Rationale and design of the randomised Treatment of sleep apnoea Early After Myocardial infarction with Adaptive Servo-Ventilation trial (TEAM-ASV I).
自适应伺服通气试验 (TEAM-ASV I) 随机治疗心肌梗死后早期睡眠呼吸暂停的原理和设计。
- 作者列表："Fox H","Hetzenecker A","Stadler S","Oldenburg O","Hamer OW","Zeman F","Bruch L","Seidel M","Buchner S","Arzt M","TEAM-ASV I Investigators.
AIMS:In acute myocardial infarction (AMI), impaired myocardial salvage and large infarct size result in residual heart failure, which is one of the most important predictors of morbidity and mortality after AMI. Sleep-disordered breathing (SDB) is associated with reduced myocardial salvage index (MSI) within the first 3 months after AMI. Adaptive servo-ventilation (ASV) can effectively treat both types of SDB (central and obstructive sleep apnoea). The Treatment of sleep apnoea Early After Myocardial infarction with Adaptive Servo-Ventilation trial (TEAM-ASV I) will investigate the effects of ASV therapy, added to percutaneous coronary intervention (PCI) and optimal medical management of AMI, on myocardial salvage after AMI. METHODS/DESIGN:TEAM ASV-I is a multicentre, randomised, parallel-group, open-label trial with blinded assessment of PCI outcomes. Patients with first AMI and successful PCI within 24 h after symptom onset and SDB (apnoea-hypopnoea index ≥ 15/h) will be randomised (1:1 ratio) to PCI and optimal medical therapy alone (control) or plus ASV (with stratification of randomisation by infarct location; left anterior descending (LAD) or no LAD lesion). The primary outcome is the MSI, assessed by cardiac magnetic resonance imaging. Key secondary outcomes are change of infarct size, left ventricular ejection fraction and B-type natriuretic peptide levels and disease-specific symptom burden at 12 weeks. CONCLUSION:TEAM ASV-I will help to determine whether treatment of SDB with ASV in the acute phase after myocardial infarction contributes to more myocardial salvage and healing. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02093377. Registered on March 21, 2014.
目的: 在急性心肌梗死 (AMI) 中，心肌挽救受损和大梗死面积导致残余心力衰竭，是 AMI 后发病率和死亡率的最重要预测因素之一。睡眠呼吸障碍 (SDB) 与 AMI 后前 3 个月内心肌挽救指数 (MSI) 降低相关。自适应伺服通气 (ASV) 可有效治疗两种 SDB (中枢性和阻塞性睡眠呼吸暂停)。自适应伺服通气试验 (TEAM-ASV I) 治疗心肌梗死后早期睡眠呼吸暂停将研究 ASV 治疗的效果，加入经皮冠状动脉介入治疗 (PCI) 和 AMI 的最佳医疗管理，对 AMI 后的心肌挽救。 方法/设计: ASV-I 团队是一项多中心、随机、平行组、开放标签试验，盲法评估 PCI 结局。首次 AMI 并在症状发作后 24 h 内成功 PCI 且 SDB (呼吸暂停低通气指数 ≥ 15/h) 的患者将被随机分组 (1:1 比) PCI 和最佳药物治疗单独 (对照) 或加 ASV (按梗死部位随机分层; 左前降支 (LAD) 或无 LAD 病变)。主要结局是通过心脏磁共振成像评估的 MSI。关键的次要结局是 12 周时梗死面积、左心室射血分数和 b型钠尿肽水平的变化以及疾病特异性症状负担。 结论: ASV-I 团队将有助于确定心肌梗死后急性期应用 ASV 治疗 SDB 是否有助于更多的心肌挽救和愈合。 试用注册: ClinicalTrials.gov，nct02093377。2014年3月21日注册。
METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.
METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.
METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.