Left ventricular hypertrophy (LVH) is a leading

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1 Left Ventricular Hypertrophy Is a Common Echocardiographic Abnormality in Severe Obstructive Sleep Apnea and Reverses With Nasal Continuous Positive Airway Pressure* Tom V. Cloward, MD, FCCP; James M. Walker, PhD; Robert J. Farney, MD, FCCP; and Jeffrey L. Anderson, MD Study objectives: To determine cardiac structural abnormalities by echocardiography in subjects with severe obstructive sleep apnea (OSA), and to determine the long-term effects of nasal continuous positive airway pressure (CPAP) on such abnormalities. Design: Polysomnography was conducted on oximetry-screened patients who showed a desaturation index > 40/h and > 20% cumulative time spent below 90%. From these, 25 patients with severe OSA but without daytime hypoxemia underwent echocardiography prior to, then 1 month and 6 months following initiation of CPAP treatment. Setting: Outpatient sleep disorders center. Results: Of the 25 patients, 13 patients (52%) had hypertension by history or on physical examination. Baseline echocardiograms showed that severe OSA was associated with numerous cardiovascular abnormalities, including left ventricular hypertrophy (LVH) [88%], left atrial enlargement (LAE) [64%], right atrial enlargement (RAE) [48%], and right ventricular hypertrophy (16%). In all patients (intent to treat) as well as those patients compliant with CPAP therapy (84% > 3 h nightly), there was a significant reduction in LVH after 6 months of CPAP therapy as measured by interventricular septal distance (baseline diastolic mean, 13.0 mm; 6-month mean after CPAP, 12.3 mm; p < 0.02). RAE and LAE were unchanged after CPAP therapy. Conclusions: LVH was present in high frequency in subjects with severe OSA and regressed after 6 months of nasal CPAP therapy. (CHEST 2003; 124: ) Key words: echocardiography; hypertension; left ventricular hypertrophy; nasal continuous positive airway pressure; obstructive sleep apnea; right ventricular hypertrophy Abbreviations: AHI apnea/hypopnea index; BMI body mass index; CPAP continuous positive airway pressure; IVSD interventricular septal distance; LAE left atrial enlargement; LVH left ventricular hypertrophy; LVPWT left ventricular posterior wall thickness; OSA obstructive sleep apnea; RAE right atrial enlargement; RDI respiratory disturbance index; RVH right ventricular hypertrophy; Sao 2 arterial oxygen saturation *From the Intermountain Sleep Disorders Center (Drs. Cloward, Walker, and Farney), LDS Hospital; and Division of Cardiology (Dr. Anderson), University of Utah, Salt Lake City, UT. Financial support was provided by Deseret Foundation, LDS Hospital. Manuscript received April 9, 2002; revision accepted February 27, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Tom V. Cloward, MD, FCCP, Intermountain Sleep Disorders Center, LDS Hospital, Eighth Ave and C St, Salt Lake City, UT 84143; ldtclowa@ihc.com Left ventricular hypertrophy (LVH) is a leading cause of morbidity and mortality. An increase in left ventricular mass predicts a higher incidence of clinical events, including death, attributable to cardiac disease. 1 6 A report 7 from the Framingham Heart Study found that the presence of LVH resulted in a twofold greater risk of sudden death compared to those without LVH. The adverse cardiac consequences from LVH are likely ultimately related to coronary ischemia, with increased muscle mass that is inadequately perfused, and which may compress endocardial capillaries. 5,8,9 LVH may also cause electrophysiologic changes that predispose the heart to arrhythmias and sudden death Obstructive sleep apnea (OSA) is now recognized as an independent risk factor for hypertension and imposes several adverse effects on the heart. During an obstructive apnea, large negative intrathoracic pressures are generated during inspiratory efforts, which increases transmural pressures across the myocardium, thus increasing afterload. An increase in preload and pulmonary congestion may also occur due to increased venous return. Secondly, the 594 Clinical Investigations

