Cardiac involvement is the main cause of death in Becker muscular dystrophy (BMD). Identification of left ventricular (LV) function is crucial, but standard echocardiographic measurements such as LV ejection fraction (LVEF) might not be sensitive enough to detect early myocardial dysfunction. We explored the value of LV global longitudinal strain (GLS) as a more accurate echocardiographic parameter to detect and monitor LV dysfunction in BMD. Furthermore, we studied possible factors associated with LV dysfunction and progression. A total of 40 patients with BMD (age 39.0 ± 13.2 years) and 21 matched controls were included. Clinical variables, pulmonary tests, serum biomarkers, and echocardiograms were collected at baseline and after 2 years. LV systolic function was assessed by LVEF and LV GLS; a significant progression in LV dysfunction was defined as an absolute LV GLS deterioration ≥15%. Responsiveness to cardiac disease progression was determined using standardized response means. Patients showed impaired LVEF and LV GLS compared with controls (p <0.001). Of interest, 31 patients (77.5%) showed impaired LV GLS (defined as greater than −18%), whereas only 24 patients (60%) had reduced LVEF. LV GLS and LVEF correlated with troponin I (ρ = 0.553 and −0.523) and N-terminal pro-b-type natriuretic peptide (ρ = 0.506 and −0.585), but not with skeletal muscle or pulmonary function. At follow-up (2.0 ± 0.5 years, n = 29), LV GLS worsened significantly (−1.3 ± 0.8%, p = 0.002, standardized response mean = 0.70, annually = 0.60%), whereas LVEF remained stable. No risk factors for LV dysfunction progression were identified. In BMD, LV GLS is frequently impaired and shows deterioration over time compared with LVEF. LV GLS could be used as a more sensitive parameter to identify and monitor LV dysfunction.
Becker muscular dystrophy (BMD) is caused by inframe mutations in the DMD gene, resulting in slowly progressive skeletal muscle weakness. As heart failure is the main cause of death, close cardiac monitoring is of great importance. Conventional echocardiographic parameters, such as left ventricular (LV) ejection fraction (EF), are currently used as primary diagnostic tool to monitor LV function in BMD. The possible low sensitivity of LVEF to detect subtle myocardial dysfunction could, however, lead to underestimation of cardiac involvement and delay specific treatments because initiation of medication is suggested only in case of reduced LVEF. Advanced echocardiographic techniques, such as speckle tracking echocardiography (STE), may improve assessment of early myocardial involvement. Global longitudinal strain (GLS), quantified by STE, has been shown to be more sensitive and reproducible compared with LVEF and of significant prognostic value, , and it could detect early LV dysfunction (with preserved LVEF) in several diseases. In this study, we explored the value of LV GLS for detecting and monitoring LV systolic dysfunction compared with LVEF and LV volumes. We studied correlations with serum biomarkers and clinical and functional parameters and tried to identify baseline characteristics associated with a deterioration in LV GLS over time.
Methods
This study consisted of 2 patient populations. The first population consisted of patients with BMD recruited from the Dutch Dystrophinopathy Database in the 4-year prospective BMD natural history study that started in 2014 at the Leiden University Medical Center (LUMC). Inclusion criteria were male patients, aged 18 years or older, diagnosed with BMD based on genetic confirmation (inframe mutation), and/or on clinical phenotype (ambulant >16 years). Specific pathogenic variants are described in Supplementary Table 1 . The protocol included yearly 1-day visits with measurements of several clinical characteristics, pulmonary and skeletal muscle function tests, and venous blood sampling. Echocardiographic measurements were performed at baseline and at the third follow-up visit (thus with 2 years apart). The study was approved by the medical ethical committee. Written informed consent was obtained from all participants.
The second patient population consisted of retrospectively included patients aged 18 years or older, diagnosed with BMD based on genetic confirmation (inframe mutation) and/or on clinical phenotype (ambulant >16 years), and who had visited the outpatient clinic at the LUMC for regular follow-up. During these annual consultations, patients were seen by a neurologist, physiotherapist, and cardiologist among others. The 2 most recent echocardiograms were selected with, whenever available, approximately 2 years in between. Ethical approval was obtained from the medical ethical committee, and informed consent was waived for these patients. An age- and gender-matched control group with structural normal hearts and no cardiovascular disease or risk factors was selected from the echocardiography database at the cardiology department of the LUMC.
Data on age, body mass index, systolic blood pressure and diastolic blood pressure, cardiac medication use, medical history, and the presence of a cardiac device were recorded. Functional tests included the North Star Ambulatory Assessment (NSAA), 10-meter run/walk test velocity and 6-minute walk test and were performed as previously described. , Pulmonary function was measured 3 times using a handheld spirometer (Microloop, Carefusion, Hants, United Kingdom). The measurement with correct curves and the highest value was used for the analysis. High sensitivity cardiac troponin I was measured from the blood on the Abbott Architect c module, using the STAT High Sensitive troponin I reagents. N-terminal pro-b-type natriuretic peptide (NT-proBNP) was measured on the Roche Cobas 8000 (E602) using the Elecsys proBNP II reagents.
