Rate of Change in Cardiac Magnetic Resonance Imaging Measures Is Associated With Death in Duchenne Muscular Dystrophy.

BACKGROUND: Cardiovascular disease is the leading cause of death among patients with Duchenne muscular dystrophy (DMD). Identifying patients at risk of early death could allow for increased monitoring and more intensive therapy. Measures that associate with death could serve as surrogate outcomes in clinical trials. METHODS AND RESULTS: Duchenne muscular dystrophy subjects prospectively enrolled in observational studies were included. Models using generalized least squares were used to assess the difference of cardiac magnetic resonance measurements between deceased and alive subjects. A total of 63 participants underwent multiple cardiac magnetic resonance imaging and were included in the analyses. Twelve subjects (19.1%) died over a median follow-up of 5 years (interquartile range, 3.1-7.0). Rate of decline in left ventricular ejection fraction was faster in deceased than alive subjects (P<0.0001). Rate of increase in indexed left ventricular end-diastolic (P=0.0132) and systolic (P<0.0001) volumes were higher in deceased subjects. Faster worsening in midcircumferential strain was seen in deceased subjects (P=0.049) while no difference in global circumferential strain was seen. The rate of increase in late gadolinium enhancement, base T1, and mid T1 did not differ between groups. CONCLUSIONS: Duchenne muscular dystrophy death is associated with the rate of change in left ventricular ejection fraction, midcircumferential strain, and ventricular volumes. Aggressive medical therapy to decrease the rate of progression may improve the mortality rate in this population. A decrease in the rate of progression may serve as a valid surrogate outcome for therapeutic trials.

Cardiovascular Measures of All-Cause Mortality in Duchenne Muscular Dystrophy.

BACKGROUND: Cardiopulmonary failure is the leading cause of death in Duchenne muscular dystrophy (DMD). Research into DMD-specific cardiovascular therapies is ongoing, but there are no Food and Drug Administration-approved cardiac end points. To adequately power a therapeutic trial, appropriate end points must be chosen and the rate of change for these end points reported. The objective of this study was to evaluate rate of change for cardiac magnetic resonance and blood biomarkers and to determine which measures associate with all-cause mortality in DMD. METHODS: Seventy-eight DMD subjects underwent 211 cardiac magnetic resonance studies analyzed for left ventricular (LV) ejection fraction, indexed LV end diastolic and systolic volumes, circumferential strain, late gadolinium enhancement presence and severity (global severity score, and full width half maximum), native T1 mapping, T2 mapping, and extracellular volume. Blood samples were analyzed for BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and troponin I. Cox proportional hazard regression modeling was performed with all-cause mortality as the outcome. RESULTS: Fifteen subjects (19%) died. LV ejection fraction, indexed end systolic volumes, global severity score, and full width half maximum worsened at 1 and 2 years while circumferential strain and indexed LV end diastolic volumes worsened at 2 years. LV ejection fraction, indexed LV end diastolic and systolic volumes, late gadolinium enhancement full width half maximum, and circumferential strain associated with all-cause mortality (P<0.05). NT-proBNP was the only blood biomarker that associated with all-cause mortality (P<0.05). CONCLUSIONS: LV ejection fraction, indexed LV volumes, circumferential strain, late gadolinium enhancement full width half maximum, and NT-proBNP are associated with all-cause mortality in DMD and may be the best end points for use in cardiovascular therapeutic trials. We also report change over time of cardiac magnetic resonance and blood biomarkers.

Cardiorespiratory management of Duchenne muscular dystrophy: emerging therapies, neuromuscular genetics, and new clinical challenges.

The life-limiting complications of Duchenne muscular dystrophy (DMD) include loss of lung function and progressive cardiomyopathy; when patients are treated with assisted ventilation, cardiac function becomes the main determinant of survival. Therapy for DMD is changing rapidly, with the emergence of new genetic and molecular therapeutic options, the proliferation of which has fostered the perception that DMD is a potentially curable disease. However, data for respiratory and cardiac outcomes are scarce and available evidence is not uniformly positive. Patients who share a dystrophin (DMD) genotype can have highly divergent cardiorespiratory phenotypes; genetic modifiers of DMD gene expression are a probable cause of respiratory and cardiac phenotypic variability and discordance. In this Personal View, we provide an overview of new and emerging DMD therapies, highlighting the limitations of current research and considering strategies to incorporate cardiorespiratory assessments into clinical trials. We explore how genetic modifiers could be used to predict cardiorespiratory natural history and how manipulation of such modifiers might represent a promising therapeutic strategy. Finally, we examine the changing role of respiratory physicians, cardiologists, and intensive care clinicians on the frontline of a challenging new clinical landscape.

