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* From the Departments of Internal Medicine II (Drs. Lentini, Manka, Scholtyssek, Lüderitz, and Tasci) and Clinical Biochemistry (Dr. Stoffel-Wagner), University of Bonn, Bonn, Germany.
Correspondence to: Selçuk Ta
ci, MD, Department of Internal Medicine II, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany; e-mail: Selcuk.Tasci{at}ukb.uni-bonn.de
Abstract
Study objectives: To evaluate the impact of obstructive sleep apnea syndrome (OSAS) on serum creatine phosphokinase (CK) levels.
Design: Single-center prospective cross-sectional study.
Setting: Academic sleep disorder center.
Patients: Two hundred one consecutive patients (mean [± SD] age, 54.9 ± 11.0 years; 155 men and 46 women; mean body mass index, 31.3 ± 6.9 kg/m2) with suspected sleep-disordered breathing.
Measurements and results: OSAS was confirmed in182 patients (apnea-hypopnea index [AHI], > 5 events per hour) and was ruled out in 19 patients (control subjects) by standard polysomnography. Sixty-six OSAS patients and 1 control patient showed an unexplained CK elevation. The mean baseline CK level was significantly higher in patients with severe OSAS (AHI, > 30 event per hour; n = 89) compared to those with mild-to-moderate OSAS (AHI, 5 to 30 events per hour; n = 93) and control subjects (191.4 ± 12.9 vs 134.3 ± 7.5 vs 107.1 ± 7.9 U/L, respectively; p < 0.01). Receiver operating curve analysis identified an optimal cutoff value of > 148 U/L (r = 0.660) for CK, which yielded a positive predictive value of 99%, a sensitivity of 43%, and a specificity of 95% for the diagnosis of OSAS. The mean nocturnal oxyhemoglobin saturation was the main predictor of CK level (r = 0.47; p < 0.001). Continuous positive airway pressure (CPAP) treatment resulted in a significant decline of CK levels both in patients with mild-to-moderate OSAS (n = 38; 129.7 ± 13.4 vs 96.7 ± 7.6 U/L, respectively; p < 0.001) and in patients with severe OSAS (n = 39; 187.7 ± 18.9 vs 132.2 ± 12.9 U/L, respectively; p < 0.001).
Conclusions: One third of our study population showed a mild-to-moderate elevation in CK level, which was highly predictive of OSAS. The application of CPAP therapy in OSAS patients resulted in a significant decrease in CK level. We speculate that OSAS may account for a substantial number of cases of unexplained CK elevation (ie, hyperCKemia). Further studies should address the prevalence of OSAS in patients with mild-to-moderate hyperCKemia.
Key Words: creatine phosphokinase • hyperCKemia • obstructive sleep apnea syndrome • sleep-disordered breathing
Obstructive sleep apnea syndrome (OSAS) is characterized by repetitive pharyngeal collapse and oxygen desaturation during sleep, resulting in sleep fragmentation and daytime sleepiness. Moderate-to-severe OSAS (defined as at least 15 apneas and hypopneas per hour of sleep) affects approximately 4% of women and 9% of men in a middle-aged population, as shown by the Wisconsin Sleep Cohort Study.1 Muscle activity in the upper airway is modulated by sleep stages, chemoreceptors, and intrathoracal pressure. In healthy individuals, protective mechanisms maintain the patency of the upper airways during wakefulness and sleep.2 In contrast, OSAS patients show a hyperactivation of pharyngeal dilator muscles during wakefulness, as shown by increased electromyographic activity.34 To the best of our knowledge, the elevation of serum creatine phosphokinase (CK) levels has not been reported in OSAS patients. Mechanisms linking OSAS to CK elevation may include repetitive hypoxemic and/or mechanical stress on respiratory and skeletal muscles.
CK is an energy transfer enzyme that catalyzes the reaction of phosphocreatine and adenosine diphosphate to creatine and adenosine triphosphate. The combinations of the two molecular CK subunits, M and B, produce the following three isoenzymes: CK-MM (isolated primarily from skeletal muscle); CK-MB (isolated from the myocardium); and CK-BB (isolated from the brain). CK concentrations in healthy subjects are normally composed mainly of the CK-MM fraction, but depend on gender, race, age, and physical activity.56 Transient elevations in CK levels are typically due to excessive muscle exercise or hypoxia induced by exposure to high altitudes (with or without exercise).789
Incidentally elevated CK concentrations in asymptomatic patients are frequently detected during routine blood chemistry profiles. A substantial number of these patients undergo time-intensive and cost-intensive workups for cardiac or neuromuscular disease. However, in up to 10% of patients the cause for CK elevation remains unclear. In these cases, the term idiopathic hyperCKemia applies.101112
We frequently observed an unexpected and otherwise unexplained elevation of CK in untreated OSAS patients. Therefore, we decided to evaluate the association of OSAS and CK concentrations in patients who were referred to us for suspected and untreated sleep-disordered breathing (SDB). Moreover, we decided to investigate the effect of continuous positive airway pressure (CPAP) treatment on CK concentrations in these patients.
