Successful transcatheter mitral valve repair with the MitraClip system in a patient with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a congenital X-linked muscular dystrophy, and cardiomyopathy typically develops in the second decade of life. In those patients with severe heart failure, the use of mechanical circulatory support is considered one of the treatment options, however, the decision to implant the assist device should be made after gauging the inherent risks and potential benefits. Transcatheter mitral valve repair (TMVr) is performed in adults with heart failure due to severe mitral regurgitation (MR) refractory to guideline-directed medical therapies. Data on MitraClip-based treatment (Abbott Vascular, Menlo Park, CA, USA) of young patients with cardiomyopathy-associated severe heart failure remain limited. We present the first report on the safety and effectiveness of TMVr with the MitraClip in an 18-year-old man with DMD and severe MR who was at a prohibitive risk for mitral valve surgery or left ventricular assist device therapy due to comorbidities. He was discharged without complications and, is now asymptomatic at one year after TMVr. Learning objective: Readers will be able to:Understand the mechanism of mitral regurgitationUnderstand the less invasiveness and usefulness of this procedure.Discuss the indication of transcatheter mitral valve repair in young patients with severe heart failure.

Tranilast for advanced heart failure in patients with muscular dystrophy: a single-arm, open-label, multicenter study.

BACKGROUND: The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. TRPV2 overexpression in the sarcolemma of skeletal and cardiac myocytes causes calcium influx into the cytoplasm, which triggers myocyte degeneration. In animal models of cardiomyopathy and muscular dystrophy (MD), TRPV2 inhibition was effective against heart failure and motor function. Our previous pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Thus, this single-arm, open-label, multicenter study aimed to evaluate the safety and efficacy of tranilast for heart failure. METHODS: The study enrolled MD patients with advanced heart failure whose serum BNP levels were > 100 pg/mL despite receiving standard cardioprotective therapy. Tranilast was administered orally at 100 mg, thrice daily. The primary endpoint was the change in log (BNP) (Δlog [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous multicenter study of carvedilol results in a mean population Δlog (BNP) of 0.18. TRPV2 expression on peripheral blood mononuclear cell surface, cardiac events, total mortality, left ventricular fractional shortening, human atrial natriuretic peptide, cardiac troponin T, and creatine kinase, and pinch strength were also assessed. RESULTS: Because of the poor general condition of many patients, only 18 of 34 patients were included and 13 patients could be treated according to the protocol throughout the 6-month period. However, there were no serious adverse events related to tranilast except diarrhea, a known adverse effect, and the drug was administered safely. TRPV2 expression on the mononuclear cell surface was elevated at baseline and reduced after treatment. Cardiac biomarkers such as BNP, human atrial natriuretic peptide, and fractional shortening remained stable, suggesting a protective effect against the progression of heart failure. In the per protocol set group, Δlog [BNP] was - 0.2 and significantly lower than that in the null hypothesis. CONCLUSIONS: Tranilast is safe and effective in inhibiting TRPV2 expression, even in MD patients with advanced heart failure. Further trials are needed to evaluate the efficacy of tranilast in preventing myocardial damage, heart failure, motor impairment, and respiratory failure. Clinical trial registration The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/ ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/ ) [November 12, 2021]. Patient registration was started in December 19, 2018.

Assessment of thrombocytopenia, sleep apnea, and cardiac involvement in GNE myopathy patients.

INTRODUCTION: We previously identified UDP-N-acetylglucosamine 2-epimerase (GNE) myopathy patients with sleep apnea and a past history of thrombocytopenia, but without disease-specific cardiac involvement. This study aimed to clarify the occurrence, severity, and serial changes of these complications. METHODS: Thirty-three genetically confirmed GNE myopathy patients who participated in a 5-y longitudinal observational history study underwent platelet count and platelet-associated immunoglobulin G (PA-IgG) measurements, a sleep study, and electrocardiography (ECG), Holter ECG, and echocardiogram examinations. RESULTS: Among the 33 patients, three had low platelet counts and 17 out of 26 were PA-IgG positive. No patient exhibited bleeding tendencies, and 3 out of 28 had low platelet counts. Muscle weakness was more pronounced, and summed MMT and grip power significantly lower, in PA-IgG-positive patients than in PA-IgG-negative patients. Of 19 patients, 7, 4, and 3 who underwent a sleep study had mild, moderate, and severe sleep apnea, respectively, and three started continuous positive airway pressure (CPAP). The respiratory disturbance index was not significantly correlated with physical evaluation items or forced vital capacity. All patients underwent ECG, 32 underwent cardiac ultrasound, and 25 underwent Holter ECG. No disease-specific cardiac involvement was noted, no serial changes during the follow-up period were observed for ECG and echocardiography, and none of the patients required therapy for cardiac abnormalities. DISCUSSION: PA-IgG is a potential disease biomarker in GNE myopathy patients, although its significance needs to be clarified. While none of the patients in this study experienced cardiomyopathy or arrythmia due to myopathy, sleep apnea was identified as a frequent complication.

