Continuous Positive Airway Pressure Therapy Improves Cardiovascular Autonomic Function for Persons With Sleep-Disordered Breathing

Original Research SLEEP MEDICINE

Continuous Positive Airway Pressure Therapy Improves Cardiovascular Autonomic Function for Persons With Sleep-Disordered Breathing* Raelene E. Maser, PhD; M. James Lenhard, MD; Albert A. Rizzo, MD, FCCP; and Anthony A. Vasile, DO

Background: Sleep-disordered breathing (SDB) is an independent risk factor for cardiovascular morbidity. Dysfunction of the cardiovascular autonomic nervous system may be a potential mechanism whereby SDB is linked to cardiovascular disease. Repetitive sympathetic activation during apneic episodes may impair cardiovascular reflex function, and increased sympathetic activity can stimulate renin release. Given that patients with SDB may have reduced cardiovascular autonomic function, the purpose of this study was to determine whether treatment with continuous positive airway pressure (CPAP) for 6 weeks would improve autonomic function. Methods: Twenty-nine participants with a diagnosis of SDB, who completed 6 weeks of CPAP therapy, were evaluated for cardiovascular autonomic nerve fiber function at baseline and post therapy. Autonomic function tests included the following: R-R interval variation during deep breathing measured by vector analysis (ie, mean circular resultant [MCR]) and expiration/ inspiration (E/I) ratio; and the Valsalva maneuver. Participants were also evaluated prior to CPAP therapy for plasma renin activity levels. Results: Participants in this study showed improved cardiovascular autonomic function after 6 weeks of treatment (baseline vs follow-up) as assessed by the mean (ⴞ SD) MCR (33.2 ⴞ 22.5 vs 36.9 ⴞ 24.2, respectively; p < 0.05) and E/I ratio (1.20 ⴞ 0.12 vs 1.24 ⴞ 0.14, respectively; p < 0.01). Improved vagal tone was also noted for subjects with elevated renin levels. Conclusions: Treatment of SDB with CPAP for 6 weeks improved vagal tone and may be beneficial in reducing the risk of developing clinical manifestations of cardiovascular autonomic dysfunction (eg, increased risk of mortality). (CHEST 2008; 133:86 –91) Key words: cardiovascular autonomic function; continuous positive airway pressure; sleep-disordered breathing Abbreviations: ACE ⫽ angiotensin-converting enzyme; AHI ⫽ apnea-hypopnea index; ARB ⫽ angiotensin receptor blocker; CAN ⫽ cardiovascular autonomic neuropathy; CPAP ⫽ continuous positive airway pressure; CVD ⫽ cardiovascular disease; DBP ⫽ diastolic BP; E/I ⫽ expiration/inspiration; MAP ⫽ mean arterial pressure; MCR ⫽ mean circular resultant; SBP ⫽ systolic BP; SDB ⫽ sleep-disordered breathing

breathing (SDB) has been shown S leep-disordered to be an independent risk factor for the development of hypertension and consequent cardiovascular morbidity.1 The potential mechanisms that link SDB and cardiovascular disease (CVD) are not clear. There is increasing evidence that cardiovascular autonomic dysfunction may be a potential mechanism whereby SDB is linked to CVD. Autonomic imbalance (ie, increased sympathetic and decreased parasympathetic activity) has been implicated in the pathophysiology of arrhythmogenesis.2 During sleep, 86

repetitive episodes of obstructive apnea increase sympathetic drive.3 Increased activity of the sympathetic nervous system can stimulate renin release.4 Elevated plasma renin activity has been shown to predict myocardial infarction.5 Cardiovascular autonomic neuropathy (CAN) is associated with abnormalities in heart rate control and vascular dynamics. CAN is clinically significant, given its association with exercise intolerance, intraoperative cardiovascular lability, and orthostatic hypotension in patients with diabetes6 and asymptomOriginal Research

