- Email: [email protected]
Left ventricular function in children with sleep-disordered breathing
develop in patients with DM as a result of insulin resistance, which independently stimulates LV growth. The LV mass was not greater in our patients with DM. Our method of gated SPECT does not allow the assessment of diastolic LV function or systolic LV function during stress. These were not the objectives of our study, which specifically evaluated systolic LV function, volume, and mass in gender-matched patients with and without DM in the absence of ischemia or infarction. Our results therefore do not apply to patients with DM who have ischemia or infarction. The SPECT imaging method does not have the same degree of resolution as other imaging methods, such as 2-dimensional echocardiography or magnetic resonance imaging. These modalities are superior for measuring the muscle mass, especially when the heart size is small, as is the case in women. However, our method is automated and was used in an identical fashion in consecutive patients separated by their gender and DM. We did not require coronary angiography to exclude ischemia or scar and relied on the results of stress perfusion imaging, because luminography has limitations in assessing the physiology of coronary circulation in patients with DM. 1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595– 602. 2. Romanens M, Fankhauser S, Saner B, Michaud L, Saner H. No evidence for systolic or diastolic left ventricular function at rest in selected patients with long-term type I diabetes mellitus. Eur J Heart Fail 1999;1:169 –175. 3. Cosson S, Kevorkian JP. Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab 2003;29:455– 466.
4. Mustonen JN, Uusitupa MI, Laakso M, Vanninen E, Lansimies E, Kuikka JT, Pyorala K. Left ventricular systolic function in middle-aged patients with diabetes mellitus. Am J Cardiol 1994;73:1202–1208. 5. Manchikalapudi P, Biederman R, Dayle M, Fuisz A, Pohost GM, Howard G, Paine T, Rogers WJ, Iskandrian AE. Validation of left ventricular mass by SPECT sestamibi imaging (abstr). J Nucl Cardiol 2000;7:185. 6. Butler RA, MacDonald TM, Struthers AD, Morris AD. The clinical implications of diabetic heart disease. Eur Heart J 1998;19:1617–1627. 7. Aronow WS, Ahn C. Incidence of heart failure in 2,737 older persons with and without diabetes mellitus. Chest 1999;115:867– 868. 8. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: Framingham study. Am J Cardiol 1974;34:29 –34. 9. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001;161:996 –1002. 10. Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepantalo M, Laatikainen L, et al. Risk factors for mortality in type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 1998;41:1253– 1262. 11. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035–2038. 12. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Cardiovasc Drugs Ther 1994;8:65–73. 13. Bell DS. Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care 1995;18:708 –714. 14. Neely JR, Rovetto MJ, Oram JF. Myocardial utilization of carbohydrate and lipid. Prog Cardiovasc Dis 1972;15:289 –329. 15. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 2001;107:813– 822. 16. Galderisi M, Anderson KM, Wilson PF, Levy D. Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (the Framingham Heart Study). Am J Cardiol 1991;68:85– 89. 17. Raev DC. Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care 1994;17:633– 639. 18. Harrower AD, Railton R, Small D. Comparison by nuclear angiography of resting left ventricular function on insulin-dependent diabetic patients and normal subjects and the effect of diabetic control. Diabetes Res 1984;1:227–229. 19. Fang ZY, Najos-Valencia O, Leano R, Marwick TH. Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 2003;42:446 – 453. 20. Struthers AD, Morris AD. Screening for and treating left ventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths. Lancet 2002;359:1430 –1432.
Left Ventricular Function in Children With SleepDisordered Breathing Raouf S. Amin, MD, Thomas R. Kimball, MD, Maninder Kalra, MD, Jenny L. Jeffries, RN, John L. Carroll, MD, Judy A. Bean, PhD, Sandra A. Witt, RDCS Betty J. Glascock, RDCS, and Stephen R. Daniels, MD, PhD Severe obstructive sleep apnea in children leads to congestive heart failure. We studied the early changes in left ventricular function across a range of severity of the disorder. A dose-dependent decrease From the Departments of Pulmonary Medicine, Cardiology,and Biostatistics, Cincinnati Children’s Hospital Medical Center, Sleep Disorder Center, Cincinnati, Ohio; and the Department of Pediatric Pulmonary Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. This study was supported by a grant-in-aid from the American Heart Association, Dallas, Texas, and Grant RO1HL70907-02A1 from the National Institutes of Health, Bethesda, Maryland. Dr. Amin’s address is: Cincinnati Children’s Hospital Medical Center, Division of Pulmonary Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229. E-mail: [email protected]. Manuscript received July 14, 2004; revised manuscript received and accepted November 12, 2004. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 March 15, 2005
in diastolic function with increased severity of obstructive apnea was demonstrated. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:801– 804)
