Introduction Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). Methods A cross-sectional analysis of clinical data from a multi-institutional, international CINRG DMD Natural History Study of 340 DMD patients aged 2 to 28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. Results 231 participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47/174), and it was significantly associated with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P>0.68). In patients with cardiomyopathy, 57 % (27/47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15/127) of patients without cardiomyopathy. Discussion Echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.

Increased activity of the renin-angiotensin system is thought to play a major role in the pathogenesis of salt retention and edema formation in congestive heart failure. The present study evaluates the effects of chronic inhibition of angiotensin-converting enzyme on the response to infusion of exogenous atrial natriuretic factor (ANF) in salt-retaining rats with chronic arteriovenous (a-v) fistula, an experimental model of high-output congestive heart failure. Administration of ANF in incremental doses (5-50 micrograms.kg-1.h-1) to Inactin-anesthetized, sham-operated control rats resulted in dose-dependent increases in urine flow, sodium excretion, and glomerular filtration rate, and significant decreases in mean arterial blood pressure. These effects of atrial peptide were markedly attenuated in salt-retaining rats with a-v fistula. However, chronic oral treatment with the angiotensin-converting-enzyme inhibitor enalapril restored the natriuretic response of sodium-retaining rats with a-v fistula to high doses of ANF. At a dose of 50 micrograms.kg-1.h-1, fractional excretion of Na (FENa) in a-v fistula rats given enalapril was 4.0 +/- 0.5%, which was significantly greater than that in a-v fistula rats without enalapril (0.5 +/- 0.4%, P less than 0.05) and not different from the response in sham-control rats (4.9 +/- 0.7%). The improvement in the natriuretic response after enalapril was not associated with a significant increase in GFR and occurred despite a decrease in mean arterial pressure. Moreover, chronic enalapril treatment did not significantly alter the plasma levels of immunoreactive ANF in either the sham controls or in the rats with a-v fistula.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats with chronic aortocaval (AV) fistula, an experimental model of congestive heart failure, display high plasma levels of atrial natriuretic factor (ANF) and a blunted natriuretic response to ANF infusion. We previously reported that rats with AV fistula either develop progressive sodium retention (urinary sodium excretion, UNaV less than 100 microeq/24 h) or compensate (UNaV greater than 1,200 microeq/24 h). To gain further insight into the mechanism of renal hyporesponsiveness to ANF, we evaluated the effect of ANF on renal guanosine 3',5'-cyclic monophosphate (cGMP) production in sham-operated control rats and in the two groups of rats with AV fistula. Infusion of synthetic ANF-(99-126) (at either 10 or 50 micrograms.kg-1.h-1) resulted in a reduced fractional sodium excretion (P less than 0.05) in both compensated rats (0.7 +/- 0.2 and 7.9 +/- 1.6%) and sodium-retaining rats (0.3 +/- 0.1 and 0.5 +/- 0.1%) compared with controls (8.5 +/- 1.2 and 13.7 +/- 2.3% for low and high doses, respectively). Similarly, urinary cGMP excretion corrected by glomerular filtration rate (UcGMPV/GFR) during low-dose ANF infusion was significantly reduced (P less than 0.05) in both groups with AV fistula (compensated: 39 +/- 10 pmol/ml; sodium-retaining: 55 +/- 13 pmol/ml) compared with controls (115 +/- 16 pmol/ml). During high-dose ANF infusion, compensated rats, but not sodium-retaining rats, displayed a significant increase in UcGMPV/GFR. The differences in UcGMPV/GFR are probably not due to variations in urine flow because furosemide infusion to a separate group of rats with AV fistula increased urine flow approximately eightfold but did not increase UcGMPV/GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Early clinical trials of therapies to treat Duchenne muscular dystrophy (DMD), a fatal genetic X-linked pediatric disease, have been designed based on the limited understanding of natural disease progression and variability in clinical measures over different stages of the continuum of the disease. The objective was to inform the design of DMD clinical trials by developing a disease progression modelbased clinical trial simulation (CTS) platform based on measures commonly used in DMD trials. Data were integrated from past studies through the Duchenne Regulatory Science Consortium founded by the Critical Path Institute (15 clinical trials and studies, 1505 subjects, 27,252 observations). Using a nonlinear mixedeffects modeling approach, longitudinal dynamics of five measures were modeled (NorthStar Ambulatory Assessment, forced vital capacity, and the velocities of the following three timed functional tests: time to stand from supine, time to climb 4 stairs, and 10 meter walk-run time). The models were validated on external data sets and captured longitudinal changes in the five measures well, including both early disease when function improves as a result of growth and development and the decline in function in later stages. The models can be used in the CTS platform to perform trial simulations to optimize the selection of inclusion/ exclusion criteria, selection of measures, and other trial parameters. The data sets and models have been reviewed by the US Food and Drug Administration and the European Medicines Agency; have been accepted into the Fit-for-Purpose and Qualification for Novel Methodologies pathways, respectively; and will be submitted for potential endorsement by both agencies.

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