Obstructive Sleep Apnea Syndrome Affects Left Ventricular Diastolic Function
http://www.100md.com
《循环学杂志》
Servicios de Cardiología (M.A.A.) and Neumología (F.G.-R., A.A.-F., O.M., J.V.) and Laboratorio de Bioquímica (I.M.)
Hospital Universitario La Paz, Madrid, Spain.
Abstract
Background— The purpose of this study was to determine the role of obstructive sleep apnea syndrome (OSAS) as an independent risk factor for the development of left ventricular diastolic abnormalities. Moreover, we tested the hypothesis that nasal continuous positive airway pressure (nCPAP) improves such alterations in OSAS patients by eliminating apneic events.
Methods and Results— In this prospective, randomized, placebo-controlled, double-blind crossover study, 27 consecutive newly diagnosed middle-aged OSAS men with neither controllable factors nor conditions affecting left ventricular diastolic function and 15 healthy control subjects were selected. OSAS patients were randomized to 12 weeks on sham nCPAP and 12 weeks on effective nCPAP application. Echocardiographic parameters, blood pressure recordings, and urinary catecholamine levels were obtained at baseline and after both treatment modalities. At baseline, an abnormal left ventricular filling pattern was present in 15 of the 27 OSAS patients and only in 3 of the 15 control subjects (P=0.020). Impaired relaxation was by far the most common abnormal pattern in both groups (11 and 3 patients, respectively). In OSAS patients, 12 weeks on effective nCPAP induced a significant increase in E/A ratio (P<0.01), as well as reductions in mitral deceleration (P<0.01) and isovolumic relaxation (P<0.05) times.
Conclusions— OSAS can affect left ventricular diastolic function independently of other possible factors. Chronic application of nCPAP could avoid the progression of diastolic abnormalities, and indeed, it might reverse these alterations, at least in the initial stages before severe structural changes can be developed.
Key Words: physiology ; echocardiography ; diastole ; pulmonary heart disease ; sleep
Introduction
Obstructive sleep apnea syndrome (OSAS) is characterized by periodic reduction or cessation of breathing due to narrowing of the upper airways during sleep. Prevalence surveys estimate that 2% of women and 4% of men of middle age are affected by this syndrome.1 Cardiovascular disturbances are the most important complications, producing severe morbidity and mortality.2 However, many risk factors for OSAS, including male gender, advanced age, and obesity, are the same for cardiovascular disease, which makes it difficult to recognize the role of OSAS as an independent risk factor. At the present time, only the association with systemic hypertension has been well established.3,4
Heart failure is a major public health problem in developed countries. Approximately half of patients with heart failure have preserved left ventricular systolic function, with high morbidity and mortality rates and with major socioeconomic implications derived from their management.5 The majority of patients who present with heart failure and normal systolic function do not have a defined myocardial disease, but it has been demonstrated that they have abnormalities in active relaxation and passive stiffness.6 That is, they have alterations in mechanical function during diastole that lead to the development of diastolic heart failure. Hypertension, diabetes mellitus, left ventricular hypertrophy, and myocardial ischemia are frequently associated with diastolic dysfunction.
The link between OSAS, left ventricular dysfunction, and congestive heart failure is less known, although OSAS is frequent in both systolic and diastolic heart failure patients.7,8 Proposed mechanisms that affect left ventricular performance in patients with OSAS include several mechanical, neurohumoral, inflammatory, endothelial, and oxidative effects.9
There are few data about the possible role of OSAS as an independent cause of left ventricular diastolic dysfunction in otherwise healthy patients. The goals of the present study were (1) to evaluate the frequency of abnormalities in diastolic left ventricular filling in middle-aged adult men with OSAS and no other controllable factors affecting diastolic function and (2) to test the hypothesis that nasal continuous positive airway pressure (nCPAP) therapy, the standard treatment for OSAS,10 might reverse these abnormalities.
Methods
Subjects
Twenty-seven consecutive newly diagnosed OSAS men without previous treatment for OSAS and 15 healthy men were selected. OSAS patients fulfilled the following inclusion criteria: (1) apnea-hypopnea index (AHI) 10 h–1 and excessive daytime sleepiness (Epworth sleepiness scale 10 points)11; and (2) no current drug or mechanical treatment for OSAS. Inclusion criteria for healthy control subjects were AHI <5 h–1 and Epworth sleepiness scale <10. Exclusion criteria for both study groups were as follows: (1) unwillingness or inability to perform the testing procedure; (2) obstructive or restrictive lung disease demonstrated on pulmonary function testing; (3) current use of cardioactive drugs; (4) cardiac rhythm disturbances, including sinus bradycardia and sinus tachycardia; (5) known hypertension, or 24-hour mean blood pressure of 135 and/or 85 mm Hg or more; (6) left ventricular ejection fraction <50%; ischemic or valvular heart disease; hypertrophic, restrictive, or infiltrative cardiomyopathy; pericardial disease or stroke by history or physical examination, ECG, chest radiography, conventional stress testing, and echocardiography; (7) diabetes mellitus, by history or 2 random blood glucose levels 126 mg/dL; (8) morbid obesity (body mass index >40 kg/m2); (9) daytime hypoxemia (PaO2 <70 mm Hg) or hypercapnia (PaCO2 >45 mm Hg). Withdrawal criteria were (1) clinical exacerbation that led to a change in medication, (2) hospital admission for 10 or more days, and (3) average nightly nCPAP usage <3.5 hours.
The study was approved by the Institutional Ethics Committee at the hospital. All subjects gave their written informed consent.
We performed a single-center, prospective, randomized, double-blind, placebo-controlled and crossover clinical trial, in which OSAS patients received effective nCPAP and placebo (sham nCPAP)12 for two 12-week periods (Figure 1). The sham nCPAP device consists of a conventional nCPAP device in which the area of the exhalation port is amplified, thereby nearly cancelling nasal pressure, and an orifice resistor is connected between the tubing and the nCPAP unit that loads the blower with the same airflow resistance as in effective nCPAP. All OSAS patients underwent a full-night nCPAP titration study with an automated pressure setting device (Auto Set; ResMed).13 Patients were given detailed instructions on using nCPAP equipment, but they were not informed of the type of therapy they were receiving. Compliance data were measured with a run-time counter.
