natriuretic-peptide--brain and Muscular-Dystrophy--Duchenne

Heart failure (HF) is a fatal complication in many muscular dystrophy cases and has become the most common cause of death in Duchenne muscular dystrophy (DMD) since 2001. HF deaths in DMD occur in young patients and increase, along with respiratory failure, in older patients. Managing HF, therefore, is the most important component of DMD treatment. Management of HF is necessary in DMD patients of all ages because myocardial damage progresses regardless of age and disability. Electrocardiography, echocardiography, myocardial single-photon emission computed tomography (SPECT), and natriuretic peptides are used for the diagnosis of myocardial damage and chronic HF. Tissue Doppler echocardiography is in particularly useful for early detection of minute myocardial damage and dysfunction in DMD. The first-line drugs for chronic HF are angiotensin-converting enzyme inhibitors, and the prognosis of DMD patients has been improved using these drugs and beta-blockers. Diuretics are added in the presence of pulmonary congestion. Digoxin is most effective at a blood level of 0.5-0.8 ng/mL because of its pharmacokinetics in DMD. Surgical treatment may be necessary in cases of intractable HF. Cardiac resynchronization therapy (biventricular pacing), a treatment with an artificial pacemaker, is indicated for cases that meet specific criteria, including HF with ventricular dyssynchrony. Applications of partial left ventriculectomy (Batista procedure) and left ventricular assist devices in muscular dystrophy are likely in the near future.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Cardiac Resynchronization Therapy; Cardiomyopathies; Chronic Disease; Diagnostic Imaging; Heart Failure; Humans; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain

As there is no cure in Duchenne muscular dystrophy (DMD), we must pay attention to the management of its cardiopulmonary complications. In 1984, DMD patients died at the mean age of 18.2 years in my hospital. From autopsy findings, the cause of death was respiratory failure in 75% of them, and left-sided heart failure 12.5%. First, we had to know the relationship between cardiac and respiratory systems. Based on the findings of right-sided heart catheterization, patients with respiratory failure were classified into Forrester's subset 1' normal left ventricular function. These results showed that these patients require treatment with a respirator, but not with digitalis and/or diuretics. Since 1984, we tried cuirass ventilation, which prolonged their lives by about 3 years. Since 1991, NIPPV was introduced in Japan, and prolonged their lives by about 5.5 years. Nowadays TIPPV with tracheostomy is not the first choice of treatment, but we do not hesitate to select this treatment any more. As for left-sided heart failure, brain natriuretic peptide (BNP) is now considered a useful parameter of left ventricular function. Japanese clinical researcher proposed treatment based on values of BNP in left-sided heart failure. In 1980s, the mean interval from the onset of heart failure to death was only 16 months. Recently we feel that better results have already been accomplished. In 2002 Kawai reported that average age at death in Japan was 26.8 years old. More efforts must be made until cure of this disease is found.

Topics: Biomarkers; Heart Failure; Humans; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Positive-Pressure Respiration; Respiratory Insufficiency; Stroke Volume; Survival Rate

Dystrophinopathies are due to mutations in the dystrophin gene on chromosome Xp21.1 and comprise the allelic entities Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and X-linked dilative cardiomyopathy (XLDCM). In all three entities, the heart is affected to various degrees, depending on the stage of the disease and the type of the mutation (cardiac involvement, CI). The pathoanatomic evidence of CI in dystrophinopathies is the replacement of myocardium by connective tissue or fat. In DMD/BMD, the left ventricular posterobasal and lateral walls are most extensively affected, sparing the right ventricle and the atrium. Degree and dynamics of CI vary among the three entities. In DMD/BMD, CI usually remains subclinical in the early stages of the disease. Typical initial manifestations of CI in DMD/BMD are sinus tachycardia, tall R1 in V1, prominent Q in I, aVL, V6 or in II, III, and aVF, increased QT dispersion and possibly autonomic dysfunction. Initially, echocardiography is normal or shows regional wall motion abnormalities in areas of fibrosis. With spreading of fibrosis, left ventricular dysfunction and ventricular arrhythmias additionally occur. In the final stages of the disease, systolic function may lead to heart failure and sudden death. Subclinical or clinical CI is present in about 90% of the DMD/BMD patients but is the cause of death in only 20% of the DMD and 50% of the BMD patients. XLDCM is a rapidly progressive, almost exclusively myocardial disorder, starting in teenage males as heart failure due to dilative cardiomyopathy (CMP), leading to death from intractable heart failure within 1-2 years after diagnosis. Therapy of arrhythmias and CMP in all three disorders follows the established cardiological recommendations. Due to its protective effect, ACE inhibitors are recommended already at the early stages of the disease. Beta-blockers may be an additional option if indicated.

