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* From the Third Department of Internal Medicine (Drs. Okuda, Ito, Suwa, Hayashi, and Kitaura) and Department of Neuropsychiatry (Drs. Emura and Yoneda), Osaka Medical College, Takatsuki, Japan.
Correspondence to: Takahide Ito, MD, PhD, Third Department of Internal Medicine, Osaka Medical College, 2–7, Daigaku-cho, Takatsuki City, Osaka, 569-8686, Japan; e-mail: in3016{at}poh.osaka-med.ac.jp
Abstract
Background: Hypoxia has been suggested to affect myocardial contractile function in patients with obstructive sleep apnea (OSA). We sought to determine whether myocardial contractile reserve (MCR), as evaluated by echocardiographic tissue Doppler imaging with dobutamine stress (TDDS), might be depressed in OSA patients.
Methods: Thirty patients with suspected OSA (25 men and 5 women; mean age, 51 ± 11 years [± SD]) underwent overnight polysomnography and TDDS. Peak myocardial systolic velocity (Sm) and peak myocardial early diastolic velocity (Em) in the 12 myocardial segments of the left ventricular (LV) walls were averaged, and the mean Sm and Em during TDDS were compared between patients with apnea-hypopnea index (AHI) <15/h (group 1, n = 13) and those with AHI 
15/h (group 2, n = 17). MCR was calculated as the difference between the resting and peak Sm during TDDS.
Results: In both groups, Sm increased dose dependently during TDDS. However, the relative increase in Sm was significantly lower in group 2, resulting in a lower value of MCR (5.5 ± 1.2 cm/s vs 7.4 ± 1.3 cm/s, p < 0.001). The Em was lower in group 2 compared with group 1 throughout TDDS. MCR was correlated significantly with AHI (r = – 0.67, p < 0.0001), resting Em (r = 0.53, p < 0.005), and body mass index (r = – 0.46, p < 0.05) independent of the LV mass index.
Conclusions: OSA can affect MCR, implying an etiologic contribution from repetitive hypoxic events. TDDS could identify subtle abnormalities of OSA-related cardiac involvement.
Key Words: contractile reserve • Doppler ultrasound • obstructive sleep apnea • stress echocardiography
Obstructive sleep apnea (OSA) is a common medical condition that occurs in 5 to 15% of the population.1 The pathophysiology of OSA is characterized by periodic apnea or hypopnea due to narrowing of the upper airways during sleep. Substantial evidence has shown that OSA is associated with coronary heart disease, heart failure, and cardiac arrhythmias. Abnormal breathing events during sleep have been shown to cause hypoxia, sympathetic activation, and pulmonary and systemic hypertension.2345 The exact mechanisms by which OSA causes heart failure are unknown, although increased ventricular afterload during sleep may increase myocardial oxygen demand and ultimately lead to left ventricular (LV) dysfunction. Multiple episodes of hypoxia also have deleterious effects on ventricular performance. In experimental studies,678910 hypoxia has been suggested to impair myocardial contractility. With hypoxia, for instance, oxidative stress is increased and antioxidant activity is decreased, which may result in myocardial damage sufficient to cause myocardial dysfunction.6 Taken together, it might be expected that the myocardial response to stress would be abnormal in OSA patients, especially those who have frequent hypoxic events.
Studies111213 have shown that the impairment of LV diastolic function is common in OSA patients, suggesting subclinical myocardial disease that may account for the risk of heart failure. The detection of subclinical myocardial changes, however, is difficult with techniques that merely evaluate global systolic and diastolic functions. Tissue Doppler (TD) imaging has been shown to provide more sensitive indexes of systolic and diastolic function than conventional Doppler echocardiography.141516 When this new method is used in combination with dobutamine stress echocardiography,1718 one can more precisely identify abnormal myocardial response to stress. Therefore, we attempted to apply TD imaging with dobutamine stress (TDDS) to determine whether myocardial contractile reserve (MCR) might be depressed in OSA patients.
