Pediatr Cardiol DOI 10.1007/s00246-015-1192-7
ORIGINAL ARTICLE
Myocardial Fibrosis and Left Ventricular Dysfunction in Duchenne Muscular Dystrophy Carriers Using Cardiac Magnetic Resonance Imaging Sean M. Lang1 • Svetlana Shugh2 • Wojciech Mazur3 • Joshua J. Sticka2 Mantosh S. Rattan4 • John L. Jefferies2 • Michael D. Taylor2
•
Received: 16 February 2015 / Accepted: 5 May 2015 Ó Springer Science+Business Media New York 2015
Abstract The goal of our study was to characterize the degree of myocardial fibrosis and left ventricular dysfunction in our cohort of Duchenne muscular dystrophy (DMD) carriers using cardiac magnetic resonance imaging (CMR). Seventy percent of males with DMD have mothers who are carriers of the Xp21 mutation. Carrier phenotypic characteristics range from asymptomatic to left ventricular (LV) dysfunction and cardiomyopathy. The true prevalence of cardiac involvement in DMD carriers is unknown. We performed a retrospective observational study. All female DMD carriers who underwent clinical CMR studies at Cincinnati Children’s Hospital Medical Center from December 6, 2006, to August 28, 2013, were evaluated. Patients underwent standard CMR assessment with LV function assessment and late gadolinium enhancement (LGE). In addition, offline feature tracking strain analysis was performed on the basal, mid, and apical short axis. Twenty-two patients were studied, of which 20 underwent adequate testing for myocardial LGE. Four of 22 patients (18 %) were found to have LV dysfunction (ejection fraction \55 %). Seven of 20 DMD carriers (35 %) were
S.M. Lang and S. Shugh contributed equally to this manuscript. & Sean M. Lang [email protected] 1
Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, 1 Children’s Way, Little Rock, AR, USA
2
The Heart Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA
3
The Ohio Heart and Vascular Center at The Christ Hospital, 2123 Auburn Ave, Suite 138, Cincinnati, OH, USA
4
Department of Radiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA
found to have LGE. The patients with evidence of LGE had an overall trend to lower absolute deformation parameters; however, this did not meet statistical significance when correcting for multiple comparisons. Our study demonstrates a high rate of LGE as well as LV dysfunction in DMD carriers. Cardiovascular and musculoskeletal symptoms were not statistically different between those with and without cardiac involvement. This study demonstrates the importance of surveillance CMR evaluation of DMD carriers. Keywords Late gadolinium enhancement Cardiomyopathy Feature tracking Myocardial strain Abbreviations AAP American Academy of Pediatrics ACE Angiotensin-converting enzyme CMR Cardiac magnetic resonance DMD Duchenne muscular dystrophy EF Ejection fraction FT Feature tracking Gd-DTPA Gadolinium diethylene triamine penta-acetic acid LGE Late gadolinium enhancement LV Left ventricle SSFP Steady-state free precession
Introduction Duchenne muscular dystrophy (DMD) is a genetic condition occurring in one of every 3500 live male births [5, 9]. It is caused by a mutation in Xp21 that results in a lack of
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Pediatr Cardiol
dystrophin production [5, 9, 19]. About 70 % of males with DMD have mothers who are carriers of the Xp21 mutation [5, 9]. Due to random X chromosome inactivation, female DMD carriers may be asymptomatic or may develop neuromuscular or cardiovascular sequelae similar to DMD [5, 9, 17]. It has been estimated that 10 % of DMD carriers develop cardiomyopathy; however, the prevalence of more occult cardiac involvement is unclear [1, 23]. Cardiac magnetic resonance (CMR) has been used in the DMD population to diagnose occult cardiac dysfunction and myocardial fibrosis [12, 24, 26]. Previously, the description of cardiac involvement in DMD carriers has been limited to echocardiography studies, CMR case reports, and a single institution’s CMR experience [11, 17, 21, 23, 25, 27]. The goal of our study was to characterize cardiac involvement in a cohort of DMD carriers. To assess cardiac involvement, we evaluated global LV function (LV ejection fraction), LV deformation (circumferential strain, systolic strain rate, and early diastolic strain rate), and myocardial fibrosis burden using late gadolinium enhancement (LGE).