2 presence of hypoxemia decreases oxygen delivery to the myocardium, which may promote angina or arrhythmias. Lastly, frequent arousals from sleep due to respiratory events lead to increased sympathetic nervous system activity, with subsequent elevation in urinary and plasma catecholamines levels. Consequently, the adverse consequences of repetitive episodes of increased afterload on the heart during sleep may persist into the daytime. In this context, it would be expected that OSA may contribute to LVH, but results are equivocal Nasal continuous positive airway pressure (CPAP) has been shown to reduce BP in subjects with OSA Classic studies from the hypertension literature show that treatment of hypertension with medications (compared to no treatment) over a 3- to 5-year period prevents progression to severe hypertension, reduces LVH, and reduces congestive heart failure. 35 Furthermore, regression of LVH (as measured by ECG or echocardiography) has favorable prognostic implications for reduction of cardiovascular events For these reasons, it is important to achieve a better understanding of the relationship of LVH to OSA and the possible effects of CPAP therapy. The purposes of this study were as follows: (1) to determine the incidence of LVH as well as other cardiac structural abnormalities in patients with severe OSA and nocturnal hypoxemia without daytime hypoxemia, and (2) to determine if changes in LVH occurred after 6 months of CPAP therapy. The rationale was that LVH, if present, would be accentuated in patients with severe OSA associated with nocturnal hypoxemia, and that LVH regression with CPAP therapy might be more evident in such a population. Design and Setting Materials and Methods All patients were evaluated at the Intermountain Sleep Disorders Center at LDS Hospital in Salt Lake City, UT (elevation 1,371 m). The Institutional Review Board approved the design and methods of this study. All patients referred for evaluation of OSA were initially screened by overnight pulse oximetry (Nonin 8500M; Nonin Medical; Plymouth, MN) [sampling rate, once every 4 s]. All patients with a desaturation index of 40/h (based on a 3% drop in saturation) and 20% cumulative time spent with arterial oxygen saturation (Sao 2 ) 90% (Profox version PFD 06/97; PROFOX Associates; Escondido, CA) were targeted as possible study subjects. The intent of performing screening oximetry was to readily and inexpensively identify subjects with a high likelihood of having severe sleep apnea. Patients were excluded if daytime hypoxemia was present (defined at this elevation as resting Sao 2 88% or Pao 2 55 mm Hg). 39 Patients with known valvular heart disease or congestive heart failure were also excluded. The first 25 patients who met the criteria as outlined above, and who agreed to participate, were enrolled for study. All patients who were enrolled then underwent a full night of diagnostic polysomnography, baseline echocardiography, followed by a full night of polysomnography with nasal CPAP titration. Echocardiography and compliance checks were then performed at 1 month and 6 months after CPAP was initiated, during routine clinic follow-up visits (Table 1). Polysomnography All patients underwent an entire night of diagnostic polysomnography while breathing room air, followed by a second night of polysomnography with nasal CPAP titration. Attended polysomnography was conducted measuring the following: central (C3/A2 or C4/A1) and occipital (O1/A2 or O2/A1) EEG; right and left electrooculography; submentalis electromyography; ECG; anterior tibialis electromyography; airflow, by oronasal pressure transducers; and respiratory effort, determined by measurement of chest and abdominal motion using piezo electric bands and pulse oximetry. Data were acquired on either a CNS Sleep Lab 2000 (CNS; Minneapolis, MN) or an Aequitron 1000P (Aequitron-Medical; Plymouth, MN) using Matrix software (Jaeger-Toennies; Hoechberg, Germany). Sleep was manually scored page by page in 30-s epochs for sleep stages using standard criteria of Rechtschaffen and Kales. 