lthough early reports of obstructive sleep apnea (OSA) in children have shown that severe upper A airway obstruction during sleep is associated with congestive heart failure,1,2 the subclinical forms of cardiac dysfunction in children with OSA have not been well characterized. There are reasons to expect that OSA has a negative impact on left ventricular (LV) function in children, because the geometry and structure of the left ventricle are altered in children with this disorder.3 The objectives of this study were to describe LV diastolic and systolic function in children with varying severity of 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.11.044
801
TABLE 1 Demographic and Polysomnographic Characteristics of the Study Population Obstructive Sleep Apnea Primary Snoring Group 1 (n ⫽ 15)
Group 2 (n ⫽ 23) Apnea Hypopnea Index
Group 3 (n ⫽ 25)
⬍1
1–5
⬎5
p Value
10.5 ⫾ 3.5 8 (53%) 87% 23.7 ⫾ 8 112 ⫾ 13 64 ⫾ 9
10.2 ⫾ 3.7 17 (73%) 61% 25.3 ⫾ 9.3 115 ⫾ 11 70 ⫾ 6
12.1 ⫾ 3.9 16 (64%) 64% 31 ⫾ 11† 117 ⫾ 15 65 ⫾ 9
NS NS NS 0.02 NS NS
2.8 (2.1–3.5)*
24 (10–33)†‡
⬍0.0001
Variable Demographic variables Age (yrs) No. of males No. of Caucasians Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Polysomnographic variables Apnea hypopnea index (25–75% quartiles) Desaturation index (no./ h) Lowest saturation Maximum CO2 (mm Hg) Arousal index (no./h)
0.1 (0.1–0.1) 0.6 92 49 12.3
(0.1–1.2) (90–93) (48–51) (7–14)
1.5 90 52 9.4
(0.4–2.6) (86–92) (49–54) (7–11)
11 83 54 17
†
(5–19) (78–86)†‡ (50–57)† (11–25)†‡
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
Demographic characteristics are expressed as mean ⫾ SD. Polysomnographic characteristics are expressed as median and interquartile range (25%–75%) *p ⬍0.05 group 1 versus group 2; †p ⬍0.05 group 1 versus group 3; ‡p ⬍0.05 group 2 versus group 3.
FIGURE 1. Decreases in mitral inflow velocity with increasing AHI. The overall difference among the 3 groups is reflected in the p value. #p <0.05 for group 1 versus 3 and group 2 versus 3. Shaded background, mean ⴞ 1 SD of published normal values for the E/A ratio.5
obstructive breathing during sleep and to measure the degree of reversibility after treatment. •••
Patients aged 5 to 18 years who were referred to the pediatric Sleep Disorder Clinic for evaluation for obstructive breathing during sleep were recruited sequentially and underwent polysomnography3 followed by echocardiography. The study excluded children with genetic syndromes and chronic medical conditions, including cardiac diseases. Informed consent was obtained from the parents or legal guardian of each child, and assent was obtained from children ⬎11 years old. The institutional review board of Children’s Hospital Medical Center approved the study. Polysomnographic results were used to subdivide 802 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 95
subjects into those with primary snoring (group 1) and those with OSA. The severity of OSA was measured by the frequency of apnea and hypopnea index (AHI). Subjects with AHI ⬎1/hour were classified as having OSA and were further classified into 2 more groups; those with AHI from 1 to 5/hour (group 2) and those with AHI ⬎5/hour (group 3). A subset of children was studied for a 1-year follow-up to determine the reversibility of cardiac dysfunction with resolution of OSA. To ensure resolution of OSA, children enrolled in the follow-up study underwent polysomnography at 8 weeks and 1 year after the initial evaluation. Two-dimensional (2-D) and 2-D– directed M-mode echocardiographic images were recorded to determine LV mass and relative wall thickness. LV systolic performance was assessed by measuring the ejection fraction, the shortening fraction, and the heart-rate– corrected velocity of circumferential fiber shortening. Delta velocity of circumferential fiber shortening, a measure of contractility, was derived by calculating the difference between the measured and the predicted fiber shortening for the measured wall stress according to the previously described equation.4 The primary measure of afterload was the meridional end-systolic wall stress. LV diastolic function was evaluated by mitral inflow velocity. The E/A ratio was derived from the velocity of the early (E) wave occurring during early diastolic filling and the velocity of the second wave (A) occurring during atrial contraction. Echocardiographic and blood pressure measurements were obtained by standardized conditions at rest with the subjects in the supine position after a minimum rest period of 5 minutes. Cardiologists and sonographers were blinded to the results of the polysomnography. For comparison of means, a 1-factor analysis of variance was performed. Multiple regression analysis MARCH 15, 2005
TABLE 2 Systolic Function and Contractile State of the Left Ventricle Primary Snoring
Obstructive Sleep Apnea
Apnea Hypopnea Index Groups
⬍1
Normal Values
Ejection fraction (%) Shortening fraction (%) Rate-corrected velocity of circumferential fiber shortening (circ/s) Delta rate-corrected velocity of circumferential fiber shortening (circ/s)
55 32 1.03 0.003
⫾ ⫾ ⫾ ⫾
5 6 0.18 0.03
62 40 1.23 0.54
⫾ ⫾ ⫾ ⫾
⬎5
1–5
5 59 ⫾ 5 42 ⫾ 0.23 1.24 ⫾ 0.22† 0.6 ⫾
6 5 0.21 0.23
60 40 1.24 0.48
⫾ ⫾ ⫾ ⫾
6 4 0.18 0.18
Normal values for different variables are shown. Results are expressed as mean ⫾ SD. p ⫽ NS.