Materials and Methods This retrospective study was approved by the Institutional Review Board (IRB) at Cincinnati Children’s Hospital Medical Center. Data were analyzed from the records of DMD female carriers who underwent clinical CMR studies at Cincinnati Children’s Hospital Medical Center between December 6, 2006, and August 28, 2013. The diagnosis of carrier status was confirmed by genetic testing. Chart reviews were performed on each patient to obtain prior medications, comorbidities, and complaints of musculoskeletal and cardiac symptoms. Cardiac MRI studies were conducted on a Philips 1.5 T Ingenia or 3.0 T Achieva Platform (Philips Healthcare, Eindhoven, the Netherlands). Cardiac functional imaging was performed using a retrospective electrocardiogram (EKG) gated, segmented k-space, steady-state free precession (SSFP) pulse sequence. Subjects were breath-held for all sequences. Standard imaging included a short axis stack of cine SSFP images from cardiac base to apex; the short axis was prescribed as the perpendicular plane to the LV long axis in two- and four-chamber views as previously described [18, 20]. Typical scan parameters included 6 mm slice thickness; no interslice gap; temporal resolution 30 ms/phase; TE 1.9 ms; and TR 2.6–3.7 ms. Myocardial LGE was performed using a segmented k-space gradient echo inversion sequence recovery pulse sequence 10 min after 0.2 mmol/kg of gadolinium diethylene triamine penta-acetic acid (Gd-DTPA) injection
123
[24, 26]. LGE imaging was considered positive if any area of the subepicardium or myocardium demonstrated enhancement in two orthogonal views (Fig. 1). The location of LGE was described according to the American Heart Association 16-segment model [4]. Ventricular volumes, mass, and ejection fraction were assessed via standard planimetry with semiautomated contour software (QMASS version 7.5, Medis Medical Imaging Systems, Leiden, the Netherlands). LV dysfunction was defined as a LV ejection fraction of \55 %. Feature tracking strain analysis (FT) was performed using Diogenes CMR FT software (TomTec Imaging Systems, Munich, Germany). Cine basal, mid, and apical short axis SSFP images were used. Epicardial and endocardial borders were manually traced at end-diastole. The software uses a vector-based analysis algorithm to propagate the contours by feature tracking throughout the cardiac cycle [13]. The temporal feature tracking allows calculation of circumferential strain, systolic strain rate, and early diastolic strain rate (Figs. 2, 3). Each contour was assessed for appropriate tracking. Contours were excluded from analysis if tracking was unstable after three attempts. Data are expressed as mean ± standard deviation. Comparisons in LV global function and deformation parameters were made using a two-sample unpaired t test, between groups with LGE and those without. Comparisons between the groups with regard to cardiovascular and musculoskeletal symptoms, and positive remodeling medication use were made using Fisher’s exact test. A p value of\0.05 was deemed statistically significant. The Bonferroni correction was performed when evaluating the multiple-comparison deformation parameters. There were nine multiple comparisons; therefore, a p value of 0.006 was deemed significant with regard to deformation parameters.
Results Clinical and CMR data for each individual patient are shown in Table 1. Patient demographics are shown in Table 2. Mean age was 40.9 years with a range of 13.2–60.0 years. Eleven of the 22 patients reported possible cardiovascular symptoms including chest pain, palpitations, and shortness of breath. Two of the 22 patients reported musculoskeletal symptoms (one patient was wheelchair bound, another patient reported hip and lowerback weakness). Only two out of the 22 patients (9 %) were receiving cardiac medications (one patient on an angiotensin-converting enzyme (ACE) inhibitor for hypertension, one patient on a beta-blocker for palpitations). Based on CMR evaluation, four of 22 patients (18 %) were diagnosed with LV dysfunction. Twenty of the 22 patients underwent adequate testing for LGE. One patient
Pediatr Cardiol Fig. 1 Late gadolinium enhancement (LGE) images. a Three-chamber left ventricular LGE image. There is subepicardial evidence of LGE in the basal and mid inferolateral segments. b Basal short axis LGE image. There is evidence of LGE in the basal inferolateral segment
Fig. 2 Circumferential strain analysis curves. Basal strain curves for an individual patient. Each separate line represents the different basal segments based on the 16-segment heart model (*peak average circumferential strain, ms milliseconds)
