High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy

Abstract

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.

Low Nasal NO in Congenital Heart Disease With Systemic Right Ventricle and Postcardiac Transplantation

“…Because the population with heterotaxy‐CHD in the study by Nakhleh et al included a large proportion of subjects with double‐outlet RV and congenitally corrected transposition of the great arteries, the high prevalence of low nNO (42%) in this cohort of patients with heterotaxy may, in fact, reflect the high proportion of patients with sysRV physiologic features 17. Similarly, in the study of Garrod et al, the proportion of patients with heterotaxy CHD was 18% compared with only 9% in our current CHD cohort and, thus, those results may have been skewed by a similar trend 18…”

“…19 nNO values (nl/min) were acquired using a CLD88sp chemiluminescence NO analyzer (EcoPhysics, Ann Arbor, MI). Patients were categorized as having normal or low nNO based on established cutoff values from the literature 17, 18, 20…”

“…In addition, for the primary analysis, we chose 5 physiologic variables to examine for correlation with nNO levels. These variables were chosen on the basis of their predilection for heart failure and potential influence on oxygen content/delivery (SV status, systemic ventricle status, ventricular function, and blood oxygenation) or on previous published findings showing correlation with nNO level (heterotaxy status) 17, 18…”

“…Measurement of nNO is commonly used in assessments of various respiratory diseases,16 and nNO measurements have also been obtained in prior studies of patients with CHD. One such study demonstrated a 42% (18/43) prevalence of low nNO in a small cohort of patients with heterotaxy CHD 17. A subsequent study of a larger cohort of patients with CHD (with and without heterotaxy) found 36% (64/180) had low nNO 18…”

Clinical care for primary ciliary dyskinesia: current challenges and future directions

“…Patients with heterotaxy experience increased post-operative mortality [75] and risk for respiratory complications [76], associated with ciliary dysfunction in 42% of cases [77]. The inference is that at least some of these patients had undiagnosed PCD, suggesting that they might benefit from routine pre-surgical screening for PCD and intense peri-surgical respiratory management [77].…”