TABLE 3 Demographic and Polysomnographic Characteristics of 10 Children Followed for One Year and 45 Children Without Follow-Up Simple Snoring
Obstructive Sleep Apnea
Groups
Follow-up (n ⫽ 9)
No Follow-up (n ⫽ 6)
Follow-up (n ⫽ 9)
Age (yrs) No. of males Apnea hypopnea index at baseline Apnea hypopnea index at of follow-up Body mass index at baseline (kg/m2) Body mass index at follow-up (kg/m2) Systolic blood pressure at baseline (mm Hg) Systolic blood pressure at follow-up (mm Hg) Diastolic blood pressure at baseline (mm Hg) Diastolic blood pressure at follow-up (mm Hg) E/A at baseline
12.3 ⫾ 2.9 6 (66%) 0.15 ⫾ 0.18 0.48 ⫾ 0.6 26 ⫾ 7.3 27.4 ⫾ 7.7 117 ⫾ 11 117 ⫾ 14 67 ⫾ 7 64 ⫾ 6 2 ⫾ 0.6
10.4 ⫾ 3.5 2 (30)% 0.1 ⫾ 0.2
12.3 ⫾ 3.9 6 (66%) 25 ⫾ 24 0.6 ⫾ 0.8 31 ⫾ 7 32 ⫾ 7 121 ⫾ 18 120 ⫾ 15 70 ⫾ 9 63 ⫾ 11 1.88 ⫾ 0.38
23 ⫾ 8 112 ⫾ 13 66 ⫾ 9 2.1 ⫾ 0.4
No Follow-up (n ⫽ 39) 11.9 ⫾ 3.9 27 (69%) 32 ⫾ 33 31 ⫾ 13 114 ⫾ 14 62 ⫾ 9 1.78 ⫾ 0.29
the E/A ratio (Figure 1). The mean ⫾ SD for the E/A ratio was 2.16 ⫾ 0.4, 2.0 ⫾ 0.4, and 1.78 ⫾ 0.3 for groups 1 to 3, respectively. The decrease in the E/A ratio was due primarily to an increase in the A-wave velocity. The difference in the E/A ratio remained statistically significant (p ⫽ 0.007) after controlling for age, gender, race, systolic and diastolic blood pressures FIGURE 2. Mitral inflow velocity in children with primary snoring and children with expressed as a percentage of the 95th OSA after 1 year. ⴱⴱp ⴝ 0.001 for the change in E/A ratio for the OSA group from percentile, and the Z score for body baseline to the end of follow-up. mass index. The model that predicted LV diwas performed to identify factors that might predict astolic function (p ⫽ 0.0014) included log AHI ( ⫽ LV function. The independent variables entered into a ⫺0.04, p ⫽ 0.0016), systolic blood pressure expressed backward elimination regression analysis were age, as a percentage of the 95th percentile ( ⫽ ⫺0.003, p gender, race, Z score for body mass index, systolic ⫽ 0.008), and Z score for body mass index ( ⫽ and diastolic blood pressures expressed as percentage ⫺0.015, p ⫽ 0.015) with R2 ⫽ 0.23. The AHI reof the 95th percentile, log AHI, desaturation index, mained statistically significant (p ⫽ 0.0006) after age, lowest oxygen saturation, maximum end-tidal carbon gender, race, and diastolic blood pressure expressed as dioxide, and LV mass index. A total sample size of 20 a percentage of the 95th percentile were forced into children was estimated to provide adequate power in the model with an overall value of p ⫽ 0.01. the follow-up study. The paired t test was performed LV end-systolic wall stress did not differ signifito compare the changes in cardiac function in each cantly among the 3 groups. Wall stress was 42 ⫾ 9, 46 group from baseline to the end of the follow-up. ⫾ 12, and 41 ⫾ 10 g/cm2 for groups 1 to 3, respecSixty-three patients satisfied the inclusion criteria and tively. The indexes of the contractile state of the left completed the study. The demographic and polysom- ventricle were not significantly different among the 3 nographic characteristics are listed Table 1. groups (Table 2). A decrease in the LV diastolic function across the 3 As previously described,3 a dose-dependent ingroups was demonstrated by the progressive decrease in crease in the LV mass index was observed with inBRIEF REPORTS
803
creased severity of OSA. The LV mass index was 32.5 ⫾ 3.6, 38.7 ⫾ 9.6, and 39.8 ⫾ 8.7 g/height2.7 for groups 1 to 3, respectively (p ⫽ 0.007). The diastolic function did not correlate with LV mass index (R ⫽ 0.1). Similarly, the change in diastolic function after treatment did not correlate with the change in the LV mass index. Children with AHI ⬎5/hour and those with AHI 1 to 5/hour who had daytime symptoms were offered treatment with tonsillectomy and adenoidectomy and/or continuous positive airway pressure. Ten adequately treated children with OSA and 10 age- and gender-matched children with primary snoring were recruited for a 1-year follow-up study. One child in the primary snoring group had a technically inadequate echocardiogram at 1 year and 1 child in the OSA group did not comply with treatment with continuous positive airway pressure. The demographic and polysomnographic characteristics are listed in Table 3. Six children had adenotonsillectomy, 1 child had an additional uvulopalatoplasty, and 3 children were managed with continuous positive airway pressure. Children managed with continuous positive airway pressure were followed quarterly in the clinic. Compliance with continuous positive airway pressure was ascertained from parental report. The E/A ratio improved by 18% (p ⫽ 0.001) in the OSA group, but no difference was observed in children with primary snoring (Figure 2). Children with primary snoring showed a trend toward a lower diastolic function at the end of the follow-up. Two of the 3 children who largely contributed to this decline developed a mild degree of OSA. •••