Topics: Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Diagnostic Imaging; Electrocardiography; Heart Conduction System; Heart Diseases; Humans; Muscular Dystrophies; Muscular Dystrophy, Duchenne; Myocardium; Natriuretic Peptide, Brain; Signal Processing, Computer-Assisted

As there is no cure in patients with Duchenne muscular dystrophy (DMD) yet, we must pay attention to manage cardiopulmonary complications in DMD. They died at 18.2 years old in 1984 in my hospital. From autopsy findings, respiratory failure occupied 75%, and left-sided heart failure occupied 12.5%. First of all, we had to know the relationship between cardiac system and respiratory system. Right-sided heart catheterization revealed that respiratory failure patients were divided into Forrester's subset 1 (left ventricular function was within normal limits). So, it is unnecessary to give digitalis and/or diuretics for patients with respiratory failure. They only need respirator treatment. We tried cuirass ventilation since 1984. This respirator elongated their lives about 3 years. Since 1991 NIPPV was introduced in Japan, this treatment elongated their lives about 5.5 years. Nowadays TIPPV with tracheostomy is not first choice of treatment but we select this treatment not so unwillingly as before. As for left-sided heart failure, BNP (brain natriuretic peptide) is now considered useful parameter for left ventricular function. Japanese clinical researcher proposed treatment based on Values of BNP in left-sided heart failure. In 1980s, from the onset of heart failure until death was only 16 months, we feel that better results already accomplished. Kawai reported that average age at death in Japan was 26.8 years old in 2002. Our efforts must be done more and more until cure of this disease can be found.

Topics: Adolescent; Adult; Age Factors; Biomarkers; Cause of Death; Child; Heart Failure; Humans; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Positive-Pressure Respiration; Respiratory Insufficiency; Ventricular Function, Left

Early mortality in Duchenne muscular dystrophy (DMD) is related to cardiac and respiratory complications. A phase IIa double-blind randomized placebo-controlled clinical trial was conducted to investigate the tolerability and efficacy of idebenone therapy in children with DMD. Twenty-one DMD patients (aged 8-16 years) were randomly assigned to daily treatment with 450 mg idebenone (Catena®) (n=13) or placebo (n=8) for 12 months. All subjects completed the study and idebenone was safe and well tolerated. Idebenone treatment resulted in a trend (p=0.067) to increase peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. A significant respiratory treatment effect on peak expiratory flow was observed (p=0.039 for PEF and p=0.042 for PEF percent predicted). Limitations of this study were the small sample size, and a skewed age distribution between treatment groups. Data from this study provided the basis for the planning of a confirmatory study.

Topics: Adolescent; Antioxidants; Child; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Forced Expiratory Volume; Humans; Longitudinal Studies; Male; Muscle Strength; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Treatment Outcome; Troponin I; Ubiquinone; Vital Capacity

Since growth hormone (GH) has proven beneficial in experimental heart failure, and the natural history of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is frequently complicated by the development of dilated cardiomyopathy, we administered GH to six patients with DMD and 10 with BMD, with the evidence of cardiac involvement.. Patients were randomized to receive for 3 months either placebo or recombinant human GH, in a double-blind fashion. In GH-treated patients, left ventricular (LV) mass increased by 16% in BMD and by 29% in DMD (both p<0.01), with a significant increase of relative wall thickness (+19%). Systemic blood pressure remained unchanged, while LV end-systolic stress fell significantly by 13% in BMD and by 33% in DMD, with a slight increase of systolic function indexes. No changes were observed related to cardiac arrhythmias and skeletal muscle function in the patient groups during the treatment period, nor any side effects were observed. Brain natriuretic peptide, interleukin-6, and tumor necrosis factor-alpha circulating levels were elevated at baseline. While brain natriuretic peptide decreased by 40%, cytokine levels did not exhibit significant variations during the treatment period.. The 3-month GH therapy in patients with DMD and BMD induces a hypertrophic response associated with a significant reduction of brain natriuretic peptide plasma levels and a slight improvement of systolic function, no changes in skeletal muscle function, and no side effects.

