ORIGINAL RESEARCH Sleep-disordered Breathing in Children with Cardiomyopathy Suhail Al-Saleh1,5, Paul F. Kantor3, Neil K. Chadha4, Yamilet Tirado2, Adrian L. James2,5, and Indra Narang1,5 1 Division 3 Division 4
of Respiratory Medicine and 2Department of Otolaryngology, Hospital for Sick Children, Toronto, Ontario, Canada; of Cardiology, University of Alberta, and Department of Pediatrics, Stollery Children’s Hospital, Edmonton, Alberta, Canada; and Division of Otolaryngology, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada; and 5Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
Abstract Rationale: Cardiomyopathy is a rare condition in children that is associated with high mortality. Although sleep-disordered breathing is prevalent, its frequency and patterns in children with cardiomyopathy are unknown. Objectives: To evaluate the frequency and patterns of sleepdisordered breathing and their relationship to cardiac function in children with primary cardiomyopathy. Methods: This study comprised a prospective, uncontrolled case series. Children with cardiomyopathy completed a sleep questionnaire, overnight polysomnography, blood pressure monitoring, otolaryngological assessment, and transthoracic echocardiography at the Hospital for Sick Children in Toronto, Canada. Measurements and Main Results: Twenty-one patients (17 males) were recruited. The median age of the patients was 10.7 years, and the median body mass index z score was 0.8. Sleepdisordered breathing was observed in 10 (48%) of 21 patients. Significant central sleep apnea was the main finding in 5 (24%) of 21 of the cohort and in 50% of the sleep-disordered breathing
population. The left ventricular end diastolic volume index was greater in children with central sleep apnea than in children without sleep-disordered breathing (P = 0.03). There were significant correlations between the central apnea–hypopnea index and both left ventricular end diastolic and end systolic volume indexes (Spearman’s r = 0.55, P = 0.01; Spearman’s r = 0.47, P = 0.03, respectively). Snoring, sleep architecture, blood pressure, and otolaryngological findings were not significantly different between children with sleep-disordered breathing versus those without sleep-disordered breathing. Conclusions: Sleep-disordered breathing is common in children with cardiomyopathy. In our present study, 24% of participants exhibited primarily central sleep apnea. The severity of cardiac dysfunction, as measured by left ventricular end diastolic volume index and left ventricular end systolic volume index, is associated with central sleep apnea. Longitudinal research is necessary to better characterize sleep disorders and their impact on cardiac function in a large pediatric cardiomyopathy population. Keywords: cardiomyopathies; sleep apnea, obstructive; sleep apnea, central; pediatrics; polysomnography
(Received in original form September 26, 2013; accepted in final form March 11, 2014 ) Author contributions: S.A.-S.: study design, patient recruitment, detailed data collection, statistical analyses, manuscript writing. P.F.K.: review of clinical examination and echocardiography studies for data acquisition, critical revision of the manuscript. N.K.C.: patient examination, critical revision of the manuscript. Y.T.: patient examination, critical revision of the manuscript. A.L.J.: patient examination, critical revision of the manuscript. I.N.: study design, detailed review of data collection and statistical results, manuscript writing. Correspondence and reprint requests should be sent to Indra Narang, MBBCH, FRCPCH, M.D., Division of Respiratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 Canada. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 5, pp 770–776, Jun 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201309-325OC Internet address: www.atsjournals.org
Primary cardiomyopathies (CMs) are heart muscle disorders that affect ventricular systolic function, diastolic function, or both. They are classified according to phenotype as (1) dilated cardiomyopathy (DCM), (2) hypertrophic cardiomyopathy (HCM), (3) restrictive cardiomyopathy (RCM), and
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(4) arrhythmogenic right ventricular dysplasia/CM (1). Recently, left ventricular noncompaction (LVNC) has been added as a specific primary CM class. CM is rare in children, but it is a serious and life-threatening condition with an annual incidence of 1.1–1.2/100,000 (2, 3).
Two-thirds of all pediatric CM cases are thought to be idiopathic (3), and the rest of the cases are either familial or secondary to neuromuscular disorders, myocarditis, malformation syndromes, and inborn errors of metabolism. The prognosis for children with CM is guarded, with high
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ORIGINAL RESEARCH rates of morbidity and mortality. Overall, 32–46% of symptomatic pediatric patients with DCM and 13% of symptomatic children with HCM will either receive a heart transplant or die within 5 years of diagnosis (4, 5). Sleep-disordered breathing (SDB) is a characteristic of a group of respiratory disorders specific to or exacerbated by sleep, which includes central sleep apnea (CSA) and obstructive sleep apnea (OSA). OSA and CSA are diagnosed on the basis of the gold standard: polysomnogram (PSG) (6, 7). OSA, the commonest SDB in children, is characterized by prolonged partial upper-airway obstruction (obstructive hypopnea) and/or intermittent complete obstruction (obstructive apnea). The prevalence of childhood OSA is 2–4% (8), with adenotonsillar hypertrophy being the commonest underlying etiologic factor in OSA. Resolution of OSA in children can occur following an adenotonsillectomy (9, 10). CSA and central hypoventilation syndromes are less common in children, the causes of which include congenital central hypoventilation syndrome and Arnold–Chiari malformations (11, 12). OSA has more recently received significant attention because of the potential for significant cardiovascular and neurocognitive sequelae if it is left untreated (13–19). Thus it can be hypothesized that OSA in the context of underlying heart disease may further potentiate cardiovascular damage. Indeed, data derived from adult patients with CM indicate that cardiovascular morbidity is increased in patients with OSA compared with those without OSA. Importantly, treatment of OSA with positive airway pressure has been reported to improve cardiovascular function (20–24). Of significance is that severe CSA characterized by Cheyne–Stokes respiration (CSR) in adults with congestive heart failure was found to be an independent risk factor for mortality (25, 26). CSA is less common in children, but nonetheless it has been found to be associated with changes in heart rate and blood pressure (BP) (27). To the best of our knowledge, OSA and CSA disorders have not been described to date in children with known cardiovascular diseases. Our aim in this pilot study was to determine the frequency and nature of SDB in children with known primary CM and to characterize the relationship between SDB and cardiac function.
