Marly Conceição Silva

Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy: A Randomized Clinical Trial

Importance In Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), interventions reducing the progression of myocardial disease could affect survival. Objective To assess the effect of early angiotensin-converting enzyme (ACE) inhibitor therapy in patients with normal left ventricular function on the progression of myocardial fibrosis (MF) identified on cardiovascular magnetic resonance (CMR). Design, Setting, and Participants A randomized clinical trial conducted in 2 centers included 76 male patients with DMD or BMD undergoing 2 CMR studies with a 2-year interval for ventricular function and MF assessment. In a non–intent-to-treat trial, 42 patients with MF and normal left ventricular ejection fraction (LVEF) were randomized (1:1) to receive or not receive ACE inhibitor therapy. The study was conducted from June 26, 2009, to June 30, 2012. Data analysis was performed from June 30, 2013, to October 3, 2016. Interventions Randomization (1:1) to receive or not receive ACE inhibitor therapy. Main Outcomes and Measures Primary outcome was MF progression from baseline to the 2-year CMR study. Results Of the 76 male patients included in the study, 70 had DMD (92%) and 6 had BMD (8%); mean (SD) age at baseline was 13.1 (4.4) years. Myocardial fibrosis was present in 55 patients (72%) and LV systolic dysfunction was identified in 13 patients (24%). Myocardial fibrosis at baseline was an independent indicator of lower LVEF at follow-up (coefficient [SE], −0.16 [0.07]; P = .03). Among patients with MF and preserved LVEF (42 [55%]), those randomized (21 patients in each arm) to receive ACE inhibitors demonstrated slower MF progression compared with the untreated group (mean [SD] increase of 3.1% [7.4%] vs 10.0% [6.2%] as a percentage of LV mass; P = .001). In multivariate analysis, ACE inhibitor therapy was an independent indicator of decreased MF progression (coefficient [SE], −4.51 [2.11]; P = .04). Patients with MF noted on CMR had a higher probability of cardiovascular events (event rate, 10 of 55 [18.2%] vs 0 of 21 [0%]; log-rank P = .04). Conclusions and Relevance In this 2-year, follow-up, randomized clinical trial of patients with Duchenne or Becker muscular dystrophy whose LVEF was preserved and MF was present as determined on CMR, ACE inhibitor therapy was associated with significantly slower progression of MF. The presence of MF was associated with worse patient prognosis. Trial Registration clinicaltrials.org Identifier: NCT02432885

Rest left ventricular function and contractile reserve by dobutamine stress echocardiography in peripartum cardiomyopathy

AIMS To assess whether contractile reserve during dobutamine stress echocardiography (DSE) can predict left ventricular functional recovery in patients with peripartum cardiomyopathy and to assess myocardial fibrosis by magnetic resonance imaging (MRI) in these patients. METHODS Nine patients with peripartum cardiomyopathy were enrolled. All patients underwent DSE and were followed for six months, when a rest Doppler echocardiogram was repeated. MRI was also performed at the beginning of follow-up to identify myocardial fibrosis. RESULTS Mean age was 29±7.9 years and mean left ventricular ejection fraction at baseline was 39.4±8.6% (range 24-49%). Eight of the nine patients showed left ventricular functional recovery with mean ejection fraction at follow-up of 57.1±13.8%. The ejection fraction response to DSE did not predict recovery at follow-up. On the other hand, left ventricular ejection fraction at baseline correlated with ejection fraction at follow-up. Mild fibrosis was detected in only one patient. CONCLUSION Left ventricular ejection fraction at baseline was a predictor of left ventricular functional recovery in patients with peripartum cardiomyopathy. Dobutamine stress echocardiography at presentation of the disease did not predict recovery at follow-up. Myocardial fibrosis appeared to be uncommon in this cardiomyopathy.

Progression of myocardial fibrosis by magnetic resonance imaging in patients with Duchenne and Becker muscular dystrophy and preserved left ventricular ejection fraction - a randomized clinical trial for treatment with ACE inhibitors.

Background Duchenne (DMD) and Becker (BMD) muscular dystrophies ( MD) are inherited X-linked diseases characterized by absence or decrease of dystrophin, a sarcolemal protein that is essential for maintenance of the muscular membrane integrity during muscular contraction. Cardiac involvement is as high, it can be clinically silent, but is often complicated by severe heart failure and high mortality. Angiotensin-converting enzyme inhibitors (ACEI) is recommended for patients with left ventricular dysfunction. We previously described that CMR can identify myocardial fibrosis (MF) even in the early stages of cardiomyopathy in MD before overt LV dysfunction (J Am Coll Cardiol 2007;49:1874-9). The impact of treatment with ACE inhibitors in the progression of fibrosis in patients with MD and preserved LV function is still unknown.

