RESEARCHS THAT WILL BE PRESENTED IN ATS (AMERICAN THORACIC SOCIETY) MEETING - 2007, SAN FRANCISCO, MAY, 18-23.

1) Longitudinal Study of Ventilatory Parameters and Inspiratory Muscle Strength in DMD Patients

S. Matecki, M.D., PhD., J. Gayraud, PhD., F. Rivier, M.D., Ph, C. Prefaut, M.D., M. Ramonatxo, PhD., Montpellier, France

Duchenne muscular dystrophy ( DMD ) is a neuromuscular disorder characterized by a progressive muscle weakness which leads to a restrictive pattern. The aim of this study was to better define the more accurate parameters of disease progression with age. We thus evaluated maximal inspiratory pressure ( MIP ) changes with age and compared it with ventilatory parameters rate of decline with age in a longitudinal study of 10 patients with DMD, 9.3 + 0.7 to 16.3 + 0.6 yr-old, with on average 6.8 +0.4 yr of follow-up. Vital capacity ( VC ), total lung capacity ( TLC ) and forced expiratory volume in one second ( FEV1 ) when expressed in percent predicted value, increased to 11.5+0.7, 11.0 + 0.9 and 11.6 + 0.8 yr and then decreased with age. The mean slopes of decrease with age of VC, TLC and FEV1 in % pred were 10.7 + 6.0, 9.2 + 6.0 and 10.4+- 6 per year. Contrary to ventilatory parameters, Pimax decreases in most subjects after the first measure. The mean slope of decrease of Pimax was 6.9 + 1.3 % pred per year. This decrease was significantly lower than this of VC ( P< 0.01 ). The individual slopes of decrease in % pred of VC, TLC and FEV1 % pred are significantly correlated with those of Pimax. The individual relationship between VC, TLC and FEV1 % pred with Pimax % pred showed that if the differences in % pred between VC and FEV1 with Pimax were high at an early stage of the disease, they decrease thereafter as disease progresses and that the differences with TLC persist.
In conclusion we shows that: 1/ TLC is a poor indicator of disease progression; 2/ FEV1 seems the parameter which reflects more the decrease of Pimax; 3/ Pimax is a better marker of disease progression only at an early stage of the disease.

2) Long-Term Non-Invasive Ventilation in Neuromuscular Disorders: Impact of Underlying Disease

M. Dreher, M.D., I. Rauter, J.H. Storre, M.D., J. Geiseler, M.D., W. Windisch, M.D., Freiburg, Baden Wuertemberg, Munich, Bavaria, Germany

Rationale: There is at present still uncertainty when to start home mechanical ventilation (HMV) in neuromuscular disorders which can lead to chronic ventilatory failure. In addition, current indicators following guidelines globally and non-specifically focus on all potential diseases without addressing the possible clinical differences between underlying disorders.
Methods:The impact of the underlying disease on the time when HMV was started, on ventilatory strategies and on outcome was retrospectively investigated in patients with neuromuscular disorders who were established on non-invasive positive pressure ventilation between January 1997 and April 2006.
Results: HMV was established in 66 patients with 31 patients having rapidly progressive disease: amyotrophic lateral sclerosis (ALS, N=19), Duchenne muscular dystrophy (DMD, N=12). Mean forced vital capacity (FVC) at NPPV onset was 40.3+17.5% predicted in all patients, but was even >50% predicted in eight patients (12%). Compared to DMD patients at HMV onset, patients with ALS were significantly more hypercapnic (62.1+9.7 vs. 44.2+5.6; p=0.03) and more hypoxemic (61.2+14.5 vs. 86.4+11.1; p<0.001), but had better forced expiratory volume in 1 sec (FEV₁) (42.0+9.8 vs. 25.2+13; p=0.005). Ventilator settings tended to be higher in ALS compared to DMD patients. Following two months of HMV FVC improved in slowly progressive disease (p<0.05), but not in rapidly progressive disease. Five year survival was 39%, 75% and 16% in all, DMD and ALS patients, respectively.
Conclusion: Different neuromuscular disorders substantially differ with regard to HMV onset, ventilatory strategies and outcome. Therefore, detailed indicators for different disorders are clearly needed to overcome the uncertainty regarding NPPV establishment in neuromuscular disorders.
 

