Duchenne muscular dystrophy (DMD) is a clinically common X-linked recessive myopathy, with an incidence in live male infants of approximately 1/3500–1/5000 [1, 2]. Most children with DMD begin to exhibit abnormal gait at 3–4 years of age, gradually lose their walking ability at 10–12 years and die of circulatory and respiratory failure at 18–20 years of age [3, 4]. With improvements in care and multidisciplinary treatment, the lifespan of DMD patients has been markedly prolonged, which has caused a shift in the leading cause of death in DMD patients from respiratory failure to heart failure [5]. Previous study has showed that the subendocardial dysfunction of left ventricular (LV) such as altered LV strain occurred as early as in the age of 3 years and some variants in the DMD encoding the cytoskeletal protein and dystrophin could cause a severe cardiomyopathy in the early phase [6]. Despite differences among LV dysfunctional indexes, left ventricular ejection fraction (LVEF) still remained a cornerstone of conducting therapeutic decisions that are related to myocardial performance in most clinical disease [7, 8]. Thus, it is essential to detect reduced LV systolic dysfunction in DMD patients for further improving the care and treatment of dystrophin-deficient cardiomyopathy.

Recent studies have demonstrated that electrocardiogram (ECG), which consists of general ECG and vectorcardiogram (VCG), retains an extremely powerful role in the assessment of patients with reduced LV systolic dysfunction [9]. Similarity, accumulating evidences have also demonstrated that ECG can be used to diagnose arrhythmia and preliminarily assess the scope of myocardial damage in children with suspected DMD, which provide important clues for clinicians to confirm the disease and judge prognosis [10]. However, ECG describes the cardiac signal as amplitude but not the orientation of the heart vector direction. Therefore, a mild, or even moderate degree of LV systolic dysfunction may not necessarily result in noticeable changes in the ECG. In addition, as our previous review suggested [11], almost all current studies focused on the characteristics of conventional ECG, data regarding VCG recordings in DMD patients were lacking.

VCG is the methodological elaboration of the ECG, which measures the dynamic cardiac electrical field with both the magnitude and vector direction. The VCG could improve the performance of ECG-based myocardial ischemia detection by affording temporal-spatial characteristics related to myocardial ischemia and capturing subtle changes in ST-T segment in continuous cardiac cycles [12]. Additionally, both the sagittal and frontal QRS-T angle not only have prognostic values on development of cardiovascular events but also have implications on cardiac functional performance. In addition, the spatial QRS maximum magnitude and area of QRS loop were also used to evaluate the degree of myocardial damage [13, 14, 15, 16, 17]. However, the prognostic value of VCG indices for decreased LVEF of DMD have never been reported.

Therefore, the purpose of the current study was (1) to uncover the VCG features in a large DMD population with broad age range; (2) to explore the predictive values of VCG parameters in occurrence of decreased LVEF in DMD within small age span.

To our knowledge, this is the first study to describe the VCG recordings in a large population with a wide age range in DMD boys around the world. Among 486 VCGs, we comprehensively analyzed the trend of VCG parameters of DMD patients compared with age-matched children across the different age span. The result shows that DMD patients already have marked abnormal right ventricular changes, which manifested as a higher R wave in lead V1, higher QRS loop percentage in the right anterior quadrant in the horizontal plane as well as QRS loop percentage in the superior anterior quadrant in the sagittal plane in VCG than normal children as early as before 5 years old.

Given the nature of progressive cardiac muscle damage of DMD, ECG abnormalities may be an early manifestation of dystrophin deficiency in contracting and/or electrically active cardiomyocytes [11]. In the study of James [10], who enrolled seventy-eight DMD patients who are less than 6 years of age, the result showed that 22% demonstrating R $>$98th percentile in lead V1. In the study of Girija [22], who enrolled ECGs from 252 patients with DMD (2–21 years) and ECGs from 151 age-matched healthy controls, the result found that taller R wave in V1 were significantly seen across all age group of DMD in comparison to controls. In another cross-sectional study including patients ranging in 5 to 11 years and found that 64% have a tall R wave over V1 with an abnormal R/S ratio [23]. The above findings were similar with our study that higher R wave on V1 get noticed starting from small age group. It is true that distinctive ECG pattern associated with DMD results from multifocal degenerative changes involving myocardium, predominantly the posterobasal region of the left ventricle and the posterior papillary muscle at the early stage of the disease [24]. With the increasing age of DMD boys, whose progressive cardiac dysfunction such as early LV fibrosis, LV enlargement, increased LV diastolic function and the scoliosis, lower respiratory function as well as secondary pulmonary hypertension due to hypohyoxemia would make the right ventricle be secondary hypertrophy [25]. Therefore, considering the concept that ECG abnormalities predate the development of overt hypertrophy or damaged function, the higher RV1 might be alerted that possible earlier complication with the diagnosis of secondary right ventricle hypertrophy (RVH) and involved LV dysfunction than we anticipated, and thus when the ECG of RVH path appear in routine follow-up and closer monitor is needed.

Furthermore, the association of VCG signals has never been explored with LV systolic dysfunction characterized with LVEF. We firstly prospectively enrolled 75 DMD patients with normal LVEF and explored the possible VCG risk factors of rapid deterioration of LVEF in those patients in 1 year follow up CMR. The major finding of this study is that in DMD patients, a higher QRS loop percentage in the superior anterior quadrant in the sagittal plane was significantly independently correlated with the reduced LVEF, with 53.3% and specificity of 88.3% for detecting abnormality associated with LVEF in boys with DMD, and most importantly, R wave in V1 or R/S ratio in V1 did not show a significant predictive ability between the LVEF 55% and LVEF $>$55% groups, which suggest that VCG might be more sensitive when evaluating LVEF. Therefore, the present study added new finding that higher QRS loop percentage in the superior anterior quadrant in the sagittal plane could be not specific but might be early markers of cardiac dysfunction.