Fig. 3 Circumferential strain rate analysis curves. Basal strain rate curves for an individual patient. Each separate line represents a different basal segment based on the 16-segment heart model (s seconds, ms milliseconds, Sys SR peak systolic strain rate, Dias SR peak early diastolic strain rate)
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Pediatr Cardiol Table 1 Patient clinical and CMR data Carrier
Age (yrs)
Symptoms
Cardiac medications
LV EF (%)
LGE
1
47
Palpitations
Atenolol
68
No
2
33
Frequent chest pain and palpitations
Lisinopril
49
Yes
3
41
Palpitations
No
64
No
4
39
Syncopal episodes
No
62
No
5
13
Muscle weakness, wheelchair bound
No
62
No
6
27
Palpitations
No
67
No
7
43
Occasional shortness of breath, previous mitral valve surgery secondary to mitral valve prolapse
No
63
No
8
42
Intermittent dull chest pain
No
62
No
9
59
N/Aa
N/Aa
64
No
10
28
Palpitations
No
67
No
11
37
Weak hips and lower back
No
59
No
12
41
Non-exertional chest pain
No
62
No
13
37
None
No
67
No
14
43
Intermittent chest pain
No
51
Yes
15
47
None
No
59
No
16
44
Shortness of breath on exertion
No
62
No
17
45
None
No
60
N/Ab
18 19
42 45
None Shortness of breath on exertion, palpitations
No No
57 48
Yes N/Ac
20
39
None
No
62
Yes
21
44
None
No
65
No
22
56
None
No
53
Yes
Patients’ symptoms and medication history obtain via chart review. CMR indicates cardiac magnetic resonance imaging yrs years, EF ejection fraction, LGE late gadolinium enhancement, N/A not available a
No clinic documentation available for this patient prior to CMR
b
Patient unable to complete full study secondary to anxiety
c
LGE images of insufficient quality to determine fibrosis
had insufficient image quality to assess LGE, while the other patient was unable to tolerate that portion of the examination due to anxiety. Seven of 20 patients (35 %) were found to have LGE. Mean age of patients with LGE was 43.4 years with a range of 33–56 years. The most commonly affected segments were the mid ventricular inferolateral segment (segment 11)—6 patients, and the basal inferolateral segment (segment 5)—5 patients (Table 3). The average number of LGE-positive segments was 3.4, ranging from 1 to 7 segments involved. Two out of the 22 patients (9 %) had inadequate images with regard to feature tracking analysis. Table 4 shows the difference between the patients with LGE and those without. When compared to patients without LGE, the LGE? group had statistically significant lower left ventricular ejection fraction. The LGE? group also had an overall trend to lower absolute deformation parameters; however, with correcting for multiple comparisons, statistical significance was not reached. Box plots are shown in Fig. 4.
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Discussion The principle finding of this study was the high prevalence of LGE in female DMD carriers (35 % of patients evaluated with Gd-DTPA). Four of the seven patients with LGE had normal LV function, representing occult cardiac involvement. As previously described in the DMD population, LGE presents often before cardiac dysfunction [12, 24]. Furthering this point, comparing patients with and without LGE, there was no statistical difference between those reporting cardiac symptoms and those with muscle involvement. These results highlight the importance of surveillance for the patient population. The American Academy of Pediatrics (AAP) estimates 10 % of DMD carriers will progress to overt cardiomyopathy [1]. Despite this concern, there remains a lack of compliance with the AAP recommendations for routine follow-up. Surveys estimated that only 62.9 % of DMD carriers recognize the risk of
Pediatr Cardiol Table 2 Baseline characteristics (n = 22) Age (yrs)
40.9 (± 9.71)
Symptoms Cardiovascular
11 (50)
Musculoskeletal
2 (9)
Positive remodeling medications
2 (9)
Comorbid conditions Anxiety/depression
5 (23)
Dyslipidemia
4 (18)
Hypothyroidism
2 (9)
Obesity
1 (5)
Hypertension
1 (5)
Mitral valve prolapse/s/p repair
1 (5)
Values presented are means (SD) or n (%) yrs years
Table 3 Segments of LGE
Segment
n (%)
4
1 (14)
5
5 (71)
6
3 (43)
10
2 (29)
11
6 (86)
12
3 (43)
13
1 (14)
16
1 (14)
Segment numbers according to American Heart Association 16-segment model