All subjects underwent baseline sleep study, 24-hour ambulatory blood pressure monitoring (ABPM), and an echocardiogram. Urine specimens and demographic data were also collected. Patients were randomized to receive either effective or sham nCPAP therapy for 12 weeks. Then, they were readmitted to the hospital, and the nCPAP device was switched to the alternate mode of therapy for another 12 weeks. Echocardiogram and ABPM were repeated just after each period with either effective or sham nCPAP treatment. Urine specimens were obtained at the same time at each visit.
Sleep Study
During the same night when urine specimens were collected, a sleep study was performed in OSAS patients and healthy control subjects. We used a previously validated portable respiratory recording device (Sibel Home-300; Sibel S.A.)14 that records oronasal airflow using a thermistor, chest wall impedance, oxygen saturation, snoring, and body position.
Respiratory events were classified as either obstructive or central on the basis of presence or absence of respiratory effort. Respiratory events were scored as apnea when there was a cessation of oronasal airflow that lasted 10 seconds. Hypopnea was defined as a decrease of 50% in oronasal airflow that lasted >10 seconds, associated with a fall in arterial oxygen saturation (SaO2) >4% of the preceding baseline level. Mean nighttime SaO2, minimum SaO2 (lowest values recorded during sleep), desaturation index, and percentage of time with SaO2 <90% on nocturnal oximetry were computed as indexes of nocturnal oxygen saturation.
Twenty-Four–Hour ABPM
Twenty-four–hour ABPM was performed on each patient with a SpaceLabs device (model 90207) by an oscillometric method.15 Blood pressure was measured every 30 minutes during the day (8 AM to 11 PM) and every 60 minutes during the night (11 PM to 8 AM) on a workday. An appropriate cuff was used and placed on the nondominant arm. Patients were instructed not to move their arm during the ongoing measurement, and during the recordings, the subjects were asked to perform their ordinary daily activities and to go to bed no later than 11 PM.
Catecholamines in Urine
Urinary excretion of norepinephrine and epinephrine were determined as described previously.16 A 5-mL aliquot of a urine sample was filtered; 3,4-dihydroxybenzylamine (internal standard) and 0.1% EDTA were added to the filtrate, adjusted to pH 6.5, and subsequently placed on a Biorex 70 cation exchange column (Bio-Rad). After the sample completely entered into the resin, the column was washed with distilled water, and the catecholamines were eluted with 10 mL of 0.65 mol/L boric acid. After this procedure, 20 μL of the effluent was injected into an HPLC system composed of an HPLC pump (model 510, Waters), rheodyne injection valve (20 μL), ESA HR-80,RP-C18 chromatographic column (ESA Inc), and ESA coulometric detector (Coulochem II model), model 5011 high-sensitivity analytical cell, and model 5021 conditioning cell. Concentrations of detected compounds were calculated on a PC with 712 HPLC system controller version 1.2 (Gilson) integration software, which measures the heights of the peaks and relates them to external standards.
Intra-assay coefficients of variation were 3% for norepinephrine and 3% for epinephrine. Interassay coefficients of variation were 9% for norepinephrine and 10.5% for epinephrine. Results were expressed in terms of micrograms per gram of creatinine.
Echocardiography
Examinations were performed with patients in the supine and left-lateral positions after a minimum rest period of 30 minutes with a high-quality echocardiograph with 2.0- to 4.0-MHz probes (Hewlett Packard Sonos 5500). Echocardiographic images were obtained in the parasternal long- and short-axis, apical 2- and 4-chamber, and subcostal views with 2D, M-mode, and Doppler echocardiographic techniques. The parameters were measured from at least 3 cardiac cycles. All echocardiograms were performed by the same experienced echocardiographer, who was unaware of both the subject’s group and the patient’s treatment assignment at each visit.
Left ventricular internal end-diastolic and end-systolic dimensions, as well as posterior wall (PW) and interventricular septum thicknesses, were determined in accordance with the American Society of Echocardiography recommendations.17 Systolic function was assessed by left ventricular shortening fraction (LVSF) and left ventricular ejection fraction (LVEF).18 Left atrial end-systolic dimension was also obtained with the parasternal long or short axes. Left ventricular mass (LVM) was calculated with an anatomically validated formula,19 and LVM index was obtained from LVM corrected for body surface area. LVSF 28% and LVEF 50% were considered normal.
Left ventricular diastolic function was assessed with both 2D and Doppler echocardiography in accordance with the American Society of Echocardiography recommendations.20 The mitral inflow pattern was recorded with the sample volume between the leaflet tips by the pulsed-wave Doppler technique. The following variables were measured: peak flow velocity in early diastole (E wave), peak velocity at atrial contraction (A wave), isovolumic relaxation time (IVRT), mitral deceleration time (DT), and mitral A-wave duration. To obtain pulmonary venous flow, an apical 4-chamber view was used, and pulsed-wave Doppler sample volume was placed 1 to 2 cm into the right upper pulmonary vein. Peak systolic velocity (S wave), peak diastolic velocity (D wave), and the duration of reverse flow at atrial contraction (AR) were measured. Left ventricular filling patterns were classified as normal, impaired relaxation, pseudonormal, and restrictive by a modification of the approach of Appleton et al.21 Normal pattern was defined by E/A ratio >1, normal DT (160 to 240 ms) and IVRT (70 to 110 ms), and S/D and A/AR duration ratios >1. Impaired relaxation was determined by E/A ratio <1, prolonged DT (>240 ms) and IVRT (>110 ms), and S/D and A/AR duration ratios >1. Pseudonormal pattern was identified by E/A ratio ranging from 1 to 1.5, normal DT and IVRT, and S/D and A/AR duration ratios <1. Finally, restrictive pattern was defined by E/A ratio >1, short DT (<160 ms) and IVRT (<70 ms), and S/D and A/AR duration ratios <1.