Methods Ethics
This study was approved by the Research Ethics Board at the Hospital for Sick Children, and written informed consent was obtained from all of the participants’ parents or legal guardians. Study Design and Study Population
We conducted a prospective cross-sectional study in which eligible children were ages 1 month to 18 years, had an echocardiographic diagnosis of primary CM, and were clinically stable. Recruitment was of sequential patients identified at the Hospital for Sick Children in Toronto, Canada, between 2009 and 2011. Screening of potential recruits excluded those who met the following criteria: (1) a diagnosis of congenital or chronic lung disease; (2) structural congenital heart disease or previous surgical repair of same; (3) systemic, neurological, or neuromuscular comorbidities associated with CM or known to cause SDB (e.g., Duchenne’s muscular dystrophy, mucopolysaccharidosis); (4) children deemed unstable clinically (e.g., currently receiving intravenous inotropic support); (5) the use of noninvasive ventilation for any reason; (6) and any known current or previous diagnosis of SDB. The demographic data collected at the time of PSG included age, sex, height, weight, and body mass index (BMI). Detailed information collected at the time of cardiac assessment included medications, CM type, and current clinical status. Questionnaires
All parents completed a detailed sleep questionnaire tailored specifically for the sleep laboratory at the Hospital for Sick Children to evaluate children for symptoms of SDB. Because allergic rhinitis can contribute to SDB, the children’s parents or the children themselves also completed the International Study of Asthma and Allergies in Childhood validated asthma and allergic rhinitis questionnaire. Overnight Assessment
The patients underwent a standard overnight PSG using XLTEK data acquisition and analysis systems (Natus Medical, San Carlos, CA). PSG measurements included electroencephalograms, electro-oculograms,
and submental and bilateral anterior tibialis electromyograms. Chest wall and abdominal movements were measured using chest wall and abdominal belts. Other respiratory measurements included a nasal air pressure transducer, an oronasal thermal sensor, oxygen saturation (SaO2), transcutaneous carbon dioxide (TcCO2), and end tidal carbon dioxide (etCO2). Video- and audiotape recordings were obtained, and body positions were noted. Neck circumference measurements were performed before and after the overnight PSG. Sleep architecture was assessed by using standard techniques (28). All respiratory events were scored according to the American Academy of Sleep Medicine guidelines (28) by a registered, certified polysomnographic technician who was blinded to the clinical status of the patients. All of the studies were reviewed and interpreted by an experienced pediatric sleep physician (I.N.). OSA severity was graded according to the obstructive apnea– hypopnea index (OAHI), the number of obstructive apneas, the number of mixed apneas, and the number of obstructive hypopneas per hour during sleep. OAHI scores of 2.0 or more were considered abnormal (10): scores from >2.0 to ,5 were considered to indicate mild OSA; scores from >5 to ,10 were categorized as moderate OSA; and scores >10 were considered to represent severe OSA (29). The central apnea–hypopnea index (CAHI) was defined as the number of central apneas and central hypopneas per hour during sleep, and its classification scheme was similar to the OAHI. A CAHI score >2.0 is abnormal, and a CAHI >5.0 was considered clinically significant (12). Cardiac assessment. Nocturnal BP was measured on an hourly basis using a portable BP monitoring system (90217 Ultralite Ambulatory Blood Pressure Monitor; Spacelabs Healthcare, Hertford, UK). Mean systolic and diastolic BPs during the night were converted to BP z scores, which were calculated using published normative data (30, 31). Patients underwent a detailed cardiac assessment by the treating cardiologist, as well as a detailed echocardiography. The cardiac clinical assessment included an evaluation of current symptoms, medications, and grading of functional capacity on the basis of the patient’s history
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ORIGINAL RESEARCH and a physical assessment conducted using the Ross classification staging system for heart failure (32) and the New York University Pediatric Heart Failure Index (33). Because previous adult heart failure and CM studies have focused on LV dimensions and function and have demonstrated more associations between CSA and LV diastolic diameters, the echocardiographic protocol included a comprehensive assessment of systolic and diastolic dimensions and function indices, including tissue Doppler evaluation of diastolic function, as well as LV mass assessment. These assessments were done in the scheduled cardiology clinic on the day after the PSG was obtained. Echocardiography was conducted using the Vivid 7 platform (GE Healthcare, Horten, Norway) according to a standardized protocol. Using probes appropriate for patient size, we acquired images from a four-chamber apical view, an apical longaxis view, a two-chamber apical view, and a parasternal short-axis view at the LV basal, papillary muscle, and apical levels. Images were optimized for compression and gain. Sweep speed was set at 100 cm/s. Image depth and sector width were optimized to achieve frame rates between 60–90 frames/s for tissue Doppler assessment. Images were transferred to a dedicated workstation for offline analysis (EchoPAC 6.0.1; GE Healthcare). Otolaryngological assessment. The upper aerodigestive tract was assessed by an otolaryngologist either on the day of their cardiology clinic visit or following the overnight PSG. Adenoid size was determined by flexible nasopharyngoscopy according to standard clinical practice. Accepted grading systems were used to classify the size of the adenoids (34), tonsillar hypertrophy, and position of the soft palate (35) Statistical Analyses
The statistical analyses involved descriptive statistics and included frequencies, percentages, means, medians, and/or range values, which were obtained for all baseline demographics and cardiac and PSG data. Maximum and minimum values were recorded for both SaO2 and tcCO2. Frequency statistical analyses were employed to observe the prevalence of SDB in this patient population. Comparison between patients with SDB and patients without SDB were carried out using the 772
Wilcoxon signed-rank test or x2 test/ Fisher’s exact test for comparison between both groups. Comparisons between CM subgroups were made using Kruskal– Wallis one-way analysis of variance or x2 tests. The assessment of the correlation between different cardiac variables and PSG variables was done using Spearman’s correlation coefficient. A standard statistical software package was used (SAS version 9.2; SAS Institute, Cary, NC). In this pilot study, we sought to determine the nature of SDB in children with CM, and therefore the sample size was limited to the number of patients with this rare condition.