Electrocardiographic prediction of late gadolinium enhancement on cardiac magnetic resonance in Becker muscular dystrophy.

Dystrophin deficiency results in cardiomyopathy and fibrosis with variable onset. Little is known about electrocardiographic abnormalities in Becker muscular dystrophy and their relationship to underlying cardiac pathology. We hypothesized QRS fragmentation is associated with myocardial fibrosis on cardiac magnetic resonance imaging in Becker muscular dystrophy patients. We retrospectively evaluated 44 patients, and extracted data from clinically obtained electrocardiogram and cardiac magnetic resonance. Ventricular function and presence or absence late gadolinium enhancement representing myocardial fibrosis were recorded from imaging. Nearly half (19/42, 45%) of patients interrogated had myocardial fibrosis on cardiac magnetic resonance. Total number of electrocardiogram leads with QRS fragmentation (median 1 vs 4, p < 0.001) and either right or left axis deviation from median was significantly increased (13.6 vs. 44.8°, p < 0.001) in patients with myocardial fibrosis. Decreased leftward voltage in V6 correlated to both increased fibrosis and decreased cardiac function (p < 0.01). The positive likelihood ratio for underlying myocardial fibrosis in patients with two of the three findings on electrocardiogram was 8.47 (p < 0.0001). QRS fragmentation and axis deviation on electrocardiography are strongly predictive of myocardial fibrosis in Becker muscular dystrophy and may inform the use of advanced imaging in evaluation of these patients.

The effect of emerging molecular and genetic therapies on cardiopulmonary disease in Duchenne muscular dystrophy.

Gene therapy is an attractive approach being intensively studied to prevent muscle deterioration in patients with Duchenne muscular dystrophy. While clinical trials are only in early stages, initial reports are promising for its effects on ambulation. Cardiopulmonary failure, however, is the most common cause of mortality in Duchenne muscular dystrophy (DMD) patients, and little is known regarding the prospects for gene therapy on alleviating DMD-associated cardiomyopathy and respiratory failure. Here we review current knowledge regarding effects of gene therapy on DMD cardiomyopathy and discuss respiratory endpoints that should be considered as outcome measures in future clinical trials.

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial.

Importance: Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). Objective: To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. Design, Setting, and Participants: This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). Interventions: A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). Main Outcomes and Measures: Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. Results: Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. Conclusions and Relevance: This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03375164.

Stabilization of Early Duchenne Cardiomyopathy With Aldosterone Inhibition: Results of the Multicenter AIDMD Trial.

Background Duchenne muscular dystrophy incurs nearly universal dilated cardiomyopathy by the third decade of life, preceded by myocardial damage and impaired left ventricular strain by cardiac magnetic resonance. It has been shown that (1) mineralocorticoid receptor antagonist therapy with spironolactone attenuated damage while maintaining function when given early in a mouse model and (2) low-dose eplerenone stabilized left ventricular strain in boys with Duchenne muscular dystrophy and evident myocardial damage but preserved ejection fraction. We hypothesized that moderate-dose spironolactone versus eplerenone would provide similar cardioprotection in this first head-to-head randomized trial of available mineralocorticoid receptor antagonists, the AIDMD (Aldosterone Inhibition in Duchenne Muscular Dystrophy) trial. Methods and Results This was a multicenter, double-blind, randomized, noninferiority trial. Subjects were randomized to eplerenone, 50 mg, or spironolactone, 50 mg, orally once daily for 12 months. The primary outcome was change in left ventricular systolic strain at 12 months. Among 52 enrolled male subjects, aged 14 (interquartile range, 12-18) years, spironolactone was noninferior to eplerenone (∆strain, 0.4 [interquartile range, -0.4 to 0.6] versus 0.2 [interquartile range, -0.2 to 0.7]; P=0.542). Renal and pulmonary function remained stable in both groups, and no subjects experienced serious hyperkalemia. Infrequent adverse events included gynecomastia in one subject in the spironolactone arm and facial rash in one subject in the eplerenone arm. Conclusions In boys with Duchenne muscular dystrophy and preserved left ventricular ejection fraction, spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354352.

Use of Cardiac MRI to Assess Antitumor Efficacy of Everolimus in Sporadic Cardiac Rhabdomyoma.