This study shows the independent effect of OSA on LV function in children without clinical evidence of cardiac dysfunction. The negative correlation between the severity of OSA and LV diastolic function is independent of obesity, blood pressure, and LV mass. To our knowledge, this study also shows for the first time that LV diastolic function in children with OSA improves after the disorder is adequately treated. The importance of this observation stems from the knowledge that diastolic dysfunction in adults is now increasingly emphasized as an early indicator of cardiac disability and may precede systolic dysfunction and heart failure6,7 Whether LV diastolic dysfunction in children has the same clinical significance as in adults is not known. O’Leary et al5 showed that children with increased end-diastolic LV pressure proved by cardiac catheterization have a lower E/A ratio (1.9 vs 2.3) compared with healthy controls. These findings suggest that in children, small deviations of E/A ratio from normal values may reflect early LV hemodynamic abnormalities. LV hypertrophy is a well-recognized mechanism for LV dysfunction in adults and in children8 –10 This study could not demonstrate that LV hypertrophy is a mechanism for LV dysfunction, however. In some hypertensive patients and patients with diabetes mellitus, diastolic dysfunction has been observed in the absence of LV
804 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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hypertrophy11,12 In these patients, altered myocardial energy metabolism was associated with LV dysfunction.13 Classically, OSA in children has been linked to right ventricular dysfunction and pulmonary hypertension; however, the mechanisms of pulmonary hypertension in children with OSA have not been thoroughly investigated. Several studies that examined the contributing factors to pulmonary hypertension in adult subjects with OSA have demonstrated that an increase in pulmonary venous pressure contributes to an elevation of pulmonary artery pressure14,15 To our knowledge, the relation between LV diastolic function and pulmonary wedge pressure has not been studied in subjects with OSA. However, in patients with coronary artery disease and diastolic dysfunction, the E/A ratio was found to be the most important determinant of pulmonary wedge pressure.16 In our study, limited data on pulmonary artery pressure did not allow the relation between LV dysfunction and pulmonary hypertension to be examined. 1. Brouillette RT, Fernbach SK, Hunt CE. Obstructive sleep apnea in infants and
children. J Pediatr 1982;100:31– 40. 2. Brown OE, Manning SC, Ridenour B. Cor pulmonale secondary to tonsillar
and adenoidal hypertrophy: management considerations. Int J Pediatr Otorhinolaryngol 1988;16:131–139. 3. Amin RS, Kimball TR, Bean JA, Jeffries JL, Willging JP, Cotton RT, Witt SA, Glascock BJ, Daniels SR. Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:1395–1399. 4. Kimball TR, Daniels SR, Khoury P, Meyer RA. Age-related variation in contractility estimate in patients less than or equal to 20 years of age. Am J Cardiol 1991;68:1383–1387. 5. O’Leary PW, Durongpisitkul K, Cordes TM, Bailey KR, Hagler DJ, Tajik J, Seward JB. Diastolic ventricular function in children: a Doppler echocardiographic study establishing normal values and predictors of increased ventricular end-diastolic pressure. Mayo Clin Proc 1998;73:616 – 628. 6. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003;289: 194 –202. 7. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001;37:1042–1048. 8. Salmasi AM, Alimo A, Jepson E, Dancy M. Age-associated changes in left ventricular diastolic function are related to increasing left ventricular mass. Am J Hypertens 2003;16:473– 477. 9. Mitsnefes MM, Kimball TR, Border WL, Witt SA, Glascock BJ, Khoury PR, Daniels SR. Abnormal cardiac function in children after renal transplantation. Am J Kidney Dis 2004;43:721–726. 10. Mitsnefes MM, Kimball TR, Border WL, Witt SA, Glascock BJ, Khoury PR, Daniels SR. Impaired left ventricular diastolic function in children with chronic renal failure. Kidney Int 2004;65:1461–1466. 11. Banerjee A, Mendelsohn AM, Knilans TK, Meyer RA, Schwartz DC. Effect of myocardial hypertrophy on systolic and diastolic function in children: insights from the force-frequency and relaxation-frequency relationships. J Am Coll Cardiol 1998;32:1088 –1095. 12. Johnson MC, Bergersen LJ, Beck A, Dick G, Cole BR. Diastolic function and tachycardia in hypertensive children. Am J Hypertens 1999;12:1009 –1014. 13. Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, Romijn JA, de Roos A, Radder JK. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol 2003;42:328 –335. 14. Hetzel M, Kochs M, Marx N, Woehrle H, Mobarak I, Hombach V, Hetzel J. Pulmonary hemodynamics in obstructive sleep apnea: frequency and causes of pulmonary hypertension. Lung 2003;181:157–166. 15. Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997;157:2483–2487. 16. Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982.