Materials and Methods
Between January 2003 and November 2004, we performed a prospective cross-sectional study of 251 consecutive white patients who had been referred to our sleep medicine center for suspected SDB. All patients were asked about their regular medications and medical history, and underwent physical examination. Fifty patients were excluded from the study according to the following exclusion criteria: history of ischemic or nonischemic dilated cardiomyopathy; unstable coronary artery disease; significant valvular disease; severe obstructive lung disease, as quantified by spirometry (ie, FEV1/vital capacity ratio, < 60%); history of neuromuscular disease or malignant hyperthermia; hypothyroidism; recent muscle trauma; and excessive muscle activity or drug intake, which could probably lead to elevated CK concentrations. The Institutional Review Board of the hospital approved the study protocol, and informed consent was obtained from all patients. Full night polysomnography (polysomnography) assessed the appearance and severity of OSAS according to standard criteria.13
Patients underwent routine blood testing, including assessment of CK (Dimension RxL; Dade Behring; Marburg, Germany) [reference range, < 145 U/L for women and < 171 U/L for men] between 9:00 AM and 11:00 AM on day one 1 of hospital admission before polysomnography. In patients with elevated CK concentrations, CK isoenzyme bands were qualitatively and quantitatively evaluated according to their electrophoretic mobility on agarose gel. CK-BB (CK1) is the fastest moving, most anodic band, CK-MM (CK3) is the slowest moving, most cathodic band, and CK-MB (CK2) migrates intermediate to CK-MM and CK-BB.
Sleep Studies
Patients underwent standard full night polysomnography to assess the presence and severity of SDB. Polysomnography screening included the use of EEG, electrooculogram, electromyogram (genioglossus muscle and anterior tibialis muscle), ECG, a microphone (for snoring), and a body position electrode. Additionally, nasal and oral flow were recorded with thermistors, and thoracic and abdominal movements were recorded with inductance plethysmography. Arterial oxygen saturation (SaO2) was monitored by pulse oximetry. Sleep stages and arousals were scored according to the standard criteria of Rechtschaffen and Kales.14 All signals were recorded on the polysomnographic system.
Respiratory events were analyzed visually, and apneas and hypopneas were scored according to international criteria.13 Apneas were defined as a cessation of oronasal airflow of < 20%, lasting 
10s regardless of oxygen desaturations. Hypopneas were defined as an airflow reduction of > 50%, compared to a 10-s peak amplitude during the preceding 2 min, lasting 10 s and associated with either oxygen desideration of 3% or an arousal. The apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas occurring per hour of sleep.
OSAS, defined as an AHI > 5 events per hour of sleep as shown by polysomnography, was confirmed in 182 patients. None of the patients demonstrated oscillatory breathing patterns (ie, Cheyne-Stokes respiration and periodic breathing). OSAS was categorized as mild to moderate (AHI, 5 to 30 events per hour; n = 93) and severe (AHI, > 30 events per hour; n = 89). Subjects with an AHI of < 5 events per hour were considered not to have OSAS and were enrolled into the study as control subjects (n = 19). A subgroup of 77 consecutive OSAS patients underwent a second full night polysomnography for CPAP titration, and a second CK measurement was conducted between 9:00 AM and 11:00 AM post-CPAP titration after the second full night polysomnography.
Statistical Analysis
Data analysis was performed with two commercially available statistical packages (SPSS, version 11.0 for Windows; SPSS; Chicago, IL; and MedCalc, version 7.4.1.0; MedCalc Software; Mariakerke, Belgium). All variables were tested for normality (Kolmogorov-Smirnov test). Variables with a skewed distribution were logarithmically transformed to achieve normal distribution. Logarithmically transformed variables were used in all analyses if appropriate. One-way analysis of variance, followed by post hoc contrast (Bonferonni correction) for continuous variables and 
2 testing for dichotomous variables, were used to assess the statistical significance of differences between groups.
A two-tailed paired t test was used to compare within-group data at baseline and after the application of CPAP therapy in OSAS patients. Multiple linear regression modeling using the stepwise technique was performed with CK as the dependent variable and clinical characteristics (ie, age and body mass index [BMI]), and sleep-related measures (ie, AHI, respiratory effort related arousals, periodic leg movements, and mean and lowest nocturnal SaO2) as independent variables. We determined the optimal cutoff levels for CK and BMI based on the calculated sensitivities and specificities derived from receiver operating characteristic (ROC) curves. ROC curves were constructed by stepwise changes of the decision threshold to demonstrate the ability of the markers to discriminate between OSAS patients (AHI, < 5 events per hour) and healthy subjects. The area under the curve (AUC, the minimal value of 0.5 indicates no discrimination, the maximum value of 1.0 indicates perfect discrimination) and its standard error (SE) were calculated.15 Values are reported as mean ± SEM. For all statistical analyses, a value of < 0.05 was considered significant.
