Estimates of 10-year risk of cardiovascular death and adherence to cardiovascular risk factor management in Danish patients investigated for obstructive sleep apnea.

OBJECTIVE: Obstructive sleep apnea (OSA) increases the risk of cardiovascular disease (CVD) in both morbidity and mortality. We used the risk chart of Systemic Coronary Risk Evaluation (SCORE) from European Society of Cardiology (ESC) to determine the 10-year risk of cardiovascular death, and adherence to cardiovascular risk factor management in Danish patients investigated for obstructive sleep apnea. RESEARCH DESIGN AND METHODS: In a prospective cohort study, 303 patients with mild, moderate and severe OSA were investigated for cardiovascular risk factors before initiating CPAP therapy. Primary outcome was estimates of 10-year risk of cardiovascular death assessed from the ESC risk chart SCORE based on sex, age, smoking status, systolic blood pressure and s-total cholesterol. Furthermore we analyzed treatment indication with statins in patients with mild (apnea-hypopnea index, AHI <15), moderate (AHI 15-29.9) and severe OSA (AHI ≥30). RESULTS: Patients with mild OSA predominately had low or moderate 10-year risk of CVD (low risk 55.4%, moderate risk 30.8%) while patients with moderate and severe OSA were more likely to have high or very high risk of 10-year CVD (p = 0.001). The large majority of included OSA patients had dyslipidemia, 235 (77.6%) and of those, only 27.4% were treated with cholesterol lowering drugs while additional 27.7% were eligible for oral statin supplement as risk-estimated by the ESC SCORE. In multiple regression analysis among statin naive patients, AHI was positively associated with statin eligibility when adjusted for age and sex. CONCLUSION: Patients with moderate and severe OSA had an elevated 10-year risk of fatal CVD and were undertreated with CVD risk lowering agents such as statins.

Prevalence of silent atrial fibrillation and cardiovascular disease in patients with obstructive sleep apnea.

OBJECTIVE: Patients with silent and undiagnosed atrial fibrillation (AF) have increased risk of ischemic stroke. Patients with obstructive sleep apnea (OSA) have an increased risk of both AF and ischemic stroke. Our aim was to investigate the prevalence of silent AF and associated risk factors in patients investigated for OSA or with known OSA. METHODS: This prospective observational study was performed in two sites; one outpatient sleep-clinic at Zealand University Hospital and one private Ear-Nose- and Throat clinic. Patients were investigated with a type-3 portable sleep-monitoring device, while heart rhythm was home-monitored for 7 days with an event-triggered loop recorder. Patients were stratified in groups of mild, moderate and severe OSA based on Apnea-Hypopnea-Index (AHI). RESULTS: In a cohort of 303 patients, 238 (78.5%) were diagnosed with moderate/or severe OSA and 65 (21.5%) with no/mild OSA who constituted the control group. In 238 patients with moderate and severe OSA, AF was detected in 21 patients (8.8%) vs. 1 patient (1.5%,[p=0.045]) with mild OSA. Candidates for anticoagulation therapy were referred for further cardiovascular treatment. The majority of patients had known hypertension (n = 200,66%) and dyslipidemia (n = 235,[77.6%]) In patients with moderate/or severe OSA (AHI≥15), hypertension was more dysregulated (p=0.005) and more patients suffered from unknown prediabetes (n = 36, 3.1% vs. 14.3%[p<0.001]). CONCLUSION: Undiagnosed AF and undertreated cardiovascular modifiable risk factors are common in a cohort of patients with OSA. With this study we propose that long-period home-monitoring in these patients is useful for identifying candidates for preventive anticoagulation, cardiovascular treatment and possibly prevent future ischemic stroke.

Silent atrial fibrillation detected by home-monitoring: Cardiovascular disease and stroke prevention in patients with diabetes.

