Elsevier

International Journal of Cardiology

Volume 316, 1 October 2020, Pages 257-265
International Journal of Cardiology

Duchenne and Becker muscular dystrophy carriers: Evidence of cardiomyopathy by exercise and cardiac MRI testing

https://doi.org/10.1016/j.ijcard.2020.05.052Get rights and content

Highlights

  • Female carriers of DMD/BMD have a high prevalence of cardiac fibrosis by CMR.

  • Functional testing by treadmill was feasible in this muscular dystrophy group.

  • Functional treadmill results in carriers of DMD mutations were the same as controls.

  • RecVE, age, and serum CK levels were predictors of fibrosis by CMR.

  • Serum CK levels suggest global dystrophin levels are associated with cardiac fibrosis.

Abstract

Background

Varied detection methods have resulted in conflicting reports on the prevalence of cardiac disease in Duchenne and Becker muscular dystrophy carriers (MDC).

Methods

We performed a prospective cohort study of 77 genetically-confirmed MDC mothers, 22 non-carrier mothers, and 25 controls. All participants underwent Cardiopulmonary Exercise Testing (CPET) and Cardiac Magnetic Resonance imaging (CMR).

Results

25% of carriers had ventricular ectopy in recovery of exercise (RecVE) as compared to 1 non-carrier and no controls (p = .003). No difference in age or maximal oxygen consumption was noted. 11 carriers had abnormal (<55%) left ventricular ejection fraction by CMR. Evidence of late gadolinium enhancement (LGE) was noted in 48% of MDC, 1 non-carrier patient and no control subjects (p < .0001). Subset analysis of LGE+ and LGE- subjects revealed differences in age (44.1 v 38.6 yrs.; p = .005), presence of RecVE, (38.9% v 10.5%, p = .004), and high serum creatine kinase (CK) (> 289 U/l; 52.8% v 31.6%, p = .065).

Conclusion

We describe the prevalence of disease using CPET and CMR in genetically-proven MDC. 49% of carriers had fibrosis, opposed to 5% of non-carriers, highlighting the importance of genetic testing in this population. Despite cardiomyopathy, functional assessment by treadmill was normal, illustrating the discrepancy in cardiac and skeletal muscle impacts. Age, RecVE and serum CK appear to have an important role in predicting cardiomyopathy. Serum CK levels suggest that a systemic higher global disease severity and not tissue heterogeneity may be the etiology for greater cardiac disease and relatively spared skeletal muscle disease in this population.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT02972580?term=mendell&cond=Duchenne+Muscular+Dystrophy&rank=5; ClinicalTrials.gov Identifier: NCT02972580

Introduction

Duchenne and Becker muscular dystrophy are progressive neuromuscular diseases caused by mutations in the DMD gene, which encodes dystrophin [1]. Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy, seen in 1/5000 live births [2,3]. Manifestations of DMD in affected boys include profound progressive muscle weakness with loss of ambulation and the development of cardiomyopathy in early adolescence [4,5]. Becker muscular dystrophy (BMD) is less common, presenting in 1/19,000 live births. Dystrophic degeneration of muscle cells, reflected in serum creatine kinase (CK) levels, peak by age 6 years in DMD and 10–15 years in BMD patients [6,7]. BMD subjects generally have less severe disease, although the clinical spectrum of BMD is broad [8,9]. At present, boys with DMD have life expectances on average in their 20's. With improvements in respiratory support, steroid therapy, and respiratory care, cardiomyopathy is now the leading cause of death [[10], [11], [12], [13], [14], [15]].

In 70% of subjects with DMD, an identified DMD gene mutation is causative. In-frame mutations result in the BMD phenotype. The mutation is inherited in an X-linked recessive pattern from a maternal carrier. Fifty percent of the male offspring of female DMD mutation carriers will manifest a DMD phenotype while 50% of female offspring will be carriers. In 30% of DMD boys, the mutation is a de novo occurrence [16,17]. Female carriers should theoretically be spared from phenotypic disease given the presence of a normal DMD gene on their second X-chromosome; however, they have long been reported to demonstrate some manifestations of similar dystrophin-deficient disease. Muscle weakness, abnormal gait, fatigue and cardiac involvement have all been reported [18]. Additionally, there are overtly manifesting young female carriers who present with onset and progression of disease like affected boys that offer evidence of clinical impacts of having one abnormal gene [19]. Many studies describe a non-random X-chromosome inactivation pattern in some manifesting patients, which offers a genetic basis for this varied expression [20].