Statistical Analysis
Values are expressed as mean±SD or percentage. The comparisons between patients groups were performed by means of the Mann-Whitney U statistic, whereas the 2 test was used to compare proportions. Relationships between variables were determined by Pearson correlation analysis and by stepwise multiple regression. A multiple logistic regression analysis was performed to identify the factors that determined abnormal diastolic function. Comparisons on effects of the treatments over time were made with repeated-measures ANOVA with treatment as a within-subject factor and order as a between-subject factor. When ANOVA results showed significant differences between treatment conditions, post hoc multiple comparisons were performed with the Bonferroni test. Statistical calculations were performed with SPSS version 10.0 (SPSS Inc). A value of P<0.05 was considered statistically significant.
Results
Characteristics of the Subjects
Baseline Left Ventricular Filling Patterns and Ventricular Structure
At baseline, an abnormal left ventricular pattern was present in 15 (56%) of the 27 OSAS patients and only in 3 (20%) of the 15 healthy control subjects (P=0.020). Impaired relaxation was by far the most common abnormal pattern in both groups, whereas a pseudonormal pattern was present only in 3 patients with OSAS (Figure 2). OSAS patients had significantly longer IVRT and DT and lower E/A ratio. There were no significant differences in left atrial size, E wave, and A wave between the 2 groups. Although the values were normal, OSAS patients had higher values of PW and interventricular septum thickness, LVM, and LVM index (Table 2).
In OSAS patients, relationships between diastolic echocardiographic parameters and demographic data, blood pressure recordings, urinary catecholamines, and sleep parameters were analyzed. The study showed a significant correlation between age and A wave (r=0.424, P<0.05), E/A ratio (r=–0.590, P<0.001), DT (r=0.653, P<0.01), and IVRT (r=0.439, P<0.05). There was also a positive correlation between PW thickness and IVRT (r=0.537, P<0.01) and between LVM index and both IVRT (r=0.478, P<0.05) and DT (r=0.438, P<0.05). We analyzed separately OSAS patients with normal filling pattern (n=12) and those with impaired relaxation (n=11) at baseline to facilitate the exploratory analysis of diastolic echocardiographic parameters (Table 3). Patients with impaired relaxation were of more advanced ages, having higher AHIs than those with normal pattern. Moreover, PW thickness, LV mass, and LV mass index were higher in OSAS patients with impaired relaxation. Of the independent variables included in the logistic regression model (age, AHI, PW thickness, LV mass, and LV mass index), diastolic dysfunction was only predicted by AHI (area under the receiver operating characteristic curve=0.812, standard error=0.086).
Effects of nCPAP
Two patients, 1 with normal left ventricular pattern and the other with a pseudonormal pattern, failed to complete the trial because of an average nightly usage of nCPAP of <3.5 hours. There were no significant differences in sleep study findings, baseline demographic characteristics, smoking habit, lung function data, sympathetic tone, or ABPM between the patients who withdrew and those who completed the trial.
Complete measurements were available in 25 patients who went home on effective nCPAP for an average of 104±31 days and on sham nCPAP for 98±22 days. Mean nCPAP pressure was 10±2 cm H2O, and the average nightly usage was similar on effective nCPAP and sham nCPAP (6±1 versus 6±2 hours, respectively).
There were no differences in heart rate, weight, blood pressure recordings, or urinary catecholamines at baseline and after sham or effective nCPAP in OSAS patients (Table 4). After 12 weeks on effective nCPAP, left ventricular filling patterns were not modified, but a significant increase in E/A ratio and reduction in DT and IVRT values were induced (Table 5; Figure 3). These changes were mainly produced in OSAS patients with impaired relaxation, although DT was the only variable that reached statistical significance (Table 3). After both modes of treatment, no significant differences were observed in either systolic function or ventricular structure parameters.
Discussion
The main findings of this study are that abnormalities in diastolic function, substantially related to repetitive obstructive apneic events during sleep, are very common in OSAS patients and that these alterations could be reversible, at least in part, with nCPAP therapy. Previous studies had reported contradicting data about the relationship between OSAS and left ventricular diastolic function.22–29 The effects of cardioactive drugs, hypertension, or other possible diseases that affect diastolic function could affect the results in some of them.23–26,28,29 Indeed, incomplete assessment of diastolic function by echocardiography, lack of quantification of heart rate at the time of the echocardiographic studies,22–29 and absence of a control group of subjects24,25,27,28 limits the information derived from these studies. To the best of our knowledge, there are no placebo-controlled studies to assess the effects of nCPAP on left ventricular diastolic function in OSAS and otherwise healthy patients.
In the present study, we tried to eliminate the confounding effects of other disease states or pharmacological interventions on diastolic function. All of the OSAS patients in the present study were free of other diseases and were receiving no medication, either before or during the study period. The presence of a control group of patients with no significant differences in demographic data with respect to the OSAS patients and the response to a placebo-controlled therapeutic intervention such as nCPAP support the causal role of OSAS to explain our results.
The mechanisms underlying diastolic dysfunction in OSAS patients are not well known. Elevations in nocturnal blood pressure and sympathetic nervous system activity30 in OSAS subjects create ventricular pressure overload.31 It could be speculated that, as occurs in other processes such as chronic hypertension and aortic stenosis, increased pressure overload at the cellular level would mainly result in decreased levels of sarcoplasmic reticulum calcium ATPase pump and increased phospholamban.32 It slows the removal of calcium from the cytosol, which leads to impaired ventricular relaxation. In experimental studies, it has been demonstrated that ventricular pressure overload on its own impairs myocardial relaxation.33 On the other hand, pressure overload causes activation of multiple cellular signals that create myocardial tissue hypertrophy and interstitial fibrosis that increases passive stiffness.34 Indeed, an impaired coronary flow reserve would cause silent ischemia, worsening ventricular active relaxation when left ventricular diastolic pressure begins to rise.