atic ischemia and increased risk of mortality in persons with and without diabetes.6 –9 Reduced heart rate variation is the earliest indicator of CAN.10 Variance of the R-R interval has been shown to be reduced significantly in patients with obstructive sleep apnea.11 The repetitive sympathetic activation and BP surges occurring during apneic episodes may cause an impairment of baroreflex and other cardiovascular reflex functions.11 Given that patients with SDB may have impaired autonomic balance, we hypothesized that treatment with continuous positive airway pressure (CPAP) would improve autonomic function. Thus, in this study we evaluated the effect of 6 weeks of CPAP therapy on autonomic function in patients with SDB. Materials and Methods Subjects Thirty-eight participants, with a diagnosis of SDB determined via polysomnographic recording, were evaluated for cardiovascular autonomic nerve fiber function at the Diabetes and Metabolic Research Center, Christiana Care Health Services, Newark, DE. This study had the approval of the Institutional Review Board of Christiana Care Corporation, and written informed consent was obtained. All participants were newly diagnosed with SDB and had never been treated for their sleep disorder. Although 38 subjects were initially enrolled, 9 subjects refused to initiate/continue with CPAP therapy, had an irregular heart beat making the interpretation of autonomic results difficult, or had a change in BP medication during follow-up. Thus, a sample size of 29 was available for final analysis. An ECG was performed to exclude participants with acute ischemia. Resting BP was monitored electronically with the patient in the supine posture using an oscillometric automatic recorder. The average of four BP readings, measured 1 min apart, was used for analysis. Orthostatic changes were assessed by averaging four BP readings, taken 1 min apart over 4 min, on standing from the supine position. Daytime sleepiness was assessed using the Epworth sleepiness scale. This is an eight-question scale that measures sleepiness as a reflection of an individual’s tendency to fall asleep during various situations12 and can be used to demonstrate the response of daytime sleepiness to treatment with CPAP.13 Compliance with CPAP was self-reported by having participants keep a diary of the amount of time CPAP was used *From the Department of Medical Technology (Dr. Maser), University of Delaware, Newark, DE; the Diabetes and Metabolic Research Center (Dr. Lenhard), Christiana Care Health Services, Newark, DE; Pulmonary Associates (Dr. Rizzo), Newark, DE; and Christiana Care Health Services (Dr. Vasile), Wilmington, DE. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received June 22, 2007; revision accepted September 17, 2007. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Raelene E. Maser, PhD, Department of Medical Technology, 305F Willard Hall Education Building, University of Delaware, Newark, DE 19716; e-mail: [email protected] DOI: 10.1378/chest.07-1580 www.chestjournal.org

daily. Subjects were excluded from the study if they had any changes in the type or dosage of medications used to treat diabetes or hypertension 2 months prior to beginning CPAP therapy or during the treatment period. It should be noted, however, that one subject had a change in their diuretic medication at approximately the time of the beginning of CPAP therapy. Exclusion of the results for this individual did not change the effect of CPAP on autonomic function. Tests of Cardiovascular Autonomic Function Autonomic function, testing of which was performed after an overnight fast, was assessed before the participant began receiving CPAP therapy and after 6 weeks of CPAP use. At these visits, participants were asked to refrain from taking any prescribed medications (eg, insulin) or nonprescription medications; to avoid consuming tobacco products, or caffeine-containing or alcoholic beverages; and to refrain from engaging in any vigorous exercise 8 to 10 h before testing. Cardiovascular autonomic function was assessed by determining R-R interval variation during deep breathing and the Valsalva maneuver (ANS2000 ECG Monitor and Respiration Pacer; DE Hokanson, Inc; Bellevue, WA). R-R interval variation during deep breathing performed for 6 min was measured by vector analysis (ie, mean circular resultant [MCR]) and by the expiration/inspiration (E/I) ratio of the first six breath cycles. R-R interval variation is a measure of the change in heart rate resulting from the variation in intrathoracic pressure due to respiration.14 Although the sympathetic nervous system may effect this measure, R-R interval variation is predominantly a function of parasympathetic activity.15 There are several methods used to analyze R-R interval variation (eg, E/I ratio, spectral analysis, and MCR). The E/I ratio, determined during a 1-min breathing procedure that comprised six maximal expirations and inspirations, was calculated by the mean value of the longest R-R interval during expiration and the shortest R-R interval during inspiration. The E/I ratio is affected by ectopic beats16; therefore, the E/I results of four participants could not be used. The MCR computed by vector analysis is resistant to ectopic beats, is not affected by intrinsic heart rate, and thus is a preferred method for the assessment of parasympathetic function.16 –18 The heart rate response to the Valsalva maneuver was determined by having participants expire into the mouthpiece of a manometer, maintaining a pressure of 40 mm Hg for 15 s. The Valsalva ratio was defined as the longest R-R interval the minute following the maneuver to the shortest R-R interval during the maneuver. Due to a small theoretical risk of intraocular hemorrhage,19 diabetic individuals who had proliferative retinopathy or active retinal hemorrhages, or those without an eye examination in the last year did not perform the Valsalva maneuver. The results for the Valsalva maneuver were incomplete for 11 participants due to ophthalmologic issues or the presence of an ectopic beat, which also affects the Valsalva ratio. All autonomic function tests were performed by the same investigator (R.E.M.) at baseline and follow-up with the reproducibility of these measures previously having been reported.20 Biochemical Evaluation Renin activity and aldosterone levels were determined at a second study visit, prior to the initiation of CPAP therapy. Subjects were asked to consume a high-salt diet (2,000 to 3,000 mg/d) for 3 days prior to testing plasma renin activity levels and the collection of a 24-h urine for measurement of sodium, creatinine, and aldosterone levels. The blood collection for renin levels was performed after an overnight fast, and blood samples were drawn into a chilled ethylenediaminetetraacetic acid tube CHEST / 133 / 1 / JANUARY, 2008