The mechanism of cardiomyopathy is an absence of functional dystrophin protein (DMD) or deficient levels of dystrophin (BMD). Dystrophin is a large protein, binding actin on the N-terminus and the extra-cellular matrix of the cell at the C-terminus. It functions to stabilize the plasma membrane by transmitting forces from the sarcomeric contraction to the extra-cellular matrix [21,22]. Without dystrophin, myocyte contraction results in membrane damage and fibrofatty replacement, resulting in cardiomyopathy [23,24]. This cardiomyopathy has been increasingly well-described by cardiac magnetic resonance imaging (CMR) for affected boys as a predictable pattern of subepicardial fibrosis [5,[25], [26], [27]] preceding a decrease in left ventricular ejection fraction (LVEF) [[28], [29], [30]]. However, prevalence and characterization of cardiomyopathy in female muscular dystrophy carriers (MDC) has thus far been incomplete. Few have included evaluation by CMR and varied detection methods have resulted in conflicting reports on the prevalence of cardiomyopathy in MDC [[31], [32], [33]]. Lang et al., reported a retrospective study on 22 genetically-confirmed DMD carriers (ages 13.2–60.0 years) utilizing traditional CMR measures, including LVEF and LGE status. They noted that 7/22 patients had LGE and 4/22 (18%) had LV dysfunction (LVEF <55%) [34]. CMR Native T1 mapping is a relatively novel technique to detect myocardial edema and diffuse fibrosis as evidence of occult cardiomyopathy [[35], [36], [37], [38], [39]]. Pre-contrast native T1 mapping for diffuse myocardial fibrosis in DMD boys has been reported to be abnormal and precedes LGE as well as global functional decline.40 T1 mapping has not been reported in DMD carriers.

In addition, studies thus far on the cardiac status of carriers have rested entirely on traditional imaging assessments, with reports of a dilated cardiomyopathy phenotype in a small fraction of patients. Interestingly, exercise stress testing has not been utilized in this population, despite evidence in large scale ischemic and non-ischemic heart failure studies that cardiopulmonary exercise testing (CPET) offers a robust method of prognostication for disease severity in heart failure. Measures of oxygen consumption (peak VO2) and regression slope relating minute ventilation to carbon dioxide output (VE/VCO2 slope) are metrics which are most directly related to outcomes in heart failure [41,42]. We sought to evaluate the prevalence of occult cardiomyopathy in genetically-confirmed MDC subjects using CPET and CMR, including native T1 mapping.

Section snippets

Subjects

Potential MDC subjects were prospectively recruited from a tertiary care muscular dystrophy clinic where their family member was clinically evaluated and from postings at ClinicalTrials.Gov and Parent Project Muscular Dystrophy's website. The study was approved by our institutional review board. Subjects could have no contraindication to CMR or CPET. Control patients were age-matched women from a volunteering cohort responding to an email solicitation sent to the employees at the same hospital.

Subject characteristics

Of the 77 carriers of a DMD mutation, the average age was 41.3 ± 8.5 years and did not differ from the non-carrier (40.6 ± 10.3 years) or control groups (42.9 ± 7.2 years). There were 117 Caucasian, 6 Asian, 1 Hispanic and 1 Middle Eastern subjects in the study. Of MDC subjects, 49% self-identified as having a “musculoskeletal disorder” along with 50% of non-carrier mothers (Table 1). Despite this, only 4 MDC and 1 non-carrier mom reported that exercise was limited by musculoskeletal complaints

Discussion

This study highlights the importance of genetic testing for mothers of boys with DMD/BMD as our data support that heterozygote DMD mutation conveys a risk for cardiac disease manifestations with 48% of MDC showing subepicardial LGE patterns. The decline in LVEF appears to trail the LGE findings, which is similar to affected males. The use of CMR allows early detection of fibrofatty replacement of myocardium, a pathognomonic finding of dystrophin-associated cardiomyopathy that occurs prior to

Conclusion

Based upon our work, we would advocate for genetic testing of all potential carriers of DMD mutations and for CMR in the cardiac evaluation of proven carriers of dystrophin mutations. Additional longitudinal studies are required to determine the predictive quality of cardiac fibrosis in this unique population. Of particular interest in our longitudinal assessments will be the false-positive subjects with RecVE but without fibrosis in our baseline CMR, in particular given evidence of diffuse

Funding

Parent Project Muscular Dystrophy, Hackensack, New Jersey.

The Heart Center, Nationwide Children's Hospital, Columbus Ohio.

Disclosures

Dr. Mah is an Advisory Board Member for Catabasis. Dr. Mendell is a consultant for AveXis, Inc. Sarepta Therapeutics, Exonics Therapeutics, and Myonexus Therapeutics. He has no investments in products that are under study. Dr. Al-Zaidy is a paid consultant for AveXis, Inc. Dr. Camino was employed at Nationwide Children's Hospital during collection of this data but now is an employee of Parent Project Muscular Dystrophy. Dr. Hor is a consultant for Medtronics and Catabasis as well as an Advisory

Acknowledgements

We would like to thank the many Nationwide Children's Hospital team members that supported the successful recruitment and execution of the longitudinal trial. Special thanks to Kathleen R. Church from the Center for Gene Therapy; Taylor Perdue, Ross Edwards, Heather Hermiller, Amy Tipton, Paula Woods, Angela Montgomery and Teresa Alley from Cardiac Imaging; Carine E. Leslie BS, Jennifer Cotto MS from the Center for Biobehavioral Health; Vidu Garg MD from The Heart Center and Ann Salvator, MS

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