40 Apneas and hypopneas were manually scored. Apneas were defined as an absence ( 20% baseline) of airflow for 10 s. Hypopneas were defined as a reduction in airflow (20 to 50% baseline), associated with a desaturation of 3%. Obstructive and mixed events are defined by the presence of respiratory effort and/or characteristic changes of the inspiratory flow pattern. Central apneas lacked respiratory effort and airflow. The apnea/hypopnea index (AHI) was computed as the total of all respiratory events divided by the total sleep time in hours. Patients were then prescribed nasal CPAP (Resmed Elite V; ResMed Corporation; Poway, CA), including use of a heated humidifier. The CPAP machines were equipped with compliance monitors that measured CPAP use, in order to observe CPAP usage/compliance at home. Echocardiography On enrollment, an echocardiogram (HP Sonos 5500, using version B.2.1 software; Philips Sonos; Andover, MA) was obtained on each patient prior to initiation of nasal CPAP, in the Cardiology Laboratory at LDS Hospital. Patients were imaged from standard transthoracic windows using two-dimensional, M-mode, and Doppler echocardiographic techniques. Echocardiographic images were obtained in the parasternal long and short axis, apical two-chamber, four-chamber, and subcostal views. The left ventricular internal dimension was obtained at both end-diastole and systole. The chamber size and wall thickness were measured manually by technicians who were blind to Time of Test Prescreening Baseline Table 1 Study Design Tests Performed Overnight oximetry Echocardiography BP measurement Diagnostic polysomnography Polysomnography with nasal CPAP titration 1 mo Echocardiography BP measurement Nasal CPAP compliance check 6 mo Echocardiography BP measurement Nasal CPAP compliance check CHEST / 124 / 2/ AUGUST,

3 the purpose of the study, and formally reviewed by cardiologists blinded to the patients involved with this study. Left ventricular size was determined by measuring diastolic interventricular septal distances (IVSDs), and left ventricular posterior wall thickness (LVPWT). Left atrial enlargement (LAE) was defined as left atrial diameter of 4.5 cm on parasternal short-axis or long-axis views. Right atrial enlargement (RAE) was defined as right atrial diameter 2.5 cm on short-axis view. Right ventricular hypertrophy (RVH) was defined as a right ventricular free-wall diastolic thickness 5 mm. 41 Protocol Echocardiograms were obtained following the diagnosis of OSA and prior to initiation of CPAP, and again at 1 month and 6 months. During 1-month and 6-month follow-up visits, compliance data were downloaded (Resmed Autoscan Version 3.0; ResMed Corporation), and echocardiography was repeated. BP measurements were obtained at each follow-up visit. Routine troubleshooting took place in an effort to maximize compliance with nasal CPAP. Patients were considered to be CPAP compliant if they used CPAP an average 3 h per night at the 6-month follow-up. Hypertension was defined as the presence of an office sphygmomanometer systolic BP 140 mm Hg, diastolic BP 90 mm Hg, or if the subject was receiving antihypertensive medications. Twenty-four hour BP measurements were not obtained. Statistical Analysis A t test for related measurements (two tailed) was used to compare primary outcome variables of LVH (IVSD and LVPWT), at baseline, 1 month, and 6 months. Comparisons were considered significant with a p 0.05 (Bonferroni correction, %:0.05/2 measures of LVH 0.025). Results Echocardiographic Data The 25 subjects were predominantly men (23 of 25 subjects), and ages ranged from 31 to 68 years. All subjects were obese (mean BMI, ), with normal awake oxygenation by arterial blood gas (mean Pao 2, 66 mm Hg; mean Sao 2, 92%). Polysomnography revealed severe OSA, with a mean AHI of 81/h, associated with significant nocturnal hypoxemia (mean time spent with Sao 2 90% equaled 64% of recording time) [Table 2]. Of the 25 subjects, 23 subject (92%) had structural abnormalities on echocardiography (Fig 1). LVH was the most common finding (present in 22 of 25 subjects) and occurred in those both with and without hypertension. Hypertension was present in 13 of 25 subjects (52%). All 13 subjects with hypertension had LVH. Of the 12 subjects without hypertension, 10 subject had LVH. LVH was defined as an IVSD or LVPWT 12 mm. There were 16 subjects who had LAE (64%), 13 subjects who had RAE (48%), and 4 subjects who had RVH (16%). Only 2 of the 25 subjects had completely normal echocardiographic Table 2 Demographic Characteristics of OSA Subjects Referred to the Sleep Clinic* Variables Data (n 25) Age, yr 49.6 (31 68) Education, yr 14.1 (11 18) Male gender, No. (%) 23 (92) Weight, kg Height, m BMI Hypertension, No. (%) 13 (52) Awake supine Pao 2, mm Hg, by