MARCH 15, 2005
4. Mustonen JN, Uusitupa MI, Laakso M, Vanninen E, Lansimies E, Kuikka JT, Pyorala K. Left ventricular systolic function in middle-aged patients with diabetes mellitus. Am J Cardiol 1994;73:1202–1208. 5. Manchikalapudi P, Biederman R, Dayle M, Fuisz A, Pohost GM, Howard G, Paine T, Rogers WJ, Iskandrian AE. Validation of left ventricular mass by SPECT sestamibi imaging (abstr). J Nucl Cardiol 2000;7:185. 6. Butler RA, MacDonald TM, Struthers AD, Morris AD. The clinical implications of diabetic heart disease. Eur Heart J 1998;19:1617–1627. 7. Aronow WS, Ahn C. Incidence of heart failure in 2,737 older persons with and without diabetes mellitus. Chest 1999;115:867– 868. 8. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: Framingham study. Am J Cardiol 1974;34:29 –34. 9. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001;161:996 –1002. 10. Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepantalo M, Laatikainen L, et al. Risk factors for mortality in type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 1998;41:1253– 1262. 11. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035–2038. 12. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Cardiovasc Drugs Ther 1994;8:65–73. 13. Bell DS. Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care 1995;18:708 –714. 14. Neely JR, Rovetto MJ, Oram JF. Myocardial utilization of carbohydrate and lipid. Prog Cardiovasc Dis 1972;15:289 –329. 15. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 2001;107:813– 822. 16. Galderisi M, Anderson KM, Wilson PF, Levy D. Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (the Framingham Heart Study). Am J Cardiol 1991;68:85– 89. 17. Raev DC. Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care 1994;17:633– 639. 18. Harrower AD, Railton R, Small D. Comparison by nuclear angiography of resting left ventricular function on insulin-dependent diabetic patients and normal subjects and the effect of diabetic control. Diabetes Res 1984;1:227–229. 19. Fang ZY, Najos-Valencia O, Leano R, Marwick TH. Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 2003;42:446 – 453. 20. Struthers AD, Morris AD. Screening for and treating left ventricular abnormalities in diabetes mellitus: a new way of reducing cardiac deaths. Lancet 2002;359:1430 –1432.
Left Ventricular Function in Children With SleepDisordered Breathing Raouf S. Amin, MD, Thomas R. Kimball, MD, Maninder Kalra, MD, Jenny L. Jeffries, RN, John L. Carroll, MD, Judy A. Bean, PhD, Sandra A. Witt, RDCS Betty J. Glascock, RDCS, and Stephen R. Daniels, MD, PhD Severe obstructive sleep apnea in children leads to congestive heart failure. We studied the early changes in left ventricular function across a range of severity of the disorder. A dose-dependent decrease From the Departments of Pulmonary Medicine, Cardiology,and Biostatistics, Cincinnati Children’s Hospital Medical Center, Sleep Disorder Center, Cincinnati, Ohio; and the Department of Pediatric Pulmonary Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. This study was supported by a grant-in-aid from the American Heart Association, Dallas, Texas, and Grant RO1HL70907-02A1 from the National Institutes of Health, Bethesda, Maryland. Dr. Amin’s address is: Cincinnati Children’s Hospital Medical Center, Division of Pulmonary Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229. E-mail: [email protected]. Manuscript received July 14, 2004; revised manuscript received and accepted November 12, 2004. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 March 15, 2005
in diastolic function with increased severity of obstructive apnea was demonstrated. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:801– 804)
lthough early reports of obstructive sleep apnea (OSA) in children have shown that severe upper A airway obstruction during sleep is associated with congestive heart failure,1,2 the subclinical forms of cardiac dysfunction in children with OSA have not been well characterized. There are reasons to expect that OSA has a negative impact on left ventricular (LV) function in children, because the geometry and structure of the left ventricle are altered in children with this disorder.3 The objectives of this study were to describe LV diastolic and systolic function in children with varying severity of 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.11.044
801
TABLE 1 Demographic and Polysomnographic Characteristics of the Study Population Obstructive Sleep Apnea Primary Snoring Group 1 (n ⫽ 15)
Group 2 (n ⫽ 23) Apnea Hypopnea Index
Group 3 (n ⫽ 25)
⬍1
1–5
⬎5
p Value
10.5 ⫾ 3.5 8 (53%) 87% 23.7 ⫾ 8 112 ⫾ 13 64 ⫾ 9
10.2 ⫾ 3.7 17 (73%) 61% 25.3 ⫾ 9.3 115 ⫾ 11 70 ⫾ 6
12.1 ⫾ 3.9 16 (64%) 64% 31 ⫾ 11† 117 ⫾ 15 65 ⫾ 9
NS NS NS 0.02 NS NS
2.8 (2.1–3.5)*
24 (10–33)†‡
⬍0.0001
Variable Demographic variables Age (yrs) No. of males No. of Caucasians Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Polysomnographic variables Apnea hypopnea index (25–75% quartiles) Desaturation index (no./ h) Lowest saturation Maximum CO2 (mm Hg) Arousal index (no./h)
0.1 (0.1–0.1) 0.6 92 49 12.3
(0.1–1.2) (90–93) (48–51) (7–14)
1.5 90 52 9.4
(0.4–2.6) (86–92) (49–54) (7–11)
11 83 54 17
†
(5–19) (78–86)†‡ (50–57)† (11–25)†‡
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
Demographic characteristics are expressed as mean ⫾ SD. Polysomnographic characteristics are expressed as median and interquartile range (25%–75%) *p ⬍0.05 group 1 versus group 2; †p ⬍0.05 group 1 versus group 3; ‡p ⬍0.05 group 2 versus group 3.