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Table 1—Subject Characteristics at Baseline* Completers Noncompleters (n ⫽ 29) (n ⫽ 9)

Characteristics Age, yr Gender Male Female Body mass index, kg/m2 SBP, mm Hg DBP, mm Hg Use of antihypertensive medications, yes/no ACE inhibitors/ARBs Epworth sleepiness scale score Initial AHI, events/h AHI with CPAP titration, events/h Self-reported CPAP use, h/night Diabetes, yes/no Duration of diabetes, yr Hemoglobin A1c, % (n ⫽ 22) Autonomic dysfunction, yes/no

55 ⫾ 10

50 ⫾ 16

16 13 38 ⫾ 9 141 ⫾ 20 80 ⫾ 13 21/8

4 5 38 ⫾ 9 144 ⫾ 21 74 ⫾ 11 7/2

10/7 12 ⫾ 5 41 ⫾ 26 7⫾9 6 ⫾ 1.2 17/12 13 ⫾ 13 7.5 ⫾ 1.2 8/21

4/0 10 ⫾ 5 18 ⫾ 9† 3⫾4 5/4 12 ⫾ 11 8.0 ⫾ 0.5 3/6

*Values are given as the mean ⫾ SD or No. †p ⬍ 0.05.

while subjects were in a seated position. Specimens were placed immediately in an ice bath until thoroughly cooled, centrifuged at 4°C, and frozen until performed. Urinary aldosterone and plasma renin activity levels were determined via radioimmunoassay. Renin values of ⬎ 4.3 ng/mL/h were considered to be elevated for subjects 18 to 39 years old, and values of ⬎ 3.0 ng/mL/h were considered to be elevated for subjects ⱖ 40 years old. Two participants were found to have biochemical indexes consistent with primary hyperaldosteronism, and two participants did not cooperate with collection of the 24-h urine specimen; thus, four individuals were excluded from this part of the analysis. Hemoglobin A1c was measured by high-performance ion-exchange liquid chromatography for subjects with diabetes. Statistical Analysis The distribution of the variables was examined by the Kolmogorov-Smirnov goodness-of-fit test. Univariate analyses included the Student t test for continuous variables, the ␹2 test

for dichotomous variables, and the paired Student t test to evaluate autonomic function before and after 6 weeks of treatment with CPAP.

Results Table 1 provides the baseline characteristics for all participants who completed 6 weeks (mean [⫾ SD], 42 ⫾ 4 days; range, 25 to 49 days) of CPAP therapy (n ⫽ 29) compared with subjects who did not complete the study (n ⫽ 9). The study cohort was obese and experienced a moderate degree of daytime sleepiness, and over half had severe SDB defined as an apnea-hypopnea index (AHI) of ⬎ 30 events/h. Approximately 72% were using antihypertensive medications and 59% had diabetes. The only difference between the study cohort and those who did not complete the study was an increased initial AHI for completers. Table 2 shows that cardiovascular autonomic function, as measured by the MCR and E/I ratio, improved as a result of CPAP therapy. On average participants self-reported 6 h of use of CPAP per night. The effect of CPAP on autonomic function was similar with the inclusion or exclusion of individuals who were considered to be noncompliant with CPAP therapy (ie, used CPAP for ⬍ 4 h each night [n ⫽ 3] or failed to keep a diary of CPAP use [n ⫽ 1]). Similar results of improved autonomic function were shown when those using angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) [n ⫽ 17] were analyzed before and after CPAP therapy. Improvements in resting supine diastolic BP (DBP) and mean arterial pressure (MAP) were also noted as a result of CPAP (Table 3). In addition, the amount of change in DBP and MAP (borderline statistically significant) on standing from the supine position was reduced following CPAP use. The exclusion of indi-