Results During the study period, 57 eligible children with CM were invited to participate in the study. A total of 21 patients (17 males) with CM were recruited. Specific diagnoses were HCM (n = 8), DCM (n = 8), RCM (n = 2), LVNC CM (n = 2), and combined HCM and DCM (n = 1). The baseline characteristics, PSG results, and cardiac data of the patients are summarized in Table 1. A summary of relevant data from the sleep questionnaires and otolaryngological assessments are summarized in Table 2. Thirty-six patients (13 females) declined to participate in the study, mainly because of the requirement that they stay overnight in the hospital for PSG. Their median age was 12.3 years (range, 0.3–17.2), and their median BMI z score was 0.28 (range, 21.87 to 12.7). There were no significant differences between patients who declined to participate in the study and those who were recruited into the study in terms of sex, CM type, age, height, weight, and BMI z score. In the recruited population, a history of snoring was recorded for 11 (52%) of 21 patients, and children with DCM were more likely than other groups to snore (88%; P = 0.01). SDB was evident in 10 (48%) of 21 patients, with a median OAHI of 2.7 events/hour and a median CAHI of 4.1 events/hour. The PSG findings of these children with SDB are given in Table 3. From among this group, 5 of 10 had clinically significant CSA and 1 had severe OSA. Of particular concern was that one patient had significant CSR (Patient 1; see Table 3). Although the sleep questionnaire for this child was not positive for restless
sleep or frequent night awakening, he did report daytime sleepiness, which could be related to either his CSR or his underlying significant cardiac disease. The remaining four children had mild OSA and/or mild CSA. There were no significant differences between the children with SDB and the children without SDB regarding age, sex, BMI, parent-reported questionnaire results (including history of snoring), allergic rhinitis, otolaryngological assessment, sleep architecture, BP, and HR data. However, the median LV end diastolic volume index (LVEDVi) was significantly higher in children with CSA than in children without SDB (72.4 versus 54.0 ml/m2; P = 0.03). There were significant correlations between CAHI and LVEDVi (Spearman’s r = 0.55, P = 0.01) and between CAHI and LV end systolic volume index (Spearman’s r = 0.47, P = 0.03). There was no significant correlation between OAHI or CAHI and LVEF (Spearman’s r = 20.11, P = 0.62; Spearman’s r = 20.08, P = 0.72, respectively). One child with severe OSA had adenotonsillar hypertrophy and subsequently underwent adenotonsillectomy with complete resolution of OSA. Table 1 also summarizes the clinical, PSG, and cardiac data of the patients segregated by phenotype into HCM, DCM, and “other CM” (which included RCM, LVNC CM, and combined DCM and HCM). Of note, on the whole, these patients were relatively mildly symptomatic at the time of assessment (with mostly low New York Heart Association or Ross classification staging system for heart failure and New York University Pediatric Heart Failure Index scores), and medication use was quite prevalent. Compared with the other groups, the children with DCM were younger (median, 3.3 yr; P = 0.045), had a different medication use profile, had a more dilated left ventricle (median LV diastolic dimension z score, 3.8; P = 0.001), and lower LV ejection fraction (median, 34%; P = 0.006). In addition, children with DCM snored significantly more, but did not have increased OAHI or CAHI scores or SDB frequency. For all patients, the mean nocturnal systolic BP ranged between 82–119 mm Hg (z score range, 21.25 to 11.6) and the mean nocturnal diastolic BP ranged between 45–71 mm Hg (z score range, 21.8 to 12.5). Children in the DCM group had a lower mean systolic BP
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ORIGINAL RESEARCH Table 1. Demographic and study results in all children with cardiomyopathy and between subgroups Demographic Characteristics Age, yr Male:female ratio BMI z score Patients on medical therapy, n (%) History of snoring, n (%) TST, minutes Sleep latency, minutes Sleep efficiency, % REM latency, minutes Stage 1% TST Stage 2% TST Slow-wave sleep % TST REM % TST Arousals, total index Mean sleep SaO2, % Minimum SaO2,% DI, events/h Highest TcCO2/etCO2, mm Hg Evidence of SDB, n (%) OAHI, events/h CAHI, events/h NYHA/Ross class (I, II, III, IV), n Mean overnight HR, beats/min Mean overnight systolic BP, mm Hg Mean overnight diastolic BP, mm Hg LVEF % (Simpson’s method) LVEDd, z score LVESVi, ml/m2 LVEDVi, ml/m2
All CMP (n = 21)
HCM (n = 8)
DCM (n = 8)
Other CM (n = 5)*
10.7 (0.5–17.7) 17:4 0.8 (22.3 to 2.6) 17 (81) 11 (52) 374 (274–453) 14 (0.0–107) 85.4 (57.3–96.5) 86.5 (22–395) 5.4 (0.6–13.5) 52.2 (25.8–64) 26.6 (17.8–37.6) 16.2 (5.8–38.2) 11.3 (2.6–32.8) 97 (93–99) 92 (50–95) 0.3 (0.0–8.8) 48 (35–54) 10 (48) 1.2 (0.0–20.6) 1.1 (0.0–17.6) (14, 5, 2, 0) 70 (50–118) 100 (82–119) 53 (45–71) 57 (9–82) 1.6 (25.2 to 10.5) 35.8 (9.3–205) 65.1 (26–248)
11.5 (0.6–17.7) 7:1 1.5 (22.3 to 2.6) 7 (88) 2 (25) 364 (274–420) 26 (2–107) 78.1 (57.8–91.1) 144 (69–307.5) 5.4 (0.7–12.3) 52.8 (40–64) 30.7 (17.8–37.6) 12.7 (5.8–27.7) 13.5 (6.3–27.6) 98 (96–99) 91 (77–95) 0.3 (0.0–2.0) 45 (43–54) 4 (50) 0.7 (0.4–2.9) 1.1 (0.3–7.3) (5, 3, 0, 0) 64 (50–85) 100 (99–119) 54 (52–66) 68 (45–82) 22.7 (25.2 to 0.5) 26.2 (17.0–49.0) 56.0 (30.6–68.2)
3.3 (0.5–13.5) 6:2 0.6 (22.1 to 1.9) 7 (88) 7 (88) 374 (299–453) 10 (0.0–72) 84.1 (57.3–96.5) 71 (22–394) 5.7 (0.6–13.5) 47.8 (25.8–59.6) 23.7 (21.2–34.2) 18.3 (14.5–38.2) 11.5 (2.6–32.8) 97 (93–99) 84 (50–94) 0.4 (0.0–8.8) 48 (35–52) 5 (63) 2.2 (0.0–20.6) 1.6 (0.0–17.6) (5, 2, 1, 0) 77 (64–118) 90 (82–101) 49 (45–55) 34 (9–58) 3.8 (2.3–10.5) 50.0 (19.9–205) 72.5 (42.9–248)
15.2 (9.3–15.8) 4:1 20.6 (22.0 to 1.2) 3 (60) 2 (40) 399 (353–437) 14 (3–24) 91.4 (81.9–94.6) 76 (70–180) 5.1 (2.1–6.8) 53.8 (46.9–58.8) 26.6 (21.7–32.2) 14.4 (12.7–18.9) 6.6 (6.2–15.6) 98 (97–99) 92 (91–95) 0.3 (0.0–1.9) 47 (43–52) 1 (20) 1.0 (0.3–1.5) 0.6 (0.2–2.5) (4, 0, 1, 0) 60 (50–71) 106 (99–116) 55 (51–71) 65 (40–67) 1.7 (21.3 to 3.7) 39.0 (9.3–83.6) 69.0 (26.0–91.1)
P Value† 0.045 1.0 0.16 0.45 0.01 0.27 0.37 0.10 0.54 0.81 0.60 0.72 0.08 0.23 0.46 0.06 0.69 0.87 0.41 0.24 0.56 0.49 0.07 0.04 0.51 0.006 0.001 0.11 0.11
Definition of Abbreviations: BP = blood pressure; CAHI = central apnea–hypopnea index; DCM = dilated cardiomyopathy; DI = desaturation index; etCO2 = end tidal carbon dioxide; HCM = hypertrophic cardiomyopathy; HR = heart rate; LVEDd = left ventricular diastolic dimension; LVEDVi = left ventricular end diastolic volume index; LVEF = left ventricular ejection fraction; LVESVi = left ventricular end systolic volume index; LVNC CM = left ventricular noncompaction cardiomyopathy; NYHA = New York Heart Association; OAHI = obstructive apnea–hypopnea index; RCM = restrictive cardiomyopathy; REM = rapid eye movement; SaO2 = oxygen saturation; SDB = sleep-disordered breathing; TcCO2 = transcutaneous carbon dioxide; TST = total sleep time. Unless otherwise specified, all data are expressed as median and range. *Other CM types: RCM (n = 2), LVNC CM (n = 2), and combined HCM and DCM (n = 1) † P values were calculated using Kruskal–Wallis one-way analysis of variance for comparison of the continuous data, and x2 test and/or Fisher’s exact test was used for comparison of proportions between CM subgroups.
compared with the other groups (P = 0.04), as would be expected.