Materials and Methods
Study Subjects
The study subjects, who had presented with daytime sleepiness and/or loud snoring, were recruited from the sleep laboratory of the Department of Neuropsychiatry at Osaka Medical College. All the subjects underwent routine overnight polysomnography, and those who agreed to undergo TDDS were enrolled in this study. Exclusion criteria were the following: age 65 years, atrial fibrillation, LV systolic dysfunction (ejection fraction < 50%), valvular heart disease, cardiomyopathy, pericardial disease, or coronary artery disease (those who had angina pectoris, or ischemic ST-T changes on their ECGs, or both). The study was approved by the Institutional Ethics Committee, and all subjects gave their written informed consent at enrollment.
Sleep Study
Overnight polysomnography was performed in the sleep laboratory using standard recording techniques (Neurofax EEG-1518; NihonKohden; Tokyo, Japan) and Polysmith software (Neurotronics; Gainesville, FL). Surface electrodes were applied to perform EEG, chin electromyography, ECG, and electro-oculography. Sleep was defined according to the criteria of Rechtschaffen and Kales.19 Airflow was monitored using an air pressure sensor placed at the nose and mouth, while arterial oxygen saturation (SaO2) was recorded continuously with a pulse oximeter. An apnea event was defined as cessation of inspiratory airflow for > 10 s. All such events were counted irrespective of the degree of desaturation or the presence of arousal. The type of apnea was defined by the analysis of thoracoabdominal movements, which were recorded by respiratory inductive plethysmography using a mercury strain gauge. An obstructive apnea event was defined as the absence of airflow in the presence of rib cage and/or abdominal excursions. A central apnea event was defined as the absence of rib cage and abdominal excursions with absence of airflow. The apnea-hypopnea index (AHI) was defined as the number of apnea and hypopnea events per hour of sleep.
Standard Echocardiography
Within 48 h after polysomnography, standard echocardiography and TDDS were performed using a commercially available echocardiographic apparatus with a 2.5-MHz transducer (Vivid 7; GE-Vingmed Ultrasound; Horten, Norway). According to the criteria of the American Society of Echocardiography,20 M-mode parameters of LV dimensions, wall thickness, and LV mass index were calculated. Changes in LV volumes and ejection fraction were assessed by the modified Simpson method. Conventional Doppler echocardiography was used to assess the parameters of LV diastolic function, including the early and atrial filling velocities at the mitral valve and their ratio (E/A), the deceleration time (DT) of the E wave, and the isovolumic relaxation time (IVRT).
TDDS
TD images were acquired in the apical two-chamber and four-chamber, and long-axis views to assess long-axis myocardial systolic and diastolic function. Gain settings, filters, and pulse repetition frequency were adjusted to optimize color saturation, and sector size and depth were optimized for the highest possible frame rate (> 130 frames per second). The imaging angle was adjusted to ensure a parallel alignment of the beam with the myocardial segment of interest. At least three consecutive beats of TD images were saved for postprocessing. After recording resting TD images, dobutamine stress echocardiography was performed using a standard 3-min incremental protocol. Dobutamine was infused at a starting dose of 5 µg/kg/min for 5 min, and then at 10 µg/kg/min (low dose) for another 3 min, and then increased by 10 µg/kg/min every 3 min to a maximum dosage of 40 µg/kg/min (peak dose). Atropine, up to 2 mg, was added at the end of the last stage if the target heart rate (85% of age-predicted heart rate) had not been achieved. Twelve-lead ECG was monitored throughout, and BP was recorded at rest and at 3-min intervals during infusion and recovery. End points of the stress protocol were completion of the protocol, progressive or severe chest pain, serious ventricular arrhythmia, systolic BP > 240 mm Hg, symptomatic hypotension or systolic BP < 100 mm Hg, or intolerable side effects.
Image Analysis
TD images were recorded at each TDDS stage and were analyzed using the software program used in the echocardiography machine. At each stage, we obtained regional myocardial velocity curves from 12 myocardial segments of the LV walls, namely the basal and mid-septum, basal and mid-lateral wall, basal and mid-anterior wall, basal and mid-inferior wall, basal and mid-anteroseptal wall, and basal and mid-posterior wall. Peak myocardial systolic velocity (Sm) and peak myocardial early diastolic velocity (Em) were calculated from each of the 12 myocardial segments, and the individual values were averaged to give mean Sm and Em. The peak wave corresponding to isovolumic contraction was excluded from the analysis. In the present study, MCR was calculated as the difference between the resting and peak Sm during TDDS.