arterial blood gas Awake supine Sao 2, mm Hg, by arterial blood gas AHI, by polysomnography Desaturation index from nocturnal oximetry, based on 3% drop from baseline Percentage of time spent with Sao 2 90% on nocturnal oximetry *Data are presented as mean (range) or mean SD unless otherwise indicated. findings, and their results are included within the final analyses. All of the patients had a normal ejection fraction, which did not change during the course of therapy (Fig 2). Compliance Of the 25 subjects, 20 subject were compliant with CPAP therapy, which we defined as 3 h of nightly use. The five patients who were noncompliant with nasal CPAP still completed participation in the study, including follow-up echocardiography and BP measurements. Subjects who were compliant with therapy averaged 5.9 h of CPAP usage per night, as determined by a compliance monitor within the CPAP machine. Subjects who were noncompliant used CPAP for 0.8 h per night. The major reasons for noncompliance were mask discomfort or pressure intolerance. All subjects were offered heated humidity, and efforts were made in all subjects to improve comfort and compliance with therapy. There was no change from baseline after 6 months in either weight or BP. Only two subjects had their BP regimen altered: one subject had the diuretic dose halved, and the other had the diuretic dose doubled. Changes in average CPAP pressure after 6 months of therapy did not change from the initial CPAP pressure that was prescribed (Table 3). LVH Regression The primary measures of LVH obtained from echocardiograms, IVSD, and LVPWT showed regression after 6 months of CPAP therapy. Table 4 depicts IVSD 596 Clinical Investigations

4 Figure 1. Echocardiographic measurements at baseline in 25 subjects with severe OSA. In solid bars, the frequency of each structural abnormality is depicted. In hatched bars, the frequency of hypertension (HTN) in each subgroup is shown. The coexistence of hypertension was present in 13 of the 23 subjects with LVH. and LVPWT values at baseline, and after 1 month and 6 months of CPAP use, respectively. Using an intentto-treat analysis, IVSD was significantly reduced after 6 months (p 0.02). Reduction in LVPWT approached, but did not reach, statistical significance after 6 months (p 0.08). Further analysis of compliant vs noncompliant subjects reveals that reduction in IVSD and LVPWT occurred in those who were compliant with nasal CPAP. Noncompliant subjects showed no reduction in either parameter (Table 4). LAE and RAE did not change during the course of therapy (data not shown). RVH was present in four patients (16%). The effect of CPAP on RVH was not analyzed due to the low number of subjects with RVH. Discussion This investigation further confirms that multiple cardiac structural abnormalities are associated with Figure 2. Ejection fraction determined by echocardiography in 25 patients with severe OSA. Normal systolic function was present at baseline, and did not significantly change after 1 month and 6 months of CPAP use, respectively. CHEST / 124 / 2/ AUGUST,

5 Table 3 Comparison of Compliant and Noncompliant Subjects at Baseline and After 6 Months of CPAP Usage* Variables AHI Weight, kg BP, mm Hg CPAP, cm H 2 O Compliance, hours per Baseline 6 mo Baseline 6 mo Baseline 6 mo night Compliant (n 20) Noncompliant (n 5) /82 14/9 133/82 13/ /83 13/10 132/83 20/ *Data are presented as mean SD. severe OSA. Only 8% of our subjects had normal echocardiographic findings. In contrast, 88% of subjects had LVH. The second-most-common structural abnormality was LAE (present in 64% of patients), followed by RAE (48% of subjects), and RVH (16% of subjects). Ejection fraction was normal in all subjects. Hypertension was present in only 52% of the subjects, so daytime hypertension alone does not account for the high prevalence of LVH observed in this study. Ten of 12 normotensive subjects had LVH. This suggests that the nocturnal consequences of OSA, including increased transmural pressure due to respiratory effort during an apneic event, hypoxemia, and increased sympathetic neural activity, may account for the development of LVH in patients with OSA. An alternative explanation is that our subjects may have had a higher incidence of hypertension if measured by 24-h ambulatory monitoring. There is evidence that LVH may precede the presence of hypertension. 