cardiomyopathy, 64.4 % have ever undergone any form of cardiac testing, and 18.3 % have seen a cardiologist over the last year [3]. The AAP currently recommends treating DMD carriers with evidence of cardiac involvement similar to DMD males [1]. In DMD patients exhibiting signs of cardiomyopathy, numerous studies have shown the benefit of implementing ACE inhibitors alone or in combination with beta-blockers. These medications have been shown to improve subjective symptoms and delay the progression of cardiomyopathy and ultimately heart failure [6, 7, 14, 15, 25]. The benefit of early detection of cardiac involvement can also be supported from observations in murine models. In a DMD mouse model, those treated earlier with lisinopril and spironolactone demonstrated less cardiomyocyte damage and improved myocardial strain [22]. In our patients with documented LGE and/or LV dysfunction, only two of the eight patients were currently being treated with a positive remodeling medication, prior to undergoing CMR. A prior letter to the editor from Mavrogeni et al. demonstrated a majority of their cohort of Duchenne carriers (18/25 patients) had evidence of LGE [17]. That group’s description also had a relatively small cohort. In comparison, our patient cohort represents a younger group with a mean of 40.9 years and range of 13–60 years, compared to a median of 48 years with a range of 33–65 years. As this is a progressive disease, the difference in ages may explain the difference in LGE prevalence. Our work and that of Mavrogeni highlight the importance of a larger multi-institutional investigation to determine the true prevalence of cardiac involvement in DMD carriers. Larger studies with wider age ranges will also be important to help guide the proper age of surveillance. Our
Table 4 Comparison of LGE? versus LGE- patients
LGE? N = 7
LGE- N = 13
p
Age (mean ± SD)
43.4 yrs (±7.1)
38.9 (±9.8)
0.293
CV symptoms
4
7
NS
MSK symptoms
0
2
NS
Positive remodeling medications
1
1
NS
LV EF (%)
56.2 (±5.3)
64.0 (±2.7)
0.007
Basal circumferential strain (%)
-21.57 (±3.1)
-25.37 (±4.24)
0.050
Mid circumferential strain (%)
-18.81 (±2.7)
-22.38 (±2.95)
0.025
Apical circumferential strain (%)
-23.90 (±4.58)
-26.64 (±6.00)
0.301
Basal systolic strain rate (s-1)
-1.13 (±0.22)
-1.38 (±0.23)
0.048
Mid systolic strain rate (s-1)
-1.06 (±0.23)
-1.30 (±0.19)
0.057
-1.35 (±0.23) 1.45 (±0.28)
-1.69 (±0.49) 1.79 (±0.42)
0.059 0.062
Mid early diastolic strain rate (s-1)
1.16 (±0.29)
1.41 (±0.33)
0.128
Apical early diastolic strain rate (s-1)
1.69 (±0.46)
2.12 (±0.97)
0.212
-1
Apical systolic strain rate (s ) Basal early diastolic strain rate (s-1)
Values presented are means (SD) EF ejection fraction
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Pediatr Cardiol Fig. 4 LGE? versus LGEbox plots. Box plots comparing those with and without late gadolinium enhancement. The first and third quartiles are represented by the ends of the box. The median is marked by the horizontal line inside the box. The outer lines represent the maximum and minimum values. p values were obtained using two-sample unpaired t tests. (LGE? evidence of late gadolinium enhancement, LGE- no evidence of late gadolinium enhancement)
results are in agreement with the AAP recommendations of surveillance beginning at 25–30 years of age [1]. The youngest patient in our group with LGE was 33 years old; however, we only evaluated three younger carriers (13, 27, and 28 years old). Our study also investigated the use of deformation parameters in DMD carriers. Circumferential strain, systolic strain rate, and early diastolic strain rate have been recognized as an advantageous tool in the evaluation of patients with heart failure of different etiologies [8]. Systolic strain rate and early diastolic strain rate are sensitive measures for myocardial contraction and relaxation [8, 10]. As an entire cohort, our strain indices were comparable to historical controls [2, 16]. These results are in keeping with the wide phenotypic range of cardiovascular symptoms in DMD carriers with a significant proportion of asymptomatic patients. Despite an overall trend toward lower absolute deformation parameters in patients with LGE, statistical significance was not reached correcting for multiple comparisons. Prior work by our group in DMD patients has shown abnormal mid ventricular circumferential strain despite normal ejection fraction [12]. Larger investigation will be required in the carrier population to determine whether deformation analysis can aid in uncovering occult cardiac involvement.
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This study is limited by being retrospective in nature. There was the possibility for selection bias in those DMD carriers referred for CMR. However, given the percentage of patients with LGE and normal LV function, it is unknown whether the selection bias underestimates or overestimates the actual prevalence of LGE in DMD carriers. In addition, this was a relatively small cohort without power to reach statistical significance when analyzing deformation parameters in LGE-positive patients. Lastly, this study was cross-sectional in nature, and longitudinal analysis was not performed. Acknowledgments ing interests.
The authors declare that they have no compet-
Conflict of interest
No conflicts to disclose.