Discussion To our knowledge, to date, this study is the first in which children with primary CM for SDB have been assessed. We prospectively studied an unselected group of children with primary CM for SDB using standard in-hospital attended PSG. The main findings were that more than half of the children snored and 48% of the children had evidence of SDB—both CSA and OSA. The striking observation was the high frequency of clinically significant CSA observed in children with CM and the correlation of the CAHI score with LV volume indices. We
observed that a history of snoring, nasal congestion, or otolaryngological findings were not predictive of OSA. Currently, there are no published studies that have explored the relationship
between OSA in children with underlying CM. Investigators in two studies explored SDB in patients with underlying cardiac diseases (36, 37). Peer and colleagues evaluated 10 children with congestive heart
Table 2. Summary of the sleep questionnaire results and otolaryngological assessments Patient Characteristics (n = 21) History of snoring, n (%) History of mouth breathing, n (%) History of gasping for air during sleep, n (%) History of observed apneas during sleep, n (%) Adenoid size (I, II, III, IV, not done) Tonsil size (I, II, III, IV, not done, previous tonsillectomy) Palate position (I, II, III, IV, not done)
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Results 11 12 2 1
(52%) (57%) (10%) (5%) (8, 8, 1, 0, 4) (6, 5, 7, 0, 3, 1) (16, 2, 1, 0, 2)
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ORIGINAL RESEARCH Table 3. Polysomnographic results of individual CM subjects with SDB Patient
1 2 3 4 5 6 7 8 9 10
Age
Sex
BMI z Score
CM Diagnosis
LVEF* (%)
LVEDVi* (ml/m2)
LVESVi* (ml/m2)
DI
OAHI
CAHI
Mean sleep SaO2 (%)
Minimum SaO2 (%)
Highest TcCO2/ etCO2 (mm Hg)
13.5 17.7 0.5 2.9 9.3 0.7 17.3 17.5 10.5 0.8
M M M M M F M M M M
0.94 1.57 22.05 1.46 22.04 0.33 2.55 0.8 0.08 1.84
DCM HCM DCM DCM DCM 1 HCM DCM HCM HCM HCM DCM
9 72 16 50 67 23 78 82 57 34.8
178 58 248 55 74.8 70 64.3 54 67 75
145 17 205 30.6 42.4 51 41.8 35.8 29 49
4.0 0.6 8.8 5.2 0.4 0.6 2 1.5 0.0 8.9
1.2 2.9 3.0 20.6 1.4 3 2.6 2.4 0.6 2.8
17.6 7.3 5.2 1.1 2.5 5.5 6.3 0.6 2.9 2
93.2 97.6 95.6 97.3 97.5 99.2 97.9 97.9 96.9 95.1
85 92 84.2 49.9 93.1 83.6 79.2 91.8 92.9 76
35.4 44.3 48 52 51.7 48 44.2 45.6 54 49.6
Arousal Index
32.8 27.6 11.3 27.5 6.6 17.1 12.3 7.2 15 0
Definition of Abbreviations: BMI = body mass index; CAHI = central apnea–hypopnea index; DCM = dilated cardiomyopathy; DI = desaturation index; etCO2 = end tidal carbon dioxide; HCM = hypertrophic cardiomyopathy; LVEDVi = left ventricular end diastolic volume index; LVEF = left ventricular ejection fraction; LVESVi = left ventricular end systolic volume index; OAHI = obstructive apnea–hypopnea index; RCM = restrictive cardiomyopathy; SaO2 = oxygen saturation; TcCO2 = transcutaneous carbon dioxide. *Normative reference echocardiography values (mean 6 SD): LVEF (63 6 6%), LVEDVi (50 6 10 ml/m2), LVESVi (19 6 5 ml/m2).
failure due to different types of congenital heart disease and found no evidence of CSR, but specific details regarding the apnea–hypopnea index data in their study are not available (36). Ykeda and colleagues evaluated infants with cyanotic (n = 7) and acyanotic (n = 7) congenital heart disease and found that they had increased apnea–hypopnea index scores in comparison to a control infant group (37). Importantly, it has been observed that otherwise healthy children with OSA have systemic hypertension (14, 38), impaired LV diastolic function (15, 16, 39), and increased LV wall dimensions (16, 17), as well as increased pulmonary pressure and pulmonary hypertension (18, 19, 40, 41). It has been postulated that increased sympathetic nervous system activation and sympathetic–parasympathetic nervous system imbalance secondary to hypoxemia and swings in intrathoracic pressure play etiologic roles in cardiovascular dysfunction (42). Moreover, the documented association of systemic inflammatory responses secondary to oxidative stress (42–45) and functional disruption of the vascular endothelium (46–48) may further potentiate cardiovascular morbidity in adult and pediatric patients with OSA. Although we did not find any association between OAHI and cardiac function, this may be related to the fact that the majority of the SDB observed was in the mild range. Furthermore, the majority of the children with CM had good cardiac function, and subtle abnormalities related to SDB may be hard to appreciate. In the present study, it is important to consider the possible pathophysiological processes for the observed high frequency of 774
SDB, particularly CSA, in children with CM. A unifying novel mechanism for the presence of CSA and OSA in heart disease has been proposed by Yumino and colleagues. In their study, 57 medically stable adults with heart failure were assessed with a PSG (49). From among those patients, 35 had mostly OSA and 22 had CSA and CSR. The authors demonstrated that during sleep, a rostral fluid shift of as little as 190 ml was displaced from the legs either to around the neck or to the pulmonary interstitium. They hypothesized that excess fluid in the pulmonary interstitium stimulates the pulmonary irritant receptors, with resultant hyperventilation. Hyperventilation causes a lowering of CO2 level below the apneic threshold, resulting in central apnea. OSA results from the excess accumulation of fluid around the neck and consequent upper-airway narrowing. However, we did not measure fluid shift in this study and are unable to corroborate those previous findings in this study. Adult data indicate that LV end diastolic volume is a risk factor for CSA rather than low LV function (50). Researchers in a recent study of adult patients with CM and SDB found a significant correlation between LV end diastolic diameter and the severity of the apnea–hypopnea index (51). Also, in our present study, we found significant correlations between CAHI and LV volumes. Furthermore, our finding that patients with CSA had higher LVEDVi values than children with no SDB, which also is in accord with data derived from adults with CM (52). Specifically, these findings may be relevant because CSA is associated with changes in heart rate and BP in children (27)
and also was found to be a predictor of poor outcomes in adults with heart failure (50). Additional limitations of our study include the relatively small sample size of patients with mild cardiac disease, which prevented us from seeking further significant associations between SDB, CM subtypes, and cardiac function variables beyond LVEDVi, such as LVEF. In addition, the wide age range and different subgroups in this small sample made it difficult to assess these associations. However, as this disease is uncommon, our sample size was limited by the number of the patients with the disease who met our inclusion criteria. Therefore, our findings are likely applicable to other children with CM. Further work with a larger sample size is needed to confirm our findings and to assess these associations. We did not have contemporaneous controls with normal cardiac function; however, investigators in multiple previous PSG studies have shown that the frequency of significant CSA and OSA in children is lower than that in our present study (8).
