Duchenne muscular dystrophy patients: troponin leak in asymptomatic and implications for drug toxicity studies.

BACKGROUND: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), but studies suggest heart failure biomarkers correlate poorly with cardiomyopathy severity. DMD clinical trials have used troponin I (cTnI) as a biomarker of toxicity, but it is unclear if asymptomatic DMD patients have elevated cTnI. We longitudinally evaluated cTnI, brain natriuretic peptide (BNP), and N-terminal pro-BNP (NT-proBNP) in a DMD cohort. METHODS: DMD patients were prospectively enrolled and followed for 3 years. Serum was drawn at the time of cardiac magnetic resonance (CMR). Normal biomarker values were derived from healthy subjects. Biomarkers were correlated with CMR markers. RESULTS: All subjects were asymptomatic at the time of enrollment. Several DMD subjects had transiently elevated cTnI. Those with elevated cTnI were more likely to have late gadolinium enhancement on baseline CMR. NT-proBNP correlated with indexed left ventricular end diastolic and maximum left atrial volumes. Otherwise, standard cardiac biomarkers did not correlate with CMR markers of cardiomyopathy. CONCLUSIONS: CTnI, BNP, and NT-proBNP do not correlate with CMR assessment of cardiomyopathy progression. A subset of DMD patients have asymptomatic cTnI leak of uncertain clinical significance, though of critical importance if cTnI is used to assess for cardiac toxicity in future drug trials. IMPACT: Asymptomatic patients with Duchenne muscular dystrophy (DMD) exhibit transient troponin I leak. NT-proBNP correlated with indexed left ventricular end diastolic volume and indexed maximum left atrial volume. Other cardiac biomarkers did not correlate with cardiac magnetic resonance (CMR) markers of cardiomyopathy.

The BDNF rs6265 Polymorphism is a Modifier of Cardiomyocyte Contractility and Dilated Cardiomyopathy.

Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.

Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication.

Copy-number variations cause genomic disorders. Triplications, unlike deletions and duplications, are poorly understood because of challenges in molecular identification, the choice of a proper model system for study, and awareness of their phenotypic consequences. We investigated the genomic disorder Charcot-Marie-Tooth disease type 1A (CMT1A), a dominant peripheral neuropathy caused by a 1.4 Mb recurrent duplication occurring by nonallelic homologous recombination. We identified CMT1A triplications in families in which the duplication segregates. The triplications arose de novo from maternally transmitted duplications and caused a more severe distal symmetric polyneuropathy phenotype. The recombination that generated the triplication occurred between sister chromatids on the duplication-bearing chromosome and could accompany gene conversions with the homologous chromosome. Diagnostic testing for CMT1A (n = 20,661 individuals) identified 13% (n = 2,752 individuals) with duplication and 0.024% (n = 5 individuals) with segmental tetrasomy, suggesting that triplications emerge from duplications at a rate as high as ~1:550, which is more frequent than the rate of de novo duplication. We propose that individuals with duplications are predisposed to acquiring triplications and that the population prevalence of triplication is underascertained.

Correlation of heart rate and cardiac dysfunction in Duchenne muscular dystrophy.

Sinus tachycardia is common in cases of Duchenne muscular dystrophy (DMD). The authors hypothesized that an elevated heart rate would herald cardiomyopathy onset. A retrospective case-control study was performed with 55 DMD boys and 150 age-matched control boys. The variables were age, heart rate, shortening fraction, and left ventricular end-diastolic dimension. Cardiomyopathy was defined as a shortening fraction less than 28%. The DMD boys had a higher initial heart rate with no baseline echocardiographic evidence of cardiomyopathy. The control subjects showed a statistically significant age-related decline in heart rate (p = 0.001) but not the DMD boys. Cardiomyopathy developed in 17 of the 55 DMD boys over a period of 4.6 ± 1.6 years. The DMD upper and lower heart rate groups were similar in age, follow-up time, and initial shortening fraction, yet cardiomyopathy developed in 14 (42%) of 33 upper quartile boys but only 3 (14%) of 22 lower quartile DMD boys (odds ratio, 6.5 (95% confidence interval, 1.15-18.92; p < 0.05). Compared with the control subjects, the DMD boys had a higher resting heart rate and a lack of age-related heart rate decline. The DMD boys in the upper heart rate quartile were more likely to progress to cardiomyopathy than those in the lower quartiles. This study establishes heart rate elevation as a statistically significant risk factor for cardiomyopathy. Further studies may define heart rate cutoffs for early pharmacologic intervention for incipient cardiomyopathy.

Improving Access and Guideline Adherence in Pulmonary Care in Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a devastating, progressive neuromuscular disease that results in cardiopulmonary failure and death. In 2018, the DMD Care Considerations guidelines were updated to improve the multidisciplinary approach to care and promote early respiratory management. We sought to evaluate the impact of a multidisciplinary clinic on access to pulmonary care and adherence to respiratory care guidelines. METHODS: Utilizing retrospective data, we assessed for pulmonary care between 2016-2019 and congruence with guidelines from March 2018-February 2019. Using a standardized visit protocol, subjects were monitored for adherence to pulmonary function testing (PFT) and polysomnography (PSG) recommendations. RESULTS: Of the 84 subjects with DMD, only 51.2% had prior pulmonary involvement, and approximately one-third were seen in the year prior to clinic onset. Only 23% of subjects with a pulmonary referral completed this visit. After clinic initiation, the average age of a subject's first pulmonary contact decreased from 11.8 y to 7.9 y (P < .001), and 45% of the 77 unique clinic subjects had no previous pulmonary encounter. Adherence to PFT guidelines increased in both ambulatory (8.7% to 86.1%) and non-ambulatory subjects (25.9% to 90.1%). Approximately 79% of subjects seen in clinic either completed or had an order for PSG in the last 12 months. CONCLUSIONS: Development of a multispecialty clinic expanded access to pulmonary care and evaluation in subjects with DMD. Continued care in this clinic will allow a better understanding of barriers to access and the opportunity to monitor long-term pulmonary health.

Multidisciplinary Perioperative Care for Children with Neuromuscular Disorders.

Children with neuromuscular diseases present unique challenges to providing safe and appropriate perioperative care. Given the spectrum of disease etiologies and manifestations, this is a population that often requires specialized multidisciplinary care from pediatricians, geneticists, neurologists, dieticians, and pulmonologists which must also be coordinated with surgeons and anesthesiologists when these patients present for surgery. Several of these diseases also have specific pharmacologic implications for anesthesia, most notably mitochondrial disease and muscular dystrophies, which put them at additional risk during the perioperative period particularly in patients presenting without a formal diagnosis. Techniques and strategies to fully evaluate and optimize these patients preoperatively, manage them safely intraoperatively, and return them to their baseline status postoperative are particularly important in this vulnerable group of patients. Utilizing a review of inherited neuromuscular conditions, generalized perioperative concerns, and specific complications related to anesthesia, this article provides an overview of pertinent considerations and recommends a framework for management of these patients.