Abstract
Duchenne and Becker muscular dystrophies are X-linked hereditary myopathies secondary to a dystrophinopathy resulting in progressive cardiomyopathy and heart failure. The most commonly associated cardiac involvements in these patients are dilated cardiomyopathy and conduction abnormalities; however, recent studies have shown a high prevalence of left ventricular noncompaction cardiomyopathy in patients with Duchenne muscular dystrophy. Furthermore, there is increasing awareness of cardiomyopathy in female heterozygous dystrophinopathy carriers. We report a case series of two dystrophinopathy carriers with the dilated form of left ventricular noncompaction cardiomyopathy, a newly identified association.
<Learning objective: Dystrophinopathy carriers can manifest cardiac disease in the form of cardiomyopathy. We present a novel finding of carriers who manifest their cardiomyopathy in the form of left ventricular noncompaction, dilated phenotype. This has been described previously in patients with Duchenne muscular dystrophy.>
Keywords: Duchenne muscular dystrophy, Becker muscular dystrophy, Dystrophinopathy, Left ventricular noncompaction
Introduction
Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked hereditary myopathies stemming from mutations in the dystrophin gene and result in inexorably progressive cardiomyopathy. Dilated cardiomyopathy and conduction abnormalities are the hallmark of cardiac involvement in this disease process; however, recent studies have shown a high prevalence of left ventricular noncompaction cardiomyopathy (LVNC) in patients with DMD as well 1, 2.
Female heterozygous dystrophinopathy carriers are known to be at risk for the development of cardiomyopathy, and thus ongoing surveillance in these patients is warranted [3]. In fact, the American Academy of Pediatrics issued recommendations in 2005 on the appropriate approach to female carriers including: education regarding the risk, complete evaluation in late adolescence or early adulthood, and reevaluation at least every 5 years thereafter [4].
We report a case series of two dystrophinopathy carriers with LVNC, a newly identified association. The aim of this case series is to heighten the awareness of LVNC in dystrophinopathy carriers, as this diagnosis may be missed. Additionally LVNC is a distinct cardiomyopathy and its diagnosis should lead to unique surveillance and treatment strategies in affected patients.
Case reports
Patient 1
Patient 1 is a 57-year-old female with duplication of exons 46–48 of the dystrophin gene. She underwent cardiac testing after knowledge of her carrier status. Holter monitor showed rare premature ventricular contractions (PVCs) and a single 6-beat episode of nonsustained ventricular tachycardia. Electrocardiogram was normal, with sinus rhythm at 60 beats per minute. Cardiac magnetic resonance imaging (CMR) revealed a mildly dilated left ventricle with mildly reduced left ventricular systolic function (ejection fraction 48%) as well as LVNC (Fig. 1, Videos 1 and 2). Additionally, late gadolinium enhancement was noted in basal inferolateral and anterolateral segments, and the mid ventricle inferior, inferolateral, and anterolateral and apical anterior and lateral segments.
Fig. 1.
Patient 1: cardiac magnetic resonance (CMR) left ventricular noncompaction images. Patient 1 had a CMR that demonstrated prominent trabeculations seen in the midventricular and apical portion of the left ventricle with a noncompacted to compacted ratio of 2.4:1 in end-diastole. (Left) Short-axis bright blood still image. (Right) Four-chamber bright blood still image.
Given these findings the treatment of the patient was started with spironolactone, losartan, and extended-release metoprolol. Low-dose aspirin was also initiated secondary to diminished left ventricular function in the setting of LVNC that poses a thromboembolic risk. Repeat evaluation has shown stable magnetic resonance imaging and electrocardiographic findings. She remains asymptomatic and will continue to be monitored annually at this point.
Patient 2
Patient 2 is a 33-year-old woman who had three sons affected by DMD and was found herself to have a point mutation in exon 34 of the DMD gene (c.4843A>T mutation), identical to her affected sons. She was referred for consultation in the DMD/BMD carrier clinic at our institution. She had been asymptomatic from a cardiac standpoint.
Initial cardiac work-up included a Holter monitor which showed rare PVCs and ventricular couplets, as well as rare premature atrial contractions (PACs). Electrocardiogram demonstrated normal sinus rhythm at 62 beats per minute and T-wave inversion in the inferior leads. CMR revealed a mildly dilated left ventricle with mildly reduced left ventricular ejection fraction (49%). The CMR also showed a segmental wall motion abnormality: hypokinesis of the mid and basal inferolateral segments with partial thickness epicardial late gadolinium enhancement in the same regions (Fig. 2). There were also prominent trabeculations in the left ventricular apex and extending along the free wall to the midventricular level, consistent with LVNC (Fig. 3, Videos 3 and 4).
Fig. 2.
Patient 2: cardiac magnetic resonance late gadolinium enhancement imaging. Short-axis image of cardiac magnetic resonance showing a thinned appearance of the midventricular inferolateral region with late-gadolinium enhancement (arrow).
