Beth McCarthy

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.

In vivo atherosclerotic plaque characterization using magnetic susceptibility distinguishes symptom-producing plaques.

OBJECTIVES We investigated the role of iron deposition in atherosclerotic plaque instability using a novel approach of in vivo plaque characterization by a noninvasive, noncontrast magnetic resonance-based T2* measurement. This approach was validated using ex vivo plaque analyses to establish that T2* accurately reflects intraplaque iron composition. BACKGROUND Iron catalyzes free radical production, a key step for lipid peroxidation and atherosclerosis development. The parameter T2* measures tissue magnetic susceptibility, which historically has been used to quantify hepatic and myocardial iron. The T2* measurement has not been used for in vivo plaque characterization in patients with atherosclerosis. METHODS Thirty-nine patients referred for carotid endarterectomy were prospectively enrolled to undergo preoperative carotid magnetic resonance imaging (MRI) and postoperative analysis of the explanted plaque. Clinical history of any symptoms attributable to each carotid lesion was recorded. We could not complete MRI in 4 subjects because of their claustrophobia, and 3 patients scanned before the institution of a neck stabilizer had motion artifact, precluding quantification. RESULTS Symptomatic patients had significantly lower plaque T2* values (20.0 +/- 1.8 ms) compared with asymptomatic patients (34.4 +/- 2.7 ms, p < 0.001). Analytical methods demonstrated similar total iron (138.6 +/- 36.5 microg/g vs. 165.8 +/- 48.3 microg/g, p = NS) but less low molecular weight Fe(III) (7.3 +/- 3.8 microg/g vs. 17.7 +/- 4.0 microg/g, p < 0.05) in the explanted plaques of symptomatic versus asymptomatic patients, respectively, which is consistent with a shift in iron from Fe(III) to greater amounts of T2*-shortening forms of iron. Mass spectroscopy also showed significantly lower calcium (37.5 +/- 10.8 mg/g vs. 123.6 +/- 19.3 mg/g, p < 0.01) and greater copper (3.2 +/- 0.5 microg/g vs. 1.7 +/- 0.1 microg/g, p < 0.01) in plaques from symptomatic patients. CONCLUSIONS In vivo measurement of intraplaque T2* using MRI is feasible and distinguishes symptom-producing from non-symptom-producing plaques in patients with carotid artery atherosclerosis. Symptom-producing plaques demonstrated characteristic changes in iron forms by ex vivo analysis, supporting the dynamic presence of iron in the microenvironment of atherosclerotic plaque.

Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome

AIMS Cardiomyopathy produces significant mortality in patients with Friedreich ataxia (FA), a genetic disorder that produces intra-mitochondrial iron accumulation. We sought to test the hypothesis that abnormal myocardial perfusion reserve and fibrosis represent early manifestations of cardiomyopathy. METHODS AND RESULTS Twenty-six patients with genetically proven FA ages 36 ± 12 years without cardiomyopathy and eight controls underwent cardiac magnetic resonance with adenosine. Precontrast imaging for myocardial iron estimation was performed. Myocardial perfusion reserve index (MPRI) was quantified using the normalized upslope of myocardial enhancement during vasodilator stress vs. rest. Left ventricular (LV) mass and volumes were computed from short-axis cine images. Serologies included lipids, and platelets were isolated for iron quantification using inductively coupled plasma mass spectrometry. Left ventricular ejection fraction and mass averaged 64.1 ± 8.3% and 62.7 ± 16.7 g/m², respectively, indicating preserved systolic function and absence of significant hypertrophy. Myocardial perfusion reserve index quantification revealed significantly lower endocardial-to-epicardial perfusion reserve in patients vs. controls (0.80 ± 0.18 vs. 1.22 ± 0.36, P = 0.01). Lower MPRI was predicted by increased number of metabolic syndrome (met-S) features (P < 0.01). Worse concentric remodelling occurred with increased GAA repeat length (r = 0.64, P < 0.001). Peripheral platelet iron measurement showed no distinction between patients and controls (5.4 ± 8.5 × 10⁻⁷ vs. 5.5 ± 2.9 × 10⁻⁷ ng/platelet, P = 0.88), nor did myocardial T2* measures. CONCLUSIONS Patients with FA have abnormal myocardial perfusion reserve that parallels met-S severity. Impaired perfusion reserve and fibrosis occur in the absence of significant hypertrophy and prior to clinical heart failure, providing potential therapeutic targets for stage B cardiomyopathy in FA and related myocardial diseases.

Mid-Myocardial Fibrosis by Cardiac Magnetic Resonance in Patients with Lamin A/C Cardiomyopathy: Possible Substrate for Diastolic Dysfunction

AIMS We sought to identify patterns of myocardial fibrosis in vivo in patients with lamin cardiomyopathy, and to determine its functional significance. METHODS AND RESULTS Eleven patients sharing the identical mutation in LMNA without contraindication to magnetic resonance were identified from a 1016-member pedigree. Eight autopsy hearts from deceased relatives were reviewed. Patients and age-matched controls underwent cardiac magnetic resonance that included measures of cardiac function and late gadolinium enhancement (LGE). LGE-CMR identified midmyocardial fibrosis of the basal interventricular septum in 5 of 11 LMNA patients that was identical to that seen in 6 autopsy specimens of related genotype-positive family members; this was not present in any of 11 controls. LGE-CMR was positive in the 5 oldest patients in the cohort, age 46 +/- 6 years compared to 24 +/- 10 years for LGE-negative subjects (p = 0.003). Systolic function was abnormal in 2 subjects, both with myocardial fibrosis. LGE-positivity distinguished patients with diastolic dysfunction by mitral inflow velocities from those with normal diastolic function; these patients also had significant left atrial enlargement compared to controls (p < 0.05). CONCLUSIONS LGE-CMR can identify myocardial fibrosis under genetic control in vivo in patients with heritable cardiomyopathy similar in distribution to that observed at autopsy. Mid-myocardial fibrosis may form the substrate for diastolic dysfunction in these patients.