In addition, our results firstly demonstrated that cardiac injury-induced early changes can be reflected in the VCG before the age of 5 years, and this abnormal performance might significantly develop with an increasing age. Overlapped evidence suggest that myocardial damage might be slowly progressive in small age group of DMD [10]. However, for these small age span, most were treated only with steroids, which could not prevent progression of the cardiac impairment. Previous evidence-based studies providing that angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers, beta-blockers and/or aldosterone antagonists might improve or preserve left ventricular systolic function and may delay the progression of cardiomyopathy [26, 27, 28, 29, 30, 31]. Actually, several types of treatment such as ACEI, beta-blockers, aldosterone antagonists, combination ACEI + beta-blockers, and aldosterone antagonists plus ACEI + beta-blockers treatments, for DMD-associated cardiac dysfunction are now available for exploring the effectiveness on LV dysfunction [32]. Though it is uncertain whether it is preferable to prophylactically treat asymptomatic patients with normal or nearly normal LV function, some of studies have reported that cohorts with younger patients with reduced LVEF had the most cardiac improvement following therapy [27, 31]. However, lack of standardization such as medication, dose, duration of treatment, differing patient ages, symptomatology, cohort size, study duration as well as baseline heart function limits the comparability of the studies and complicates assessment of the primary cardiac therapies under investigation. In addition, the newly demonstrated cardiac protective drug derived from adult such as sacubitril/valsartan, dapagliflozin as well as ivabradine have been also suggested might be effective in children with heart failure or cardiomyopathy [33, 34, 35], however, larger studies are needed to evaluate safety and efficacy of these drugs in this population. Most importantly, though the above-mentioned cardiac therapy might do suggest effective for improving the quality of life in children with symptomatic patients or in reduced LVEF, considering the pathogenesis of DMD, therapies to restore or augment dystrophin, as well as therapies that act downstream of dystrophin, may be more promising options for preserving cardiac function than standard heart failure drugs [32].

Until now, most diagnostic standard of cardiac dysfunction was relied on CMR, the price and risk of sedation as well as age span limited the small age group to perform it. And since the VCG represents magnitude, direction and the polarity of the instantaneous cardiomyocyte, the more sensitive and probable that VCG might be to show and to find cardiac abnormal demonstration. Therefore, the easily performed, good price as well as no-limited age of VCG make it possible to evaluate the cardiac function of small age group. Therefore, a larger and prospective cohort on the effects of the cardiac therapy in small age span with preserved left ventricular function is expected to explore in the future.

The strengths of this study were its prospective design and relatively large sample size. However, the present study has several limitations. Firstly, this study was performed at a single institution, which could be seen as a limitation or a strength as it facilitated VCG interpretation. Secondly, since one of the purposes was to define the natural history of electrical evolution in the DMD population; future studies should focus on electrical correlations with different drug intervention and genotype-phenotype correlations in a large cohort. In addition, though some of VCG morphology features have been shown to be sensitive and specific for possible cardiac disease in this study, clinically promising and widespread study of VCG measurements has been limited because they require additional computer processing and specialized software, which can be time consuming to develop and test because variations in filtering, signal baseline definition, and signal processing preclude the direct comparison of measurements. Nevertheless, the artificial intelligence VCG algorithms as well as innovative, mobile-ECG technology have made electrical data more convenient. A larger, prospective study is needed to validate the clinical importance of these VCG morphology descriptors. Despite these limitations, this study is based on the establishment of relatively large sample prospective study cohort, prospectively combined with VCG and CMR technology to systematically evaluate cardiac function in children with DMD, analyzed the relationship between electrical abnormalities and cardiac function under different age spans, explore the 3D-electrical indicators that could change before the DMD associated cardiac disease.

Our study firstly showed that QRS loop percentage in the superior anterior quadrant in the sagittal plane and QRS loop percentage in the superior anterior quadrant in the sagittal plane could be abnormal in DMD boys as early as before 5 years old. In addition, the value of QRS loop percentage in the superior anterior quadrant in the sagittal plane in predicting declined LVEF were also firstly reported and depicted. Evaluation of the myocardium by VCG in early age to predict the presence of possible cardiac systolic dysfunction may have important implications for the ongoing management of DMD boys.

DMD, Duchenne muscular dystrophy; ECG, electrocardiogram; CMR, cardiac magnetic resonance; VCG, vectorcardiogram; LGE, late gadolinium enhancement; LGE+, late gadolinium enhancement positive; LGE–, late gadolinium enhancement negative; ROC, receiver operating characteristic; LVEF, left ventricular ejection fraction; RVH, right ventricular hypertrophy; LV, left ventricular; RV, right ventricular; MRI, magnetic resonance imaging; ACEI, angiotensin converting enzyme inhibitors.

Data generated or analyzed during this study are included in this published article.

YC, SS and LZ reviewed the literatures and drafted the manuscript. LT and PX participated in the collection of patient baseline data. LW, YH and HD participated the analysis of the study; CW, KZ and XC designed the research study and revised the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Informed written consent was obtained from the parents of DMD patients after the nature of this study had been fully explained to them. The study was approved by the University Ethics Committee on Human Subjects at Sichuan University (2010002).

Not applicable.

This work was supported by Science-Technology Support Plan Projects in Sichuan Province (2023ZYD0119, 2023YFH0036) and National Natural Science Foundation of China (No. 82370236, No. 82070324).

The authors declare no conflict of interest.