Table 2—Effect of CPAP Therapy on Autonomic Function* Variables For all participants (n ⫽ 29) E/I ratio (n ⫽ 25) MCR (n ⫽ 29) Valsalva ratio (n ⫽ 18) For participants that used CPAP ⱖ 4 h/night (n ⫽ 25) E/I ratio (n ⫽ 21) MCR (n ⫽ 25) Valsalva ratio (n ⫽ 17) For participants using ACE inhibitors/ARBs during the study (n ⫽ 17) E/I ratio (n ⫽ 15) MCR (n ⫽ 17) Valsalva ratio (n ⫽ 9)

Baseline

After 6 Weeks of CPAP Use

p Value

1.20 ⫾ 0.12 33.2 ⫾ 22.5 1.60 ⫾ 0.41

1.24 ⫾ 0.14 36.9 ⫾ 24.2 1.60 ⫾ 0.44

0.004 0.040 0.961

1.18 ⫾ 0.12 31.0 ⫾ 22.4 1.55 ⫾ 0.37

1.23 ⫾ 0.14 35.8 ⫾ 25.1 1.53 ⫾ 0.34

0.003 0.011 0.542

1.15 ⫾ 0.09 24.9 ⫾ 17.1 1.33 ⫾ 0.16

1.20 ⫾ 0.14 29.8 ⫾ 21.4 1.34 ⫾ 0.15

0.005 0.038 0.818

*Values are given as the mean ⫾ SD, unless otherwise indicated. 88

Original Research

Table 3—Effect of CPAP Therapy on BP (n ⴝ 29)* Variables

Baseline

After 6 Weeks of CPAP Use

p Value

SBP DBP MAP Change in SBP upon standing Change in DBP upon standing Change in MAP upon standing

141 ⫾ 20 80 ⫾ 13 100 ⫾ 15 ⫺ 6.0 ⫾ 12

136 ⫾ 16 74 ⫾ 13 95 ⫾ 13 ⫺ 3.8 ⫾ 11

0.129 0.002 0.014 0.389

⫺ 4.5 ⫾ 5

⫺ 0.93 ⫾ 5

0.013

⫺ 5.0 ⫾ 6

⫺ 1.9 ⫾ 6

0.052

*Values are given as the mean ⫾ SD, unless otherwise indicated.

viduals who were noncompliant with CPAP use produced similar results for resting DBP, resting MAP, and change in DBP on standing, while change in MAP on standing was not significantly different before and after CPAP use. Improvement in autonomic function was also examined based on renin activity levels (ie, normal vs elevated levels) [Table 4]. Those with elevated renin levels were shown to have improved autonomic function as measured by the E/I ratio and the MCR. All but one of the subjects with elevated renin levels had diabetes, while only one third of those subjects with normal renin levels had diabetes. It should be noted that six of eight nondiabetic individuals in the normal renin group had a fingerstick glucose value in the prediabetes range. For those subjects with elevated renin levels, 8 of 13 subjects were categorized as morbidly obese. Both groups (elevated vs normal renin levels) were similar (ie, no statistical differences) in terms of daytime sleepiness, AHI, selfreported use of CPAP, BP, and autonomic function (ranging from normal to significantly impaired) at baseline. Discussion The novel and important finding of this present study is that 6 weeks of use of CPAP therapy Table 4 —Effect of CPAP Therapy on Autonomic Function for Subjects With Normal vs Elevated Renin Activity Levels* Variables E/I ratio Elevated renin (n ⫽ 12) Normal renin (n ⫽ 11) MCR Elevated renin (n ⫽ 13) Normal renin (n ⫽ 12) Valsalva ratio Elevated renin (n ⫽ 7) Normal renin (n ⫽ 9)