Conclusions and Future Directions In this study, we observed that children with CM have an increased frequency of clinically significant CSA. In addition, 48% of our cohort had some evidence of SDB. Furthermore, our finding of a significant correlation between LVEDVi and CSA in patients with CM suggests some relationship between SDB and cardiac function. Children with CM may therefore benefit from sleep surveillance. In particular, children with very high LVEDVi levels may require PSG
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ORIGINAL RESEARCH screening, regardless of symptomatology or cardiac function. Further large-scale studies are needed to verify the prevalence of, and the relationships between, SDB, various CM
subtypes, and cardiac function, as well as the impact of SDB on chronic cardiac disease. Future research should also be directed at exploring the effects of routine sleep surveillance, early diagnosis, and
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of Respiratory Medicine and 2Department of Otolaryngology, Hospital for Sick Children, Toronto, Ontario, Canada; of Cardiology, University of Alberta, and Department of Pediatrics, Stollery Children’s Hospital, Edmonton, Alberta, Canada; and Division of Otolaryngology, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada; and 5Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
Abstract Rationale: Cardiomyopathy is a rare condition in children that is associated with high mortality. Although sleep-disordered breathing is prevalent, its frequency and patterns in children with cardiomyopathy are unknown. Objectives: To evaluate the frequency and patterns of sleepdisordered breathing and their relationship to cardiac function in children with primary cardiomyopathy. Methods: This study comprised a prospective, uncontrolled case series. Children with cardiomyopathy completed a sleep questionnaire, overnight polysomnography, blood pressure monitoring, otolaryngological assessment, and transthoracic echocardiography at the Hospital for Sick Children in Toronto, Canada. Measurements and Main Results: Twenty-one patients (17 males) were recruited. The median age of the patients was 10.7 years, and the median body mass index z score was 0.8. Sleepdisordered breathing was observed in 10 (48%) of 21 patients. Significant central sleep apnea was the main finding in 5 (24%) of 21 of the cohort and in 50% of the sleep-disordered breathing
population. The left ventricular end diastolic volume index was greater in children with central sleep apnea than in children without sleep-disordered breathing (P = 0.03). There were significant correlations between the central apnea–hypopnea index and both left ventricular end diastolic and end systolic volume indexes (Spearman’s r = 0.55, P = 0.01; Spearman’s r = 0.47, P = 0.03, respectively). Snoring, sleep architecture, blood pressure, and otolaryngological findings were not significantly different between children with sleep-disordered breathing versus those without sleep-disordered breathing. Conclusions: Sleep-disordered breathing is common in children with cardiomyopathy. In our present study, 24% of participants exhibited primarily central sleep apnea. The severity of cardiac dysfunction, as measured by left ventricular end diastolic volume index and left ventricular end systolic volume index, is associated with central sleep apnea. Longitudinal research is necessary to better characterize sleep disorders and their impact on cardiac function in a large pediatric cardiomyopathy population. Keywords: cardiomyopathies; sleep apnea, obstructive; sleep apnea, central; pediatrics; polysomnography
(Received in original form September 26, 2013; accepted in final form March 11, 2014 ) Author contributions: S.A.-S.: study design, patient recruitment, detailed data collection, statistical analyses, manuscript writing. P.F.K.: review of clinical examination and echocardiography studies for data acquisition, critical revision of the manuscript. N.K.C.: patient examination, critical revision of the manuscript. Y.T.: patient examination, critical revision of the manuscript. A.L.J.: patient examination, critical revision of the manuscript. I.N.: study design, detailed review of data collection and statistical results, manuscript writing. Correspondence and reprint requests should be sent to Indra Narang, MBBCH, FRCPCH, M.D., Division of Respiratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 Canada. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 5, pp 770–776, Jun 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201309-325OC Internet address: www.atsjournals.org
Primary cardiomyopathies (CMs) are heart muscle disorders that affect ventricular systolic function, diastolic function, or both. They are classified according to phenotype as (1) dilated cardiomyopathy (DCM), (2) hypertrophic cardiomyopathy (HCM), (3) restrictive cardiomyopathy (RCM), and
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(4) arrhythmogenic right ventricular dysplasia/CM (1). Recently, left ventricular noncompaction (LVNC) has been added as a specific primary CM class. CM is rare in children, but it is a serious and life-threatening condition with an annual incidence of 1.1–1.2/100,000 (2, 3).
Two-thirds of all pediatric CM cases are thought to be idiopathic (3), and the rest of the cases are either familial or secondary to neuromuscular disorders, myocarditis, malformation syndromes, and inborn errors of metabolism. The prognosis for children with CM is guarded, with high
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ORIGINAL RESEARCH rates of morbidity and mortality. Overall, 32–46% of symptomatic pediatric patients with DCM and 13% of symptomatic children with HCM will either receive a heart transplant or die within 5 years of diagnosis (4, 5). Sleep-disordered breathing (SDB) is a characteristic of a group of respiratory disorders specific to or exacerbated by sleep, which includes central sleep apnea (CSA) and obstructive sleep apnea (OSA). OSA and CSA are diagnosed on the basis of the gold standard: polysomnogram (PSG) (6, 7). OSA, the commonest SDB in children, is characterized by prolonged partial upper-airway obstruction (obstructive hypopnea) and/or intermittent complete obstruction (obstructive apnea). The prevalence of childhood OSA is 2–4% (8), with adenotonsillar hypertrophy being the commonest underlying etiologic factor in OSA. Resolution of OSA in children can occur following an adenotonsillectomy (9, 10). CSA and central hypoventilation syndromes are less common in children, the causes of which include congenital central hypoventilation syndrome and Arnold–Chiari malformations (11, 12). OSA has more recently received significant attention because of the potential for significant cardiovascular and neurocognitive sequelae if it is left untreated (13–19). Thus it can be hypothesized that OSA in the context of underlying heart disease may further potentiate cardiovascular damage. Indeed, data derived from adult patients with CM indicate that cardiovascular morbidity is increased in patients with OSA compared with those without OSA. Importantly, treatment of OSA with positive airway pressure has been reported to improve cardiovascular function (20–24). Of significance is that severe CSA characterized by Cheyne–Stokes respiration (CSR) in adults with congestive heart failure was found to be an independent risk factor for mortality (25, 26). CSA is less common in children, but nonetheless it has been found to be associated with changes in heart rate and blood pressure (BP) (27). To the best of our knowledge, OSA and CSA disorders have not been described to date in children with known cardiovascular diseases. Our aim in this pilot study was to determine the frequency and nature of SDB in children with known primary CM and to characterize the relationship between SDB and cardiac function.