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ORIGINAL ARTICLE
Myocardial Fibrosis and Left Ventricular Dysfunction in Duchenne Muscular Dystrophy Carriers Using Cardiac Magnetic Resonance Imaging Sean M. Lang1 • Svetlana Shugh2 • Wojciech Mazur3 • Joshua J. Sticka2 Mantosh S. Rattan4 • John L. Jefferies2 • Michael D. Taylor2
•
Received: 16 February 2015 / Accepted: 5 May 2015 Ó Springer Science+Business Media New York 2015
Abstract The goal of our study was to characterize the degree of myocardial fibrosis and left ventricular dysfunction in our cohort of Duchenne muscular dystrophy (DMD) carriers using cardiac magnetic resonance imaging (CMR). Seventy percent of males with DMD have mothers who are carriers of the Xp21 mutation. Carrier phenotypic characteristics range from asymptomatic to left ventricular (LV) dysfunction and cardiomyopathy. The true prevalence of cardiac involvement in DMD carriers is unknown. We performed a retrospective observational study. All female DMD carriers who underwent clinical CMR studies at Cincinnati Children’s Hospital Medical Center from December 6, 2006, to August 28, 2013, were evaluated. Patients underwent standard CMR assessment with LV function assessment and late gadolinium enhancement (LGE). In addition, offline feature tracking strain analysis was performed on the basal, mid, and apical short axis. Twenty-two patients were studied, of which 20 underwent adequate testing for myocardial LGE. Four of 22 patients (18 %) were found to have LV dysfunction (ejection fraction \55 %). Seven of 20 DMD carriers (35 %) were
S.M. Lang and S. Shugh contributed equally to this manuscript. & Sean M. Lang [email protected] 1
Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, 1 Children’s Way, Little Rock, AR, USA
2
The Heart Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA
3
The Ohio Heart and Vascular Center at The Christ Hospital, 2123 Auburn Ave, Suite 138, Cincinnati, OH, USA
4
Department of Radiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA
found to have LGE. The patients with evidence of LGE had an overall trend to lower absolute deformation parameters; however, this did not meet statistical significance when correcting for multiple comparisons. Our study demonstrates a high rate of LGE as well as LV dysfunction in DMD carriers. Cardiovascular and musculoskeletal symptoms were not statistically different between those with and without cardiac involvement. This study demonstrates the importance of surveillance CMR evaluation of DMD carriers. Keywords Late gadolinium enhancement Cardiomyopathy Feature tracking Myocardial strain Abbreviations AAP American Academy of Pediatrics ACE Angiotensin-converting enzyme CMR Cardiac magnetic resonance DMD Duchenne muscular dystrophy EF Ejection fraction FT Feature tracking Gd-DTPA Gadolinium diethylene triamine penta-acetic acid LGE Late gadolinium enhancement LV Left ventricle SSFP Steady-state free precession
Introduction Duchenne muscular dystrophy (DMD) is a genetic condition occurring in one of every 3500 live male births [5, 9]. It is caused by a mutation in Xp21 that results in a lack of
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Pediatr Cardiol
dystrophin production [5, 9, 19]. About 70 % of males with DMD have mothers who are carriers of the Xp21 mutation [5, 9]. Due to random X chromosome inactivation, female DMD carriers may be asymptomatic or may develop neuromuscular or cardiovascular sequelae similar to DMD [5, 9, 17]. It has been estimated that 10 % of DMD carriers develop cardiomyopathy; however, the prevalence of more occult cardiac involvement is unclear [1, 23]. Cardiac magnetic resonance (CMR) has been used in the DMD population to diagnose occult cardiac dysfunction and myocardial fibrosis [12, 24, 26]. Previously, the description of cardiac involvement in DMD carriers has been limited to echocardiography studies, CMR case reports, and a single institution’s CMR experience [11, 17, 21, 23, 25, 27]. The goal of our study was to characterize cardiac involvement in a cohort of DMD carriers. To assess cardiac involvement, we evaluated global LV function (LV ejection fraction), LV deformation (circumferential strain, systolic strain rate, and early diastolic strain rate), and myocardial fibrosis burden using late gadolinium enhancement (LGE).