Baseline

After 6 Weeks of CPAP Use p Value

1.15 ⫾ 0.10 1.23 ⫾ 0.12

1.21 ⫾ 0.15 1.24 ⫾ 0.11

0.006 0.565

27.0 ⫾ 18.4 38.1 ⫾ 22.9

33.0 ⫾ 23.2 37.4 ⫾ 19.0

0.041 0.733

1.34 ⫾ 0.18 1.69 ⫾ 0.44

1.34 ⫾ 0.17 1.75 ⫾ 0.53

0.920 0.333

*Values are given as the mean ⫾ SD, unless otherwise indicated. www.chestjournal.org

improved vagal tone. Several therapeutic interventions have been previously investigated with the hope of preventing the development or slowing the progression of cardiovascular autonomic dysfunction. The results of some interventions (eg, tight glycemic control21 and antioxidants22) have shown some improvement in autonomic function, while other studies have presented conflicting results (eg, aldose reductase inhibitors23,24 and ACE inhibitors25,26). The findings in this study are exciting in that the measures of parasympathetic function that were utilized (ie, MCR and E/I ratio) have shown improvement after 6 weeks of CPAP therapy. Also of interest is the improvement in autonomic function noted by those with elevated renin levels. The mechanism by which CPAP therapy improves autonomic function is not clear. Previous studies3 have shown that obstructive sleep apnea increases sympathetic activity. Recently, Reynolds et al27 confirmed that sympathetic activity increased as apnea severity increased, particularly during rapid eye movement sleep. Thus, one possible mechanism that could explain improved vagal tone as a result of CPAP use is a concomitant decrease in sympathetic activity restoring a balanced autonomic profile. Decreased sympathetic activity was previously shown by Somers et al28 in four patients following treatment with CPAP. An increase in sympathetic function is also known to stimulate renin release4; thus, we suggest that the elevated renin activity shown at baseline was associated with increased sympathetic activity. It is also possible, however, that the elevation in renin levels could have resulted from the use of ACE inhibitors and/or ARBs. All of the subjects with elevated renin levels were using ACE inhibitors or ARBs. Each participant, however, had been receiving a stable dose of the ACE inhibitors/ARBs 2 months prior to and during CPAP therapy. Thus, although these medications could have been responsible for the increased renin levels, it is also possible that elevated renin activity is a marker of increased sympathetic activity and that CPAP use resulted in improved vagal tone restoring autonomic balance. Prospective studies would determine whether disturbed autonomic function is the cause of an altered renin/angiotensin system. Alternatively, the use of ACE inhibitors/ARBs could be causative of SDB, as has been suggested by others.29 Previous investigators have shown that certain ACE inhibitors (quinapril)25 and ARBs30 improved vagal function. Other investigators,20,26 however, have shown no improvement in autonomic function with these types of medications. Unfortunately, there is not always a consistent pattern of the effect of medications on autonomic dysfunction even for drugs within the same class. We find the results of CHEST / 133 / 1 / JANUARY, 2008

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this study extremely encouraging; in a previous study20 performed by us in which the effect of 1 year of treatment with an ARB was evaluated using the same assessment modalities as in this study, no improvement or worsening in vagal function was shown. The evaluation of autonomic function results for individuals using ACE inhibitors or ARBs before and after CPAP therapy showed that both the MCR and E/I ratio were significantly higher after CPAP therapy. Thus, although we cannot totally rule out the possibility that the change in vagal tone that we observed was due to the presence of ACE inhibitors/ ARBs, all subjects were receiving a stable dose prior to and during CPAP therapy; thus, the effect of CPAP therapy would appear to be the most likely reason for the improved autonomic function. Long-term (ie, 14 months) CPAP therapy has previously been shown to reduce BP. The decrease in BP was shown to be correlated with reductions in plasma renin and angiotensin II levels.31 After 6 weeks of CPAP therapy, individuals in this study had a reduction in DBP and MAP, while there was also a reduction in the change in DBP on standing. Although systolic BP (SBP) was reduced, no statistical reduction was observed. Longer treatment may be required. Moller et al31 observed a reduction, but only in nighttime SBP, not in daytime SBP. Unfortunately, we only assessed renin levels at baseline; thus, we cannot show that the improved autonomic function was associated with a reduction in BP and renin levels in this study. Nonetheless, our results suggest that the increased risk for CVD associated with SDB is likely to be multifactorial with impaired autonomic balance and the renin-angiotensin-aldosterone system potentially being contributing factors. This study has several strengths. Participants were newly diagnosed with SDB, had never been treated for SDB, and the assessment modalities of cardiovascular autonomic function have been recommended by others.16 –18,32 There are, however, some potential limitations. Our measures of cardiovascular autonomic function reflect mainly the activity of the parasympathetic system. We did not have a measure of sympathetic function such as the lowfrequency component from frequency domain analysis of heart rate variability. It should be noted that some33 view the low-frequency component as a parameter that includes both sympathetic and vagal influences. It would be interesting to examine the effect of CPAP therapy on additional measures of autonomic function including pharmacologic blockade. These assessments are, however, more complex and not easy to perform for repeated measurements in the same subject.34 We did not observe an improvement in the Valsalva ratio with CPAP use, but it should be noted that 38% of subjects in the study 90