Real-time cine and myocardial perfusion with treadmill exercise stress cardiovascular magnetic resonance in patients referred for stress SPECT

BackgroundTo date, stress cardiovascular magnetic resonance (CMR) has relied on pharmacologic agents, and therefore lacked the physiologic information available only with exercise stress.Methods43 patients age 25 to 81 years underwent a treadmill stress test incorporating both Tc99m SPECT and CMR. After rest Tc99m SPECT imaging, patients underwent resting cine CMR. Patients then underwent in-room exercise stress using a partially modified treadmill. 12-lead ECG monitoring was performed throughout. At peak stress, Tc99m was injected and patients rapidly returned to their prior position in the magnet for post-exercise cine and perfusion imaging. The patient table was pulled out of the magnet for recovery monitoring. The patient was sent back into the magnet for recovery cine and resting perfusion followed by delayed post-gadolinium imaging. Post-CMR, patients went to the adjacent SPECT lab to complete stress nuclear imaging. Each modalitys images were reviewed blinded to the others results.ResultsPatients completed on average 9.3 ± 2.4 min of the Bruce protocol. Stress cine CMR was completed in 68 ± 14 sec following termination of exercise, and stress perfusion CMR was completed in 88 ± 8 sec. Agreement between SPECT and CMR was moderate (κ = 0.58). Accuracy in eight patients who underwent coronary angiography was 7/8 for CMR and 5/8 for SPECT (p = 0.625). Follow-up at 6 months indicated freedom from cardiovascular events in 29/29 CMR-negative and 33/34 SPECT-negative patients.ConclusionsExercise stress CMR including wall motion and perfusion is feasible in patients with suspected ischemic heart disease. Larger clinical trials are warranted based on the promising results of this pilot study to allow comparative effectiveness studies of this stress imaging system vs. other stress imaging modalities.

Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I

BackgroundLimb girdle muscular dystrophies (LGMD) are inclusive of 7 autosomal dominant and 14 autosomal recessive disorders featuring progressive muscle weakness and atrophy. Studies of cardiac function have not yet been well-defined in deficiencies of dysferlin (LGMD2B) and fukutin related protein (LGMD2I). In this study of patients with these two forms of limb girdle muscular dystrophy, cardiovascular magnetic resonance (CMR) was used to more specifically define markers of cardiomyopathy including systolic dysfunction, myocardial fibrosis, and diastolic dysfunction.MethodsConsecutive patients with genetically-proven LGMD types 2I (n = 7) and 2B (n = 9) and 8 control subjects were enrolled. All subjects underwent cardiac magnetic resonance (CMR) on a standard 1.5 Tesla clinical scanner with cine imaging for left ventricular (LV) volume and ejection fraction (EF) measurement, vector velocity analysis of cine data to calculate myocardial strain, and late post-gadolinium enhancement imaging (LGE) to assess for myocardial fibrosis.ResultsSixteen LGMD patients (7 LGMD2I, 9 LGMD2B), and 8 control subjects completed CMR. All but one patient had normal LV size and systolic function; one (type 2I) had severe dilated cardiomyopathy. Of 15 LGMD patients with normal systolic function, LGE imaging revealed focal myocardial fibrosis in 7 (47%). Peak systolic circumferential strain rates were similar in patients vs. controls: εendo was -23.8 ± 8.5vs. -23.9 ± 4.2%, εepi was -11.5 ± 1.7% vs. -10.1 ± 4.2% (p = NS for all). Five of 7 LGE-positive patients had grade I diastolic dysfunction [2I (n = 2), 2B (n = 3)]. that was not present in any LGE-negative patients or controls.ConclusionsLGMD2I and LGMD2B generally result in mild structural and functional cardiac abnormalities, though severe dilated cardiomyopathy may occur. Long-term studies are warranted to evaluate the prognostic significance of subclinical fibrosis detected by CMR in these patients.

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.

The feasibility of combining low-level exercise with vasodilator stress in patients referred for stress perfusion cardiac MRI

Background Adenosine, an agonist of the A2a receptor, is widely used for stress CMR. However, target receptors for adenosine are heterogeneous in their location and facilitated physiologic effects. A2b and A3 receptors are responsible for bronchospasm and peripheral arteriolar vasodilation; A1 receptors are responsible for AV block. The rate of adverse reactions with adenosine approaches 80%, consisting of dyspnea, headache, flushing, chest/ abdominal discomfort, angina, ST depression, dizziness, nausea, and dysgeusia. In SPECT protocols, use of vasodilators has been previously established as safe during low level exercise, and results in fewer adverse reactions. Our hypothesis is that adenosine administered during low level exercise treadmill stress cardiac MRI is safe, feasible, and results in diagnostic quality imaging.