Ingo Fietze

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10−11, OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10−19, OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767.

Association of sleep duration with chronic diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study.

Background In view of the reduced number of hours devoted to sleep in modern western societies the question arises what effects might result from sleep duration on occurrence of chronic diseases. Methods Data from 23 620 middle-aged participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, that were recruited between 1994–1998, were analyzed by using Cox proportional hazard regression to examine the association between self-reported sleep duration at baseline and incidence of chronic diseases, such as diabetes, myocardial infarction, stroke, and cancer. Results During a mean follow-up period of 7.8 years 841 incident cases of type 2 diabetes, 197 cases of myocardial infarction, 169 incident strokes, and 846 tumor cases were observed. Compared to persons sleeping 7-<8 h/day, participants with sleep duration of <6 h had a significantly increased risk of stroke (Hazard Ratio (HR) = 2.06, 95% confidence interval (CI): 1.18–3.59), cancer (HR = 1.43, 95% CI: 1.09–1.87), and overall chronic diseases (HR = 1.31, 95% CI: 1.10–1.55) in multivariable adjusted models. Self-reported daytime sleep at baseline was not associated with incident chronic diseases in the overall study sample. However, there had been an effect modification of daytime sleep by hypertension showing that daytime sleep was inversely related to chronic disease risk among non-hypertensive participants but directly related to chronic diseases among hypertensives. Conclusion Sleep duration of less than 6 h is a risky behavior for the development of chronic diseases, particularly stroke and cancer, and should be therefore addressed in public health campaigns.

Pulmonary involvement in diffuse cutaneous systemic sclerosis: broncheoalveolar fluid granulocytosis predicts progression of fibrosing alveolitis

OBJECTIVE The clinical course of fibrosing alveolitis (FA) in patients with systemic sclerosis (SSc) may vary considerably from stable condition for years to continuous fatal progression. This prospective study aimed at identifying the prognostic value of bronchoalveolar lavage fluid (BALF) analysis in FASSc. METHODS Seventy three consecutive patients with SSc and clinical signs of pulmonary involvement were enrolled. Every patient underwent clinical examination, lung function tests, computed tomography (CT), gallium scan, echocardiography, and bronchoalveolar lavage (BAL). Forty nine patients, 26 with pathological and 23 with normal BALF findings were prospectively followed up for two years and re-evaluated annually. RESULTS At baseline, 51 subjects (70%) showed radiological signs of lung fibrosis and/or alveolitis by CT and diffusion capacity for carbon monoxide (DLco) was decreased in 47 patients (64%). Thirty five patients (48%) had pathological BALF findings. BALF differential counts included BALF granulocytosis in 18, BALF lymphocytosis in 12, and a mixed increase of both granulocytes and lymphocytes in five patients. On follow up, a progression of FA with a significant decrease of DLco was only observed in patients with BALF granulocytosis. In contrast, patients with BALF lymphocytosis or normal BALF cell count had stable lung funtion parameters during the study period. In none of our patients echocardiography showed evidence of pulmonary hypertension. CONCLUSION BALF granulocytosis predicts progression of FA with deterioration of lung function, which is most sensitively monitored by DLco. Immunosuppressive treatment is recommended in patients with granulocytic FASSc.

Diabetes Mellitus Prevalence and Control in Sleep-Disordered Breathing: The European Sleep Apnea Cohort (ESADA) Study

BACKGROUND OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population. METHODS We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects. RESULTS T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) (P < .001), respectively, for prevalent T2DM. Diabetic subjects with more severe OSA had worse glycemic control, with adjusted mean HbA1c levels 0.72% higher in patients with severe OSA than in those without sleep-disordered breathing (analysis of covariance, P < .001). CONCLUSIONS Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM.