Materials and Methods This retrospective study was approved by the Institutional Review Board (IRB) at Cincinnati Children’s Hospital Medical Center. Data were analyzed from the records of DMD female carriers who underwent clinical CMR studies at Cincinnati Children’s Hospital Medical Center between December 6, 2006, and August 28, 2013. The diagnosis of carrier status was confirmed by genetic testing. Chart reviews were performed on each patient to obtain prior medications, comorbidities, and complaints of musculoskeletal and cardiac symptoms. Cardiac MRI studies were conducted on a Philips 1.5 T Ingenia or 3.0 T Achieva Platform (Philips Healthcare, Eindhoven, the Netherlands). Cardiac functional imaging was performed using a retrospective electrocardiogram (EKG) gated, segmented k-space, steady-state free precession (SSFP) pulse sequence. Subjects were breath-held for all sequences. Standard imaging included a short axis stack of cine SSFP images from cardiac base to apex; the short axis was prescribed as the perpendicular plane to the LV long axis in two- and four-chamber views as previously described [18, 20]. Typical scan parameters included 6 mm slice thickness; no interslice gap; temporal resolution 30 ms/phase; TE 1.9 ms; and TR 2.6–3.7 ms. Myocardial LGE was performed using a segmented k-space gradient echo inversion sequence recovery pulse sequence 10 min after 0.2 mmol/kg of gadolinium diethylene triamine penta-acetic acid (Gd-DTPA) injection
123
[24, 26]. LGE imaging was considered positive if any area of the subepicardium or myocardium demonstrated enhancement in two orthogonal views (Fig. 1). The location of LGE was described according to the American Heart Association 16-segment model [4]. Ventricular volumes, mass, and ejection fraction were assessed via standard planimetry with semiautomated contour software (QMASS version 7.5, Medis Medical Imaging Systems, Leiden, the Netherlands). LV dysfunction was defined as a LV ejection fraction of \55 %. Feature tracking strain analysis (FT) was performed using Diogenes CMR FT software (TomTec Imaging Systems, Munich, Germany). Cine basal, mid, and apical short axis SSFP images were used. Epicardial and endocardial borders were manually traced at end-diastole. The software uses a vector-based analysis algorithm to propagate the contours by feature tracking throughout the cardiac cycle [13]. The temporal feature tracking allows calculation of circumferential strain, systolic strain rate, and early diastolic strain rate (Figs. 2, 3). Each contour was assessed for appropriate tracking. Contours were excluded from analysis if tracking was unstable after three attempts. Data are expressed as mean ± standard deviation. Comparisons in LV global function and deformation parameters were made using a two-sample unpaired t test, between groups with LGE and those without. Comparisons between the groups with regard to cardiovascular and musculoskeletal symptoms, and positive remodeling medication use were made using Fisher’s exact test. A p value of\0.05 was deemed statistically significant. The Bonferroni correction was performed when evaluating the multiple-comparison deformation parameters. There were nine multiple comparisons; therefore, a p value of 0.006 was deemed significant with regard to deformation parameters.
Results Clinical and CMR data for each individual patient are shown in Table 1. Patient demographics are shown in Table 2. Mean age was 40.9 years with a range of 13.2–60.0 years. Eleven of the 22 patients reported possible cardiovascular symptoms including chest pain, palpitations, and shortness of breath. Two of the 22 patients reported musculoskeletal symptoms (one patient was wheelchair bound, another patient reported hip and lowerback weakness). Only two out of the 22 patients (9 %) were receiving cardiac medications (one patient on an angiotensin-converting enzyme (ACE) inhibitor for hypertension, one patient on a beta-blocker for palpitations). Based on CMR evaluation, four of 22 patients (18 %) were diagnosed with LV dysfunction. Twenty of the 22 patients underwent adequate testing for LGE. One patient
Pediatr Cardiol Fig. 1 Late gadolinium enhancement (LGE) images. a Three-chamber left ventricular LGE image. There is subepicardial evidence of LGE in the basal and mid inferolateral segments. b Basal short axis LGE image. There is evidence of LGE in the basal inferolateral segment
Fig. 2 Circumferential strain analysis curves. Basal strain curves for an individual patient. Each separate line represents the different basal segments based on the 16-segment heart model (*peak average circumferential strain, ms milliseconds)