FIGURE 1. Decreases in mitral inflow velocity with increasing AHI. The overall difference among the 3 groups is reflected in the p value. #p <0.05 for group 1 versus 3 and group 2 versus 3. Shaded background, mean ⴞ 1 SD of published normal values for the E/A ratio.5
obstructive breathing during sleep and to measure the degree of reversibility after treatment. •••
Patients aged 5 to 18 years who were referred to the pediatric Sleep Disorder Clinic for evaluation for obstructive breathing during sleep were recruited sequentially and underwent polysomnography3 followed by echocardiography. The study excluded children with genetic syndromes and chronic medical conditions, including cardiac diseases. Informed consent was obtained from the parents or legal guardian of each child, and assent was obtained from children ⬎11 years old. The institutional review board of Children’s Hospital Medical Center approved the study. Polysomnographic results were used to subdivide 802 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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subjects into those with primary snoring (group 1) and those with OSA. The severity of OSA was measured by the frequency of apnea and hypopnea index (AHI). Subjects with AHI ⬎1/hour were classified as having OSA and were further classified into 2 more groups; those with AHI from 1 to 5/hour (group 2) and those with AHI ⬎5/hour (group 3). A subset of children was studied for a 1-year follow-up to determine the reversibility of cardiac dysfunction with resolution of OSA. To ensure resolution of OSA, children enrolled in the follow-up study underwent polysomnography at 8 weeks and 1 year after the initial evaluation. Two-dimensional (2-D) and 2-D– directed M-mode echocardiographic images were recorded to determine LV mass and relative wall thickness. LV systolic performance was assessed by measuring the ejection fraction, the shortening fraction, and the heart-rate– corrected velocity of circumferential fiber shortening. Delta velocity of circumferential fiber shortening, a measure of contractility, was derived by calculating the difference between the measured and the predicted fiber shortening for the measured wall stress according to the previously described equation.4 The primary measure of afterload was the meridional end-systolic wall stress. LV diastolic function was evaluated by mitral inflow velocity. The E/A ratio was derived from the velocity of the early (E) wave occurring during early diastolic filling and the velocity of the second wave (A) occurring during atrial contraction. Echocardiographic and blood pressure measurements were obtained by standardized conditions at rest with the subjects in the supine position after a minimum rest period of 5 minutes. Cardiologists and sonographers were blinded to the results of the polysomnography. For comparison of means, a 1-factor analysis of variance was performed. Multiple regression analysis MARCH 15, 2005
TABLE 2 Systolic Function and Contractile State of the Left Ventricle Primary Snoring
Obstructive Sleep Apnea
Apnea Hypopnea Index Groups
⬍1
Normal Values
Ejection fraction (%) Shortening fraction (%) Rate-corrected velocity of circumferential fiber shortening (circ/s) Delta rate-corrected velocity of circumferential fiber shortening (circ/s)
55 32 1.03 0.003
⫾ ⫾ ⫾ ⫾
5 6 0.18 0.03
62 40 1.23 0.54
⫾ ⫾ ⫾ ⫾
⬎5
1–5
5 59 ⫾ 5 42 ⫾ 0.23 1.24 ⫾ 0.22† 0.6 ⫾
6 5 0.21 0.23
60 40 1.24 0.48
⫾ ⫾ ⫾ ⫾
6 4 0.18 0.18
Normal values for different variables are shown. Results are expressed as mean ⫾ SD. p ⫽ NS.