Topics: Adolescent; Adult; Analysis of Variance; Cardiomegaly; Child; Double-Blind Method; Electrocardiography; Heart Diseases; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Interleukin-6; Lung; Male; Middle Aged; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Regression Analysis; Tumor Necrosis Factor-alpha

Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (

Topics: Adult; Cardiomyopathies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dystrophin; Exome Sequencing; Female; Genetic Predisposition to Disease; Heart Function Tests; Humans; Magnetic Resonance Imaging, Cine; Male; Muscular Dystrophy, Duchenne; Mutation, Missense; Natriuretic Peptide, Brain; Peptide Fragments; Stroke Volume; Ventricular Dysfunction, Left

The longer survival of patients with Duchenne muscular dystrophy due to advances in clinical care has increased the incidence of Duchenne muscular dystrophy-associated cardiomyopathy, a nearly consistent feature in the third decade of life. A 26-year-old patient with Duchenne muscular dystrophy experienced severe acute heart failure triggered by pneumonia. Levosimendan was effective in improving heart function.

Topics: Acute Disease; Adult; Cardiomyopathies; Cardiotonic Agents; Heart Failure; Humans; Lactic Acid; Male; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Pneumonia; Simendan

Progressive cardiomyopathy (CMP) is one main cause of death in DMD. This cross-sectional assessment of different cardiac diagnostic procedures focusses on preterm diagnosis of cardiac dysfunction.. 39 male DMD patients aged 6-20 years were included. 6 patients were still ambulatory, 21 patients received corticosteroid therapy.. All patients were investigated by ECG, Holter ECG and heart rate variability (HRV), B-type natriuretic peptide (BNP), echocardiography (TTE), tissue Doppler Imaging (TD) and magnetic resonance imaging (MRI) with Late Gadolinium enhancement (LE) and segmental wall motion analysis (WMA).. 56% of the patients showed repolarization abnormalities and 76% altered HRV. Subnormal ventricular function was found in 25% by TTE and in 34% by MRI. TD differed from normal controls only in the apical septum. In MRI 89% of the patients showed different distribution and intensity of LE and WM restriction. The extent of LE was less in patients after steroid treatment (p<0.05).. MRI with segmental LE- and WM-analysis seems to be superior to TTE and TD in exploring regional distribution and severity of damage of the myocardium. ECG and HRV abnormalities are common in DMD-patients but not tightly predictive for segmental and global left ventricular dysfunction. Targeted treatment of CMP in DMD needs prospective evaluation.. A timely cardiac MRI is the most sensitive investigation for the identification of early myocardial changes in DMD which is a prerequisite for early interventions and therapeutic strategies.

Topics: Adolescent; Autonomic Nervous System Diseases; Cardiomyopathies; Child; Contrast Media; Diagnostic Imaging; Echocardiography, Doppler; Elasticity Imaging Techniques; Electrocardiography; Electrocardiography, Ambulatory; Heart Rate; Hemodynamics; Heterocyclic Compounds; Humans; Magnetic Resonance Imaging; Male; Muscular Dystrophy, Duchenne; Myocardial Contraction; Natriuretic Peptide, Brain; Organometallic Compounds; Reference Values; Young Adult

A boy with Duchenne muscular dystrophy was admitted to our hospital due to a transient loss of consciousness. Transthoracic echocardiography revealed left ventricular (LV) dilatation and diffuse hypokinesis of the LV wall. The LV wall was thin, and both non-compaction of the LV wall and marked thinning of the posterior LV wall resulting from a lesion were observed. The plasma B-type natriuretic peptide (BNP) level ultimately increased to 7,795 pg/mL, and the patient died of cardiac arrest following ventricular tachycardia. Severe heart failure, a critical condition, and thinning of the LV wall may have contributed to the markedly high plasma BNP level in this case.

