Prediction of long-term prognosis by heteroplasmy levels of the m.3243A>G mutation in patients with the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.

BACKGROUND AND PURPOSE: Our aim was to determine the prognostic value of urine and blood heteroplasmy in patients with the m.3243A>G mutation. METHODS: Adults with the m.3243A>G mutation referred to our institution between January 2000 and May 2014 were retrospectively included. The relationship between their baseline clinical characteristics, their mutation load in urine and blood, and major adverse events (MAEs) during follow-up, defined as medical complications requiring a hospitalization or complicated by death, was studied. RESULTS: Of the 43 patients (age 45.6 ± 13.3 years) included in the study, 36 patients were symptomatic, including nine with evidence of focal brain involvement, and seven were asymptomatic. Over a 5.5 ± 4.0 year mean follow-up duration, 14 patients (33%) developed MAEs. Patients with MAEs had a higher mutation load than others in urine (60.1% ± 13.8% vs. 40.6% ± 26.2%, P = 0.01) and in blood (26.9% ± 18.4% vs. 16.0% ± 12.1%, P = 0.03). Optimal cutoff values for the prediction of MAEs were 45% for urine and 35% for blood. In multivariate analysis, mutation load in urine ≥45% [odds ratio 25.3; 95% confidence interval (CI) 1.1-567.8; P = 0.04], left ventricular hypertrophy (odds ratio 16.7; 95% CI 1.3- 222.5; P = 0.03) and seizures (odds ratio 48.3; 95% CI 2.5-933; P = 0.01) were associated with MAEs. CONCLUSIONS: Patients with the m.3243A>G mutation are at high risk of MAEs, which can be independently predicted by mutation load in urine ≥45%, a personal history of seizures, and left ventricular hypertrophy.

Myofibrillar myopathies: State of the art, present and future challenges.

Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.

Dilated cardiomyopathy in patients with mutations in anoctamin 5.

BACKGROUND: Homozygous mutations in ANO5, a gene encoding anoctamin 5, a putative calcium-activated chloride channel, have recently been reported in patients with adult-onset myopathies or isolated high-CK levels. Cardiomyopathy has not previously been reported in these populations despite a proven expression of anoctamin 5 in the cardiac muscle. METHODS: Patients presenting for the management of high-CK levels or overt myopathy with proven ANO5 mutations were prospectively investigated between June 2010 and March 2012 in Pitié Salpêtrière Hospital, according to a standardised protocol. Neurological and cardiological clinical examinations, CK assessment, electrocardiogram (ECG), and echocardiography were performed, as well as cardiac MRI and coronary CT angiography in patients with left ventricular (LV) dysfunction. RESULTS: Our study included 19 consecutive patients (male=15, age=46.2 ± 12.7 years) from 16 families. Five had asymptomatic high-CK levels and 14 had overt myopathy. One patient had a personal history of stable coronary artery disease with normal ventricular function. ECG showed ventricular premature beats in one patient. Echocardiography displayed LV dilatation in two patients, LV dysfunction in one, and both abnormalities in two who fulfilled criteria for dilated cardiomyopathy which was confirmed by cardiac MRI and normal CT angiography. CONCLUSIONS: Dilated cardiomyopathy is a potential complication in patients with myopathies due to mutations in the ANO5 gene whose screening requires specific procedures.

Cardiac involvement is frequent in patients with the m.8344A>G mutation of mitochondrial DNA.

BACKGROUND: Cardiac complications, such as myocardial disease and arrhythmias, are frequent and may be severe in patients with mitochondrial disease. We sought to determine the prevalence and the prognostic value of cardiac abnormalities in a series of patients carrying the m.8344 A>G mutation. METHODS: We retrospectively collected data concerning a cohort of patients carrying the m.8344A>G mutation. Patients systematically underwent neurologic examination, muscular biopsy, measurement of forced vital capacity, and cardiac evaluation including electrocardiogram, echocardiography, and 24-hour ambulatory electrocardiogram at diagnosis. Neurologic and cardiac evaluations were repeated during follow-up at least every 2 years. RESULTS: Eighteen patients (mean age 39.3 +/- 17.3 years, 10 women) from 8 families were investigated. Mean follow-up duration was 5.0 +/- 2.7 years. Cardiac abnormalities were identified at diagnosis in 8 patients (44.4%, age 39.1 +/- 17.7 years), including dilated cardiomyopathy in 4, Wolff-Parkinson-White syndrome in 3, incomplete left bundle branch block in 1, and ventricular premature beats in 1. Two additional patients developed left ventricular dysfunction during follow-up and 2 patients died due to heart failure. Subgroup analyses identified early age at disease onset as the only factor significantly associated with myocardial dysfunction. CONCLUSIONS: We identified a high prevalence of ventricular dysfunction and Wolff-Parkinson-White syndrome. Myocardial involvement was associated with an increased risk of cardiac death due to heart failure, suggesting that cardiac investigations should be systematically considered in patients carrying the m.8344A>G mutation.

