ Cardiovasc Imaging 2011;4:67–76. Turillazzi E, Neri M, Riezzo I, Di Palo M, Evangelisti L, Fineschi V. Cardiac fibrosis, arrhythmia and sudden death in myotonic dystrophy type 1: could TGF-β1 improve the predictive accuracy of patients at risk, opening new therapeutic challenges? Int J Cardiol 2013;168:4976–8.