Commercially available ultrasound systems equipped with M5S transducers (Vivid-7 or E9 systems, General Electric Vingmed, Horten, Norway) were used to acquire 2-dimensional, color, continuous, and pulsed wave Doppler data from parasternal and apical views with the patient in the left lateral decubitus position. Images were stored digitally on hard disks for offline analysis (EchoPac version 202; GE Medical Systems). LV end-diastolic and end-systolic volumes were measured from the apical 2- and 4-chamber views using Simpson’s method and the LVEF was derived. LV mass was calculated and defined according to current recommendations and guidelines. Normal LVEF was defined as ≥52%.
LV GLS was measured by 2-dimensional STE with commercially available software (EchoPac version 202; GE Medical Systems). On the apical 3-, 4-, and 2-chamber views, the LV endocardial border was traced, and the software displayed a region of interest automatically encompassing the LV myocardial wall; if needed, the region of interest was adjusted manually. LV GLS was then calculated as the average of longitudinal strain values of each apical view, and a color-coded 17-segment bull’s eye plot was provided ( Figure 1 ). As currently recommended, LV GLS was considered as normal if less than −18%, and a substantial deterioration in LV GLS at follow-up was defined as a percentual change of ≥15% from the absolute baseline value, as previously proposed.
Results are presented as mean ± SD if normally distributed or median (interquartile range [IQR]) for non-normally distributed continuous variables. Categorical data are reported as frequency (percentage). Patients with BMD were compared with healthy controls using the independent samples t test or Mann-Whitney U test. Fisher’s exact test was used for the comparison of categorical variables. Correlations were made using Pearson or Spearman’s correlation coefficient. Differences between baseline and follow-up were assessed using the paired samples t test or Wilcoxon signed-rank test. Linear regression was used to calculate the deterioration in LV GLS per year using the difference in LV GLS and amount of time in years between baseline and follow-up. To identify potential baseline clinical characteristics and serum biomarkers associated with a substantial deterioration in LV GLS, univariate logistic regression analyses were performed. Standardized response means (SRMs) were calculated as the mean change between follow-up and baseline divided by the SD of the mean change. The SRM can be used to measure outcome measure responsiveness for hypothetical clinical trials. A variable with SRM 0.20 <0.50, 0.50 to 0.80, or ≥0.80 is considered to have small, moderate, or high responsiveness, respectively. SRMs were used to calculate the sample size of a clinical trial using Lehr’s formula as described by Morrow et al. In this calculation, we assumed a 50% slower disease progression over 24 months as a result of the hypothetical treatment, a power of 80%, and an α <0.05 in a 1:1 randomization. Statistical analysis was conducted using SPSS version 25.0 (IBM, Armonk, New York). Significance was set at 2-sided p ≤0.05 for all tests.
Results
A total of 36 patients participated in the BMD natural history study. Echocardiograms were not available for 2 patients, and 1 patient was excluded because of poor echocardiographic window. An addition of 7 patients had visited the LUMC outpatient clinic, leading to a total of 40 patients who were included in the baseline analysis. The control group consisted of 21 healthy men. Mean age, body mass index, blood pressure, and heart rate were comparable between the patients and healthy controls ( Table 1 ).
| Variable | Patients with BMD (n = 40 * ) | Controls (n = 21) | p value |
|---|---|---|---|
| Age (years) | 39.0 (13.2) | 43.2 (15.7) | 0.275 |
| BMI (m 2 /kg) | 24.3 (4.8) † | 23.6 (2.9) | 0.444 |
| SBP (mm Hg) | 121.6 (17.5) ‡ | 121.5 (13.5) | 0.958 |
| DBP (mm Hg) | 73.8 (9.4) ‡ | 75.8 (9.2) | 0.437 |
| HR (beats/min) | 77.0 (15.1) | 71.7 (13.4) | 0.280 |
| Implantable cardiac device | 5 (12.5%) | – | |
| Pacemaker | 1 (2.5%) | – | |
| Skeletal muscle function tests | |||
| NSAA (points), median + IQR | 16.0 (26) † | – | |
| 10-meter run/walk test (m/s), median + IQR | 1.0 (2.3) ‡ | – | |
| 6MWT (m), median + IQR | 343 (510) § | – | |
| Pulmonary function test | |||
| FEV1 (%) | 89.3 (18.7) § | – | |
| FVC (%) | 88.5 (20.4) § | – | |
| NT-proBNP (ng/L) | 139.9 (194.7) ∥ | – | |
| Troponin-I (ug/L) | 0.02 (0.01) ¶ | – | |
| Medication | |||
| ACEi/ARB | 23 (57.5%) | 0 | |
| Beta blockers | 10 (25%) | 0 | |
| Ca 2+ channel blocker | 2 (5%) | 0 | |
| Diuretics | 6 (15%) | 0 | |
| Oral anticoagulation | 6 (15%) | 0 | |
| Antiplatelet | 1 (2.5%) | 0 | |
| Steroids | 0 |
⁎ Applies to all variables unless otherwise stated.
† 4 patients with missing data.
‡ 6 patients with missing data.
§ 5 patients with missing data.
∥ 12 patients with missing data.
¶ 15 patients with missing data. 6MWT = 6-minute walk test; ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; BMD = Becker muscular dystrophy; BMI = body mass index; DBP = DBP = diastolic blood pressure; FEV1 = forced expiratory volume in 1 second percent of predicted value; FVC = forced vital capacity percent of predicted value; HR = heart rate; IQR = interquartile range; NSAA = North Star ambulatory assessment; SBP = systolic blood pressure.
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