Sleep Disorders Laboratory, Department of Veterans Affairs Medical Center, Divisions of Pulmonary and Critical Care Medicine, and Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
* Correspondence to: S. Javaheri, M.D., Professor Emeritus of Medicine, Pulmonary Section (111F), VA Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA. Tel: (513) 475-6395; fax: (513) 475-6399
E-mail address: Shahrokh.Javaheri{at}med.va.gov
Received 22 May 2003; revised 19 October 2003; accepted 30 October 2003
Abstract
Background Obesity, a major risk factor for obstructive sleep apnoea, is common after cardiac transplantation. Case reports have shown development of obstructive sleep apnoea in cardiac transplantation recipients. The present study represents the first systematic evaluation of sleep disorders after cardiac transplantation.
Objective To determine the prevalence and clinical impact of sleep disorders in a cohort of cardiac transplant recipients.
Methods This was a cross-sectional study at the Veterans Affairs Medical Center. Forty-five of 60 eligible subjects agreed to take part in the study. Polysomnography, sleep and health survey questionnaires, and laboratory tests were recorded.
Results Thirty-six percent had obstructive sleep apnoea-hypopnoea with an index of 15 or more per hour. The average apnoea-hypopnoea index was about 50±27 (SD) per hour. Sleep apnoea resulted in arterial oxyhaemoglobin desaturation, excessive arousals, unrefreshing sleep, excessive daytime sleepiness, poor health-related quality of life, and hypertension (all P values <0.05). Weight gain since transplantation was significantly greater in recipients with obstructive sleep apnoea than those without. Thirty-three percent of patients had periodic limb movement with an index of 15/hour and an average of 55±43/hour. Forty-five percent of these patients had restless legs syndrome.
Conclusion Thirty-six percent of cardiac transplant recipients have moderate to severe obstructive sleep apnoea. Sleep apnoea results in disrupted sleep, desaturation and impaired quality of life. Polysomnography should be routinely considered in the ongoing management of most cardiac transplant recipients. Treatment of obstructive sleep apnoea may improve quality of life and other outcomes of cardiac transplantation.
Key Words: Coronary allograft atherosclerosis Sleep apnea Restless legs syndrome Ejection fraction Hypertension
1. Introduction
Selected patients with end-stage heart failure undergo cardiac transplantation, which improves survival and quality of life.13Unfortunately, transplant recipients commonly gain weight, and obesity is prevalent.4Since obesity is the major risk factor for the development of obstructive sleep apnoea, a disorder characterized by repetitive episodes of complete (apnoea) or incomplete (hypopnoea) upper airway occlusion,5obese cardiac transplant recipients might be at risk for its development, as case report studies suggest.610
Disordered breathing events result in hypoxaemia, hypercapnia, and a host of neurohormonal abnormalities such as increased sympathetic activity,1114hypercoagulopathy,1521release of endothelin,22,23activation of white blood cells,24and increased concentration of adhesion molecules.25Obstructive sleep apnoea is a cause of systemic hypertension,26and may also cause stroke and heart failure,5,27and contribute to coronary artery disease and increased cardiovascular mortality.2830
If obstructive sleep apnoea occurs in cardiac transplant recipients, as case report studies suggest,610it may also shorten the survival of the transplanted heart. In this regard, after the first year, the main cause of mortality in cardiac transplant recipients is allograft atherosclerosis,31an inflammatory process32which, in the long run, could conceivably be accelerated by some of the aforementioned risk factors associated with obstructive sleep apnoea. Detection and treatment of obstructive sleep apnoea may therefore improve survival of cardiac transplant recipients. Thus, we designed this study to investigate the prevalence of sleep apnoea and its impact on sleep, cardiovascular parameters, and quality of life in cardiac transplant recipients.
2. Methods
The investigation conforms with the principles outlined in the Declaration of Helsinki. The protocol was approved by the Institutional Review Board at the University of Cincinnati. Each subject signed an informed consent.