Age-related creatinophosphokinase and myocardial fibrosis changes in patients with muscular dystrophy

Background Duchenne (DMD) and Becker (BMD) muscular dystrophy (MD) are characterized by progressive peripheral muscular damage. The cardiac involvement is high and often complicated by severe heart failure and high mortality. Cardiovascular magnetic resonance (CMR) can identify early stages of cardiomyopathy, as presence of myocardial fibrosis (MF). Several studies have shown negative correlation between creatinophosphokinase (CPK) levels and worst stages of peripheral muscular dystrophy, but have not evaluated their possible association with myocardial damage. Our objective was to investigate CPK levels and magnitude of myocardial damage in patients with MD. Methods

Association between specific dystrophin gene mutations and myocardial fibrosis by cardiovascular magnetic resonance imaging in patients with Duchenne and Becker muscular dystrophy.

Background Duchenne (DMD) and Becker (BMD) muscular dystrophies (MD) are allelic X-linked recessive disorders, caused by mutation of the dystrophin gene located at locus Xp21 that consists of 79 exons, characterized by progressive skeletal muscle degeneration and replacement by fibro fatty tissue. Dystrophin is a sarcolemal protein that links the cytoskeleton to the basal lamina and is essential for maintenance of the muscular membrane integrity during muscular contraction. Cardiac involvement is frequent, 70 - 80% of patients, and often develops clinically silent, without any evident early clinical signs. CMR can identify myocardial fibrosis (MF) and may be useful for detecting the early stages of cardiomyopathy in MD. In a previous study, DNA analyses in 47 pts with DMD revealed significant association between dilated cardiomyopathy (DCM) and specific exons and possible protection against DCM by other exons. The association between specific exons mutation of the dystrophin gene and myocardial fibrosis is until unknown.

Progression of myocardial fibrosis by magnetic resonance imaging in patients with Duchenne and Becker muscular dystrophy

Background Duchenne (DMD) and Becker (BMD) muscular dystrophy (MD) are inherited X-linked disease characterized by progressive skeletal muscle degeneration and myocardial involvement and caused by a mutation on dystrophin gene (Xp21). Dystrophin is a sarcolemal protein that links the cytoskeleton to the basal lamina and is essential for maintenance of the muscular membrane integrity during muscular contraction. In a previous study, our group described for the first time, in a small group of 10 patients, that CMR can identify myocardial fibrosis (MF) and may be useful for detecting the early stages of cardiomyopathy in MD [1]. The evolution of the myocardial fibrosis over time in this group of patient is still unknown. Methods We enrolled 76 pts, 70 pts with DMD and 6 BMD. Mean age was 13.1 ± 4.4 years. 74 patients underwent 2 CMR exams within a mean of 2.3 years, performed on a 1.5-T Siemens Avanto (Erlangen, Germany). Breath-hold LV short-axis and long-axis images were obtained by 2-pulse sequences at the same locations, allowing precise comparisons between LV function (gradient-echo sequence, steady-state free precession) and myocardial structure (inversion-recovery prepared gradient-echo sequence, 10 min after intravenous bolus or 0.2 mmol/kg gadolinium-based contrast), acquired with the following parameters, respectively: TR 2.0/ 9.0, TE 1.07/ 5.0; flip angle 69/50; cardiac phases 20/1; VPS 8/16 to 32; matrix 192 x 162 / 256 x 192; ST 8/8 mm; gap 2/2 and FOV 32 to 38/32 to 38 cm; TI none/150 to 390 ms; receiver bandwidth 930/150 Hz; number of excitations 1/1; acquisition every other heartbeat for MDE. The images were analyzed by two experienced observers. End-systolic LV volume, end-diastolic LV volume and LV ejection fraction were measured by the Simpson method using Argus software, Siemens. For the MDE short axis images, we evaluated the MF mass per patient, using a 5 standard deviation thresholding technique, on a CMR42 software, version 3.4.2 (Circle Cardiovascular Imaging, Calgary, Alberta, Canada). Normal LVEF was defined as above 50%. Test of Wilcoxon was used for comparison of myocardial fibrosis between baseline and follow-up CMR studies. Results Two patients died before the follow-up CMR. For all 74 patients, MF increased significantly from 11.3 ± 12.2 g on the baseline CMR to 15.9 ± 15.4 g, p<0.001. The number of segments with MF increased from 3.7 ± 3.3 to 5.1 ± 3.6, p<0.001. In a sub-group with LV dysfunction (n=11) MF increased from 26.9 ± 13.0 g to 35.5 ± 20.2 g, p=0.021. In a sub-group of patients with normal LVEF and no fibrosis (n=21) on the baseline CMR, MF progressed from 0 g to 1.5 ± 3.7 g, p=0.08. Conclusions Myocardial fibrosis detected by CMR progressively increases in patients with Duchenne and Becker muscular dystrophy over a period of 2.3 years. The progression occurs not only in patients with more advanced cardiomyopathy and LV dysfunction, but also in patients with normal function and no myocardial fibrosis at the baseline CMR.

Original ArticleRest left ventricular function and contractile reserve by dobutamine stress echocardiography in peripartum cardiomyopathyFunção ventricular esquerda em repouso e reserva contrátil pelo ecocardiograma de estresse com dobutamina na miocardiopatia periparto

Aims To assess whether contractile reserve during dobutamine stress echocardiography (DSE) can predict left ventricular functional recovery in patients with peripartum cardiomyopathy and to assess myocardial fibrosis by magnetic resonance imaging (MRI) in these patients.