42 Other investigators have characterized cardiac structure and function in OSA Hedner et al 20 compared 61 men with OSA to 61 control subjects, and reported that left ventricular mass and left ventricular mass index were significantly higher among the OSA patients. Left ventricular mass index was approximately 15% higher in the normotensive OSAS patients compared to normotensive control Table 4 Measures of LVH at Baseline, and After Nasal CPAP Therapy* Variables Baseline 1 mo 6 mo p Value Overall (n 25) IVSD 13.0 (1.6) 12.7 (2.5) 12.3 (1.6) LVPWT 12.8 (2.0) 12.2 (2.0) 12.2 (1.6) Compliant (n 20) IVSD 13.1 (1.8) 12.9 (2.6) 12.3 (1.7) LVPWT 13.0 (2.1) 12.3 (2.1) 12.3 (1.6) Noncompliant (n 5) IVSD 12.8 (0.4) 12.0 (1.7) 12.4 (1.5) LVPWT 12.2 (1.1) 11.8 (1.7) 12.4 (2.6) *Data are presented as mean (SD). Difference between baseline and 6-month values. subjects. The study was limited by lack of polysomnography data in both groups. Noda et al 22 examined 51 subjects with hypertension, and reported LVH in 50% of those with an AHI 20/h, compared to 21.4% in those with an AHI 20/h. LVH and RVH were more likely in the presence of high AHI, sustained hypoxemia, and obesity. Davies et al 23 did not find any significant difference in left ventricular mass between 19 subjects with OSA, 19 nonapneic snorers, and 38 control subjects matched for age, sex, BMI, and tobacco and alcohol use. Niroumand and coworkers 25 studied 533 subjects in a clinic population and found that OSA does not independently increase left ventricular mass or impair left ventricular diastolic filling. Although left ventricular mass was higher in OSA subjects, it was predominantly related to coexisting obesity, in addition to the effects of aging and presence of hypertension. Kraiczi et al 26 studied 81 subjects and examined the relationship of OSA with hypertension and left ventricular thickness after adjusting for age, gender, use of antihypertensives, smoking, BMI, coronary artery disease, hyperlipidemia, and circulating c-peptide concentrations. OSA severity and left ventricular muscle thickness were primarily linked via the presence of coexisting increased BP. Alchanatis et al 27 studied 15 OSA subjects (mean AHI, 52/h) and found left ventricular diastolic dysfunction and increased diastolic BP, each of which improved following 12 to 14 weeks of nasal CPAP therapy. Fung et al 28 reported that severe OSA (in 68 patients) was associated with left ventricular diastolic dysfunction. Amin et al 29 found that OSA in children is associated with increased left ventricular mass. The Framingham Heart Study 43 showed that obesity is significantly correlated with left ventricular mass, even after controlling for age and BP. The increase in left ventricular mass associated with increased body weight reflects both left ventricular wall thickness and left ventricular internal dimension. This association is present even in those with mild-to-moderate obesity. The presence or absence of OSA in obese subjects was not considered as a potential confounding variable that may contribute 598 Clinical Investigations

6 to LVH in this population-based epidemiologic study. In fact, Narkiewicz and colleagues 44 have shown that obesity alone, in the absence of OSA, is not accompanied by increased sympathetic activity to muscle blood vessels. MacMahon and colleagues 45 demonstrated that weight loss in overweight, hypertensive subjects reduced left ventricular mass and posterior wall thickness. Patients in our investigation were obese (mean BMI, 38). The effects of obesity alone in our study population cannot be discounted as a potential confounding contributor to underlying LVH; however, the fact that there was a significant regression of LVH over a 6-month period following CPAP therapy, without concomitant weight loss, strongly suggests that OSA was at least a contributory factor. The second important finding in this study was the finding of LVH regression after initiation of nasal CPAP. After 1 month of nasal CPAP, regression of LVH was not significant. After 6 months of nasal CPAP, IVSD was significantly reduced. LVPWT also decreased after 6 months of therapy and approached, but did not reach, statistical significance. It is unknown if extending duration of therapy would have resulted