Agreement of different methods for assessing sleep characteristics: a comparison of two actigraphs, wrist and hip placement, and self-report with polysomnography

OBJECTIVE To assess the agreement of sleep parameters measured by two actigraphs (SOMNOwatch plus, ActiGraph GT3X+) at two different placements (wrist, hip) and of self-reported sleep with polysomnography (PSG). METHODS We estimated agreement with PSG for total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), number of awakenings after sleep onset (NASO), and sleep efficiency (SE%) for 100 participants of the general population, aged 18-75 years by judging mean differences to PSG and intervals of agreement using Bland-Altman plots. RESULTS Mean difference to PSG for TST was 8.3 min (95% confidence intervals [CI] -7.4; 24.1) for SOMNOwatch plus (wrist), 39.8 min (95% CI 24.3; 55.3) for self-report, -79.0 min (95% CI -89.0; -68.9) for SOMNOwatch plus (hip), and -81.1 min (95% CI -91.9; -70.4) for GT3X+ (hip), respectively. The width of intervals of agreement differed with the placement of the devices. Mean differences to PSG were higher for hip-based measurements compared with wrist placement for most parameters. CONCLUSIONS Agreement of sleep parameters assessed by actigraphy with PSG differs with the placement of the device and is limited for hip-based measurements. Agreement of self-report with PSG is comparable to that of actigraphy for some parameters.

SLEEP QUALITY IN PROFESSIONAL BALLET DANCERS

Ballet dancers are competitive athletes who undergo extreme physical and mental stress and work according to an irregular schedule, with long days of training, rehearsal, and performance. Their most significant potential risks entail physical injury and altered sleep. The elaborate training requirements for ballet dancers do not allow regular chronobiological patterns or a normal sleep-wake rhythm. Our aim was to investigate the sleep-wake rhythm and sleep quality during rehearsal phases prior to a ballet premiere. We used wrist actigraphy and sleep diaries for a period of 67 days before the ballet premiere performance to study 24 classical ballet dancers. We likewise applied the Epworth Sleepiness Score (ESS), Pittsburgh Sleep Quality Index (PSQI), SF-12 Quality of life Assessment, and d2 Test of Attention to assess quality of sleep, aspects of cognitive performance, and health status. We found significant reduction in sleep duration, from 418 ± 43 min to 391 ± 42 min, and sleep efficiency, from 81 ± 4% to 79 ± 5%, over the 67-day course of the rehearsal. We also found a decline in time in bed and an increase in wakefulness after sleep onset. Sleep onset latency did not change. However, the changes in sleep as documented by actigraphy were not reflected by the subjective data of the sleep diaries and sleep scores. As a result of the facts that total sleep efficiency and sleep duration values were already lower than usual for the dancers’ age group at the beginning of the study and that mental acuity, concentration, and speed were likewise impaired, we observed exacerbated health deterioration in terms of sleep deprivation in ballet dancers during preparation for a premier. We conclude that individual activity-rest schedules, including daytime naps, may be helpful, especially during the stressful training and rehearsal experienced prior to ballet premieres. (Author correspondence: martin.glos@charite.de)

The European sleep apnoea database (ESADA) –report from 22 European sleep laboratories

The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 program. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5103 patients (1426 females, age 51.8±12.6 years, 79.4% with AHI≥5 events·hr−1) were included from March 15, 2007 to August 1, 2009. Morbid obesity (BMI≥35 kg·m−2) was present in 21.1% of males and 28.6% of women. Cardiovascular, metabolic, and pulmonary comorbidities were frequent (49.1, 32.9 and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 vs. 29.1±26.3 events·hour−1, p<0.0001). The ESADA is a rapidly growing multicentric patient cohort that enables unique outcome research opportunities and genotyping. The first cross sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSAS.The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 programme. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5,103 patients (1,426 females, mean±sd age 51.8±12.6 yrs, 79.4% with apnoea/hypopnoea index (AHI) ≥5 events·h−1) were included from March 15, 2007 to August 1, 2009. Morbid obesity (body mass index ≥35 kg·m−2) was present in 21.1% of males and 28.6% of females. Cardiovascular, metabolic and pulmonary comorbidities were frequent (49.1%, 32.9% and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 versus 29.1±26.3 events·h−1, p<0.0001). The ESADA is a rapidly growing multicentre patient cohort that enables unique outcome research opportunities and genotyping. The first cross-sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSA.