Impact of cardiac magnetic resonance imaging for assessment of Churg-Strauss syndrome: a cross-sectional study in 20 patients.

OBJECTIVE: To examine the diagnostic contributions of cardiac magnetic resonance imaging (CMRI) with delayed-enhancement (DE) in patients with Churg-Strauss syndrome (CSS). METHODS: We consecutively recruited 14 men and 6 women (mean age: 50+/-14 years) with CSS (mean disease duration: 4.5+/-3.6 years) and investigated them independently of the presence/absence of cardiac manifestations. Cardiac manifestations included heart failure in 6 patients, angina pectoris in 1, isolated ECG abnormality in 1, and isolated echocardiography and ECG abnormalities in 1. T1-weighted sequences were recorded after gadolinium injection to study myocardial DE. RESULTS: CMRI abnormalities were found in 13/20 patients, including all 9 patients with myocardial manifestations, and 4 of the 11 asymptomatic patients. DE was centromyocardial in 6 patients, subepicardial in 4, and subendocardial in 3. Most enhanced lesions were in the anteroseptal or lateral walls. Patients with myocardial symptoms and DE had higher transmyocardial wall DE scores (mean: 9.4 vs. 3.7, respectively; p=0.01) and lower left ventricular ejection fractions (mean: 42% vs. 59%; p=0.001) than asymptomatic patients with DE. CONCLUSION: CMRI with DE enabled the detection of myocardial involvement in CSS patients with or without clinical symptoms. The clinical relevance of CMRI abnormalities in patients without clinical, echocardiographic and ECG signs of cardiac involvement remains unknown and needs to be evaluated in future studies. It seems premature to intensify treatment or to prescribe systematically steroids and cytotoxic agents based on the presence of isolated CMRI anomalies.

Delayed-enhanced cardiac magnetic resonance imaging features in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a rare disorder in which left ventricular systolic dysfunction and symptoms of heart failure occur in the peripartum period. Although cardiac magnetic resonance (CMR) is largely used for diagnosis and prognosis assessment in cardiomyopathies, its interest in PPCM is unknown. We reported two cases of patients with PPCM who underwent CMR. One patient had no CMR abnormality, while the second patient had several areas of myocardial delayed enhancement (MDE) on CMR images. During follow up, the patient with normal CMR was asymptomatic and had full recovery of cardiac function, whereas the patient with MDE was still symptomatic with persistence of a left ventricular dysfunction. CMR could have prognosis value in PPCM as demonstrated in other cardiomyopathies.

Increased arterial pressure is not predictive of haemodynamic instability in patients undergoing adrenalectomy for phaeochromocytoma.

BACKGROUND: Pre-operative hypotensive drugs are assumed to have dramatically decreased operative mortality and morbidity in patients undergoing phaeochromocytoma removal only in non-controlled studies. We evaluated the predictive value of pre-operative high systolic arterial pressure (SAP) on intra- and post-operative haemodynamic instability, in 96 patients undergoing laparoscopic adrenalectomy for phaeochromocytoma. METHODS: Ninety-six consecutive patients underwent laparoscopic adrenalectomy for phaeochromocytoma. Pre-operative SAP was not systematically normalised, provided that increased SAP was clinically tolerated. Intravenous nicardipine, esmolol and norepinephrine were intraoperatively titrated to treat SAP increase >150 mmHg, tachycardia >90-110/min, arrhythmia or SAP decrease under 90 mmHg, respectively. Volume expanders were not systematically administered. Patients with increased and normal pre-operative SAP were compared with respect to (a) nicardipine, esmolol and norepinephrine requirement, (b) highest intraoperative SAP and heat rate, (c) lowest intraoperative SAP, (d) duration of surgery and (e) norepinephrine requirement following tumour removal. RESULTS: Groups did not differ significantly with respect to data defined as being indicative of perioperative haemodynamic instability (all P values>0.05). DISCUSSION: As previously demonstrated, in patients undergoing phaeochromocytoma removal, perioperative haemodynamic changes are mainly due to catecholamine release during tumour manipulation, and to the decrease in catecholamine level following tumour removal. Whether pre-operative hypotensive drugs are likely to alter these changes remains questionable. CONCLUSION: For most patients scheduled for laparoscopic phaeochromocytoma removal, surgery can be carried out without systematic pre-operative arterial pressure normalisation.