Study Groups
The subjects were classified into two groups according to AHI: patients with mild OSA (AHI < 15/h, group 1) and patients with moderate-to-severe OSA (AHI 15/h, group 2).21 Variables obtained were compared between the two groups.
Observer Variability
Both interobserver and intraobserver variability were assessed by linear regression with Bland-Altman analysis.22 Ten TD images (from five patients) were randomly selected, and 120 consecutive segments were analyzed for Sm and Em.
Statistical Analysis
All data are expressed as the mean ± SD. A Student unpaired t test and a Welch t test (does not assume equal variances) were used to compare clinical and echocardiographic variables, including MCR, between the two groups. Bonferroni multiple comparison tests were applied to assess changes in the Sm and Em during TDDS for each group. Single linear regression analysis was performed to examine the correlation between the two parameters. A p value < 0.05 was considered statistically significant.
Results
Clinical Characteristics
Thirty patients participated in the study. There were 25 men and 5 women (mean age, 51±11 years; range, 29 to 64 years). There were 13 subjects in group 1 (AHI range, 3.2 to 12.8/h) and 17 subjects in group 2 (AHI range, 18.0 to 44.6/h). Clinical characteristics of the study groups are listed in Table 1
. There were no significant differences between the groups with regard to age or gender distribution, although group 2 patients had a greater body mass index. The prevalence of the patients with hypertension, diabetes, and hyperlipedemia was similar, and the patients with hypertension had been treated satisfactorily with antihypertensive drugs such as calcium-channel blockers (n = 5) and angiotensin-II antagonists (n = 1). The plasma B-type natriuretic peptide concentration was comparable in the two groups.
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Discussion
The present study demonstrated that patients with moderate-to-severe OSA had less MCR compared with patients with less severe OSA. There were no differences between the groups in either resting global systolic or diastolic functional parameters, except LV mass index, of which MCR was not dependent. These findings indicate that limited MCR is related exclusively to repetitive hypoxic events during sleep. To the best of our knowledge, this is the first report to assess MCR in OSA patients.
Role of TDDS in Assessing Myocardial Function
Subclinical myocardial disease is common in patients with systemic and myocardial disorders such as hypertension, diabetes, and hypertrophic cardiomyopathy.232425 Although LV ejection fraction is usually preserved in these patients, there may be abnormal LV filling demonstrated by pulsed Doppler echocardiography, implying impaired LV relaxation and compliance. Parameters of the pulsed Doppler method, however, are dependent on multiple factors that interact, including age, heart rate, and loading conditions.26 Likewise, LV ejection fraction is definitely load dependent and may be influenced by compensatory hyperkinesia. In addition, detection of the endocardial border is difficult especially when the heart rate is markedly increased. In contrast, TD-derived parameters are less load dependent and sensitive to changes that cannot be identified by the conventional technique.141516 Moreover, TD signals are little affected by tissue interfaces between the region of interest and the transducer, which allows examining subjects with poor two-dimensional echocardiographic images. We used dobutamine stress to evaluate MCR,1718 which could most likely detect subtle abnormalities of cardiac function in subjects with apparently normal resting systolic function.