TABLE 3 Demographic and Polysomnographic Characteristics of 10 Children Followed for One Year and 45 Children Without Follow-Up Simple Snoring
Obstructive Sleep Apnea
Groups
Follow-up (n ⫽ 9)
No Follow-up (n ⫽ 6)
Follow-up (n ⫽ 9)
Age (yrs) No. of males Apnea hypopnea index at baseline Apnea hypopnea index at of follow-up Body mass index at baseline (kg/m2) Body mass index at follow-up (kg/m2) Systolic blood pressure at baseline (mm Hg) Systolic blood pressure at follow-up (mm Hg) Diastolic blood pressure at baseline (mm Hg) Diastolic blood pressure at follow-up (mm Hg) E/A at baseline
12.3 ⫾ 2.9 6 (66%) 0.15 ⫾ 0.18 0.48 ⫾ 0.6 26 ⫾ 7.3 27.4 ⫾ 7.7 117 ⫾ 11 117 ⫾ 14 67 ⫾ 7 64 ⫾ 6 2 ⫾ 0.6
10.4 ⫾ 3.5 2 (30)% 0.1 ⫾ 0.2
12.3 ⫾ 3.9 6 (66%) 25 ⫾ 24 0.6 ⫾ 0.8 31 ⫾ 7 32 ⫾ 7 121 ⫾ 18 120 ⫾ 15 70 ⫾ 9 63 ⫾ 11 1.88 ⫾ 0.38
23 ⫾ 8 112 ⫾ 13 66 ⫾ 9 2.1 ⫾ 0.4
No Follow-up (n ⫽ 39) 11.9 ⫾ 3.9 27 (69%) 32 ⫾ 33 31 ⫾ 13 114 ⫾ 14 62 ⫾ 9 1.78 ⫾ 0.29
the E/A ratio (Figure 1). The mean ⫾ SD for the E/A ratio was 2.16 ⫾ 0.4, 2.0 ⫾ 0.4, and 1.78 ⫾ 0.3 for groups 1 to 3, respectively. The decrease in the E/A ratio was due primarily to an increase in the A-wave velocity. The difference in the E/A ratio remained statistically significant (p ⫽ 0.007) after controlling for age, gender, race, systolic and diastolic blood pressures FIGURE 2. Mitral inflow velocity in children with primary snoring and children with expressed as a percentage of the 95th OSA after 1 year. ⴱⴱp ⴝ 0.001 for the change in E/A ratio for the OSA group from percentile, and the Z score for body baseline to the end of follow-up. mass index. The model that predicted LV diwas performed to identify factors that might predict astolic function (p ⫽ 0.0014) included log AHI ( ⫽ LV function. The independent variables entered into a ⫺0.04, p ⫽ 0.0016), systolic blood pressure expressed backward elimination regression analysis were age, as a percentage of the 95th percentile ( ⫽ ⫺0.003, p gender, race, Z score for body mass index, systolic ⫽ 0.008), and Z score for body mass index ( ⫽ and diastolic blood pressures expressed as percentage ⫺0.015, p ⫽ 0.015) with R2 ⫽ 0.23. The AHI reof the 95th percentile, log AHI, desaturation index, mained statistically significant (p ⫽ 0.0006) after age, lowest oxygen saturation, maximum end-tidal carbon gender, race, and diastolic blood pressure expressed as dioxide, and LV mass index. A total sample size of 20 a percentage of the 95th percentile were forced into children was estimated to provide adequate power in the model with an overall value of p ⫽ 0.01. the follow-up study. The paired t test was performed LV end-systolic wall stress did not differ signifito compare the changes in cardiac function in each cantly among the 3 groups. Wall stress was 42 ⫾ 9, 46 group from baseline to the end of the follow-up. ⫾ 12, and 41 ⫾ 10 g/cm2 for groups 1 to 3, respecSixty-three patients satisfied the inclusion criteria and tively. The indexes of the contractile state of the left completed the study. The demographic and polysom- ventricle were not significantly different among the 3 nographic characteristics are listed Table 1. groups (Table 2). A decrease in the LV diastolic function across the 3 As previously described,3 a dose-dependent ingroups was demonstrated by the progressive decrease in crease in the LV mass index was observed with inBRIEF REPORTS
803
creased severity of OSA. The LV mass index was 32.5 ⫾ 3.6, 38.7 ⫾ 9.6, and 39.8 ⫾ 8.7 g/height2.7 for groups 1 to 3, respectively (p ⫽ 0.007). The diastolic function did not correlate with LV mass index (R ⫽ 0.1). Similarly, the change in diastolic function after treatment did not correlate with the change in the LV mass index. Children with AHI ⬎5/hour and those with AHI 1 to 5/hour who had daytime symptoms were offered treatment with tonsillectomy and adenoidectomy and/or continuous positive airway pressure. Ten adequately treated children with OSA and 10 age- and gender-matched children with primary snoring were recruited for a 1-year follow-up study. One child in the primary snoring group had a technically inadequate echocardiogram at 1 year and 1 child in the OSA group did not comply with treatment with continuous positive airway pressure. The demographic and polysomnographic characteristics are listed in Table 3. Six children had adenotonsillectomy, 1 child had an additional uvulopalatoplasty, and 3 children were managed with continuous positive airway pressure. Children managed with continuous positive airway pressure were followed quarterly in the clinic. Compliance with continuous positive airway pressure was ascertained from parental report. The E/A ratio improved by 18% (p ⫽ 0.001) in the OSA group, but no difference was observed in children with primary snoring (Figure 2). Children with primary snoring showed a trend toward a lower diastolic function at the end of the follow-up. Two of the 3 children who largely contributed to this decline developed a mild degree of OSA. •••