3) Sleep Respiratory Pattern in Steinert's Myotonic Dystrophy (DM) Patients

A. Munoz, M.D., E. Chiner, M.D., E. Gomez-Merino, M.D., C. Senent, M.D., M. Llombart, M.D., A.L. Andreu, M.D., A. Camarasa, M.D., J. Signes-Costa, M.D.

Aims: To evaluate sleep architecture and sleep breathing pattern in DM patients.
Methods: All patients attended in the Sleep Unit between December 2003 and September 2006 were included. We performed pulmonary function tests, arterial blood gas analysis, Epworth sleepiness scale (ESS) and polysomnography (PSG). Patients functional limitation was evaluated by MIRS scale of Mathieu et al (Neurology 2001).
Results: We studied 17 patients (12 men and 5 women), age 43+11 years, BMI 24.8+3.7 Kg/m2, neck circumference 37+ 4 cm, ESS 6+5 and evolution time of the disease 12+8 years. MIRS scale revealed: 8 patients (grade 2), 6 patients (grade 3), and 3 patients (grade 4). A restrictive respiratory pattern was observed in the majority, with a decrease in maximal pressures and with normal diffusion test. None had diurnal hypoxemia or hypercapnia. PSG showed: Sleep efficiency 79+22%, Arousal index 43+17, REM%28+10, Stage1% 19+12, Stage2% 34+13, Stage3% 17+13, Stage4% 0.2+0.9. All patients had respiratory disorders during sleep: RDI 43+19 (mainly obstructive events), Mean SatO2 83+22, Minimum SatO2 62+27 and Tc90 35+40. No correlation was found between RDI and functional limitation, evolution time of the disease or ESS.
Conclusion: Patients with DM have severe alterations in respiratory pattern during sleep, which include obstructive sleep apnea-hypopnea syndrome and hypoventilation. There are not correlation between these disorders and functional limitation, and neither with evolution time of disease. Subjective test for evaluated diurnal sleepiness are not valid for this patients.
 

4) Titin MDM Mutation Causes Altered Contractile Force Generating Capacity in Mouse Diaphragm

M.A. Lopez, B.S., J. Vega, G.A. Cox, PhD., A.M. Boriek, PhD., Houston, TX, Bar Harbor, ME

Rationale: The diaphragm is a respiratory muscle that functions as a pump during inspiration. Contraction of the diaphragm generates transdiaphragmatic pressure, diaphragmatic muscle shortening, and concomitant expansion of the lungs. The diaphragm is unique because in vivo it carries forces along the muscle fibers and in the transverse fiber direction. Diseases of skeletal muscle, such as Muscular Dystrophy, can cause skeletal muscle dysfunction that may lead to compromised respiratory function. In mice, a complex rearrangement mutation in the Ttn gene encoding the giant (3.1 MDa) sarcomeric protein Titin has been identified as causing Muscular Dystrophy with Myositis (MDM). We hypothesize that the MDM mutation would alter contractile force generating capacity of the mouse diaphragm. Methods: After anesthetization, left hemidiaphragms were excised from wildtype (age: 18+1 days ) and mutant (age: 26 + 11 days) B6C3Fe-a/a-mdm mice. The left hemidiaphragm was excised and perfused in a biaxial in vitro muscle apparatus with Krebs-Ringer solution bubbled with 95% O2-5% CO2. The muscle was maximally tetanically stimulated at optimal length at 10, 30, 50, 60, 100 and 150 Hz under uniaxial and biaxial loading. Results: See Figure. Conclusion: The MDM mouse diaphragm shows depressed maximal stress generation as compared to wildtype mice. The magnitude of depressed stress generation is amplified under biaxial loading.