Methods Ethics
This study was approved by the Research Ethics Board at the Hospital for Sick Children, and written informed consent was obtained from all of the participants’ parents or legal guardians. Study Design and Study Population
We conducted a prospective cross-sectional study in which eligible children were ages 1 month to 18 years, had an echocardiographic diagnosis of primary CM, and were clinically stable. Recruitment was of sequential patients identified at the Hospital for Sick Children in Toronto, Canada, between 2009 and 2011. Screening of potential recruits excluded those who met the following criteria: (1) a diagnosis of congenital or chronic lung disease; (2) structural congenital heart disease or previous surgical repair of same; (3) systemic, neurological, or neuromuscular comorbidities associated with CM or known to cause SDB (e.g., Duchenne’s muscular dystrophy, mucopolysaccharidosis); (4) children deemed unstable clinically (e.g., currently receiving intravenous inotropic support); (5) the use of noninvasive ventilation for any reason; (6) and any known current or previous diagnosis of SDB. The demographic data collected at the time of PSG included age, sex, height, weight, and body mass index (BMI). Detailed information collected at the time of cardiac assessment included medications, CM type, and current clinical status. Questionnaires
All parents completed a detailed sleep questionnaire tailored specifically for the sleep laboratory at the Hospital for Sick Children to evaluate children for symptoms of SDB. Because allergic rhinitis can contribute to SDB, the children’s parents or the children themselves also completed the International Study of Asthma and Allergies in Childhood validated asthma and allergic rhinitis questionnaire. Overnight Assessment
The patients underwent a standard overnight PSG using XLTEK data acquisition and analysis systems (Natus Medical, San Carlos, CA). PSG measurements included electroencephalograms, electro-oculograms,
and submental and bilateral anterior tibialis electromyograms. Chest wall and abdominal movements were measured using chest wall and abdominal belts. Other respiratory measurements included a nasal air pressure transducer, an oronasal thermal sensor, oxygen saturation (SaO2), transcutaneous carbon dioxide (TcCO2), and end tidal carbon dioxide (etCO2). Video- and audiotape recordings were obtained, and body positions were noted. Neck circumference measurements were performed before and after the overnight PSG. Sleep architecture was assessed by using standard techniques (28). All respiratory events were scored according to the American Academy of Sleep Medicine guidelines (28) by a registered, certified polysomnographic technician who was blinded to the clinical status of the patients. All of the studies were reviewed and interpreted by an experienced pediatric sleep physician (I.N.). OSA severity was graded according to the obstructive apnea– hypopnea index (OAHI), the number of obstructive apneas, the number of mixed apneas, and the number of obstructive hypopneas per hour during sleep. OAHI scores of 2.0 or more were considered abnormal (10): scores from >2.0 to ,5 were considered to indicate mild OSA; scores from >5 to ,10 were categorized as moderate OSA; and scores >10 were considered to represent severe OSA (29). The central apnea–hypopnea index (CAHI) was defined as the number of central apneas and central hypopneas per hour during sleep, and its classification scheme was similar to the OAHI. A CAHI score >2.0 is abnormal, and a CAHI >5.0 was considered clinically significant (12). Cardiac assessment. Nocturnal BP was measured on an hourly basis using a portable BP monitoring system (90217 Ultralite Ambulatory Blood Pressure Monitor; Spacelabs Healthcare, Hertford, UK). Mean systolic and diastolic BPs during the night were converted to BP z scores, which were calculated using published normative data (30, 31). Patients underwent a detailed cardiac assessment by the treating cardiologist, as well as a detailed echocardiography. The cardiac clinical assessment included an evaluation of current symptoms, medications, and grading of functional capacity on the basis of the patient’s history
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ORIGINAL RESEARCH and a physical assessment conducted using the Ross classification staging system for heart failure (32) and the New York University Pediatric Heart Failure Index (33). Because previous adult heart failure and CM studies have focused on LV dimensions and function and have demonstrated more associations between CSA and LV diastolic diameters, the echocardiographic protocol included a comprehensive assessment of systolic and diastolic dimensions and function indices, including tissue Doppler evaluation of diastolic function, as well as LV mass assessment. These assessments were done in the scheduled cardiology clinic on the day after the PSG was obtained. Echocardiography was conducted using the Vivid 7 platform (GE Healthcare, Horten, Norway) according to a standardized protocol. Using probes appropriate for patient size, we acquired images from a four-chamber apical view, an apical longaxis view, a two-chamber apical view, and a parasternal short-axis view at the LV basal, papillary muscle, and apical levels. Images were optimized for compression and gain. Sweep speed was set at 100 cm/s. Image depth and sector width were optimized to achieve frame rates between 60–90 frames/s for tissue Doppler assessment. Images were transferred to a dedicated workstation for offline analysis (EchoPAC 6.0.1; GE Healthcare). Otolaryngological assessment. The upper aerodigestive tract was assessed by an otolaryngologist either on the day of their cardiology clinic visit or following the overnight PSG. Adenoid size was determined by flexible nasopharyngoscopy according to standard clinical practice. Accepted grading systems were used to classify the size of the adenoids (34), tonsillar hypertrophy, and position of the soft palate (35) Statistical Analyses
The statistical analyses involved descriptive statistics and included frequencies, percentages, means, medians, and/or range values, which were obtained for all baseline demographics and cardiac and PSG data. Maximum and minimum values were recorded for both SaO2 and tcCO2. Frequency statistical analyses were employed to observe the prevalence of SDB in this patient population. Comparison between patients with SDB and patients without SDB were carried out using the 772
Wilcoxon signed-rank test or x2 test/ Fisher’s exact test for comparison between both groups. Comparisons between CM subgroups were made using Kruskal– Wallis one-way analysis of variance or x2 tests. The assessment of the correlation between different cardiac variables and PSG variables was done using Spearman’s correlation coefficient. A standard statistical software package was used (SAS version 9.2; SAS Institute, Cary, NC). In this pilot study, we sought to determine the nature of SDB in children with CM, and therefore the sample size was limited to the number of patients with this rare condition.