[Arrhythmia follow-up of children and adolescents with neuromuscular diseases]. / Surveillance rythmologique de l'enfant et l'adolescent avec maladie neuro-musculaire.

Much progress has been made over the last few years in understanding and classifying neuromuscular diseases. The heart is frequently affected but often in a dissociated manner with respect to the neuromuscular signs although it has a significant impact on the prognosis. In children and adolescents, the dystrophinopathies, especially Duchenne's muscular dystrophy, are the principal problems but the mild arrhythmic events observed seem to be related to left ventricular dysfunction. On the other hand, in myotonic dystrophies (Steinert's disease), ventricular arrhythmias or conduction defects may appear at an early stage of the disease with serious consequences justifying appropriate follow-up and invasive preventive measures. Emery Dreifuss X-linked dystrophy and other laminopathies are rare conditions but are associated with sudden death and cardiomyopathies of the young adult. Specialised cardiological follow-up is justified in childhood from the time of diagnosis. Medication or implantable electric devices may be justified before the end of the second decade of life. Progressive infra-hisian conduction defects have also been reported in Kearns-Sayre oculo-pharyngeal myopathy. Prospective studies are required at this age to determine the natural history of these pathologies that are probably under diagnosed. The present recommendations, which are based mainly on data from adult series, could then be adapted for younger patients.

[Early detection of myocardial disease in young patients with Becker's muscular dystrophy asymptomatic from the cardiac point of view: value of myocardial doppler tissue imaging]. / Detection précoce de l'atteinte myocardique chez des jeunes patients atteints de dystrophie musculaire de Becker asymptomatique sur le plan cardiaque Intérêt du doppler tissulaire myocardique.

Becker's muscular dystrophy is an X-linked hereditary disorder characterised by progressive muscle weakness and possible cardiac disease. Cardiac involvement is assumed to be rare in young patients. Early diagnosis could lead to earlier treatment at an infra-clinical stage of the disease. The object of the study was to evaluate systolic and diastolic cardiac function of young patients with Becker's disease by echocardiography and using Doppler tissue imaging. Consecutive patients under 20 years of age with Becker's disease confirmed genetically were included and compared with paired normal subjects. Subendocardial and subepicardial myocardial velocities were obtained by Doppler tissue imaging and the corresponding velocity gradients were measured. Twelve patients were included (17.4 +/- 2.5 years). None of them had disabling muscle disease. No significant difference was observed from normal subjects with respect to: ventricular dimensions, wall thickness, fractional shortening, E/A ratio measured by transmitral Doppler. Nevertheless, patients with Becker's disease had lower systolic and diastolic intra-myocardial velocity gradients: 2.2 +/- 1.1 vs. 4.7 +/- 2.4 s(-1), p = 0.006, and 3.6 +/- 2.0 vs. 5.6 +/- 1.3 s(-1), p = 0.048, respectively, compared with the control group. These results show that myocardial disease is possible in patients with Becker's muscular dystrophy under the age of 20. Myocardial Doppler tissue imaging is a sensitive method for detecting these early abnormalities and should be recommended in the young patients.

Effects of corticosteroids and immunosuppressors on idiopathic inflammatory myopathy related myocarditis evaluated by magnetic resonance imaging.