Another plausible mechanism to explain the presence of diastolic dysfunction and the effects of nCPAP therapy on diastolic function in this patient population is related to futile inspiratory efforts.31 This results in exaggerated negative intrathoracic pressure, which leads to an increase in left ventricular transmural pressure and hence afterload without increasing blood pressure. Another consequence of the increased negative intrathoracic pressure is the leftward shift of the interventricular septum related to enhanced venous return and right ventricle dilatation. All of the aforementioned effects of enhanced negative intrathoracic pressure have been demonstrated to affect left ventricular filling.35,36
It is difficult to define how each of those mechanisms affects diastolic function in a single OSAS patient, because they would act in synergy. However, in the initial stages of the disease, we hypothesize that mechanical effects of obstructive events mainly create ventricular pressure overload, which by itself might lead to slowed ventricular relaxation. As the disease progresses, ventricular structural abnormalities such as remodeling, alterations in collagen structure, and muscle hypertrophy37,38 can develop, which would worsen alterations in normal left ventricular filling.34 In this sense, it is important to observe that the OSAS patients with impaired relaxation in the present study had higher values of LV mass, PW, and interventricular septum thickness than patients with a normal pattern, although in both groups, values were within normal limits. Indeed, LVM index showed a positive correlation with DT and IVRT, and PW thickness showed a positive correlation with IVRT; both of these results support the idea that these structural changes probably contribute to the diastolic abnormalities observed in the patients in the present study. This, along with the short duration of treatment, could explain the only partial reversal of such alterations despite the elimination of apneic events after nCPAP.
The higher mean age of patients with impaired relaxation compared with patients with normal pattern (49±12 versus 61±5 years) could also be responsible in part for the differences observed in diastolic parameters. However, an attenuation of changes caused only by aging with nCPAP therapy would be an unexpected finding.
Partial reversal of left ventricular diastolic function abnormalities after nCPAP treatment in our thoroughly selected OSAS patients supports the pathogenic relationship between diastolic dysfunction and OSAS. Changes in echocardiographic diastolic parameters after nCPAP therapy have been reported in several non–placebo-controlled studies, some with different patient selection criteria.22,24,27 Effects of nCPAP on diastolic dysfunction might be related to diminished sympathetic activation39 and left ventricular afterload40 and be related to elimination of exaggerated negative intrathoracic pressure as a result of the abolition of apneic events. In OSAS patients in the present study, these effects would result in diminished ventricular pressure overload, probably being responsible for changes observed in diastolic parameters.33 However, significant changes in urinary excretion of catecholamines and blood pressure levels were not obtained after nCPAP therapy in the present study. That could be because urinary excretion of norepinephrine and epinephrine and ABPM lack sensitivity to detect the elimination of surges in blood pressure and nocturnal sympathetic nerve traffic drive in OSAS patients receiving nCPAP. In spite of the evident acute effects on blood pressure surges with nCPAP, a continued reduction in either nocturnal or diurnal blood pressure may be apparent only in hypertensive OSAS patients and not in normotensive patients, probably in relation to the pressor effect of decreased levels of atrial natriuretic peptide induced by nCPAP application despite the reduction in sympathetic drive.41
The results of the present study do not allow us to determine whether longer therapy with nCPAP might result in a more significant reversal of diastolic abnormalities in OSAS patients. This could be possible, especially in OSAS patients with left ventricular hypertrophy, in view of the information reported by Cloward et al37 with regression of ventricular hypertrophy after a minimum of 6 months with nCPAP. In patients with ventricular hypertrophy, regression of hypertrophy is accompanied by a reversal of diastolic dysfunction.42 However, no changes in ventricular structure were observed after 12 weeks on nCPAP therapy in OSAS patients without ventricular hypertrophy in the present study.
The absence of changes in body weight, resting heart rate, and blood pressure before and after treatment with nCPAP discounts the possible influence of such factors contributing to attenuation of diastolic dysfunction observed after nCPAP therapy. These findings are concordant with data published by Narkiewicz et al,39 who reported a decrease in muscle sympathetic traffic without changes in heart rate and blood pressure in normotensive and otherwise healthy OSAS patients after treatment with nCPAP. By contrast, in a prospective, placebo-controlled study, Becker et al43 demonstrated a significant reduction in daytime and nocturnal blood pressure with long-term nCPAP treatment, although 21 of 32 OSAS patients were hypertensive.
Our study has several limitations, the main one being the limited number of patients studied. The process of including only middle-aged patients with newly diagnosed OSAS, having no other diseases and taking no cardioactive medication, to achieve the purpose of the present study was very arduous. Indeed, we are not able to predict in which patients diastolic abnormalities can develop, nor the time necessary to affect left ventricular filling once obstructive respiratory events have begun to occur. It is possible that the duration and severity of OSAS, along with individual genetically predisposed factors, determine this fact. Another limitation is the possible clinical significance of diastolic abnormalities in asymptomatic patients assessed by conventional echocardiographic parameters. In this regard, there is information about the importance of not only having impaired left ventricular relaxation determined by standard Doppler parameters but also of an elevated left ventricular filling pressure as a predictor of reduced exercise tolerance.44 However, the purpose of the present study was only to demonstrate that OSAS can affect left ventricular diastolic function and how nCPAP application can modify diastolic left ventricular filling. Doppler indexes of transmitral and pulmonary venous flow have been shown to correlate well with left ventricular filling pressures, especially in patients with systolic dysfunction45; however, the correlation has been poorer in patients with normal systolic function. It is generally considered that tissue Doppler echocardiography and color M-mode Doppler may be more useful in assessing left ventricular diastolic dysfunction and filling pressures in patients with normal left ventricular systolic function.45 Therefore, further studies are required to assess the impact of these echocardiographic variables on the diagnosis of diastolic dysfunction in OSAS patients.
To the best of our knowledge, this is the first prospective, randomized, placebo-controlled, crossover study to evaluate the consequences of OSAS on diastolic left ventricular filling and to assess the response of diastolic function to nCPAP therapy. In conclusion, left ventricular impaired relaxation is frequently observed in OSAS patients, which suggests that it may be an early response to cardiac overload caused by this disease independently of other possible factors. Chronic application of nCPAP could avoid the progression of diastolic abnormalities, and indeed, it might reverse these alterations, at least in the initial stages before severe ventricular structural changes develop.
