The prevalence and associated factors of myocardial involvement in Duchenne muscular dystrophy patients in the first decade of life.

Abstract

To the Editor: Duchenne muscular dystrophy (DMD) is a rare X-linked inherited disorder caused by dystrophin deficiency, which results in sarcolemmal fragility and degeneration of skeletal and cardiac myocytes.[1] Cardiac involvement is manifested as DMD cardiomyopathy, which is the leading cause of disease-related morbidity and mortality among DMD patients.[2] However, the signs and symptoms of cardiomyopathy frequently are subtle and often overlooked during the ambulatory and early non-ambulatory stages. Therefore, non-invasive imaging methods are recommended for the assessment of myocardial involvement of DMD patients in the updated diagnosis and management statement, and echocardiography (Echo) and cardiac magnetic resonance (CMR) are two of the most commonly used imaging methods.[3] However, conventional Echo cannot evaluate the characteristics of myocardial tissue and has a limited role in early diagnosis. CMR with multiple sequences and parameters allows detailed feature evaluation, and especially the evaluation of myocardial fibrosis by late gadolinium enhancement (LGE) is highly consistent with pathology. Previous studies have reported the assessment of myocardial fibrosis in DMD patients by LGE,[4,5] but studies investigating the prevalence of myocardial fibrosis in DMD patients during the first decade of life is still lacking. Moreover, DMD is a multisystem disease, loss of dystrophy protein function could occur in skeletal muscle and cardiomyocytes. In practice, individuals with DMD start skeletal muscle management early but are not referred to a cardiac specialist until late in the disease. Therefore, it is important to clarify the association between skeletal muscle involvement and myocardial involvement in the early stages of disease, which may help clinicians start multidisciplinary management earlier and improve the quality of life of patients further. In the currently study, the prevalence of LGE presence at the first decade life of DMD patients was described. Logistic regression analysis was used to determine the association factors of LGE presence. In this prospective study, 115 consecutive DMD patients were diagnosed by a skeletal muscle biopsy showing absent dystrophin and/or DNA analysis demonstrating a characteristic dystrophin mutation. All patients were boys, aged 3 to 10 years old and were screened between January 2018 and December 2020 in the West China Second University Hospital. The study was approved by the Institutional Review Board of the institute and registered on the clinical trials database (NCT: ChiCTR1800018340). Before patient enrollment, written informed consent to participate was obtained from the child's parent or guardian. Baseline clinical characteristics including age, height, weight, skeletal muscle characteristics, Echo, biomarkers of skeletal muscle and myocardial injury, and treatment in all patients were recorded. Cardiac and hip magnetic resonance imaging (MRI) examinations were performed in all patients using a 3.0 T scanner (Magnetom Skyra, Siemens Healthcare, Erlangen, Germany) with a standard scanning protocol. All patients underwent cine imaging and LGE imaging scans for the assessment of cardiac function and myocardial involvement, respectively. CMR analysis was performed using commercially available software (CVI 42, Calgary, Canada). Left ventricular (LV) functional parameters included volume; myocardial mass (MASS) and ejection fraction (EF) were assessed from the cine images. The presence of LGE (LGE positive) was considered direct evidence of myocardial involvement and documented as LGE (+); patients presented with LGE negative were documented as LGE (−). Hip and thigh MRIs were performed before the CMR scan on the same day. T1-weighted spin-echo axial imaging scans were performed to assess skeletal muscle fat score. The degree of single muscle involvement in patients with DMD was scored with a five-grade scale, and the total points were the sum of 13 muscle points; the higher the total score, the more severe the muscle fatty infiltration. The schematic diagram of different muscle fat infiltration scores is shown in Supplementary Figure 1, https://links.lww.com/CM9/B174. Continuous variables were compared among the different groups using the independent sample test, whereas categorical variables were compared using the Wilcoxon two-sample test/Fisher's exact test. Logistic regression analyses were applied to explore the association between LGE presence with other covariates, including age, body mass index (BMI), glucocorticoid use, LV function, and hip/thigh muscle fatty infiltration score. Statistical analysis and visual presentation were performed using SPSS software for Windows (version 22.0, SPSS, Chicago, IL, USA) and R software (version 4.0.2; https://www.r-project.org/). All tests were two-sided, and P values < 0.05 were considered statistically significant. All clinical characteristics are summarized in Supplementary Table 1, https://links.lww.com/CM9/B174. The median age of the study cohort was 8 (interquartile range: 7–9) years old. All patients had a structurally normal heart on 2D-Echo, but there were 26 (22.6%) patients who presented with LGE (+) on CMR imaging. The LGE (+) patients (56.1 ± 8.4%) had