This study shows the independent effect of OSA on LV function in children without clinical evidence of cardiac dysfunction. The negative correlation between the severity of OSA and LV diastolic function is independent of obesity, blood pressure, and LV mass. To our knowledge, this study also shows for the first time that LV diastolic function in children with OSA improves after the disorder is adequately treated. The importance of this observation stems from the knowledge that diastolic dysfunction in adults is now increasingly emphasized as an early indicator of cardiac disability and may precede systolic dysfunction and heart failure6,7 Whether LV diastolic dysfunction in children has the same clinical significance as in adults is not known. O’Leary et al5 showed that children with increased end-diastolic LV pressure proved by cardiac catheterization have a lower E/A ratio (1.9 vs 2.3) compared with healthy controls. These findings suggest that in children, small deviations of E/A ratio from normal values may reflect early LV hemodynamic abnormalities. LV hypertrophy is a well-recognized mechanism for LV dysfunction in adults and in children8 –10 This study could not demonstrate that LV hypertrophy is a mechanism for LV dysfunction, however. In some hypertensive patients and patients with diabetes mellitus, diastolic dysfunction has been observed in the absence of LV
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hypertrophy11,12 In these patients, altered myocardial energy metabolism was associated with LV dysfunction.13 Classically, OSA in children has been linked to right ventricular dysfunction and pulmonary hypertension; however, the mechanisms of pulmonary hypertension in children with OSA have not been thoroughly investigated. Several studies that examined the contributing factors to pulmonary hypertension in adult subjects with OSA have demonstrated that an increase in pulmonary venous pressure contributes to an elevation of pulmonary artery pressure14,15 To our knowledge, the relation between LV diastolic function and pulmonary wedge pressure has not been studied in subjects with OSA. However, in patients with coronary artery disease and diastolic dysfunction, the E/A ratio was found to be the most important determinant of pulmonary wedge pressure.16 In our study, limited data on pulmonary artery pressure did not allow the relation between LV dysfunction and pulmonary hypertension to be examined. 1. Brouillette RT, Fernbach SK, Hunt CE. Obstructive sleep apnea in infants and
children. J Pediatr 1982;100:31– 40. 2. Brown OE, Manning SC, Ridenour B. Cor pulmonale secondary to tonsillar
and adenoidal hypertrophy: management considerations. Int J Pediatr Otorhinolaryngol 1988;16:131–139. 3. Amin RS, Kimball TR, Bean JA, Jeffries JL, Willging JP, Cotton RT, Witt SA, Glascock BJ, Daniels SR. Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:1395–1399. 4. Kimball TR, Daniels SR, Khoury P, Meyer RA. Age-related variation in contractility estimate in patients less than or equal to 20 years of age. Am J Cardiol 1991;68:1383–1387. 5. O’Leary PW, Durongpisitkul K, Cordes TM, Bailey KR, Hagler DJ, Tajik J, Seward JB. Diastolic ventricular function in children: a Doppler echocardiographic study establishing normal values and predictors of increased ventricular end-diastolic pressure. Mayo Clin Proc 1998;73:616 – 628. 6. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003;289: 194 –202. 7. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001;37:1042–1048. 8. Salmasi AM, Alimo A, Jepson E, Dancy M. Age-associated changes in left ventricular diastolic function are related to increasing left ventricular mass. Am J Hypertens 2003;16:473– 477. 9. Mitsnefes MM, Kimball TR, Border WL, Witt SA, Glascock BJ, Khoury PR, Daniels SR. Abnormal cardiac function in children after renal transplantation. Am J Kidney Dis 2004;43:721–726. 10. Mitsnefes MM, Kimball TR, Border WL, Witt SA, Glascock BJ, Khoury PR, Daniels SR. Impaired left ventricular diastolic function in children with chronic renal failure. Kidney Int 2004;65:1461–1466. 11. Banerjee A, Mendelsohn AM, Knilans TK, Meyer RA, Schwartz DC. Effect of myocardial hypertrophy on systolic and diastolic function in children: insights from the force-frequency and relaxation-frequency relationships. J Am Coll Cardiol 1998;32:1088 –1095. 12. Johnson MC, Bergersen LJ, Beck A, Dick G, Cole BR. Diastolic function and tachycardia in hypertensive children. Am J Hypertens 1999;12:1009 –1014. 13. Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, Romijn JA, de Roos A, Radder JK. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol 2003;42:328 –335. 14. Hetzel M, Kochs M, Marx N, Woehrle H, Mobarak I, Hombach V, Hetzel J. Pulmonary hemodynamics in obstructive sleep apnea: frequency and causes of pulmonary hypertension. Lung 2003;181:157–166. 15. Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997;157:2483–2487. 16. Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982.
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