sample were not able to perform this test due to ophthalmologic issues and/or ectopic beats affecting the results. Second, compliance with CPAP treatment was self-reported. Third, few individuals in the study had significantly impaired autonomic function at baseline; therefore, the effectiveness of CPAP therapy in this group remains unclear. Fourth, no measures of cardiac function (eg, echocardiogram) were assessed; thus, any potential association between improvement in autonomic function and cardiac function as a result of CPAP therapy cannot be determined. Given the clinical significance of autonomic dysfunction, the treatment of SDB may prove beneficial in reducing the risk of developing the clinical manifestations of CAN. This may be especially important for diabetic patients with elevated renin activity who have SDB. References 1 Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378 –1384 2 Sztajzel J. Heart rate variability: a noninvasive electrocardiographic method to measure the autonomic nervous system. Swiss Med Wkly 2004; 134:514 –522 3 Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand 2003; 177:385– 390 4 Iliescu R, Yanes LL, Bell W, et al. Role of the renal nerves in blood pressure in male and female SHR. Am J Physiol Regul Integr Comp Physiol 2006; 290:R341–R344 5 Hailpern SM, Sealey JE, Laragh JH, et al. Plasma renin activity predicts myocardial infarction/revascularization among hypertensive patients [abstract]. Am J Hypertens 2005; 18:1A 6 Vinik AI, Maser RE, Mitchell BD, et al. Diabetic autonomic neuropathy. Diabetes Care 2003; 26:1553–1579 7 Kurpesa M, Trzos E, Drozdz J, et al. Myocardial ischemia and autonomic activity in dippers and non-dippers with coronary artery disease: assessment of normotensive and hypertensive patients. Int J Cardiol 2002; 83:133–142 8 Maser RE, Mitchell BD, Vinik AI, et al. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 2003; 26:1895–1901 9 Dekker JM, Crow RS, Folsom AR, et al. Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC Study; Atherosclerosis Risk In Communities. Circulation 2000; 102:1239 –1244 10 Ziegler D. Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metab Rev 1994; 10:339 –383 11 Narkiewicz K, Montano N, Cogliati C, et al. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998; 98:1071–1077 12 Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea: the Epworth Sleepiness Scale. Chest 1993; 103:30 –36 13 Hardinge FM, Pitson DJ, Stradling JR. Use of the Epworth Sleepiness Scale to demonstrate response to treatment with nasal continuous positive airways pressure in patients with obstructive sleep apnoea. Respir Med 1995; 89:617– 620 Original Research

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24 Johnson BF, Nesto RW, Pfeifer MA, et al. Cardiac abnormalities in diabetic patients with neuropathy: effects of aldose reductase inhibitor administration. Diabetes Care 2004; 27: 448 – 454 25 Athyros VG, Didangelos TP, Karamitsos DT, et al. Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol 1998; 53:201–209 26 Malik RA, Williamson S, Abbott C, et al. Effect of angiotensinconverting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet 1998; 352:1978 –1981 27 Reynolds EB, Seda G, Ware JC, et al. Autonomic function in sleep apnea patients: increased heart rate variability except during REM sleep in obese patients. Sleep Breath 2007; 11:53– 60 28 Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897–1904 29 Cicolin A, Mangiardi L, Mutani R, et al. Angiotensin-converting enzyme inhibitors and obstructive sleep apnea. Mayo Clin Proc 2006; 81:53–55 30 Didangelos TP, Arsos GA, Karamitsos DT, et al. Effect of quinapril or losartan alone and in combination on left ventricular systolic and diastolic functions in asymptomatic patients with diabetic autonomic neuropathy. J Diabetes Complications 2006; 20:1–7 31 Moller DS, Lind P, Strunge B, et al. Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnea. Am J Hypertens 2003; 16:274 –280 32 Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005; 28:956 –962 33 Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 1996; 93:1043– 1065 34 Esposito K, Marfella R, Gualdiero P, et al. Sympathovagal balance, nighttime blood pressure, and QT intervals in normotensive obese women. Obes Res 2003; 11:653– 659

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