Fig. 3.
Patient 2: cardiac magnetic resonance (CMR) left ventricular noncompaction images. Patient 2 had a CMR that demonstrated prominent trabeculations within the left ventricular apex and extending along the lateral free wall to the midventricular level with a noncompacted to compacted ratio of 2.3:1 in end-diastole. (Left) Short-axis bright blood still image. (Right) Four-chamber bright blood still image.
Given the above findings, the treatment of the patient was started with carvedilol and lisinopril. Low-dose aspirin was also started similar to the reasoning in patient 1. At most recent follow-up (1 year following diagnosis) she has remained asymptomatic. A recent echocardiogram showed persistence of a mildly dilated left ventricle but normalization of her left ventricular function. She has not been restricted from activities and will have ongoing monitoring with serial imaging (echocardiography or CMR), electrocardiograms, and Holter monitors.
Discussion
LVNC is a unique cardiomyopathy characterized by a compacted thin layer underlying a much thicker noncompacted endocardial layer of deep trabeculae. Several proposed diagnostic imaging criteria have been proposed for LVNC and they vary slightly among authors as well as by imaging modality (echocardiogram versus CMR). The patients above met the CMR criteria for LVNC set forth by Petersen et al. with a noncompacted to compacted ratio of >2.3/1 in end-diastole [5].
Dystrophin is the protein found in the cardiac myocyte that anchors the cytoskeleton to the extracellular matrix. Given the role of the extracellular matrix in the developing heart, including the compaction process in early fetal development, one can theorize that dystrophinopathies could result in abnormalities in compaction, thus resulting in left ventricular noncompaction cardiomyopathy [6].
Interestingly, patient 1 had one son with DMD and he had no cardiac involvement, including no evidence of LVNC at age 18 years by CMR. Similarly, patient 2 had three sons with DMD (ages 3, 5, and 9 years), all without cardiac involvement to date, including absence of LVNC (by echocardiogram only in the younger two sons and CMR in the oldest). It is known that many modifiers can play a role in how and when a cardiomyopathy develops, even among family members with the same gene defect. This could explain the phenotypic variation in our cases between affected sons and carrier mothers. However, it is possible that the carrier mothers harbor a sarcomeric gene defect that was not tested.
Regardless, the diagnosis of LVNC is important to make for reasons stated below. LVNC is associated with a variety of myocardial phenotypes including: dilated, hypertrophy, mixed (dilated and hypertrophied), restrictive, or normal cardiac dimensions and wall thickness. Some have reported LVNC as an acquired or even secondary compensatory process; however, the authors of this report strongly believe LVNC to be a primary phenotype that can result in progressive cardiac dysfunction and/or be associated with dysrhythmias or thromboembolic events. Awareness of the natural history and risks associated with LVNC is crucial for patient surveillance and management as it can reduce morbidity and mortality [7]. Once LNVC is diagnosed, independent of cardiac function, we believe that this should increase imaging and dysrhythmia surveillance as well as be a pause for anticoagulation considerations, as LVNC places patients at a higher risk for thromboembolic events. Such a strategy may result in early treatment and better outcomes.
Conclusions
We believe that this report illustrates the first case series of coincident LVNC (dilated phenotype) in dystrophinopathy carriers. Physicians should continue to recommend serial cardiac evaluations in carriers because of the increased prevalence of cardiomyopathy, which may include LVNC, in this population. Heightened awareness of LVNC in such carriers may further improve diagnostic accuracy and care in these patients and will likely alter treatment and surveillance once identified. Further studies should aim to characterize cardiomyopathies in DMD and BMD carriers more fully. LVNC may be more prominent in dystrophinopathy carriers than previously understood, just as recent studies have shown it to be in male DMD patients.
Disclosures
The authors have no disclosures.
Footnotes
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jccase.2014.08.010.
Appendix A. Supplementary data
The following are the supplementary data to this article:
Patient 1: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the apical to midventricular portion of the left ventricle. Short-axis bright blood cine stack.
Patient 1: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the apical to midventricular portion of the left ventricle. Four-chamber bright blood cine stack.
Patient 2: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the lateral free wall to the midventricular level. Short-axis bright blood cine stack.
Patient 2: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the lateral free wall to the midventricular level. Four-chamber bright blood cine series.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Patient 1: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the apical to midventricular portion of the left ventricle. Short-axis bright blood cine stack.
Patient 1: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the apical to midventricular portion of the left ventricle. Four-chamber bright blood cine stack.
Patient 2: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the lateral free wall to the midventricular level. Short-axis bright blood cine stack.
Patient 2: cardiac magnetic resonance video of left ventricular noncompaction. These are bright blood cine images demonstrating prominent trabeculations extending along the lateral free wall to the midventricular level. Four-chamber bright blood cine series.