Acknowledgments
This research was supported in part by a grant from the Fondo de Investigación Sanitaria (exp. 01/0278). The authors thank Dr José M. Oliver for his critical review of the manuscript.
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Hospital Universitario La Paz, Madrid, Spain.
Abstract
Background— The purpose of this study was to determine the role of obstructive sleep apnea syndrome (OSAS) as an independent risk factor for the development of left ventricular diastolic abnormalities. Moreover, we tested the hypothesis that nasal continuous positive airway pressure (nCPAP) improves such alterations in OSAS patients by eliminating apneic events.
Methods and Results— In this prospective, randomized, placebo-controlled, double-blind crossover study, 27 consecutive newly diagnosed middle-aged OSAS men with neither controllable factors nor conditions affecting left ventricular diastolic function and 15 healthy control subjects were selected. OSAS patients were randomized to 12 weeks on sham nCPAP and 12 weeks on effective nCPAP application. Echocardiographic parameters, blood pressure recordings, and urinary catecholamine levels were obtained at baseline and after both treatment modalities. At baseline, an abnormal left ventricular filling pattern was present in 15 of the 27 OSAS patients and only in 3 of the 15 control subjects (P=0.020). Impaired relaxation was by far the most common abnormal pattern in both groups (11 and 3 patients, respectively). In OSAS patients, 12 weeks on effective nCPAP induced a significant increase in E/A ratio (P<0.01), as well as reductions in mitral deceleration (P<0.01) and isovolumic relaxation (P<0.05) times.
Conclusions— OSAS can affect left ventricular diastolic function independently of other possible factors. Chronic application of nCPAP could avoid the progression of diastolic abnormalities, and indeed, it might reverse these alterations, at least in the initial stages before severe structural changes can be developed.
Key Words: physiology ; echocardiography ; diastole ; pulmonary heart disease ; sleep
Introduction
Obstructive sleep apnea syndrome (OSAS) is characterized by periodic reduction or cessation of breathing due to narrowing of the upper airways during sleep. Prevalence surveys estimate that 2% of women and 4% of men of middle age are affected by this syndrome.1 Cardiovascular disturbances are the most important complications, producing severe morbidity and mortality.2 However, many risk factors for OSAS, including male gender, advanced age, and obesity, are the same for cardiovascular disease, which makes it difficult to recognize the role of OSAS as an independent risk factor. At the present time, only the association with systemic hypertension has been well established.3,4
Heart failure is a major public health problem in developed countries. Approximately half of patients with heart failure have preserved left ventricular systolic function, with high morbidity and mortality rates and with major socioeconomic implications derived from their management.5 The majority of patients who present with heart failure and normal systolic function do not have a defined myocardial disease, but it has been demonstrated that they have abnormalities in active relaxation and passive stiffness.6 That is, they have alterations in mechanical function during diastole that lead to the development of diastolic heart failure. Hypertension, diabetes mellitus, left ventricular hypertrophy, and myocardial ischemia are frequently associated with diastolic dysfunction.
The link between OSAS, left ventricular dysfunction, and congestive heart failure is less known, although OSAS is frequent in both systolic and diastolic heart failure patients.7,8 Proposed mechanisms that affect left ventricular performance in patients with OSAS include several mechanical, neurohumoral, inflammatory, endothelial, and oxidative effects.9
There are few data about the possible role of OSAS as an independent cause of left ventricular diastolic dysfunction in otherwise healthy patients. The goals of the present study were (1) to evaluate the frequency of abnormalities in diastolic left ventricular filling in middle-aged adult men with OSAS and no other controllable factors affecting diastolic function and (2) to test the hypothesis that nasal continuous positive airway pressure (nCPAP) therapy, the standard treatment for OSAS,10 might reverse these abnormalities.
Methods
Subjects
Twenty-seven consecutive newly diagnosed OSAS men without previous treatment for OSAS and 15 healthy men were selected. OSAS patients fulfilled the following inclusion criteria: (1) apnea-hypopnea index (AHI) 10 h–1 and excessive daytime sleepiness (Epworth sleepiness scale 10 points)11; and (2) no current drug or mechanical treatment for OSAS. Inclusion criteria for healthy control subjects were AHI <5 h–1 and Epworth sleepiness scale <10. Exclusion criteria for both study groups were as follows: (1) unwillingness or inability to perform the testing procedure; (2) obstructive or restrictive lung disease demonstrated on pulmonary function testing; (3) current use of cardioactive drugs; (4) cardiac rhythm disturbances, including sinus bradycardia and sinus tachycardia; (5) known hypertension, or 24-hour mean blood pressure of 135 and/or 85 mm Hg or more; (6) left ventricular ejection fraction <50%; ischemic or valvular heart disease; hypertrophic, restrictive, or infiltrative cardiomyopathy; pericardial disease or stroke by history or physical examination, ECG, chest radiography, conventional stress testing, and echocardiography; (7) diabetes mellitus, by history or 2 random blood glucose levels 126 mg/dL; (8) morbid obesity (body mass index >40 kg/m2); (9) daytime hypoxemia (PaO2 <70 mm Hg) or hypercapnia (PaCO2 >45 mm Hg). Withdrawal criteria were (1) clinical exacerbation that led to a change in medication, (2) hospital admission for 10 or more days, and (3) average nightly nCPAP usage <3.5 hours.
The study was approved by the Institutional Ethics Committee at the hospital. All subjects gave their written informed consent.
We performed a single-center, prospective, randomized, double-blind, placebo-controlled and crossover clinical trial, in which OSAS patients received effective nCPAP and placebo (sham nCPAP)12 for two 12-week periods (Figure 1). The sham nCPAP device consists of a conventional nCPAP device in which the area of the exhalation port is amplified, thereby nearly cancelling nasal pressure, and an orifice resistor is connected between the tubing and the nCPAP unit that loads the blower with the same airflow resistance as in effective nCPAP. All OSAS patients underwent a full-night nCPAP titration study with an automated pressure setting device (Auto Set; ResMed).13 Patients were given detailed instructions on using nCPAP equipment, but they were not informed of the type of therapy they were receiving. Compliance data were measured with a run-time counter.