Fig. 3 Circumferential strain rate analysis curves. Basal strain rate curves for an individual patient. Each separate line represents a different basal segment based on the 16-segment heart model (s seconds, ms milliseconds, Sys SR peak systolic strain rate, Dias SR peak early diastolic strain rate)
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Pediatr Cardiol Table 1 Patient clinical and CMR data Carrier
Age (yrs)
Symptoms
Cardiac medications
LV EF (%)
LGE
1
47
Palpitations
Atenolol
68
No
2
33
Frequent chest pain and palpitations
Lisinopril
49
Yes
3
41
Palpitations
No
64
No
4
39
Syncopal episodes
No
62
No
5
13
Muscle weakness, wheelchair bound
No
62
No
6
27
Palpitations
No
67
No
7
43
Occasional shortness of breath, previous mitral valve surgery secondary to mitral valve prolapse
No
63
No
8
42
Intermittent dull chest pain
No
62
No
9
59
N/Aa
N/Aa
64
No
10
28
Palpitations
No
67
No
11
37
Weak hips and lower back
No
59
No
12
41
Non-exertional chest pain
No
62
No
13
37
None
No
67
No
14
43
Intermittent chest pain
No
51
Yes
15
47
None
No
59
No
16
44
Shortness of breath on exertion
No
62
No
17
45
None
No
60
N/Ab
18 19
42 45
None Shortness of breath on exertion, palpitations
No No
57 48
Yes N/Ac
20
39
None
No
62
Yes
21
44
None
No
65
No
22
56
None
No
53
Yes
Patients’ symptoms and medication history obtain via chart review. CMR indicates cardiac magnetic resonance imaging yrs years, EF ejection fraction, LGE late gadolinium enhancement, N/A not available a
No clinic documentation available for this patient prior to CMR
b
Patient unable to complete full study secondary to anxiety
c
LGE images of insufficient quality to determine fibrosis
had insufficient image quality to assess LGE, while the other patient was unable to tolerate that portion of the examination due to anxiety. Seven of 20 patients (35 %) were found to have LGE. Mean age of patients with LGE was 43.4 years with a range of 33–56 years. The most commonly affected segments were the mid ventricular inferolateral segment (segment 11)—6 patients, and the basal inferolateral segment (segment 5)—5 patients (Table 3). The average number of LGE-positive segments was 3.4, ranging from 1 to 7 segments involved. Two out of the 22 patients (9 %) had inadequate images with regard to feature tracking analysis. Table 4 shows the difference between the patients with LGE and those without. When compared to patients without LGE, the LGE? group had statistically significant lower left ventricular ejection fraction. The LGE? group also had an overall trend to lower absolute deformation parameters; however, with correcting for multiple comparisons, statistical significance was not reached. Box plots are shown in Fig. 4.
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Discussion The principle finding of this study was the high prevalence of LGE in female DMD carriers (35 % of patients evaluated with Gd-DTPA). Four of the seven patients with LGE had normal LV function, representing occult cardiac involvement. As previously described in the DMD population, LGE presents often before cardiac dysfunction [12, 24]. Furthering this point, comparing patients with and without LGE, there was no statistical difference between those reporting cardiac symptoms and those with muscle involvement. These results highlight the importance of surveillance for the patient population. The American Academy of Pediatrics (AAP) estimates 10 % of DMD carriers will progress to overt cardiomyopathy [1]. Despite this concern, there remains a lack of compliance with the AAP recommendations for routine follow-up. Surveys estimated that only 62.9 % of DMD carriers recognize the risk of
Pediatr Cardiol Table 2 Baseline characteristics (n = 22) Age (yrs)
40.9 (± 9.71)
Symptoms Cardiovascular
11 (50)
Musculoskeletal
2 (9)
Positive remodeling medications
2 (9)
Comorbid conditions Anxiety/depression
5 (23)
Dyslipidemia
4 (18)
Hypothyroidism
2 (9)
Obesity
1 (5)
Hypertension
1 (5)
Mitral valve prolapse/s/p repair
1 (5)
Values presented are means (SD) or n (%) yrs years
Table 3 Segments of LGE
Segment
n (%)
4
1 (14)
5
5 (71)
6
3 (43)
10
2 (29)
11
6 (86)
12
3 (43)
13
1 (14)
16
1 (14)
Segment numbers according to American Heart Association 16-segment model
