Zahid Maliha, Bais Abha, Tian Xin, Devine William, Lee Dong Ming, Yau Cyrus, Sonnenberg Daniel, Beerman Lee, Khalifa Omar, Lo Cecilia W
Dept. of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Office of Biostatistics Research, National Heart Lung Blood Institute, Bethesda, Maryland, United States of America.
PLoS One. 2018 Feb 14;13(2):e0191605. doi: 10.1371/journal.pone.0191605. eCollection 2018.
Our prior work on congenital heart disease (CHD) with heterotaxy, a birth defect involving randomized left-right patterning, has shown an association of a high prevalence of airway ciliary dysfunction (CD; 18/43 or 42%) with increased respiratory symptoms. Furthermore, heterotaxy patients with ciliary dysfunction were shown to have more postsurgical pulmonary morbidities. These findings are likely a reflection of the common role of motile cilia in both airway clearance and left-right patterning. As CHD comprising transposition of the great arteries (TGA) is commonly thought to involve disturbance of left-right patterning, especially L-TGA with left-right ventricular inversion, we hypothesize CHD patients with transposition of great arteries (TGA) may have high prevalence of airway CD with increased respiratory symptoms.
We recruited 75 CHD patients with isolated TGA, 28% L and 72% D-TGA. Patients were assessed using two tests typically used for evaluating airway ciliary dysfunction in patients with primary ciliary dyskinesia (PCD), a recessive sinopulmonary disease caused by respiratory ciliary dysfunction. This entailed the measurement of nasal nitric oxide (nNO), which is typically low with PCD. We also obtained nasal scrapes and conducted videomicroscopy to assess respiratory ciliary motion (CM). We observed low nNO in 29% of the patients, and abnormal CM in 57%, with 22% showing both low nNO and abnormal CM. No difference was observed for the prevalence of either low nNO or abnormal ciliary motion between patients with D vs. L-TGA. Respiratory symptoms were increased with abnormal CM, but not low nNO. Sequencing analysis showed no compound heterozygous or homozygous mutations in 39 genes known to cause PCD, nor in CFTR, gene causing cystic fibrosis. As both are recessive disorders, these results indicate TGA patients with ciliary dysfunction do not have PCD or cystic fibrosis (which can cause low nNO or abnormal ciliary motion).
TGA patients have high prevalence of abnormal CM and low nNO, but ciliary dysfunction was not correlated with TGA type. Differing from PCD, respiratory symptoms were increased with abnormal CM, but not low nNO. Together with the negative findings from exome sequencing analysis, this would suggest TGA patients with ciliary dysfunction do not have PCD but nevertheless may suffer from milder airway clearance deficiency. Further studies are needed to investigate whether such ciliary dysfunction is associated with increased postsurgical complications as previously observed in CHD patients with heterotaxy.
我们之前对先天性心脏病（CHD）合并内脏反位（一种涉及随机左右模式形成的出生缺陷）的研究表明，气道纤毛功能障碍（CD；18/43或42%）的高患病率与呼吸道症状增加有关。此外，有纤毛功能障碍的内脏反位患者术后肺部并发症更多。这些发现可能反映了运动性纤毛在气道清除和左右模式形成中的共同作用。由于通常认为包括大动脉转位（TGA）的CHD涉及左右模式形成的紊乱，尤其是伴有左右心室反位的左旋大动脉转位（L-TGA），我们推测患有大动脉转位（TGA）的CHD患者可能有较高的气道CD患病率及呼吸道症状增加。
我们招募了75例孤立性TGA的CHD患者，其中28%为L-TGA，72%为D-TGA。使用通常用于评估原发性纤毛运动障碍（PCD，一种由呼吸道纤毛功能障碍引起的隐性鼻窦肺部疾病）患者气道纤毛功能障碍的两项测试对患者进行评估。这需要测量鼻一氧化氮（nNO），PCD患者的nNO通常较低。我们还获取了鼻刮片并进行了视频显微镜检查以评估呼吸道纤毛运动（CM）。我们观察到29%的患者nNO较低，57%的患者CM异常，22%的患者同时表现出nNO低和CM异常。D-TGA与L-TGA患者之间，nNO低或纤毛运动异常的患病率无差异。呼吸道症状随CM异常增加，但不随nNO降低而增加。测序分析显示，在已知导致PCD的39个基因以及导致囊性纤维化的CFTR基因中，未发现复合杂合或纯合突变。由于这两种都是隐性疾病，这些结果表明有纤毛功能障碍的TGA患者没有PCD或囊性纤维化（可导致nNO低或纤毛运动异常）。
TGA患者CM异常和nNO低的患病率较高，但纤毛功能障碍与TGA类型无关。与PCD不同，呼吸道症状随CM异常增加，但不随nNO降低而增加。结合外显子组测序分析的阴性结果，这表明有纤毛功能障碍的TGA患者没有PCD，但仍可能患有较轻的气道清除缺陷。需要进一步研究调查这种纤毛功能障碍是否与如之前在内脏反位的CHD患者中观察到的术后并发症增加有关。