Study Protocol for a Multicenter, Open-Label, Single-Arm Study of Tranilast for Cardiomyopathy of Muscular Dystrophy.

Duchenne (DMD) and other forms of muscular dystrophy (MD) are collectively rare and affect approx imately 20 per 100,000 people. The on-going development of exon skipping and other novel therapies for DMD is expected to lead to improvements in motor function prognosis. However, improvements in motor dysfunction with these novel therapies are associated with the risk of increase in cardiac burden. Development of therapies to improve cardiac function, therefore, is an urgent issue. This single-arm, open-label, multicenter study will include 20 patients with MD aged 13 years or older. Tranilast, a transient receptor potential cation channel subfamily V member 2 (TRPV2) inhibitor, will be administered orally for a period of 28 weeks at a dose of 300 mg/day divided into three daily doses. If consent to continue administration is obtained at 28 weeks, the drug will be administered for an additional 116 weeks. The primary outcome will be the change in brain natriuretic peptide (BNP) at 6 months after the start of administration compared to baseline. Tranilast is an anti-allergy agent that was developed in Japan. It has been used in a large number of clinical cases, including pediatric cases, and has been shown to be safe. We expect this study to provide basic data for developing new treatment method in cardiomyopathy/skeletal myopathy using TRPV2 inhibitors. Moreover, such therapies may also be effective in treating general heart failure without MD. Therefore, if the effectiveness of TRPV2 inhibitors could be confirmed in this study, great social and economic benefits could be achieved.

Cardiac Conduction Disorders as Markers of Cardiac Events in Myotonic Dystrophy Type 1.

Background Myotonic dystrophy type 1 involves cardiac conduction disorders. Cardiac conduction disease can cause fatal arrhythmias or sudden death in patients with myotonic dystrophy type 1. Methods and Results This study enrolled 506 patients with myotonic dystrophy type 1 (aged ≥15 years; >50 cytosine-thymine-guanine repeats) and was treated in 9 Japanese hospitals for neuromuscular diseases from January 2006 to August 2016. We investigated genetic and clinical backgrounds including health care, activities of daily living, dietary intake, cardiac involvement, and respiratory involvement during follow-up. The cause of death or the occurrence of composite cardiac events (ie, ventricular arrhythmias, advanced atrioventricular blocks, and device implantations) were evaluated as significant outcomes. During a median follow-up period of 87 months (Q1-Q3, 37-138 months), 71 patients expired. In the univariate analysis, pacemaker implantations (hazard ratio [HR], 4.35; 95% CI, 1.22-15.50) were associated with sudden death. In contrast, PQ interval ≥240 ms, QRS duration ≥120 ms, nutrition, or respiratory failure were not associated with the incidence of sudden death. The multivariable analysis revealed that a PQ interval ≥240 ms (HR, 2.79; 95% CI, 1.9-7.19, P<0.05) or QRS duration ≥120 ms (HR, 9.41; 95% CI, 2.62-33.77, P < 0.01) were independent factors associated with a higher occurrence of cardiac events than those observed with a PQ interval <240 ms or QRS duration <120 ms; these cardiac conduction parameters were not related to sudden death. Conclusions Cardiac conduction disorders are independent markers associated with cardiac events. Further investigation on the prediction of occurrence of sudden death is warranted.

Respiratory Dysfunction in Becker Muscular Dystrophy Patients: A Case Series and Autopsy Report.