cardiomyopathy, 64.4 % have ever undergone any form of cardiac testing, and 18.3 % have seen a cardiologist over the last year [3]. The AAP currently recommends treating DMD carriers with evidence of cardiac involvement similar to DMD males [1]. In DMD patients exhibiting signs of cardiomyopathy, numerous studies have shown the benefit of implementing ACE inhibitors alone or in combination with beta-blockers. These medications have been shown to improve subjective symptoms and delay the progression of cardiomyopathy and ultimately heart failure [6, 7, 14, 15, 25]. The benefit of early detection of cardiac involvement can also be supported from observations in murine models. In a DMD mouse model, those treated earlier with lisinopril and spironolactone demonstrated less cardiomyocyte damage and improved myocardial strain [22]. In our patients with documented LGE and/or LV dysfunction, only two of the eight patients were currently being treated with a positive remodeling medication, prior to undergoing CMR. A prior letter to the editor from Mavrogeni et al. demonstrated a majority of their cohort of Duchenne carriers (18/25 patients) had evidence of LGE [17]. That group’s description also had a relatively small cohort. In comparison, our patient cohort represents a younger group with a mean of 40.9 years and range of 13–60 years, compared to a median of 48 years with a range of 33–65 years. As this is a progressive disease, the difference in ages may explain the difference in LGE prevalence. Our work and that of Mavrogeni highlight the importance of a larger multi-institutional investigation to determine the true prevalence of cardiac involvement in DMD carriers. Larger studies with wider age ranges will also be important to help guide the proper age of surveillance. Our
Table 4 Comparison of LGE? versus LGE- patients
LGE? N = 7
LGE- N = 13
p
Age (mean ± SD)
43.4 yrs (±7.1)
38.9 (±9.8)
0.293
CV symptoms
4
7
NS
MSK symptoms
0
2
NS
Positive remodeling medications
1
1
NS
LV EF (%)
56.2 (±5.3)
64.0 (±2.7)
0.007
Basal circumferential strain (%)
-21.57 (±3.1)
-25.37 (±4.24)
0.050
Mid circumferential strain (%)
-18.81 (±2.7)
-22.38 (±2.95)
0.025
Apical circumferential strain (%)
-23.90 (±4.58)
-26.64 (±6.00)
0.301
Basal systolic strain rate (s-1)
-1.13 (±0.22)
-1.38 (±0.23)
0.048
Mid systolic strain rate (s-1)
-1.06 (±0.23)
-1.30 (±0.19)
0.057
-1.35 (±0.23) 1.45 (±0.28)
-1.69 (±0.49) 1.79 (±0.42)
0.059 0.062
Mid early diastolic strain rate (s-1)
1.16 (±0.29)
1.41 (±0.33)
0.128
Apical early diastolic strain rate (s-1)
1.69 (±0.46)
2.12 (±0.97)
0.212
-1
Apical systolic strain rate (s ) Basal early diastolic strain rate (s-1)
Values presented are means (SD) EF ejection fraction
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Pediatr Cardiol Fig. 4 LGE? versus LGEbox plots. Box plots comparing those with and without late gadolinium enhancement. The first and third quartiles are represented by the ends of the box. The median is marked by the horizontal line inside the box. The outer lines represent the maximum and minimum values. p values were obtained using two-sample unpaired t tests. (LGE? evidence of late gadolinium enhancement, LGE- no evidence of late gadolinium enhancement)
results are in agreement with the AAP recommendations of surveillance beginning at 25–30 years of age [1]. The youngest patient in our group with LGE was 33 years old; however, we only evaluated three younger carriers (13, 27, and 28 years old). Our study also investigated the use of deformation parameters in DMD carriers. Circumferential strain, systolic strain rate, and early diastolic strain rate have been recognized as an advantageous tool in the evaluation of patients with heart failure of different etiologies [8]. Systolic strain rate and early diastolic strain rate are sensitive measures for myocardial contraction and relaxation [8, 10]. As an entire cohort, our strain indices were comparable to historical controls [2, 16]. These results are in keeping with the wide phenotypic range of cardiovascular symptoms in DMD carriers with a significant proportion of asymptomatic patients. Despite an overall trend toward lower absolute deformation parameters in patients with LGE, statistical significance was not reached correcting for multiple comparisons. Prior work by our group in DMD patients has shown abnormal mid ventricular circumferential strain despite normal ejection fraction [12]. Larger investigation will be required in the carrier population to determine whether deformation analysis can aid in uncovering occult cardiac involvement.
123
This study is limited by being retrospective in nature. There was the possibility for selection bias in those DMD carriers referred for CMR. However, given the percentage of patients with LGE and normal LV function, it is unknown whether the selection bias underestimates or overestimates the actual prevalence of LGE in DMD carriers. In addition, this was a relatively small cohort without power to reach statistical significance when analyzing deformation parameters in LGE-positive patients. Lastly, this study was cross-sectional in nature, and longitudinal analysis was not performed. Acknowledgments ing interests.
The authors declare that they have no compet-
Conflict of interest
No conflicts to disclose.
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