significantly lower EF than LGE (−) patients (60.4 ± 6.1%). The prevalence of LGE presence by age is shown in Figure 1A. No LGE (+) was found in patients <6 years old. The prevalence of LGE (+) increased to 17% between 7 and 8 years old, and there was a similar prevalence of LGE (+) between 9 and 10 years old (47.6% vs. 45.5%). The LGE extent was less than 5% before 8 years old in these DMD patients, but the LGE extent was clearly increased at 9 years old (12.2%).Figure 1: (A) The prevalence of LGE presence in different ages. The prevalence of LGE presence gradually increased after 7 years old. (B) The total point of skeletal muscle fatty score in different ages. The skeletal muscle fatty infiltration gradually increased after 4 years old. (C) The association of skeletal muscle fatty infiltration and myocardial LGE presence. BMI: Body mass index; EDV: End diastolic volume; ESV: End systolic volume; GC: Glucocorticoid; LGE: Late Gadolinium enhanced; LVEF: Left ventricular ejection fraction.The details of hip/thigh muscle fatty score are shown in Supplementary Table 2, https://links.lww.com/CM9/B174. The total muscle fat score was 14 ± 9 points, and it was significantly higher in LGE (+) patients compared with LGE (−) patients (22 ± 9 vs. 12 ± 8, P < 0.001). In the patients who presented with LGE (+), the proportion of two points (19.5% vs. 13.6%), three points (12.4% vs. 8.9%), and four points (12.7% vs. 5.3%) were slightly higher than that of LGE (−) patients. The skeletal muscle fatty score by age is shown in Figure 1B. The skeletal muscle fatty infiltration gradually increased after four years old. The extent of LGE was positively correlated with age (r = 0.32) and muscle fatty score (r = 0.43, all P < 0.05). The association of clinical characteristics, cardiac function, fat score, and LGE presence are shown in Figure 1C. The EF (OR: 0.85, 95% CI: 0.78–0.92, P < 0.001) and fatty score (OR: 1.15, 95% CI: 1.05–1.25, P = 0.002) was associated with LGE presence. The age, BMI, Glucocorticoid time, MASS, end diastolic volume, end systolic volume had no statistically significant association with LGE presence (P > 0.05). This is a rare study with a large sample size that has investigated myocardial involvement in patients with DMD during the first decade of life. The findings highlight the association between myocardial and skeletal muscle involvement, and identified the associated factors of myocardial involvement during the early stage of DMD disease. Delayed diagnosis and intervention are the main reasons for poor outcomes in DMD patients. This study describes the prevalence of myocardial involvement in DMD patients during the first decade of life. Approximately 22% of patients presented as LGE (+) in the cohort, and the prevalence of LGE (+) increased gradually in patients >7 years old and the presence of LGE increased sharply in patients >8 years old. The results indicate that the first decade may be a critical period for the onset of LGE positivity in DMD patients and that increasing age is an important factor for the presence of LGE in DMD patients. Recommendations based on these finding are that clinicians should consider assessing myocardial involvement by CMR in the first decade. Dystrophin is a commonly found protein in skeletal muscle and cardiac myocytes, and skeletal muscle and myocardial involvement may be similar pathologic processes. In this study, the prevalence of LGE positive demonstrates a similar trend with that of the skeletal muscle fat score with increasing age, and the extent of LGE was positively correlated with skeletal muscle fat score. The results demonstrate further the early association between skeletal muscle and myocardial involvement. Progression of skeletal muscle weakness and cardiomyopathy caused by the total absence or structural impairment of the dystrophin protein may occur at a similar stage. The analysis revealed that the fatty score is associated with LGE presence. These results suggest that patients with more severe skeletal muscle involvement are at high risk of myocardial involvement. This implies that early initiation of coordinated management of skeletal muscle and the heart may be important. In conclusion, myocardial involvement could occur in the first decade life of DMD patients. LGE imaging is important for the early detection of myocardial involvement in DMD patients during the first decade, especially when the patient is older than 7 years. The skeletal muscle fat infiltration and LVEF were associated with myocardial involvement. The early detection would help clinicians initiate cardiac management early and may potentially improve long-term outcome. Acknowledgements We here would like to thank all the medical staff and researchers in the multidisciplinary collaborative team for Rare Diseases in the West China Second Hospital of Sichuan University for their continuous efforts to help more DMD patients improve their quality of life. Funding This work was supported by grants from Clinical research funding of Chinese society of cardiovascular disease (CSC) of 2019 (HFCSC2019B01); National Natural Science Foundation of China (82071874, 81971586, 81901712, 81771887, and 81771897) and Sichuan Science and Technology Program (2020YFS0050, 2020YJ0029, 2017TD0005, 21ZDYF1967), Fundamental Research Funds for the Central Universities (SCU2020D4132). Conflicts of interest None.