Results During the study period, 57 eligible children with CM were invited to participate in the study. A total of 21 patients (17 males) with CM were recruited. Specific diagnoses were HCM (n = 8), DCM (n = 8), RCM (n = 2), LVNC CM (n = 2), and combined HCM and DCM (n = 1). The baseline characteristics, PSG results, and cardiac data of the patients are summarized in Table 1. A summary of relevant data from the sleep questionnaires and otolaryngological assessments are summarized in Table 2. Thirty-six patients (13 females) declined to participate in the study, mainly because of the requirement that they stay overnight in the hospital for PSG. Their median age was 12.3 years (range, 0.3–17.2), and their median BMI z score was 0.28 (range, 21.87 to 12.7). There were no significant differences between patients who declined to participate in the study and those who were recruited into the study in terms of sex, CM type, age, height, weight, and BMI z score. In the recruited population, a history of snoring was recorded for 11 (52%) of 21 patients, and children with DCM were more likely than other groups to snore (88%; P = 0.01). SDB was evident in 10 (48%) of 21 patients, with a median OAHI of 2.7 events/hour and a median CAHI of 4.1 events/hour. The PSG findings of these children with SDB are given in Table 3. From among this group, 5 of 10 had clinically significant CSA and 1 had severe OSA. Of particular concern was that one patient had significant CSR (Patient 1; see Table 3). Although the sleep questionnaire for this child was not positive for restless
sleep or frequent night awakening, he did report daytime sleepiness, which could be related to either his CSR or his underlying significant cardiac disease. The remaining four children had mild OSA and/or mild CSA. There were no significant differences between the children with SDB and the children without SDB regarding age, sex, BMI, parent-reported questionnaire results (including history of snoring), allergic rhinitis, otolaryngological assessment, sleep architecture, BP, and HR data. However, the median LV end diastolic volume index (LVEDVi) was significantly higher in children with CSA than in children without SDB (72.4 versus 54.0 ml/m2; P = 0.03). There were significant correlations between CAHI and LVEDVi (Spearman’s r = 0.55, P = 0.01) and between CAHI and LV end systolic volume index (Spearman’s r = 0.47, P = 0.03). There was no significant correlation between OAHI or CAHI and LVEF (Spearman’s r = 20.11, P = 0.62; Spearman’s r = 20.08, P = 0.72, respectively). One child with severe OSA had adenotonsillar hypertrophy and subsequently underwent adenotonsillectomy with complete resolution of OSA. Table 1 also summarizes the clinical, PSG, and cardiac data of the patients segregated by phenotype into HCM, DCM, and “other CM” (which included RCM, LVNC CM, and combined DCM and HCM). Of note, on the whole, these patients were relatively mildly symptomatic at the time of assessment (with mostly low New York Heart Association or Ross classification staging system for heart failure and New York University Pediatric Heart Failure Index scores), and medication use was quite prevalent. Compared with the other groups, the children with DCM were younger (median, 3.3 yr; P = 0.045), had a different medication use profile, had a more dilated left ventricle (median LV diastolic dimension z score, 3.8; P = 0.001), and lower LV ejection fraction (median, 34%; P = 0.006). In addition, children with DCM snored significantly more, but did not have increased OAHI or CAHI scores or SDB frequency. For all patients, the mean nocturnal systolic BP ranged between 82–119 mm Hg (z score range, 21.25 to 11.6) and the mean nocturnal diastolic BP ranged between 45–71 mm Hg (z score range, 21.8 to 12.5). Children in the DCM group had a lower mean systolic BP
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ORIGINAL RESEARCH Table 1. Demographic and study results in all children with cardiomyopathy and between subgroups Demographic Characteristics Age, yr Male:female ratio BMI z score Patients on medical therapy, n (%) History of snoring, n (%) TST, minutes Sleep latency, minutes Sleep efficiency, % REM latency, minutes Stage 1% TST Stage 2% TST Slow-wave sleep % TST REM % TST Arousals, total index Mean sleep SaO2, % Minimum SaO2,% DI, events/h Highest TcCO2/etCO2, mm Hg Evidence of SDB, n (%) OAHI, events/h CAHI, events/h NYHA/Ross class (I, II, III, IV), n Mean overnight HR, beats/min Mean overnight systolic BP, mm Hg Mean overnight diastolic BP, mm Hg LVEF % (Simpson’s method) LVEDd, z score LVESVi, ml/m2 LVEDVi, ml/m2
All CMP (n = 21)
HCM (n = 8)
DCM (n = 8)
Other CM (n = 5)*
10.7 (0.5–17.7) 17:4 0.8 (22.3 to 2.6) 17 (81) 11 (52) 374 (274–453) 14 (0.0–107) 85.4 (57.3–96.5) 86.5 (22–395) 5.4 (0.6–13.5) 52.2 (25.8–64) 26.6 (17.8–37.6) 16.2 (5.8–38.2) 11.3 (2.6–32.8) 97 (93–99) 92 (50–95) 0.3 (0.0–8.8) 48 (35–54) 10 (48) 1.2 (0.0–20.6) 1.1 (0.0–17.6) (14, 5, 2, 0) 70 (50–118) 100 (82–119) 53 (45–71) 57 (9–82) 1.6 (25.2 to 10.5) 35.8 (9.3–205) 65.1 (26–248)
11.5 (0.6–17.7) 7:1 1.5 (22.3 to 2.6) 7 (88) 2 (25) 364 (274–420) 26 (2–107) 78.1 (57.8–91.1) 144 (69–307.5) 5.4 (0.7–12.3) 52.8 (40–64) 30.7 (17.8–37.6) 12.7 (5.8–27.7) 13.5 (6.3–27.6) 98 (96–99) 91 (77–95) 0.3 (0.0–2.0) 45 (43–54) 4 (50) 0.7 (0.4–2.9) 1.1 (0.3–7.3) (5, 3, 0, 0) 64 (50–85) 100 (99–119) 54 (52–66) 68 (45–82) 22.7 (25.2 to 0.5) 26.2 (17.0–49.0) 56.0 (30.6–68.2)
3.3 (0.5–13.5) 6:2 0.6 (22.1 to 1.9) 7 (88) 7 (88) 374 (299–453) 10 (0.0–72) 84.1 (57.3–96.5) 71 (22–394) 5.7 (0.6–13.5) 47.8 (25.8–59.6) 23.7 (21.2–34.2) 18.3 (14.5–38.2) 11.5 (2.6–32.8) 97 (93–99) 84 (50–94) 0.4 (0.0–8.8) 48 (35–52) 5 (63) 2.2 (0.0–20.6) 1.6 (0.0–17.6) (5, 2, 1, 0) 77 (64–118) 90 (82–101) 49 (45–55) 34 (9–58) 3.8 (2.3–10.5) 50.0 (19.9–205) 72.5 (42.9–248)
15.2 (9.3–15.8) 4:1 20.6 (22.0 to 1.2) 3 (60) 2 (40) 399 (353–437) 14 (3–24) 91.4 (81.9–94.6) 76 (70–180) 5.1 (2.1–6.8) 53.8 (46.9–58.8) 26.6 (21.7–32.2) 14.4 (12.7–18.9) 6.6 (6.2–15.6) 98 (97–99) 92 (91–95) 0.3 (0.0–1.9) 47 (43–52) 1 (20) 1.0 (0.3–1.5) 0.6 (0.2–2.5) (4, 0, 1, 0) 60 (50–71) 106 (99–116) 55 (51–71) 65 (40–67) 1.7 (21.3 to 3.7) 39.0 (9.3–83.6) 69.0 (26.0–91.1)
P Value† 0.045 1.0 0.16 0.45 0.01 0.27 0.37 0.10 0.54 0.81 0.60 0.72 0.08 0.23 0.46 0.06 0.69 0.87 0.41 0.24 0.56 0.49 0.07 0.04 0.51 0.006 0.001 0.11 0.11
Definition of Abbreviations: BP = blood pressure; CAHI = central apnea–hypopnea index; DCM = dilated cardiomyopathy; DI = desaturation index; etCO2 = end tidal carbon dioxide; HCM = hypertrophic cardiomyopathy; HR = heart rate; LVEDd = left ventricular diastolic dimension; LVEDVi = left ventricular end diastolic volume index; LVEF = left ventricular ejection fraction; LVESVi = left ventricular end systolic volume index; LVNC CM = left ventricular noncompaction cardiomyopathy; NYHA = New York Heart Association; OAHI = obstructive apnea–hypopnea index; RCM = restrictive cardiomyopathy; REM = rapid eye movement; SaO2 = oxygen saturation; SDB = sleep-disordered breathing; TcCO2 = transcutaneous carbon dioxide; TST = total sleep time. Unless otherwise specified, all data are expressed as median and range. *Other CM types: RCM (n = 2), LVNC CM (n = 2), and combined HCM and DCM (n = 1) † P values were calculated using Kruskal–Wallis one-way analysis of variance for comparison of the continuous data, and x2 test and/or Fisher’s exact test was used for comparison of proportions between CM subgroups.
compared with the other groups (P = 0.04), as would be expected.