All subjects underwent baseline sleep study, 24-hour ambulatory blood pressure monitoring (ABPM), and an echocardiogram. Urine specimens and demographic data were also collected. Patients were randomized to receive either effective or sham nCPAP therapy for 12 weeks. Then, they were readmitted to the hospital, and the nCPAP device was switched to the alternate mode of therapy for another 12 weeks. Echocardiogram and ABPM were repeated just after each period with either effective or sham nCPAP treatment. Urine specimens were obtained at the same time at each visit.
Sleep Study
During the same night when urine specimens were collected, a sleep study was performed in OSAS patients and healthy control subjects. We used a previously validated portable respiratory recording device (Sibel Home-300; Sibel S.A.)14 that records oronasal airflow using a thermistor, chest wall impedance, oxygen saturation, snoring, and body position.
Respiratory events were classified as either obstructive or central on the basis of presence or absence of respiratory effort. Respiratory events were scored as apnea when there was a cessation of oronasal airflow that lasted 10 seconds. Hypopnea was defined as a decrease of 50% in oronasal airflow that lasted >10 seconds, associated with a fall in arterial oxygen saturation (SaO2) >4% of the preceding baseline level. Mean nighttime SaO2, minimum SaO2 (lowest values recorded during sleep), desaturation index, and percentage of time with SaO2 <90% on nocturnal oximetry were computed as indexes of nocturnal oxygen saturation.
Twenty-Four–Hour ABPM
Twenty-four–hour ABPM was performed on each patient with a SpaceLabs device (model 90207) by an oscillometric method.15 Blood pressure was measured every 30 minutes during the day (8 AM to 11 PM) and every 60 minutes during the night (11 PM to 8 AM) on a workday. An appropriate cuff was used and placed on the nondominant arm. Patients were instructed not to move their arm during the ongoing measurement, and during the recordings, the subjects were asked to perform their ordinary daily activities and to go to bed no later than 11 PM.
Catecholamines in Urine
Urinary excretion of norepinephrine and epinephrine were determined as described previously.16 A 5-mL aliquot of a urine sample was filtered; 3,4-dihydroxybenzylamine (internal standard) and 0.1% EDTA were added to the filtrate, adjusted to pH 6.5, and subsequently placed on a Biorex 70 cation exchange column (Bio-Rad). After the sample completely entered into the resin, the column was washed with distilled water, and the catecholamines were eluted with 10 mL of 0.65 mol/L boric acid. After this procedure, 20 μL of the effluent was injected into an HPLC system composed of an HPLC pump (model 510, Waters), rheodyne injection valve (20 μL), ESA HR-80,RP-C18 chromatographic column (ESA Inc), and ESA coulometric detector (Coulochem II model), model 5011 high-sensitivity analytical cell, and model 5021 conditioning cell. Concentrations of detected compounds were calculated on a PC with 712 HPLC system controller version 1.2 (Gilson) integration software, which measures the heights of the peaks and relates them to external standards.
Intra-assay coefficients of variation were 3% for norepinephrine and 3% for epinephrine. Interassay coefficients of variation were 9% for norepinephrine and 10.5% for epinephrine. Results were expressed in terms of micrograms per gram of creatinine.
Echocardiography
Examinations were performed with patients in the supine and left-lateral positions after a minimum rest period of 30 minutes with a high-quality echocardiograph with 2.0- to 4.0-MHz probes (Hewlett Packard Sonos 5500). Echocardiographic images were obtained in the parasternal long- and short-axis, apical 2- and 4-chamber, and subcostal views with 2D, M-mode, and Doppler echocardiographic techniques. The parameters were measured from at least 3 cardiac cycles. All echocardiograms were performed by the same experienced echocardiographer, who was unaware of both the subject’s group and the patient’s treatment assignment at each visit.
Left ventricular internal end-diastolic and end-systolic dimensions, as well as posterior wall (PW) and interventricular septum thicknesses, were determined in accordance with the American Society of Echocardiography recommendations.17 Systolic function was assessed by left ventricular shortening fraction (LVSF) and left ventricular ejection fraction (LVEF).18 Left atrial end-systolic dimension was also obtained with the parasternal long or short axes. Left ventricular mass (LVM) was calculated with an anatomically validated formula,19 and LVM index was obtained from LVM corrected for body surface area. LVSF 28% and LVEF 50% were considered normal.
Left ventricular diastolic function was assessed with both 2D and Doppler echocardiography in accordance with the American Society of Echocardiography recommendations.20 The mitral inflow pattern was recorded with the sample volume between the leaflet tips by the pulsed-wave Doppler technique. The following variables were measured: peak flow velocity in early diastole (E wave), peak velocity at atrial contraction (A wave), isovolumic relaxation time (IVRT), mitral deceleration time (DT), and mitral A-wave duration. To obtain pulmonary venous flow, an apical 4-chamber view was used, and pulsed-wave Doppler sample volume was placed 1 to 2 cm into the right upper pulmonary vein. Peak systolic velocity (S wave), peak diastolic velocity (D wave), and the duration of reverse flow at atrial contraction (AR) were measured. Left ventricular filling patterns were classified as normal, impaired relaxation, pseudonormal, and restrictive by a modification of the approach of Appleton et al.21 Normal pattern was defined by E/A ratio >1, normal DT (160 to 240 ms) and IVRT (70 to 110 ms), and S/D and A/AR duration ratios >1. Impaired relaxation was determined by E/A ratio <1, prolonged DT (>240 ms) and IVRT (>110 ms), and S/D and A/AR duration ratios >1. Pseudonormal pattern was identified by E/A ratio ranging from 1 to 1.5, normal DT and IVRT, and S/D and A/AR duration ratios <1. Finally, restrictive pattern was defined by E/A ratio >1, short DT (<160 ms) and IVRT (<70 ms), and S/D and A/AR duration ratios <1.