This is a cross-sectional study of cardiac transplant recipients between 1995 and 1999. Subjects who were at least 5 months post-transplant were eligible. We chose a minimum of 5 months, since an initial evaluation showed maximum weight gain occurred at about 5 to 12 months after transplantation.
Subjects were recruited over the course of two years. Of the 60 eligible subjects, 45 (75%) agreed to participate. The reasons for refusal included unwillingness to stay in the hospital-based sleep laboratory or lack of interest.
All participants were followed by the transplantation team and were clinically stable on standard therapy for cardiac transplantation. One author (SJ) obtained detailed history including sleep-related symptoms and performed physical examination. Habitual snoring was defined as snoring that occurred almost every night or every night. Excessive daytime sleepiness was defined as the presence of at least one of the following: falling asleep unintentionally at least three times in a week, falling asleep while driving a car, or taking three naps in a week despite adequate sleep at night.33Arterial blood pressure was obtained, using a mercury sphygmomanometer (Standby® Model Baumanometer, W.A. Baum Co. Inc., Copiague, NY), and according to the recommendations of the American HeartAssociation.34Hypertension was defined by a systolic blood pressure of 140mmHg or higher or diastolic blood pressure of 90mmHg or higher. A calibrated scale (Detecto, Webb City, MO, USA) was used to determine the body weight of all subjects. Spirometric pulmonary function tests and radionuclide left and right ventricular ejection fractions were obtained as described elsewhere.33,3537A venous blood sample was obtained for complete blood count, renal and thyroid tests.
Polysomnography was performed as detailed previously.33,3537We recorded electroencephalograms, submental and anterior tibialis muscle electromyogram and electro-oculogram. Thoraco-abdominal excursions and naso-oral airflow (by a thermocouple) were measured qualitatively. Arterial blood oxyhaemoglobin saturation was recorded using an oximeter. The variables were recorded on paper by a multichannel polygraph (Model 78D; Grass Instrument Company, Quincy, MA). Polysomnograms were pooled and scored blindly by one author (SJ), without knowledge of history and physical findings.
Definitions of various sleep-related breathing disorders have been detailed previously.33,3537Apnoea was defined as cessation of inspiratory airflow for 10s or more. Obstructive apnoea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. Central apnoea was defined as the absence of rib cage and abdominal excursions and absence of airflow.33,3537Hypopnoea was defined as a reduction of airflow or thoraco-abdominal excursions lasting 10s or more associated with a decrease of 4% or more in arterial oxyhaemoglobin saturation or an arousal.38We classified hypopnoea as obstructive if paradoxical thoracoabdominal excursions occurred or if the airflow decreased out of proportion to the reduction in the thoracoabdominal excursion. The apnoeahypopnoea index was the number of episodes of apnoea and hypopnoea per hour. Similarly, the number of arousals per hour is referred to as arousal index. Periodic limb movements were quantitated using standard definition39and the number of periodic limb movements per hour of sleep is referred to as periodic limb movements index. Restless legs syndrome was defined according to The International RLS Study Group Criteria.40
To assess health-related quality of life, subjects completed Short-Form Health Survey (SF-36) questionnaire.41
2.1. Statistical analysis
For the purpose of this study, subjects with either an apnoeahypopnoea index or periodic limb movements index of 15 per hour were considered to have a sleep disorder. Subjects were classified into Group I (n=15) without a clinically significant sleep disorder, Group II with periodic limb movements (n=14), and Group III with obstructive sleep apnoea (n=16). Two subjects who had both periodic limb movements and obstructive sleep apnoea were included in Group III, only. For data which were normally distributed, we used one-way ANOVA with Tukey multiple comparison tests. KruskalWallis test with Dunn's multiple comparison test were used for data which were not normally distributed. The three groups were compared if overall F value was significant (P<0.05). Dichotomous variables were analysed using Chi-squared methods. Spearman and Pearson tests were used to determine correlations among some relevant variables. A probability of P<0.05 was considered significant. Mean values±SD are reported.