Topics: Adolescent; Atrial Natriuretic Factor; Biomarkers; Diuretics; Fatal Outcome; Heart Failure; Humans; Male; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Ultrasonography; Ventricular Dysfunction, Left

Of the numerous clinical trials for Duchenne muscular dystrophy, only the corticosteroid prednisolone has shown potential for temporal improvement in motor ability. In this study, the effects of prednisolone on intellectual ability are examined in 29 cases of Duchenne muscular dystrophy because little information has been reported. And also, motor functions and cardiac functions were evaluated.. The treated group was administered prednisolone (0.75 mg/kg) orally on alternate days and the compared with the untreated control group. Gene mutations were investigated. The patients were examined for intelligence quotient adequate for age, brain natriuretic peptide, creatine kinase, and manual muscle testing before treatment and after the period 6 months to 2 years.. Intelligence quotient scores of the treated increased to 6.5 ± 11.9 (mean ± standard deviation) were compared with the controls 2.1 ± 4.9 (P = 0.009). Intelligence quotient scores of the patients with nonsense point mutations improved significantly (21.0 ± 7.9) more than those with deletion or duplication (1.9 ± 9.0; P = 0.015). Motor function, such as time to stand up, of those treated improved significantly and brain natriuretic peptide level was reduced to a normal level after treatment in 15 patients (73%).. Our results demonstrate the effectiveness of prednisolone in improving intellectual impairment as well as in preserving motor function and brain natriuretic peptide levels. We presume that prednisolone has a read-through effect on the stop codons in the central nervous systems of Duchenne muscular dystrophy because intelligence quotient of point mutation case was improved significantly.

Topics: Adrenal Cortex Hormones; Child; Child, Preschool; Creatine Kinase; Female; Humans; Intelligence Tests; Male; Muscle Strength; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Prednisolone; Psychomotor Agitation; Psychomotor Disorders; Retrospective Studies

Cardiomyopathy is reported in Duchenne and Becker muscle dystrophy patients and female carriers. Brain Natriuretic peptide (BNP) is a hormone produced mainly by ventricular cardiomyocytes and its production is up regulated in reaction to increased wall stretching. N-terminal-proBNP (NT-proBNP) has been shown to be a robust laboratory parameter to diagnose and monitor cardiac failure, and it may be helpful to screen for asymptomatic left ventricular dysfunction. Therefore we tested whether NT-proBNP can distinguish patients with Duchenne or Becker muscular dystrophy patients and carriers of a dystrophin mutation with a dilated cardiomyopathy from those without.. In a cohort of Duchenne and Becker muscle dystrophy patients (n = 143) and carriers (n = 219) NT-proBNP was measured, and echocardiography was performed to diagnose dilated cardiomyopathy (DCM).. In total sixty-one patients (17%) fulfilled the criteria for DCM, whereas 283 patients (78%) had an elevated NT-pro BNP. The sensitivity of NT-proBNP for DCM in patients or carriers was 85%, the specificity 23%, area under the ROC-curve = 0.56. In the specified subgroups there was also no association.. Measurement of NT-pro BNP in patients suffering from Duchenne or Becker muscular dystrophy and carriers does not distinguish between those with and without dilated cardiomyopathy.

Topics: Adolescent; Adult; Aged; Cardiomyopathy, Dilated; Child; Cohort Studies; Dystrophin; Echocardiography; Female; Heart Failure; Humans; Middle Aged; Muscular Dystrophy, Duchenne; Mutation; Natriuretic Peptide, Brain; Peptide Fragments; Retrospective Studies; ROC Curve; Statistics, Nonparametric; Young Adult