Statistical Analysis
Values are expressed as mean±SD or percentage. The comparisons between patients groups were performed by means of the Mann-Whitney U statistic, whereas the 2 test was used to compare proportions. Relationships between variables were determined by Pearson correlation analysis and by stepwise multiple regression. A multiple logistic regression analysis was performed to identify the factors that determined abnormal diastolic function. Comparisons on effects of the treatments over time were made with repeated-measures ANOVA with treatment as a within-subject factor and order as a between-subject factor. When ANOVA results showed significant differences between treatment conditions, post hoc multiple comparisons were performed with the Bonferroni test. Statistical calculations were performed with SPSS version 10.0 (SPSS Inc). A value of P<0.05 was considered statistically significant.
Results
Characteristics of the Subjects
Baseline Left Ventricular Filling Patterns and Ventricular Structure
At baseline, an abnormal left ventricular pattern was present in 15 (56%) of the 27 OSAS patients and only in 3 (20%) of the 15 healthy control subjects (P=0.020). Impaired relaxation was by far the most common abnormal pattern in both groups, whereas a pseudonormal pattern was present only in 3 patients with OSAS (Figure 2). OSAS patients had significantly longer IVRT and DT and lower E/A ratio. There were no significant differences in left atrial size, E wave, and A wave between the 2 groups. Although the values were normal, OSAS patients had higher values of PW and interventricular septum thickness, LVM, and LVM index (Table 2).
In OSAS patients, relationships between diastolic echocardiographic parameters and demographic data, blood pressure recordings, urinary catecholamines, and sleep parameters were analyzed. The study showed a significant correlation between age and A wave (r=0.424, P<0.05), E/A ratio (r=–0.590, P<0.001), DT (r=0.653, P<0.01), and IVRT (r=0.439, P<0.05). There was also a positive correlation between PW thickness and IVRT (r=0.537, P<0.01) and between LVM index and both IVRT (r=0.478, P<0.05) and DT (r=0.438, P<0.05). We analyzed separately OSAS patients with normal filling pattern (n=12) and those with impaired relaxation (n=11) at baseline to facilitate the exploratory analysis of diastolic echocardiographic parameters (Table 3). Patients with impaired relaxation were of more advanced ages, having higher AHIs than those with normal pattern. Moreover, PW thickness, LV mass, and LV mass index were higher in OSAS patients with impaired relaxation. Of the independent variables included in the logistic regression model (age, AHI, PW thickness, LV mass, and LV mass index), diastolic dysfunction was only predicted by AHI (area under the receiver operating characteristic curve=0.812, standard error=0.086).
Effects of nCPAP
Two patients, 1 with normal left ventricular pattern and the other with a pseudonormal pattern, failed to complete the trial because of an average nightly usage of nCPAP of <3.5 hours. There were no significant differences in sleep study findings, baseline demographic characteristics, smoking habit, lung function data, sympathetic tone, or ABPM between the patients who withdrew and those who completed the trial.
Complete measurements were available in 25 patients who went home on effective nCPAP for an average of 104±31 days and on sham nCPAP for 98±22 days. Mean nCPAP pressure was 10±2 cm H2O, and the average nightly usage was similar on effective nCPAP and sham nCPAP (6±1 versus 6±2 hours, respectively).
There were no differences in heart rate, weight, blood pressure recordings, or urinary catecholamines at baseline and after sham or effective nCPAP in OSAS patients (Table 4). After 12 weeks on effective nCPAP, left ventricular filling patterns were not modified, but a significant increase in E/A ratio and reduction in DT and IVRT values were induced (Table 5; Figure 3). These changes were mainly produced in OSAS patients with impaired relaxation, although DT was the only variable that reached statistical significance (Table 3). After both modes of treatment, no significant differences were observed in either systolic function or ventricular structure parameters.
Discussion
The main findings of this study are that abnormalities in diastolic function, substantially related to repetitive obstructive apneic events during sleep, are very common in OSAS patients and that these alterations could be reversible, at least in part, with nCPAP therapy. Previous studies had reported contradicting data about the relationship between OSAS and left ventricular diastolic function.22–29 The effects of cardioactive drugs, hypertension, or other possible diseases that affect diastolic function could affect the results in some of them.23–26,28,29 Indeed, incomplete assessment of diastolic function by echocardiography, lack of quantification of heart rate at the time of the echocardiographic studies,22–29 and absence of a control group of subjects24,25,27,28 limits the information derived from these studies. To the best of our knowledge, there are no placebo-controlled studies to assess the effects of nCPAP on left ventricular diastolic function in OSAS and otherwise healthy patients.
In the present study, we tried to eliminate the confounding effects of other disease states or pharmacological interventions on diastolic function. All of the OSAS patients in the present study were free of other diseases and were receiving no medication, either before or during the study period. The presence of a control group of patients with no significant differences in demographic data with respect to the OSAS patients and the response to a placebo-controlled therapeutic intervention such as nCPAP support the causal role of OSAS to explain our results.
The mechanisms underlying diastolic dysfunction in OSAS patients are not well known. Elevations in nocturnal blood pressure and sympathetic nervous system activity30 in OSAS subjects create ventricular pressure overload.31 It could be speculated that, as occurs in other processes such as chronic hypertension and aortic stenosis, increased pressure overload at the cellular level would mainly result in decreased levels of sarcoplasmic reticulum calcium ATPase pump and increased phospholamban.32 It slows the removal of calcium from the cytosol, which leads to impaired ventricular relaxation. In experimental studies, it has been demonstrated that ventricular pressure overload on its own impairs myocardial relaxation.33 On the other hand, pressure overload causes activation of multiple cellular signals that create myocardial tissue hypertrophy and interstitial fibrosis that increases passive stiffness.34 Indeed, an impaired coronary flow reserve would cause silent ischemia, worsening ventricular active relaxation when left ventricular diastolic pressure begins to rise.