2.2. Role of the funding source
The American Heart Association provided funding; however, AHA did not have a role in study design, collection, analysis, or interpretation of data, writing of the report, or the decision to submit the paper for publication.
3. Results
Five female and 40 male subjects participated in the study. Four female and 10 male subjects refused to participate.
At the time of the study, there were no significant differences in body weight (92±15kg vs 92±19kg) between participants and those who refused participation. However, subjects who participated in the study were older than those who refused (57±11 years vs 49±10 years, P=0.006).
At the time of the study, the dose of prednisone varied from 5 to 10mg daily. All subjects (except one) were receiving cyclosporine, commonly along with other antirejection medications. Other medications included furosemide and a vasodilator, most commonly an angiotensin converting enzyme inhibitor. The dose and the frequency used were similar among the three groups (data not shown). Five subjects were on an antidepressant, two in Groups I and III, and three in Group II.
Distribution of apnoeahypopnoea index (AHI) stratified by 5 to 10 unit intervals is shown in Fig. 1. Thirty-six percent of cardiac transplant recipients (Group III) had an AHI of 15 per hour, with an average of 50 per hour. The AHI ranged from 23 to 94 per hour. Thirty-three percent of patients had an AHI and PLMI of <15/hour (Group I). Thirty-one percent of cardiac transplant recipients (Group II) had periodic limb movements
15 per hour, with an average of 55 per hour. The PLMI ranged from 16 to 142 per hour.Obstructive apnoeas and hypopnoeas accounted for most of the breathing disorders resulting in significant arterial oxyhaemoglobin desaturation and excessive arousals (Table 1). Furthermore, the percent of total sleep time spent in rapid-eye-movement sleep was significantly lower in Group III (14±7%) than Group I (22±7%) (P=0.008) (Table 2).
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Of the 14 cardiac transplant patients who had periodic limb movement, 45% suffered from restless legs syndrome (Fig. 2).
The mean values of haemoglobin, haematocrit, white blood count, platelet count, blood urea nitrogen, serum creatinine, electrolytes, and thyroid stimulating hormone, and spirometric pulmonary function tests did not differ significantly among the three groups (data not shown).
4. Discussion
The results of this cross-sectional study show that two disorders of sleep are common in heart transplant recipients. Importantly, neither the subjects nor their physicians were aware of the presence of the underlying sleep disorders, despite the demonstrated adverse effects that these disorders exerted.
4.1. Obstructive sleep apnoea
Moderate to severe obstructive sleep apnoea was highly prevalent. Thirty-six percent had an apnoeahypopnoea index of 15 or more per hour and the average index was 50 per hour. These episodes resulted in significantarterial oxyhaemoglobin desaturation and disrupted sleep. As a result, subjects woke up unrefreshed and felt sleepy during daytime.
We found that about 90% of cardiac transplant recipients with obstructive sleep apnoea had hypertension, and the mean values for both systolic and diastolic blood pressures were significantly higher. The results are consistent with those of a prospective study demonstrating obstructive sleep apnoea as a cause of hypertension.26Hypertension could have also been due to use ofcyclosporine42and prednisone, or under-utilization of vasodilators. However, all subjects were followed by the same transplant team, and there were no significant differences in the use or doses of various medications among the three groups.
In regard to other potential cardiovascular complications of obstructive sleep apnoea, one subject with the most severe obstructive sleep apnoea, had severe left ventricular systolic dysfunction (ejection fraction of 29%) of the transplanted heart. A previous case of right ventricular failure has been reported in a cardiac transplant recipient who developed obstructive sleep apnoea.6In the present study, however, we did not observe cor pulmonale.