BACKGROUND: Few studies have examined respiratory dysfunction in patients with Becker muscular dystrophy (BMD). OBJECTIVE: This study aimed to examine the characteristics of respiratory dysfunction in patients with BMD. METHODS: The present retrospective study assessed respiratory parameters of adult BMD patients using medical records and compared these parameters with various patient characteristics to identify correlations. BMD patients aged 17 years and older who had been diagnosed genetically and/or pathologically were included in the analysis. RESULTS: Of the source population of 133 patients, respiratory function was assessed in 85. Two of these patients had no symptoms, and eight had died. Mean % forced vital capacity (% FVC) was 94.2+/-21.7% (median, 96.1%; range, 5.1-134.1%). In 16 (19%) of the 85 patients, % FVC was <80%. Of these, seven were non-ambulant. Age, ambulation, and cardiac function did not significantly differ between patients with or without respiratory dysfunction, whereas age at onset was significantly lower in patients with respiratory dysfunction (7.7+/-4.7 years vs. 14.4+/-11.9 years; p = 0.001). One non-ambulant patient was a continuous NPPV user, and one patient had been recommended NPPV use but refused. Autopsy of one patient revealed that the diaphragm and intercostal muscles were less affected than proximal skeletal muscles. CONCLUSION: BMD patients are at risk of developing respiratory dysfunction due to dystrophic changes in respiratory muscles. Respiratory function should be carefully and periodically monitored in these patients.

Left Ventricular End-Diastolic Diameter and Cardiac Mortality in Duchenne Muscular Dystrophy.

PURPOSE: This study aimed to examine weather left ventricular end-diastolic diameter (LVDd) could predict mortality from heart failure in patients with Duchenne muscular dystrophy (DMD) receiving standard cardio-protective therapies. PATIENTS AND METHODS: One hundred thirty-three patients with DMD aged ≥10 years who underwent echocardiography from 2011 to 2015 were included in this study and retrospectively followed until August 2018. Patients were divided into two groups according to LVDd at initial echocardiography: ≤ 54 mm (Group 1: n=119) and ≥ 55 mm (Group 2: n=14). To identify factors other than LVDd that may affect heart failure-related mortality, Group 2 patients who developed no left atrial (LA) enlargement, moderate mitral regurgitation (MR), or pulmonary hypertension (PH) during the observation period (Group 2A: n=5) were compared with those who newly developed one or more of those complications (Group 2B: n=7). Clinical outcomes were all-cause mortality and mortality from heart failure. RESULTS: Mean observation period was 5.5±1.5 years in Group 1 and 4.4±1.9 years in Group 2. A total of 14 patients (10.5%) died, including 6 of 119 (5.0%) patients in Group 1 and 8 of 14 (57.1%) patients in Group 2 (p<0.001). Among these, 1 (0.8%) patient in Group 1 and 8 (57.1%) patients in Group 2 died from heart failure (p<0.001). Group 2B patients had shorter survival compared to Group 2A patients (p=0.006). CONCLUSION: LVDd ≥ 55 mm is a predictive factor for mortality from heart failure in patients with DMD. Complications including LA enlargement, moderate MR, and PH were found to be predictive factors for mortality from heart failure in a short period.

Duchenne muscular dystrophy with platypnea-orthodeoxia from Chilaiditi syndrome.

INTRODUCTION: Chilaiditi syndrome is a rare pathophysiology in which the colon or other organs are interposed between the diaphragm and liver, and respiratory or digestive symptoms sometimes manifest. Although there have been some cases of Chilaiditi syndrome complicating neuromuscular disorders, none have described resulting respiratory or digestive symptoms. CASE PRESENTATION: Our patient was a 20-year-old man with DMD who had been receiving noninvasive positive-pressure ventilation during the night. He experienced respiratory distress when changing from a supine to sitting position. Ventilator adjustment did not relieve the respiratory distress. Abdominal computed tomography revealed marked constipation and interposition of the transverse colon between the diaphragm and liver, indicating Chilaiditi syndrome. The right side of the diaphragm was elevated by the interposed transverse colon when the respiratory distress was present on chest radiograph, but not when symptoms were absent. The patient was diagnosed with platypnea-orthodeoxia attributed to Chilaiditi syndrome. The respiratory distress was improved by the relief of constipation, in addition to the usage of the ventilator throughout the day. CONCLUSION: The rare symptoms and pathophysiology of DMD complicated by Chilaiditi syndrome are reported and discussed herein.

Cardiac conduction disturbances and aging in patients with Duchenne muscular dystrophy.