Discussion To our knowledge, to date, this study is the first in which children with primary CM for SDB have been assessed. We prospectively studied an unselected group of children with primary CM for SDB using standard in-hospital attended PSG. The main findings were that more than half of the children snored and 48% of the children had evidence of SDB—both CSA and OSA. The striking observation was the high frequency of clinically significant CSA observed in children with CM and the correlation of the CAHI score with LV volume indices. We
observed that a history of snoring, nasal congestion, or otolaryngological findings were not predictive of OSA. Currently, there are no published studies that have explored the relationship
between OSA in children with underlying CM. Investigators in two studies explored SDB in patients with underlying cardiac diseases (36, 37). Peer and colleagues evaluated 10 children with congestive heart
Table 2. Summary of the sleep questionnaire results and otolaryngological assessments Patient Characteristics (n = 21) History of snoring, n (%) History of mouth breathing, n (%) History of gasping for air during sleep, n (%) History of observed apneas during sleep, n (%) Adenoid size (I, II, III, IV, not done) Tonsil size (I, II, III, IV, not done, previous tonsillectomy) Palate position (I, II, III, IV, not done)
Al-Saleh, Kantor, Chadha, et al.: Sleep-disordered Breathing in Pediatric Cardiomyopathy
Results 11 12 2 1
(52%) (57%) (10%) (5%) (8, 8, 1, 0, 4) (6, 5, 7, 0, 3, 1) (16, 2, 1, 0, 2)
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ORIGINAL RESEARCH Table 3. Polysomnographic results of individual CM subjects with SDB Patient
1 2 3 4 5 6 7 8 9 10
Age
Sex
BMI z Score
CM Diagnosis
LVEF* (%)
LVEDVi* (ml/m2)
LVESVi* (ml/m2)
DI
OAHI
CAHI
Mean sleep SaO2 (%)
Minimum SaO2 (%)
Highest TcCO2/ etCO2 (mm Hg)
13.5 17.7 0.5 2.9 9.3 0.7 17.3 17.5 10.5 0.8
M M M M M F M M M M
0.94 1.57 22.05 1.46 22.04 0.33 2.55 0.8 0.08 1.84
DCM HCM DCM DCM DCM 1 HCM DCM HCM HCM HCM DCM
9 72 16 50 67 23 78 82 57 34.8
178 58 248 55 74.8 70 64.3 54 67 75
145 17 205 30.6 42.4 51 41.8 35.8 29 49
4.0 0.6 8.8 5.2 0.4 0.6 2 1.5 0.0 8.9
1.2 2.9 3.0 20.6 1.4 3 2.6 2.4 0.6 2.8
17.6 7.3 5.2 1.1 2.5 5.5 6.3 0.6 2.9 2
93.2 97.6 95.6 97.3 97.5 99.2 97.9 97.9 96.9 95.1
85 92 84.2 49.9 93.1 83.6 79.2 91.8 92.9 76
35.4 44.3 48 52 51.7 48 44.2 45.6 54 49.6
Arousal Index
32.8 27.6 11.3 27.5 6.6 17.1 12.3 7.2 15 0
Definition of Abbreviations: BMI = body mass index; CAHI = central apnea–hypopnea index; DCM = dilated cardiomyopathy; DI = desaturation index; etCO2 = end tidal carbon dioxide; HCM = hypertrophic cardiomyopathy; LVEDVi = left ventricular end diastolic volume index; LVEF = left ventricular ejection fraction; LVESVi = left ventricular end systolic volume index; OAHI = obstructive apnea–hypopnea index; RCM = restrictive cardiomyopathy; SaO2 = oxygen saturation; TcCO2 = transcutaneous carbon dioxide. *Normative reference echocardiography values (mean 6 SD): LVEF (63 6 6%), LVEDVi (50 6 10 ml/m2), LVESVi (19 6 5 ml/m2).
failure due to different types of congenital heart disease and found no evidence of CSR, but specific details regarding the apnea–hypopnea index data in their study are not available (36). Ykeda and colleagues evaluated infants with cyanotic (n = 7) and acyanotic (n = 7) congenital heart disease and found that they had increased apnea–hypopnea index scores in comparison to a control infant group (37). Importantly, it has been observed that otherwise healthy children with OSA have systemic hypertension (14, 38), impaired LV diastolic function (15, 16, 39), and increased LV wall dimensions (16, 17), as well as increased pulmonary pressure and pulmonary hypertension (18, 19, 40, 41). It has been postulated that increased sympathetic nervous system activation and sympathetic–parasympathetic nervous system imbalance secondary to hypoxemia and swings in intrathoracic pressure play etiologic roles in cardiovascular dysfunction (42). Moreover, the documented association of systemic inflammatory responses secondary to oxidative stress (42–45) and functional disruption of the vascular endothelium (46–48) may further potentiate cardiovascular morbidity in adult and pediatric patients with OSA. Although we did not find any association between OAHI and cardiac function, this may be related to the fact that the majority of the SDB observed was in the mild range. Furthermore, the majority of the children with CM had good cardiac function, and subtle abnormalities related to SDB may be hard to appreciate. In the present study, it is important to consider the possible pathophysiological processes for the observed high frequency of 774
SDB, particularly CSA, in children with CM. A unifying novel mechanism for the presence of CSA and OSA in heart disease has been proposed by Yumino and colleagues. In their study, 57 medically stable adults with heart failure were assessed with a PSG (49). From among those patients, 35 had mostly OSA and 22 had CSA and CSR. The authors demonstrated that during sleep, a rostral fluid shift of as little as 190 ml was displaced from the legs either to around the neck or to the pulmonary interstitium. They hypothesized that excess fluid in the pulmonary interstitium stimulates the pulmonary irritant receptors, with resultant hyperventilation. Hyperventilation causes a lowering of CO2 level below the apneic threshold, resulting in central apnea. OSA results from the excess accumulation of fluid around the neck and consequent upper-airway narrowing. However, we did not measure fluid shift in this study and are unable to corroborate those previous findings in this study. Adult data indicate that LV end diastolic volume is a risk factor for CSA rather than low LV function (50). Researchers in a recent study of adult patients with CM and SDB found a significant correlation between LV end diastolic diameter and the severity of the apnea–hypopnea index (51). Also, in our present study, we found significant correlations between CAHI and LV volumes. Furthermore, our finding that patients with CSA had higher LVEDVi values than children with no SDB, which also is in accord with data derived from adults with CM (52). Specifically, these findings may be relevant because CSA is associated with changes in heart rate and BP in children (27)
and also was found to be a predictor of poor outcomes in adults with heart failure (50). Additional limitations of our study include the relatively small sample size of patients with mild cardiac disease, which prevented us from seeking further significant associations between SDB, CM subtypes, and cardiac function variables beyond LVEDVi, such as LVEF. In addition, the wide age range and different subgroups in this small sample made it difficult to assess these associations. However, as this disease is uncommon, our sample size was limited by the number of the patients with the disease who met our inclusion criteria. Therefore, our findings are likely applicable to other children with CM. Further work with a larger sample size is needed to confirm our findings and to assess these associations. We did not have contemporaneous controls with normal cardiac function; however, investigators in multiple previous PSG studies have shown that the frequency of significant CSA and OSA in children is lower than that in our present study (8).
Conclusions and Future Directions In this study, we observed that children with CM have an increased frequency of clinically significant CSA. In addition, 48% of our cohort had some evidence of SDB. Furthermore, our finding of a significant correlation between LVEDVi and CSA in patients with CM suggests some relationship between SDB and cardiac function. Children with CM may therefore benefit from sleep surveillance. In particular, children with very high LVEDVi levels may require PSG
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ORIGINAL RESEARCH screening, regardless of symptomatology or cardiac function. Further large-scale studies are needed to verify the prevalence of, and the relationships between, SDB, various CM
subtypes, and cardiac function, as well as the impact of SDB on chronic cardiac disease. Future research should also be directed at exploring the effects of routine sleep surveillance, early diagnosis, and
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