Another plausible mechanism to explain the presence of diastolic dysfunction and the effects of nCPAP therapy on diastolic function in this patient population is related to futile inspiratory efforts.31 This results in exaggerated negative intrathoracic pressure, which leads to an increase in left ventricular transmural pressure and hence afterload without increasing blood pressure. Another consequence of the increased negative intrathoracic pressure is the leftward shift of the interventricular septum related to enhanced venous return and right ventricle dilatation. All of the aforementioned effects of enhanced negative intrathoracic pressure have been demonstrated to affect left ventricular filling.35,36
It is difficult to define how each of those mechanisms affects diastolic function in a single OSAS patient, because they would act in synergy. However, in the initial stages of the disease, we hypothesize that mechanical effects of obstructive events mainly create ventricular pressure overload, which by itself might lead to slowed ventricular relaxation. As the disease progresses, ventricular structural abnormalities such as remodeling, alterations in collagen structure, and muscle hypertrophy37,38 can develop, which would worsen alterations in normal left ventricular filling.34 In this sense, it is important to observe that the OSAS patients with impaired relaxation in the present study had higher values of LV mass, PW, and interventricular septum thickness than patients with a normal pattern, although in both groups, values were within normal limits. Indeed, LVM index showed a positive correlation with DT and IVRT, and PW thickness showed a positive correlation with IVRT; both of these results support the idea that these structural changes probably contribute to the diastolic abnormalities observed in the patients in the present study. This, along with the short duration of treatment, could explain the only partial reversal of such alterations despite the elimination of apneic events after nCPAP.
The higher mean age of patients with impaired relaxation compared with patients with normal pattern (49±12 versus 61±5 years) could also be responsible in part for the differences observed in diastolic parameters. However, an attenuation of changes caused only by aging with nCPAP therapy would be an unexpected finding.
Partial reversal of left ventricular diastolic function abnormalities after nCPAP treatment in our thoroughly selected OSAS patients supports the pathogenic relationship between diastolic dysfunction and OSAS. Changes in echocardiographic diastolic parameters after nCPAP therapy have been reported in several non–placebo-controlled studies, some with different patient selection criteria.22,24,27 Effects of nCPAP on diastolic dysfunction might be related to diminished sympathetic activation39 and left ventricular afterload40 and be related to elimination of exaggerated negative intrathoracic pressure as a result of the abolition of apneic events. In OSAS patients in the present study, these effects would result in diminished ventricular pressure overload, probably being responsible for changes observed in diastolic parameters.33 However, significant changes in urinary excretion of catecholamines and blood pressure levels were not obtained after nCPAP therapy in the present study. That could be because urinary excretion of norepinephrine and epinephrine and ABPM lack sensitivity to detect the elimination of surges in blood pressure and nocturnal sympathetic nerve traffic drive in OSAS patients receiving nCPAP. In spite of the evident acute effects on blood pressure surges with nCPAP, a continued reduction in either nocturnal or diurnal blood pressure may be apparent only in hypertensive OSAS patients and not in normotensive patients, probably in relation to the pressor effect of decreased levels of atrial natriuretic peptide induced by nCPAP application despite the reduction in sympathetic drive.41
The results of the present study do not allow us to determine whether longer therapy with nCPAP might result in a more significant reversal of diastolic abnormalities in OSAS patients. This could be possible, especially in OSAS patients with left ventricular hypertrophy, in view of the information reported by Cloward et al37 with regression of ventricular hypertrophy after a minimum of 6 months with nCPAP. In patients with ventricular hypertrophy, regression of hypertrophy is accompanied by a reversal of diastolic dysfunction.42 However, no changes in ventricular structure were observed after 12 weeks on nCPAP therapy in OSAS patients without ventricular hypertrophy in the present study.
The absence of changes in body weight, resting heart rate, and blood pressure before and after treatment with nCPAP discounts the possible influence of such factors contributing to attenuation of diastolic dysfunction observed after nCPAP therapy. These findings are concordant with data published by Narkiewicz et al,39 who reported a decrease in muscle sympathetic traffic without changes in heart rate and blood pressure in normotensive and otherwise healthy OSAS patients after treatment with nCPAP. By contrast, in a prospective, placebo-controlled study, Becker et al43 demonstrated a significant reduction in daytime and nocturnal blood pressure with long-term nCPAP treatment, although 21 of 32 OSAS patients were hypertensive.
Our study has several limitations, the main one being the limited number of patients studied. The process of including only middle-aged patients with newly diagnosed OSAS, having no other diseases and taking no cardioactive medication, to achieve the purpose of the present study was very arduous. Indeed, we are not able to predict in which patients diastolic abnormalities can develop, nor the time necessary to affect left ventricular filling once obstructive respiratory events have begun to occur. It is possible that the duration and severity of OSAS, along with individual genetically predisposed factors, determine this fact. Another limitation is the possible clinical significance of diastolic abnormalities in asymptomatic patients assessed by conventional echocardiographic parameters. In this regard, there is information about the importance of not only having impaired left ventricular relaxation determined by standard Doppler parameters but also of an elevated left ventricular filling pressure as a predictor of reduced exercise tolerance.44 However, the purpose of the present study was only to demonstrate that OSAS can affect left ventricular diastolic function and how nCPAP application can modify diastolic left ventricular filling. Doppler indexes of transmitral and pulmonary venous flow have been shown to correlate well with left ventricular filling pressures, especially in patients with systolic dysfunction45; however, the correlation has been poorer in patients with normal systolic function. It is generally considered that tissue Doppler echocardiography and color M-mode Doppler may be more useful in assessing left ventricular diastolic dysfunction and filling pressures in patients with normal left ventricular systolic function.45 Therefore, further studies are required to assess the impact of these echocardiographic variables on the diagnosis of diastolic dysfunction in OSAS patients.
To the best of our knowledge, this is the first prospective, randomized, placebo-controlled, crossover study to evaluate the consequences of OSAS on diastolic left ventricular filling and to assess the response of diastolic function to nCPAP therapy. In conclusion, left ventricular impaired relaxation is frequently observed in OSAS patients, which suggests that it may be an early response to cardiac overload caused by this disease independently of other possible factors. Chronic application of nCPAP could avoid the progression of diastolic abnormalities, and indeed, it might reverse these alterations, at least in the initial stages before severe ventricular structural changes develop.
Acknowledgments
This research was supported in part by a grant from the Fondo de Investigación Sanitaria (exp. 01/0278). The authors thank Dr José M. Oliver for his critical review of the manuscript.
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