BACKGROUND: Cardiac involvement in idiopathic inflammatory myopathy has been recognised as an important prognostic factor, but treatment remains empirical. OBJECTIVE: To investigate the effects of corticosteroids and immunosuppressors on myocarditis in patients with inflammatory myopathies. METHODS: Patients with inflammatory myositis of recent onset who had not received treatment were evaluated for associated myocarditis by magnetic resonance imaging (MRI) and reinvestigated after treatment with high dose corticosteroids and immunosuppressors. RESULTS: Four patients with histologically proven myositis were included. Two patients with polymyositis had cardiac clinical symptoms. Two other patients with dermatomyositis and diffuse cutaneous systemic sclerosis-polymyositis overlap syndrome were asymptomatic. In three cases the usual conventional screening tests were normal. For all patients an area of contrast enhancement and hypokinesia detected by cardiac MRI was markedly reduced after treatment with corticosteroids and immunosuppressors for 6 months. CONCLUSION: Treatment with intravenous methylprednisolone followed by prednisone and immunosuppressive therapy seems to be effective for treating myocardial involvement in patients with idiopathic inflammatory myopathies, either alone or presenting as overlap syndromes. Cardiovascular MRI is a non-invasive technique that may be a powerful tool for diagnosis and monitoring of myocardial inflammation in this setting.

Evaluation of the effect of nifedipine upon myocardial perfusion and contractility using cardiac magnetic resonance imaging and tissue Doppler echocardiography in systemic sclerosis.

BACKGROUND: Primary myocardial involvement due to microcirculation impairment is common in systemic sclerosis (SSc). Cardiovascular magnetic resonance imaging (MRI) and tissue Doppler echocardiography (TDE) were recently shown to be more sensitive than conventional methods for the respective assessment of myocardial perfusion and contractility. Previous studies have suggested that dihydropyridine-type calcium channel blockers mitigate both myocardial perfusion and function abnormalities. OBJECTIVE: To investigate the effects of nifedipine on myocardial perfusion by MRI and on contractility by TDE, in patients with SSc. PATIENTS AND METHODS: 18 patients with SSc without clinical heart failure and with normal pulmonary arterial pressure (14 women, 4 men; mean (SD) age 59 (9) years; mean (SD) disease duration 7 (4) years, 10 with diffuse and 8 with limited cutaneous forms) were prospectively evaluated. The MRI perfusion index, determined from time-intensity curves, and systolic and diastolic strain rate determined by TDE were assessed at baseline, after a 72 hour vasodilator washout period, and after 14 days of oral treatment with nifedipine 60 mg/day. RESULTS: Nifedipine treatment led to a significant increase in the MRI perfusion index (mean (SD) 0.26 (0.07) v 0.19 (0.05) at baseline, p = 0.0003) and in systolic and diastolic strain rate (2.3 (0.6) v 1.5 (0.4) s(-1) at baseline, p = 0.0002, and 4.2 (1.6) v 3.0 (1.2) at baseline, p = 0.0003, respectively). CONCLUSION: Fourteen days of treatment with nifedipine simultaneously improves myocardial perfusion and function, as evaluated by highly sensitive and quantitative methods.

Severe cardiac arrhythmias in young patients with myotonic dystrophy type 1.

Cardiac tachyarrhythmias have rarely been studied in young patients with myotonic dystrophy type 1 (DM1). The authors observed major cardiac rhythm disturbances in 11 patients aged 10 to 18 years. Tachyarrhythmic events were more frequent than impulse conduction disorders. Wide variations in CTG expansion were observed among the population. Since physical exercise was a prominent arrhythmogenic factor, systematic exercise tests with EKG monitoring may be indicated in young patients with DM1.

[Multislice CT and MRI of coronary artery disease: current and future role]. / Maladie coronaire: les questions cliniques et les réponses potentielles en scanner multicoupe et en IRM.

If the role of multislice CT and MRI is not clearly defined in ischemic heart disease, these new cardiac imaging techniques are very promising due to recent technological advances. The detection of coronary artery plaque and stenosis, as well as coronary bypass graft and stenting patency, the evaluation of left ventricular remodeling after infarction, are available in routine with a 16-slices multislice CT. MRI is the technique of choice to appreciate the impact of a coronary artery lesion on myocardium: detection of ischemia by first-pass perfusion imaging at rest and under pharmacological stress, detection and extension of infarcted myocardium and assessment of myocardial viability. The potential indications will be discussed for each technique in the light of the main clinical questions asked by the cardiologist in daily practice.