Cardiac rhabdomyoma is the most common neonatal cardiac tumor and is typically associated with tuberous sclerosis complex (TSC). Although these tumors may naturally regress, some patients require surgical resection because of cardiac instability. If not fully resected, patients may also require medical therapy to improve their hemodynamics. Everolimus, a mammalian target of rapamycin inhibitor, has shown promise in reducing rhabdomyoma in patients with TSC, but the drug's impact in patients without TSC has not been reported. Monitoring of tumor response has typically been limited to echocardiograms, which is not ideal given inherent difficulties in three-dimensional measurements. We report a case of sporadic cardiac rhabdomyoma in a neonate treated with everolimus resulting in tumor regression as documented by cardiac MRI. While on everolimus, our patient had an increased incidence of a preexisting arrhythmia, which resolved with planned cessation of therapy, suggesting that close monitoring is imperative in patients with arrhythmia.

Advances in the diagnosis and management of cardiomyopathy in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy suffer debilitating muscle destruction, resulting in loss of ambulation, diminished respiratory function, gastrointestinal disturbances and cardiomyopathy. Although it is the most common cause of death in these patients, cardiomyopathy is poorly understood in terms of distinct pathogenesis, natural history, and specific, effective therapeutic interventions. We review the state-of-the-art knowledge of Duchenne muscular dystrophy-associated cardiomyopathy including clinical evaluation, imaging, medical and perioperative management, and prospects for gene therapy. We also review cardiomyopathy in heterozygote carriers. By describing our current understanding and best practices, we hope to improve harmonization of care across institutions and identify collective knowledge gaps to guide future research efforts.

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: results of a two-year open-label extension trial.

BACKGROUND: Cardiomyopathy is a leading cause of morbidity and mortality in boys with Duchenne muscular dystrophy (DMD). We recently showed in a 12-month double-blind randomized controlled trial that adding eplerenone to background medical therapy was cardioprotective in this population. The objective of this study was to evaluate the safety and efficacy of longer-term eplerenone therapy in boys with DMD. RESULTS: Eleven subjects (phase 1 baseline median [range] age: 13 [7 - 25] years) from the original 12-month trial at a single participating center were enrolled. Importantly, those who entered the extension study who had been on eplerenone previously were significantly older than those who had originally been on placebo (median age 10.5 vs. 18.0 years, p = 0.045). During an additional 24-month open-label extension study, all boys received eplerenone 25 mg orally once daily to treat preclinical DMD cardiomyopathy, defined as evident myocardial damage by late gadolinium enhancement cardiac magnetic resonance (LGE) with preserved ejection fraction (EF). The threshold for potassium level, the primary safety measure, was not exceeded in any non-hemolyzed blood sample. Over 24 months, left ventricular (LV) systolic strain, a more sensitive marker whose more negative values indicate greater contractility significantly improved (median change -4.4%, IQR -5.8 to -0.9%) in younger subjects whereas older subjects' strain remained stable without significant worsening or improvement (median change 0.2%, IQR -1.1 to 4.3%). EF and extent of myocardial damage by LGE remained stable in both groups over 2 years. CONCLUSIONS: Eplerenone offers effective and safe cardioprotection for boys with DMD, particularly when started at a younger age. Eplerenone is a useful clinical therapeutic option, particularly if treatment is initiated earlier in life when cardiac damage is minimal. TRIAL REGISTRATION: http://ClinicalTrials.gov identifier NCT01521546. Registered 26 January 2012.

Recurrent Fat Embolic Strokes in a Patient With Duchenne Muscular Dystrophy With Long Bone Fractures and a Patent Foramen Ovale.

BACKGROUND: Individuals with Duchenne muscular dystrophy have an increased risk of long bone fractures. Such fractures are sometimes associated with brain dysfunction due to fat embolism syndrome, although this syndrome has seldom been documented in muscular dystrophy patients. PATIENT DESCRIPTION: We describe a child with Duchenne muscular dystrophy who developed fat embolism syndrome with neurological dysfunction following multiple long bone fractures. He experienced recurrent cerebral infarctions that probably resulted from embolization through a patent foramen ovale. The patent foramen ovale was closed by an occluder device in the cardiac catheterization laboratory, and he did not experience further infarctions. CONCLUSIONS: Fat embolism with ischemic cerebral infarction can occur in individuals with Duchenne muscular dystrophy following long bone fractures. In this setting it is important to identify and close atrial level shunts in order to prevent additional infarctions.

Comparison of right and left ventricular function and size in Duchenne muscular dystrophy.

