TY - JOUR
T1 - High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy
AU - Nakhleh, Nader
AU - Francis, Richard
AU - Giese, Rachel A.
AU - Tian, Xin
AU - Li, You
AU - Zariwala, Maimoona A.
AU - Yagi, Hisato
AU - Khalifa, Omar
AU - Kureshi, Safina
AU - Chatterjee, Bishwanath
AU - Sabol, Steven L.
AU - Swisher, Matthew
AU - Connelly, Patricia S.
AU - Daniels, Mathew P.
AU - Srinivasan, Ashok
AU - Kuehl, Karen
AU - Kravitz, Nadav
AU - Burns, Kimberlie
AU - Sami, Iman
AU - Omran, Heymut
AU - Barmada, Michael
AU - Olivier, Kenneth
AU - Chawla, Kunal K.
AU - Leigh, Margaret
AU - Jonas, Richard
AU - Knowles, Michael
AU - Leatherbury, Linda
AU - Lo, Cecilia W.
PY - 2012/5/8
Y1 - 2012/5/8
N2 - Background-Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. Methods and Results-We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged 6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. Conclusions-Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.
AB - Background-Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. Methods and Results-We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged 6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. Conclusions-Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.
KW - Congenital
KW - Genomic studies
KW - Heart defects
KW - Heterotaxy
KW - Nitric oxide
KW - Primary ciliary dyskinesia
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U2 - 10.1161/CIRCULATIONAHA.111.079780
DO - 10.1161/CIRCULATIONAHA.111.079780
M3 - Article
C2 - 22499950
AN - SCOPUS:84860720930
SN - 0009-7322
VL - 125
SP - 2232
EP - 2242
JO - Circulation
JF - Circulation
IS - 18
ER -