 

5) Effect of a Low Level Specific Respiratory Muscle Training in mdx Mouse on Calcium Homeostasis and Mitochondrial Respiration

S. Matecki, M.D., PhD., A. Lacampagne, PhD., J. Gayraud, PhD., D. Mornet, PhD., J. Mercier, M.D., Ph, M. Ramonatxo, M.D., Montpellier, Languedoc-Roussillon, France

The cellular mechanisms induced by a low level respiratory muscle training in children with Duchenne Muscular Dystrophy (DMD) are poorly known. The aim of this study was thus to investigate the cellular effects induced by a specific low level respiratory muscle training in mdx mouse diaphragm. In 10 mdx mouse, we reproduced by hypercapnic stimulation of ventilation (8% CO₂), during 6 weeks/ 30 min per day, a specific respiratory muscle training, 10 mdx mice served as controls. Diaphragmatic force frequency relationships showed that this specific respiratory training improves the tetanic force production of the diaphragm. We found in the training group an increase of maximal mitochondrial respiration (14.3 + 0.4 vs 9.5 + 0.3 mcmol/mn/mg) with no difference between the groups in diaphragm muscular fiber type and in citrate synthase activity. Moreover, Ca²⁺ transient measurement on individual fiber using laser scanning multiphoton microscopy showed a rise-time decrease of Ca²⁺-spark in training group (4.66 + 0.11 vs 5.59 + 0.12 ms) without any difference in amplitude, which could be interpreted as a better synchronisation of RyR opening involved in spark generation.
In conclusion, functional beneficial effect of low level of exercise on mdx diaphragm could be partially explained by an improvement of mitochondrial function and synchronisation of RyR opening which could attenuate the rise of Ca²⁺.
 

6) Sleep-Disordered Breathing (SDB) in Children with Neuromuscular Disorders Presenting to a Pediatric Sleep Laboratory

L.A. D'Andrea, M.D., L. Amos, M.D., Milwaukee, WI

Background: Children with neuromuscular disorders are known to develop SDB, but the prevalence, types, and severities, and association with PFTs have not been adequately defined. Optimal timing for testing and initiation of ventilatory support has not been established.Methods: A cross-sectional study of children with neuromuscular disorders referred to our pediatric sleep lab from 2003-2006 was undertaken to correlate PSG results with historical data and PFTs. Results: We reviewed the charts of 32 children (16 M:16 F) who underwent 71 overnight sleep studies. Diagnoses included Duchenne muscular dystrophy (12), spinal muscular atrophy, type 2 (6), mitochondrial cytopathies (3), and other (11). Subjects slept relatively well (ave TST 420 min, ave sleep latency 31 min, ave sleep efficiency 80%). There were 24 diagnostic studies with resulting diagnoses: 15 normal, 7 hypoventilation, 2 OSA. Children with normal studies tended to have SMA type 2 or were younger children with DMD (<12 yrs). Thirteen children were already on ventilatory support (BiPAP, ventilator) for management of hypoventilation and had 40 follow up studies to adjust their settings. An additional 7 children were started on ventilatory support (6 for hypoventilation, 1 for OSA). Overall, 17 children (85%) could be managed with non-invasive ventilation. The ave age for all children to be started on ventilatory support was 12.7 yrs (range 1-19 yrs) and ave FVC at initiation of support was 21% predicted. Only 6 children required urgent initiation of support; the remainder were being followed and noted to have worsening PFTs or symptoms of hypoventilation (e.g. AM headaches). Conclusion: SDB, in particular, hypoventilation is common in children with neuromuscular disorders. Treatment often requires ventilatory support. In most cases, the need for support can be anticipated based on subject characteristics and can be accomplished noninvasively.