INTRODUCTION: Right ventricular (RV) size and function in Duchenne muscular dystrophy (DMD) have not been well described. Using cardiac magnetic resonance (CMR) imaging we describe the relationship of RV and left ventricular (LV) size and function in a large DMD cohort. METHODS: Latest CMR scans of 272 patients consecutively seen at a single tertiary referral center (2011-2014) with skeletal muscle biopsy confirmed DMD were included. 1.5 and 3 Tesla CMR scanners were used. Biventricular ejection fraction (EF), end-diastolic volume index (EDVI), mass and mass index were compared across categories of LVEF. RESULTS: Mean age was 13.5 ± 4.9 years. 71% had normal (≥ 55%) LVEF while mild (EF 45-54%), moderate (EF 30-44%), and severe LV dysfunction (EF <30%) was present in 20%, 6% and 3% respectively. The correlation between RVEF and LVEF was weak. Even in patients with severe LV dysfunction, RVEF (49.7% ± 12.9%) was relatively preserved. There were no significant differences in RVEDVI and RV mass index across categories of LV function. CONCLUSION: In a large DMD cohort, RVEF was relatively preserved and RV size was preserved across categories of LV dysfunction.

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. METHODS: In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. FINDINGS: Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1·0 [IQR 0·3-2·2] vs 2·2 [1·3-3·1]; p=0·020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. INTERPRETATION: In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. FUNDING: BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.

Regional circumferential strain is a biomarker for disease severity in duchenne muscular dystrophy heart disease: a cross-sectional study.

The aim of this study is to determine the contribution of strain ε cc in mid left ventricular (LV) segments to the reduction of composite LV circumferential ε cc in assess severity of duchenne muscular dystrophy (DMD) heart disease as assessed by cardiac magnetic resonance imaging (CMR). DMD patients and control subjects were stratified by age, LV ejection fraction, and late gadolinium enhancement (LGE) status. Tagged CMR images were analyzed for global ventricular function, LGE imaging, and composite and segmental ε cc. The relationship between changes in segmental ε cc changes and LGE across patient groups was assessed by a statistical step-down model. LV ε cc exhibited segmental heterogeneity; in control subjects and young DMD patients, ε cc was greatest in LV lateral free wall segments. However, with increasing age and cardiac disease severity as demonstrated by decreased EF and development of myocardial strain the segmental differences diminished. In subjects with advanced heart disease as evidenced by reduced LV ejection fraction and presence of LGE, very little segmental heterogeneity was present. In control subjects and young DMD patients, ε cc was greatest in LV lateral free wall segments. Increased DMD heart disease severity was associated with reduced composite; ε cc diminished regional ε cc heterogeneity and positive LGE imaging. Taken together, these findings suggest that perturbation of segmental, heterogeneous ε cc is an early biomarker of disease severity in this cross-section of DMD patients.

Autonomic dysfunction: a driving force for myocardial fibrosis in young Duchenne muscular dystrophy patients?

Cardiac manifestations of Duchenne muscular dystrophy (DMD) include progressive cardiac dysfunction and an elevated resting heart rate (HR). We hypothesized this elevated HR reflects autonomic dysfunction that can be identified by heart rate variability (HRV) analyses which will be associated with myocardial fibrosis by cardiac magnetic resonance imaging (cMR). DMD patients (N = 74) and controls (N = 17) had time and frequency domain HRV analyses calculated via Holter monitoring. Cardiac magnetic resonance imaging was performed on DMD cases only. χ (2) test, T test, ANOVA, and logistic regression were used to perform comparisons between groups. A p value of <0.05 was used for statistical significance. DMD cases had higher resting average HR than controls (99.4 ± 8.9, 85.4 + 6.2, p < 0.001). Among HRV variables, decreases were seen in the following: standard deviation of R to R intervals, the percent RR intervals differing by >50 ms from previous RR interval, the root-meansquare of successive differences of RR intervals, the standard deviation of the mean R to R segment (SDANN), low frequency, and high frequency domain, all p values 0.001. Maximum HR and SDANN most significantly associated with positive LGE on cMR (p = 0.008, p = 0.016). DMD cases on beta blocker had an average HR lower than those not on beta blocker (p = 0.009), but with no difference in HRV analysis. DMD patients have reduced HRV and therefore autonomic dysfunction prior to the onset of heart failure which is associated with myocardial fibrosis.

Co-occurring Duchenne muscular dystrophy and hypertrophic cardiomyopathy in an adult with atypical cardiac phenotype.

We present the case of a 29-year-old man with mutation-positive Duchenne muscular dystrophy and mutation-positive hypertrophic cardiomyopathy. His cardiac phenotype has characteristics of both disorders; he manifests sub-epicardial left ventricular free wall late gadolinium enhancement that is consistent with Duchenne cardiomyopathy, as well as asymmetric ventricular septal hypertrophy, hyperdynamic left ventricular systolic function, and septal mid-myocardial late gadolinium enhancement, which are characteristic of hypertrophic cardiomyopathy.