[Utility of BNP measurement in the emergency room in patients with suspected unstable angina with a normal ECG]. / Utilité du dosage du BNP aux urgences chez les patients suspects d'angor instable avec ECG normal. A propos de 120 patients.

Unstable angina is a serious condition, difficult to diagnose in the emergency room. Clinical, electrocardiographic and biological signs (increased troponine) are not sensitive. The authors set out to assess whether measuring B natiuretic peptide in the emergency room was more sensitive for identifying symptomatic coronary lesions. One hundred and twenty patients admitted to the emergency room for chest pain compatible with the diagnosis of unstable angina and a normal ECG were included in this prospective study. All patients underwent coronary angiography during their hospital admission. The sensitivities of troponine at a threshold of 0.4 ng/ml and of brain natiuretic peptide (BNP) at a threshold of 10 pg/ml in this population were 66% and 92% respectively. The use of troponine and BNP together provided better results than troponine and BNP alone for the identification of patients with chest pain with significant coronary lesions.

[Value of MRI for the diagnosis of cardiac involvement in sarcoidosis]. / Apport de l'IRM dans l'exploration de l'atteinte cardiaque au cours de la sarcoïdose.

PURPOSE: The aim of the study was to assess the place of cardiac Magnetic Resonance Imaging (MRI) in patients with sarcoidosis with or without cardiac involvement. MATERIALS AND METHODS: Fifty patients with histologically-proven sarcoidosis underwent initial cardiac evaluation including MRI, ECG, holter ECG, echocardiography. Seven of them had cardiac involvement (cardiac insufficiency, auriculo-ventricular block, bundle-branch block). Fiveteen patients had a second evaluation at 10-month follow-up. MRI was classified in three stages, on the base of literature data (stage 1 "granulomatous", stage 2 "exsudative", stage 3 "fibrotic"). RESULTS: A good correlation between the type of the sarcoidosis and MRI was observed: patients with cardiac involvement had all stage 2 MRI; patients with quiescent sarcoidosis had normal or stage 3 MRI; patients without cardiac involvement had all stages on MRI. A good correlation was observed between cardiac MRI abnormalities and evolution of sarcoidosis. Patients under corticoid, with or without cardiac involvement all had regression of MRI lesions and sarcoidosis. In 2 cases, MRI was predictive of clinical cardiac involvement. CONCLUSION: Cardiac MRI is a useful non-invasive method for the early diagnosis and follow-up of cardiac sarcoidosis.

Bedside B-type natriuretic peptide and functional capacity in chronic heart failure.

OBJECTIVES: To determine if B-type natriuretic peptide (BNP) measurement could be useful in determination of functional capacity in patients suffering from chronic heart failure. BACKGROUND: Evaluating functional capacity is a crucial factor in the follow-up of patients with chronic heart failure. There are numerous methods for measuring functional capacity and their relative merits remain under discussion. Clinical classifications are very subjective and other methods are difficult to use in clinical practice. METHODS: We evaluated functional capacity in 151 consecutive patients using the 6-min walk test. All patients were clinically classified using the New York Heart Association (NYHA) classification. We measured BNP plasma levels using a bedside BNP test. RESULTS: Six minute walk test performance decreased through NYHA classes 1 to 4 (469+/-87, 411+/-82, 325+/-83 and 196+/-63 m, respectively, P<0.01) and BNP levels increased through NYHA classes 1 to 4 (26.3+/-7.2, 73+/-13, 401+/-74 and 924+/-84 pg/ml, respectively, P<0.001). There was a significant correlation between 6-min walk test performance and BNP plasma levels (R=0.69 P<0.001) and a weaker correlation between BNP and left ventricular ejection fraction (R=0.45 P<0.04). In some patients there was a mismatch between NYHA classification and 6-min walk test performance. In all cases BNP could correct the clinical estimation of functional capacity. When we divided the patients into three sub-groups within each NYHA class, we showed that using BNP could better define functional capacity in patients suffering from chronic heart failure in NYHA classes I to III. CONCLUSION: The measurement of BNP levels thus usefully supplements the clinical examination. The existence of bedside BNP testing methods facilitates its use in routine clinical practice. It also permits easier follow-up of patients with chronic heart failure.