Several studies2830have suggested that untreated obstructive sleep apnoea is a cause of cardiovascular mortality. Notably, the main cause of death after the first year of cardiac transplantation is coronary allograft vasculopathy, and we speculate that obstructive sleep apnoea might contribute to this atherosclerotic process. Potential mechanisms include hypoxia-induced activation of certain transcription factors, deleterious neurohormones and abnormal endothelium-dependent vasodilatation, growth, and apoptosis, leukocyte activation and hypercoagulopathy.11,12,24,4351
Fortunately, obstructive sleep apnoea is treatable. Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure reverses the aforementioned pathological processes14,16,18,20,23,24,5055and improves survival of subjects who are not cardiac transplant recipients.28It is, therefore, conceivable that treatment of obstructive sleep apnoea in cardiac transplant recipients may, in the long run, decrease vasculopathy and hopefully improve survival. In the present study, subjects with obstructive sleep apnoea were referred for appropriate treatment, although, it remains to be proven in future studies that treatment will improve survival.
We used the Short-Form (SF-36) health survey to determine the effect of obstructive sleep apnoea on physical and mental dimensions of health status.41Physical component scale, reflecting physical morbidity was significantly worse in cardiac transplant recipients with obstructive sleep apnoea. The results are consistent with those studies of patients with obstructive sleep apnoea and without cardiac transplantation.56,57In these studies,56,57treatment of sleep apnoea with nasal continuous positive airway pressure improved quality of life. Interestingly, Bennett et al.57reported that improvement in health status with CPAP correlated with sleep fragmentation severity, and in our study, we found a significant correlation between arousal index and health-related quality of life. We also hope that treatment of obstructive sleep apnoea with nasal continuous positive airway pressure will improve quality of life of cardiac transplant recipients. We should note, however, that in a small trial of cardiac transplant recipients, compliance with CPAP was poor.10Reasons for this are not clear.
We found that excessive weight gain since cardiac transplantation was a major risk factor for development of obstructive sleep apnoea. This should apply to subjects undergoing other organ transplantations. Furthermore, since steroid use could contribute to weight gain after transplantation, steroid-free regimens along with early intensive dietary intervention58,59may prove useful by decreasing the prevalence of obstructive sleep apnoea in cardiac transplant recipients.
4.2. Restless leg syndrome and periodic limb movement
Another finding of the present study was a high prevalence of restless legs syndrome and periodic limb movement in cardiac transplant recipients. Restless legs syndrome is a clinical diagnosis affecting 5 to 10 percent of the general population.39Periodic limb movements are defined as recurrent extensions of the great toes and dorsiflexion of the ankle, knee and sometimes hip.39Periodic limb movements are not clinically important unless they disturb the sleep of the bed partner or are associated with recurrent arousals and restless legs syndrome.39In the present study, the arousals secondary to periodic limb movements were slightly, though significantly, increased. However, 45% of cardiac transplant recipients with periodic limb movements had restless legs syndrome, and they were referred for appropriate therapy with dopaminergic drugs.39
The mechanisms underlying restless legs syndrome and periodic limb movements in cardiac transplant recipients remain to be elucidated. The known associated factors39such as anaemia, renal failure and electrolyte imbalance were not present in our subjects, and use of medications (including antidepressants) was similar. Low serum iron and ferritin may also be associated with periodic limb movement and restless legs syndrome, but were not measured in this study.
In summary, this study shows high prevalence of obstructive sleep apnoea and restless legs syndrome with periodic limb movements in a cohort of cardiac transplant recipients. Obstructive sleep apnoea contributed to poor health-related quality of life, and may potentially decrease survival of the transplanted heart. We suggest that polysomnography be considered for most cardiac transplanted subjects. Excessive weight gain, unrested sleep, excessive daytime sleepiness, hypertension and left ventricular systolic dysfunction are among indications for performing sleep study in cardiac, and probably other organ transplant recipients. Treatment of obstructive sleep apnoea may hopefully improve health-related quality of life, minimize vasculopathy and increase survival of cardiac transplant recipients.
Acknowledgments
This work was supported by a Grant from the American Heart Association.
Footnotes
1 Current affiliation is with the Ohio State University, Columbus, Ohio
References