Spectral oscillations of RR intervals in sleep apnoea/hypopnoea syndrome patients

A recent study has shown that daytime heart rate variability is reduced in obstructive sleep apnoea/hypopnoea syndrome (OSAHS) patients. In the present study, the hypothesis was that sympathovagal balance around apnoeas/hypopnoeas and nocturnal autonomic activity are altered in OSAHS patients. Frequency- and time-domain analyses of RR intervals were performed to monitor sympathovagal activity noninvasively. Fourteen untreated OSAHS patients and seven healthy subjects underwent overnight polysomnography. Low (LF) and total (TF) frequency power increased 2 min around the end of apnoeas/hypopnoeas (LF 229±38 ms2, TF 345±45 ms2) compared with undisturbed sleep (LF 106±18 ms2, TF 203±23 ms2). The increase in high frequency (HF) power was not significant. LF increase was proportionally higher than the HF increase (normalised LF (LFn) 67±1 units, normalised HF (HFn) 33±1 units) compared with undisturbed sleep (LFn 52±2 units, HFn 48±2 units). RR duration did not change around apnoeas/hypopnoeas (RR 904±28 ms). The LF and TF power increase was greater around arousal-inducing (LF 260±45 ms2, TF 390±65 ms2) compared with self-terminating (LF 161±31 ms2, TF 249±40 ms2) apnoeas/hypopnoeas; the LF and LFn increases were significant in both groups compared with undisturbed sleep and HF power differences were nonsignificant. RR intervals were longer around self-terminating apnoeas/hypopnoeas (RR 914±29 ms); the differences were not significant compared with undisturbed sleep. RR interval spectral power was not influenced by the event type. RR duration decreased (912±28 ms) and LF, HF and TF power increased (LF 111±16 ms2, HF 62±6 ms2, TF 173±21 ms2) across patients, compared with healthy controls (RR 1138±91 ms, LF 57±3 ms2, HF 35±3 ms2, TF 91±6 ms2). LFn and HFn did not change significantly. Sympathetic activity increases around apnoeas/hypopnoeas. The recurrent nocturnal fluctuations of sympathovagal balance and the overall increase of nocturnal autonomic activity may be of importance in the development of cardiovascular disease in sleep apnoea patients.

Night-to-night variation of the oxygen desaturation index in sleep apnoea syndrome.

The current study investigated the night-to-night variability and diagnostic accuracy of the oxygen desaturation index (ODI), as measured by ambulatory monitoring, in the diagnosis of mild and moderate obstructive sleep apnoea–hypopnoea syndrome. To assess the variability of the ODI, 35 patients were monitored at home during 7 consecutive nights by means of a portable recording device, the MESAM-IV®. The ODI variability factor and the influence of age, body mass index (BMI), alcohol, and body position were assessed. Furthermore, the diagnostic accuracy of the MESAM-IV was measured by comparison with polysomnographical outcomes in 18 patients. During home recording, the median ODI was 10.9 (interquartile range: 5.8–16.1) across the patients. Although the reliability of the ODI was adequate, the probability of placing the patient in the wrong severity category (ODI ≤15 or ODI >15) when only one single recording was taken is 14.4%. ODI variability was not significantly influenced by age, BMI, time spent in a supine position, or mild dosages of alcohol. A good correlation was found between the apnoea–hypopnoea index and the ODI. In conclusion, the findings suggest that the diagnostic accuracy of the MESAM-IV is strong, since the oxygen desaturation index is correlated with the apnoea–hypopnoea index. In most obstructive sleep apnoea–hypopnoea syndrome patients, oxygen desaturation index variability is rather small, and screening could be reliably based on single 1-night recordings.