The majority of patients with Duchenne muscular dystrophy (DMD) have electrocardiographic abnormalities, but the clinical significance of conduction disturbances remains unclear. This study aimed to evaluate age-dependent cardiac conduction disturbances by electrocardiogram (ECG) to identify risks of complete atrioventricular (AV) block in this patient population.In total, 47 patients with DMD (age, ≥20 ys) who recorded ECGs at our hospital from July 2015 to June 2016 were included in this study. The PR interval and QRS duration in their previous ECGs were analyzed retrospectively. Associations between ECG findings and left ventricular (LV) systolic function obtained from the latest echocardiography were examined.The mean age of patients was 27.6 ±â€Š6.0 years, and the mean observation period was 9.8 ±â€Š3.7 years. The PR interval gradually increased with age, but no ECGs showed an abnormally prolonged PR interval. On the other hand, the QRS duration tended to increase progressively with age, and some patients had an abnormally prolonged QRS duration. The QRS duration was not correlated with LV systolic function (P = 0.867). One patient who developed a complete AV block had a drastically prolonged QRS duration before the onset of the disorder.The QRS duration tended to increase progressively with age, irrespective of LV systolic function in patients with DMD. Attention should be paid to the QRS duration as an indicator of risk for complete AV block in older patients.

A case of schizophrenia comorbid for tetralogy of Fallot treated with clozapine: further considerations on a role for 22q.11.2 in the proneness for seizures.

We present a case of schizophrenia comorbid for tetralogy of Fallot, without chromosome 22q.11.2 deletion or duplication, treated successfully with a combination of clozapine and antiepileptic drugs. Although clozapine by itself initially triggered convulsive seizures, we continued it with co-administration of valproate and topiramate. This combined treatment did not affect cardiac function of the patient, who experienced a favorable clinical course in terms of symptomatology and functional outcomes. To our knowledge, we provide the first report on a patient with tetralogy of Fallot, in whom 22q.11.2 was not deleted and clozapine-induced seizures were observed.

Cardiopulmonary dysfunction in patients with limb-girdle muscular dystrophy 2A.

INTRODUCTION: Little is known about the frequency of cardiopulmonary failure in limb-girdle muscular dystrophy type 2A (calpainopathy) patients, although some studies have reported severe cardiomyopathy or respiratory failure. METHODS: To clarify the frequency of cardiopulmonary dysfunction in this patient population, we retrospectively reviewed the respiratory and cardiac function of 43 patients with calpainopathy. RESULTS: Nine of the 43 patients had forced vital capacity (FVC) < 80%, and 3 used noninvasive positive pressure ventilation. Mean FVC was significantly lower in patients who were nonambulant and had normal creatine kinase levels. Only 1 patient had a prolonged QRS complex duration. Echocardiography revealed that 1 patient had very mild left ventricular dysfunction. CONCLUSIONS: These findings suggest that patients with calpainopathy may develop severe respiratory failure, but cardiac dysfunction is infrequent. Muscle Nerve 55: 465-469, 2017.

Utility of Cystatin C for Estimating Glomerular Filtration Rate in Patients With Muscular Dystrophy.

Emerging concerns regarding heart failure, arrhythmia, and sudden death in patients with muscular dystrophy are of significant clinical importance. On the other hand, little attention has been paid to renal dysfunction because these patients have low serum creatinine levels. Serum cystatin C, unaffected by muscle quantity, is a potentially superior marker for estimating renal function. Here, we present cases with muscular dystrophy in which estimated glomerular filtration rate (GFR) by cystatin C (eGFRcys) provided good agreement with simultaneously measured GFR by inulin renal clearance (differences less than 20%). Sudden death with acute heart failure occurred in a patient with underlying renal dysfunction and elevated BNP. Neurologists and cardiologists should evaluate renal function using GFR with cystatin C in patients with muscular dystrophy.

Respiratory and cardiac function in japanese patients with dysferlinopathy.

INTRODUCTION: We retrospectively reviewed respiratory and cardiac function in patients with dysferlinopathy, including 2 autopsy cases with respiratory dysfunction. METHODS: Subjects included 48 patients who underwent respiratory evaluation (n = 47), electrocardiography (n = 46), and echocardiography (n = 23). RESULTS: Of the 47 patients, 10 had reduced percent forced vital capacity (%FVC), and 4 required non-invasive positive pressure ventilation. %FVC was significantly correlated with disease duration, and mean %FVC was significantly lower in non-ambulatory patients, as well as in those aged ≥65 years with normal creatine kinase levels. On electrocardiography, QRS complex duration was prolonged in 19 patients, although no significant association with age, disease duration, or respiratory function was found. Echocardiography indicated no left ventricular dysfunction in any patient. Histopathology of autopsied cases revealed mild cardiomyopathy and moderate diaphragm involvement. CONCLUSION: Patients with dysferlinopathy may develop severe respiratory failure and latent cardiac dysfunction. Both respiratory and cardiac function should be monitored diligently.