Results
The clinical characteristics of the study population (n = 201; mean age, 54.9 ± 11.0 years; 155 men and 46 women; mean BMI, 31.3 ± 6.9 kg/m2) are summarized in Table 1 . The appearance and severity of OSAS was assessed by standard polysomnography. Severe OSAS (ie, AHI, > 30 events per hour) was present in 89 patients, and mild-to-moderate OSAS (ie, AHI, 5 to 30 events per hour) was found in 93 patients. OSAS was ruled out (ie, AHI, < 5 events per hour) in 19 patients. BMI was significantly higher in patients with severe OSAS compared to those with mild-to-moderate OSAS and control subjects (33.5 ± 0.7 kg/m2 vs 30.2 ± 0.7 and 26.8 ± 0.8 kg/m2, respectively; p < 0.01). There were no differences in thyroid-stimulating hormone levels between the groups. C-reactive protein levels were significantly higher in patients with severe OSAS compared to control subjects (5.2 ± 0.6 vs 2.7 ± 0.5 mg/L, respectively; p < 0.01). Concentrations of CK were significantly higher in patients with severe OSAS (191.4 ± 12.9 U/L) than in patients with mild-to-moderate OSAS (134.3 ± 7.5 U/L; p < 0.01) and control subjects (107.1 ± 7.9 U/L; p < 0.01) [for individual data and medians see Fig 1 ]. Forty-three of 89 patients (48%) with severe OSAS and 23 of 93 patients (25%) with mild-to-moderate OSAS showed an elevation in CK level according to the reference range. Thus, CK elevation yielded a positive predictive value of 99%, a sensitivity of 36%, and a specificity of 95% for the diagnosis of OSAS. Only one patient in the control group showed an elevation in CK level. Electrophoresis revealed that the elevation of CK levels was attributable to CK-MM in all patients with elevated CK concentrations.
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ROC analysis regarding the diagnosis of OSAS identified an optimal cutoff value of > 148 U/L (R = 0.660; 95% confidence interval [CI], 0.590 to 0.725) for CK, which yielded a positive predictive value of 99%, a sensitivity of 43%, and a specificity of 95% for the diagnosis of OSAS (ie, AHI, > 5 events per hour). Forty-seven of 89 patients (53%) with severe OSAS had a CK concentration that exceeded 148 U/L. In contrast, only one patient of the control group showed a CK concentration of > 148 U/L (5%). Likewise, ROC analysis for BMI yielded a cutoff level of 28.65 kg/m2 (R = 0.752; 95% CI, 0.686 to 0.810), resulting in a positive predictive value of 97%, a sensitivity of 64%, and a specificity of 79% for the diagnosis of OSAS. The pairwise comparison of ROC curves for CK concentration and BMI showed no significant difference (p = 0.149) [Fig 2 ].
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To our knowledge, this is the first study to report an association between OSAS and the elevation of CK concentration. Moreover, we discovered that CK levels decline significantly in OSAS patients who have been treated with CPAP.
Elevated CK serum concentrations are an important marker of cardiovascular and neuromuscular disease. However, incidentally observed CK concentration elevations of skeletal muscle origin (CK-MM) in asymptomatic patients may represent a diagnostic dilemma. Once known causes are excluded (including metabolic or toxic causes such as hypothyroidism, rhabdomyolysis, the use of cholesterol-lowering drugs, and excessive physical exercise) and no evidence of neuromuscular disease is found, idiopathic hyperCKemia is applied as a diagnosis of exclusion.1011 Meanwhile, follow-up studies of patients with hyperCKemia have shown that two thirds of patients do not develop neuromuscular disease.12161718 In one study, Prelle and colleagues19 could not find a conclusive diagnosis in 50% of their 114 hyperCKemia patients despite an intensive workup that included muscle biopsy and genetic investigations. Moreover, 31.6% of the study population had completely healthy muscles.19
In our study, the prevalence of a slight-to-moderate elevation in CK concentration was unexpectedly high (33%). As shown by Kodatsch et al,20 up to 11% of patients admitted to a medical department show an elevation in CK concentration. In > 50% of their patients, CK concentrations were elevated only up to twofold above normal. The cause for elevated CK levels remained unclear in 10% of the cases. In our study, electrophoretic examinations revealed that CK-MM was the isoenzyme responsible for CK elevation, and elevated CK concentrations were highly predictive of OSAS (specificity, 95%; positive predictive value, 99%). Interestingly, ROC curve analysis for the identification of the optimal cutoff revealed a CK level of 148 U/L, which corresponded with the CK reference ranges of < 145 U/L for women, and < 171 U/L for men.