Potential Mechanisms
The relationship between hypoxia and myocardial contractility has been demonstrated in several experimental studies.678910 In a rat model of OSA, Chen et al6 observed that intermittent hypoxia increased myocardial oxidative stress and decreased antioxidant activity, in association with decreased indexes of LV systolic and diastolic function. The difference in LV afterload (BP) was so small in the model rats compared with control animals that they believed that this change in afterload was unlikely to have caused the large differences in LV function.6 The mechanisms for the production of oxidative stress by hypoxia are not well characterized, although repetitive myocardial reperfusion injury and adrenergic stimulation have been suggested to play roles.2728 During the chronic phase, moreover, reactive oxygen species participate in events leading to cardiac remodeling and fibrogenesis.27 Hypoxia was shown to activate anaerobic pathways in which intracellular ionic calcium decreased and inorganic phosphate increased, with a resultant decrease in myocardial contractility.89 Also, altered cardiac metabolic gene expression under hypoxic conditions could lead to the accumulation of anaerobic metabolites that impair myocardial contractility.10
An increase in sympathetic activity has been shown in OSA patients not only during apnea but also in the resting awake state.234 Therefore, reduced adrenorecepter sensitivity may also contribute to a blunted inotropic response to dobutamine. In fact, Otsuka et al29 demonstrated that cardiac sympathetic function, as shown by 123I-meta-iodobenzylguanadine imaging, was impaired in OSA patients. Repeated mechanical loading to the heart was suggested to reduce adrenorecepter responsiveness.30 Shan et al31 reported that the Em was shown to correlate with adrenorecepter density, evaluated by the fluorescent labeling method.31 In the present study, resting Em was decreased in group 2 patients compared with group 1 patients. The increased LV mass index in group 2 patients also indicates that there might be repeated short-term increases in sympathetic outflow and ventricular afterload caused by apneic attacks.
Diastolic Function
In the present study, global diastolic parameters were not clearly correlated with the severity of OSA, but the Em was. This is not surprising because the mitral E velocity is determined by both ventricular preload and relaxation,26 whereas the Em is determined directly by ventricular relaxation.16 Therefore, the Em could reveal even slight impairment of diastolic function. This finding also indicates that hypoxia may affect myocardial relaxation, consistent in part with previous observations.1213 Altered intracellular calcium transport caused by hypoxia has been suggested to prolong ventricular relaxation.32 Regional function is dependent not only on the number of normally functioning myocytes but also on the degree of myocardial integrity. Shan et al31 demonstrated that interstitial fibrosis was correlated inversely with the Em. During TDDS, the Em was persistently decreased in group 2 patients, which may reflect the status of the cardiac interstitium. We found that MCR was correlated with the resting Em, supporting the possible contribution of myocardial fibrosis to the depressed MCR.
Limitations
Sympathetic activity such as plasma and urinary noradrenaline concentrations, which might have provided a better explanation for the decreased responsiveness to the stress, was not assessed. The contribution of myocardial ischemia, including microvascular involvement, cannot be completely excluded, although the continuous increases in the Sm during TDDS make it unlikely that myocardial ischemia influenced the results. The reversibility of MCR should be demonstrated by introducing continuous positive nasal airway pressure, the standard treatment for OSA, although this therapy was reported to improve pulsed Doppler-derived parameters of diastolic function.13 Finally, the study population was relatively small. A larger number of subjects with a non-OSA control group would substantiate the contribution to the decreased MCR in OSA patients.
In conclusion, the severity of hypoxic events during sleep was associated with MCR. The relative decrease in diastolic function also contributed to the depressed contractile reserve, suggesting subclinical myocardial changes in OSA patients. Reversibility and prognostic significance of these changes require further study.
Acknowledgements
We express our thanks to Kunihisa Miwa, MD, from the Department of Cardiology, Hamamatsu Rosai Hospital, for valuable advice regarding the interpretation of the data.
Footnotes
Abbreviations: AHI = apnea-hypopnea index; DT = deceleration time; E/A = ratio of early and atrial filling velocities at the mitral valve; Em = peak myocardial early diastolic velocity; IVRT = isovolumic relaxation time; LV = left ventricular; MCR = myocardial contractile reserve; NS = not significant; OSA = obstructive sleep apnea; SaO2 = arterial oxygen saturation; Sm = peak myocardial systolic velocity; TD = tissue Doppler; TDDS = tissue Doppler imaging with dobutamine stress
The authors state that this article is not under consideration elsewhere, none of the contents of the article have been previously published, all authors have read and approved the article, and there are no conflicts of interest to disclose.
Received for publication October 10, 2006. Accepted for publication December 1, 2006.
References
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