in further improvement in either index of LVH. Another possibility is that nasal CPAP, by itself, may improve LVH, irrespective of amelioration of OSA. This seems less likely, as those subjects who were noncompliant with CPAP in this study did not have LVH regression. A control group of non- OSA patients with LVH treated with CPAP would be necessary to establish such a relationship The presence of LVH is important because of an increased association with heart failure, ventricular arrhythmias, death following myocardial infarction, and sudden cardiac death. Koren et al 2 followed up 253 hypertensive patients with and without LVH over the course of 10 years, and found that cardiac events were more frequent (26% vs 12%) and cardiovascular deaths were higher (14% vs 0.5%) if LVH was present. Liao et al 6 followed up 988 patients over 7 years. The presence of LVH was associated with a threefold greater risk of death compared to those without LVH. This was present in patients with and without coronary artery disease. The Framingham study 7 followed up 3,661 subjects with LVH over 14 years. The risk factor adjusted hazard ratio for sudden death was Regression of LVH occurs with the use of antihypertensive medications, with improvements observed relatively quickly (15 to 30 weeks). Further resolution of LVH occurs relatively slowly ( 3 years) and may reverse completely if BP is controlled. The present study shows regression of LVH by CPAP somewhere between the range of that demonstrated by angiotensin-converting enzyme inhibitors and calcium-channel blockers, but better than diuretics and beta-blockers. 46 The difference, however, is that in patients with OSA, CPAP alters potential underlying causative factors by reducing cardiac afterload associated with apneas, maintaining normal oxygenation, and reducing repetitive sympathetic activity across the night. The primary aims of this study were to document the frequency of LVH in patients with severe OSA and to determine if changes occurred with CPAP. Other echocardiographic structural abnormalities, such as bilateral atrial enlargement, were not ameliorated with CPAP therapy. There were no significant changes observed in LAE or RAE following 6 months of treatment with nasal CPAP, following an intent-to-treat analysis. Of the four subjects with RVH, three subjects were compliant with nasal CPAP; in those three patients, regression of RVH was noted. This is observational information only, as the low numbers preclude meaningful statistical analysis. Reduction in RVH with CPAP therapy is consistent with a previous report. 47 Daytime hypoxemia, postulated by some 48,49 to be a prerequisite for RVH, was not present in our patients. This study, as well as others that have shown either LVH or RVH, could be criticized on the basis of biased sampling by recruiting patients referred for sleep apnea. To circumvent sampling bias, Guidry et al 50 matched subjects in a population-based study with high respiratory disturbance index (RDI) [90th percentile] with low RDI (below 50th percentile) and found that the right ventricle was significantly thicker in the high RDI group but there were no differences in left ventricular thickness. The sample in the present study was unique from other studies for both the frequency of respiratory disturbances (mean AHI, 80/h) and the degree of nocturnal hypoxemia (64% of testing time spent with Sao 2 90%). These factors possibly accentuated cardiac abnormalities that otherwise might not be evident in less severe OSA without a larger sample size. Further studies are necessary to determine which factors are necessary for the development of LVH in patients with OSA. A larger population of study subjects would be helpful to determine the relative importance of such factors as obesity, age, AHI, degree of hypoxemia, and presence or absence of 24-h hypertension in relationship to the presence of LVH. It is also important to elucidate the reverse of this finding: does LVH on echocardiography serve as a marker for sleep-related breathing disorders? In conclusion, LVH was by far the most common echocardiographic abnormality observed in this group of patients with severe OSA. Application of nasal CPAP resulted in reduction of LVH after CHEST / 124 / 2/ AUGUST,

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