Possible pathomechanisms for elevated CK concentrations in OSAS include hyperactivation of upper airway dilator muscles to maintain patency of the upper airways,34 increased activity in inspiratory muscles, particularly the diaphragm, during apnea-related decreases in intrathoracic pressure (Mueller maneuver),21 hypoxia-induced alteration of muscle function and metabolism,2223 and local or systemic inflammatory processes.24 Whether combined effects of hypoxia and muscular stress contribute to the elevation of CK concentration in patients with OSAS, as has been shown in triathletes training at high altitude, can be hypothesized.9
Our finding that mean nocturnal SaO2 was the main predictor of CK concentration elevation may be consistent with the phenomenon that patients with OSAS and intermittent hypoxemia demonstrate changes in muscular structure and in activity of biochemical enzymes of upper airway dilator muscles and skeletal muscles. Series et al22 reported that the total number of muscle fibers (type IIA fibers in particular), protein content, and anaerobic enzyme activities (including CK concentration) in the musculus uvulae were significantly higher in OSAS patients compared to snorers. In one study,23 needle biopsies of the quadriceps femoris in 12 patients with severe OSAS revealed structural and bioenergetic changes in their skeletal muscle compared to those in healthy control subjects. Once progressive muscular recruitment contributes to CK concentration elevation in OSAS patients, effective treatment (such as the application of CPAP) should result in a normalization of CK concentration, as shown in our CPAP trial.
Our study was not designed to evaluate a serologic predictor of OSAS. Prior studies25 concerning prediction formulas for OSAS reported age, snoring history, witnessed apneas, hypertension, BMI, and neck circumference as being predictive of OSAS. However, clinical prediction models do not sufficiently discriminate between patients with or without obstructive sleep apnea.26 To the best of our knowledge, the relationship between CK concentration and OSAS has not been addressed in any prior study. The value of adding CK concentration to the prediction formulas for OSAS should be addressed in further studies.
Study Limitations
The present study has several limitations. The study population was highly selective (the prevalence of OSAS was 90%), thereby limiting the interpretation of our findings. Neuromuscular disease in the study population was assessed only by taking a medical history and by neurologic examination; the patients underwent no specific electrodiagnostic and histologic examinations. Thus, unidentified neuromuscular disease may contribute to our findings. However, none of our patients complained of muscle weakness, and none showed polysomnographic or daytime blood gas criteria for hypoventilation. Histopathologic studies were outside the scope of our study. However, because CK concentration elevation was found in one third of the OSAS patients and because the application of CPAP in OSAS patients resulted in a significant decrease in CK concentration, further studies are needed to evaluate the pathophysiologic basis of these findings. Unfortunately, we did not measure myoglobinuria, and the application of CPAP lacked a control group. A potential confounding effect is that the number of female subjects was significantly higher in our control group than in the OSAS groups. CK levels tend to be lower in female subjects, which may modify the CK levels of the control group compared to those in the OSAS groups. However, we think that this is unlikely because this measure was similar between the control group and the mild-to-moderate OSAS group.
Conclusion
In conclusion, one third of OSAS patients in our study population showed a mild-to-moderate elevation in CK concentration that was partially reversible with the application of CPAP therapy. CK concentration elevation in patients with suspected SDB was highly predictive of OSAS but showed a low sensitivity. The relationship between CK concentration elevation and chronic intermittent hypoxia supports a link to the activation of and structural and bioenergetic changes in upper airway dilator muscles and skeletal muscles in OSAS patients. Because OSAS is highly prevalent, a causal association between OSAS and CK concentration elevation could be responsible for a substantial number of cases of mild-to-moderate hyperCKemia. Thus, early workup for SDB in patients with unexplained CK concentration elevation may avoid time-intensive and cost-intensive examinations for primary neuromuscular disorders. Therefore, further studies should address OSAS in this patient population.
Footnotes
Abbreviations: AHI = apnea-hypopnea index; AUC = area under the curve; BMI = body mass index; CI = confidence interval; CK = creatine phosphokinase; CPAP = continuous positive airway pressure; OSAS = obstructive sleep apnea syndrome; ROC = receiver operating characteristic; SaO2 = arterial oxygen saturation; SDB = sleep-disordered breathing
All authors disclose all pertinent involvement in any organization with a direct financial interest in the subject of the manuscript.
Received for publication May 20, 2005. Accepted for publication June 29, 2005.
References
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