Suzanne Smart

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.

Similar Efficacy from Specific and Non-Specific Mineralocorticoid Receptor Antagonist Treatment of Muscular Dystrophy Mice

BACKGROUND Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. OBJECTIVE The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. METHODS Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus, and cardiac papillary muscle force was measured ex vivo, followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. RESULTS Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. CONCLUSIONS These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

Black-Blood CMR

Cardiac magnetic resonance is often used to provide detailed information on structures such as the myocardium, pericardium, pulmonary veins, and emanating great vessels. While blood travels throughout the heart and blood vessels, its signal may obscure the assessment of these structures depending on the clinical questions being addressed. Black blood imaging techniques seek to suppress the signal from blood and thereby improve delineation of cardiovascular anatomy. Fast spin echo-based sequences are in routine use for the suppression of blood flowing into the imaging plane. Such approaches have known limitations that may result in inadequate image quality or artifacts in the image. More recent advances have overcome some of these limitations, but it is incumbent upon the reader to recognize them as they occur. For instance, cardiac motion may lead to signal loss, and may be overcome by optimizing the cardiac phase during which data acquisition occurs. For those relying on black blood imaging to detect myocardial edema, caution must be exerted in recognizing spuriously bright areas of myocardium resulting from slow-flowing blood. While contemporary tissue mapping techniques overcome some of these limitations, black blood imaging will remain an important tool in the CMR armamentarium, particularly with increasing prevalence of implantable devices in patients with various forms of cardiovascular disease. Particularly with bright blood imaging, devices such as intravascular stents and implantable loop recorders can produce considerable susceptibility artifact obscuring visualization of the anatomy of interest; using black blood imaging can significantly reduce this artifact.

Skeletal muscle assessment to understand cardiometabolic interactions

Background Patients with diabetes and metabolic disorders have excess mortality after myocardial infarction (MI). Their mitochondrial function is often abnormal, and can be measured with phosphorus magnetic resonance spectroscopy (PMRS). Participation in a program of cardiac rehabilitation and secondary prevention (CRSP) reduces post-MI mortality, but typically involves only aerobic exercise and may not sufficiently improve mitochondrial function. An integrated assessment of skeletal muscle would potentially be useful to assess the impact of aerobic plus resistive exercise post-MI.

Tissue Characterization: T1, T2 and T2* Techniques

Noninvasive characterization of tissue has long been the unique domain of magnetic resonance imaging (MRI) when compared to other imaging modalities. Techniques for such typically emphasize one or more MR-based relaxation parameters and the corresponding image contrast or weighting. With or without administration of an exogenous contrast agent, cardiac MRI affords detailed myocardial tissue characterization via various segmented as well as single heart beat approaches. The workhorse technique for myocardial characterization has been late gadolinium enhancement (LGE); LGE is routinely performed in MRI centers around the world as an integral part of nearly every cardiac MRI exam. While originally developed to characterize infarct scar, LGE has since become an important technique to delineate other features of myocardial disease such as fibrosis in nonischemic cardiomyopathy and infiltrates such as sarcoid granuloma and amyloid protein. LGE usually provides robust myocardial characterization, but has two major limitations. First, it requires administration of gadolinium-based contrast, which may not be suitable for individuals with known allergy to such agents or patients with advanced kidney disease. Second, it may be insensitive to more diffusely diseased myocardium where one loses the ability to ‘null’ normal tissue via this technique’s key inversion time parameter. To overcome these limitations, as well as to characterize other myocardial features, imaging techniques that capture intrinsic contrast in T1, T2 and other MR-based relaxation parameters are often incorporated into the cardiac MRI examination. Accruing evidence suggests that quantitative approaches, also known as tissue mapping techniques, are helping to further advance MR-based myocardial characterization.

Effect of pulmonary function on right heart function in Duchenne muscular dystrophy patients

Background Duchenne muscular dystrophy (DMD) is an x-linked neuromuscular disorder in which cardiopulmonary disease leads to death in the third to fourth decade of life. Diaphragm and myocardium suffer progressive damage. While abnormalities in pulmonary and left ventricular function have been independently described, the relationship between pulmonary function and the right ventricle has not been evaluated. Methods Thirteen males with DMD enrolled in an ongoing clinical trial underwent CMR with multislice short axis cine imaging, using either breathhold segmented steady-state free precession or real-time acquisition techniques. Offline analysis of right ventricular volumes and ejection fractions was performed by a single reviewer blinded to PFT results using endocardial contour delineation and Simpson’s rule. Forced vital capacity (FVC%) was recorded from PFTs acquired within 10 weeks of CMR examination, and serum brain natriuretic peptide levels were measured. Subjects were classified into two groups based on having at least 80% predicted FVC. Results Of the 13 subjects aged 17.5± 6.5 years (mean ± SD) who underwent CMR and concurrent FVC assessment, 11 were non-ambulatory and all subjects were on chronic oral corticosteroids at the time of imaging. Left ventricular ejection fraction (LVEF) was normal in the study group (56.9±5.3%). The right ventricular indexed stroke volume was reduced in subjects who had less than 80% predicted FVC compared to patients who had more than 80% predicted FVC (25.2±4.9 vs. 32.4±5.3 mL/m 2 ; p=0.026, Figure). There was no significant difference in the LVEF between two groups (55.5±5.2 vs. 58.1± 5.6, mean ± SD; p=0.4).There was no correlation between indices of right ventricular size and systolic function and BNP levels. Conclusions Variable RV systolic function and pulmonary function were demonstrated in boys with DMD and normal LV systolic function as assessed by CMR. Abnormal pulmonary function is correlated with reduced RV stroke volume in boys with DMD and preserved LV systolic