We evaluated ambulatory patients with Duchenne muscular dystrophy from the cardiovascular standpoint and studied the correlation between the results of electrocardiographic (ECG) findings, left ventricular ejection fraction (LVEF), troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and patients' North Star Ambulatory Assessment scores.. Fifty patients of ages 6-12 (8.9 ± 2.8) were enrolled in this cross-sectional study. Cardiac evaluation included electrocardiography, echocardiography and cardiac enzyme tests.. North Star scores ranged from 6/34 to 34/34. Twenty-eight patients (56%) had ECG changes. The most frequently seen ECG abnormalities were short PR interval (14%, n= 7), right ventricular hypertrophy (16%, n= 8), prolonged QTc interval (10%, n= 5), prominent Q wave (10%, n= 5) and T wave inversion (44%, n= 22). In 10 patients (20%), LVEF was below 55%, troponin T and NT-proBNP levels were significantly elevated (P= 0.003 and P < 0.001, respectively). When North Star scores were compared to patients' age, enzyme levels, ECG and echocardiographic results, we discovered negative correlation with age (P < 0.001) and troponin T levels (P= 0.02) and positive correlation with LVEF (P= 0.02).. Patients with North Star scores of ≤16 are more at risk of developing cardiomyopathies. Troponin T is a cardiac index that can be used for evaluating myopathic patients and it seems to be correlated with the proBNP levels and LVEF values.

Topics: Arrhythmias, Cardiac; Cardiomyopathies; Child; Cross-Sectional Studies; Echocardiography; Electrocardiography; Humans; Male; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Peptide Fragments; Severity of Illness Index; Stroke Volume; Troponin T

Serum levels of B-type natriuretic peptide have moderate utility for detection of early ventricular dysfunction in adults and in experimental muscular dystrophy. To determine if B-type natriuretic peptide levels are useful in the detection of early left ventricular dysfunction in Duchenne muscular dystrophy patients, measurements were obtained in 21 patients being evaluated by echocardiography for left ventricular dysfunction. Two patients with clinical evidence of heart failure were excluded (mean B-type natriuretic peptide level of 352 pg/ml). Age range of the remaining 19 patients was 9-21 yrs. Fractional shortening was abnormal (<30%) in 14/19 and early diastolic tissue Doppler velocities were abnormal in 13/16. In these patients B-type natriuretic peptide levels were clearly normal (<30 pg/ml) in 15/19 and only mildly elevated (30-80 pg/ml) in 4/19. The 4 patients with mildly elevated B-type natriuretic peptide had significantly lower fractional shortening (12.6+/-5.9 versus 19.8+/-5.3, p<0.05). In conclusion, B-type natriuretic peptide levels are normal in the majority of Duchenne muscular dystrophy patients with asymptomatic left ventricular dysfunction and only mildly elevated when fractional shortening is markedly reduced.

Topics: Adolescent; Adult; Child; Humans; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain; Retrospective Studies; Ultrasonography; Ventricular Dysfunction, Left

Topics: Cardiomyopathy, Dilated; Echocardiography; Heart Ventricles; Humans; Lymphoproliferative Disorders; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain

Dilated cardiomyopathy is a common complication of Duchenne and Becker muscular dystrophies, which are caused by mutations in the dystrophin gene. The mdx mouse is an animal model for Duchenne muscular dystrophy (DMD) and shows mildly dystrophic changes in the heart. By contrast, the utrophin-dystrophin knockout (dko) mouse shows severe dystrophic changes in cardiac muscle, that more closely resembles DMD cardiomyopathy than mdx mouse. However the pathogenesis of development has not been fully understood. Recently many reports have revealed that calcineurin and stress activated protein kinase (SAPK)/p38-mitogen activated protein kinase (MAPK) hypertrophic signalling pathways are associated with the development of some forms of hypertrophic and dilated cardiomyopathies. These signalling pathways may have some roles in the development of dystrophin-deficient cardiomyopathy. Here we report that calcineurin and SAPK/p38-MAPK signalling pathways were constantly activated in dko hearts, but the activation varied in mdx hearts. The pathogenesis of the development of dystrophin-deficient cardiomyopathy may be associated with the activation of these signalling pathways.

Topics: Age Factors; Animals; Atrial Natriuretic Factor; Calcineurin; Cardiomyopathy, Dilated; Cytoskeletal Proteins; Dystrophin; Glyceraldehyde-3-Phosphate Dehydrogenases; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Muscular Dystrophy, Duchenne; Myocardium; Natriuretic Peptide, Brain; p38 Mitogen-Activated Protein Kinases; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Signal Transduction; Utrophin