OBJECTIVE: Patients with silent and undiagnosed paroxysmal atrial fibrillation and flutter (AF) have increased risk of ischemic stroke. Patients with diabetes have a higher risk of both AF and ischemic stroke compared to patients without diabetes. Our aim was to investigate the prevalence of silent AF in patients with diabetes in an outpatient cohort and to identify the possible risk factors associated with AF. RESEARCH DESIGN AND METHODS: This prospective observational study was performed in the outpatient diabetes clinic at a single University Hospital. We included 217 patients with type 1 or type 2 diabetes with at least one additional risk factor from the CHA2DS2VASc Score for Stroke Risk Assessment in Atrial Fibrillation. The primary outcome was prevalence of AF, with a duration of at least 30 s, recorded by a seven-day home-monitor, external loop recorder (ELR) in comparison to a standard resting ECG. Seventeen patients were excluded due to premature removal of the device. RESULTS: In the final cohort of 200 patients the majority were male (58.5%) with a mean age of 66 ±â€¯0.7 years. The mean BMI was 29 ±â€¯6 and patients had a mean diabetes history of 23 ±â€¯14 years with the majority diagnosed with type 2 diabetes (59%). Comorbidity was common with hypertension in 86%, and dyslipidemia in 80%. The total prevalence of silent AF [n = 20 (10%)] or flutter [n = 1 (0.5%)] was 10.5% using the ELR compared to a 0.0% detection-rate in the standard ECG method (p < 0.001). Higher age, male gender, albuminuria, and elevated systolic blood pressure were associated with AF in univariate analyses, but only age [OR 1.14 (95% CI = 1.00-2.04) (p = 0.048)], male gender [OR 4.9 (95% CI = 1.30-18.65) (p = 0.019)] and albuminuria [OR 2.7 (95% CI =1.08-6.98) (p = 0.034) were independently associated with AF. Mean CHA2DS2VASc Score was ≥2 (4.1, SD ±â€¯1.6), and patients with AF were referred to further cardiac evaluation. CONCLUSION: Undiagnosed, silent AF is common in high-risk cohort with a long history of diabetes followed in a University Hospital outpatient clinic. Non-invasive monitoring with ELR enhances detection of AF and identifies candidates for early anticoagulation treatment with the possible effect of stroke prevention.

Tonsillotomy in children with sleep-disordered breathing is safe and results in high parent satisfaction.

INTRODUCTION: Sleep-disordered breathing in children is often associated with tonsillar hypertrophy. For many years, total tonsillectomy (TE) was the treatment of choice, but performing an intracapsular tonsillotomy (TT) is becoming increasingly widespread. In this Danish study, we have investigated the long-term results on efficacy and parent satisfaction after TT performed on children. METHODS: This was a retrospective study based on a questionnaire that was sent to the parents of 335 children who underwent TT due to sleep-related obstructive symptoms. RESULTS: A total of seven children had unilateral re-TT due to tonsillar regrowth, leaving a total of 342 operations performed. The response rate was 71% and the median follow-up was 90 months. None of the patients in this study ex-perienced post-operative bleeding requiring medical assistance. A total of 97% of parents reported total or partial relief of all symptoms, whereas 3% experienced no effect of treatment on preoperative symptoms. A total of 5% of the children later underwent tonsillectomy after their primary TT. The majority of parents (89%) would choose the operation again in a similar situation. CONCLUSIONS: TT has previously been shown to have a lower morbidity and risk of post-operative bleeding and a better recovery than TE. In this study, we found it to be a long-term efficient and safe treatment for children with obstructive symptoms during sleep and it was associated with a high degree of parent satisfaction. FUNDING: none. TRIAL REGISTRATION: This was a retrospective study.

Iodine and tri-iodo-thyronine reduce the incidence of type 1 diabetes mellitus in the autoimmune prone BB rats.

Thyroid hormones modulate the immune system and metabolism, influence insulin secretion, and cause decreased glucose tolerance. Thyroid hormones have been described to change the incidence of spontaneous autoimmune thyroiditis in Bio-Breeding/Worcester (BB) rats but it is unknown how these hormones affect the development of type 1 diabetes mellitus (T1DM). The aim was to investigate the influence of changes in thyroid function during postnatal development on the prevalence of T1DM in BB rats and the influence of T3 on the beta cell mass in non-diabetic Wistar rats. BB rats were treated with sodium iodine (NaI) or thyroid stimulating hormone (TSH) neonatally or with tri-iodo-thyronine (T3) during adolescence. At the age of 19 weeks the incidence of T1DM and the degree of insulitis were evaluated. The influence of T3 treatment on the beta cell mass was evaluated in Wistar rats by unbiased stereological methods. The incidence of T1DM in control BB rats was 68% at the age of 19 weeks. NaI and T3 reduced the incidence, whereas TSH had no effect. In Wistar rats T3 treatment increased the beta cell mass per bodyweight. The modulation of thyroid function during postnatal development may thus affect the precipitation of T1DM in genetically susceptible individuals.

The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance.

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats. Female Sprague-Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3+/-7.0 versus 593.2+/-13.2g, p<0.01), body weight (306.6+/-4.2 versus 276.4+/-3.6 g, p<0.001), subcutaneous inguinal fat (3.4+/-0.3 versus 1.9+/-0.1 g, p<0.001), mesenteric fat (3.1+/-0.2 versus 1.7+/-0.2g, p<0.001), retroperitoneal fat (6.2+/-0.6 versus 2.8+/-0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906+/-66 versus 1770+/-28 mMxmin, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8+/-20.4 g, p<0.01; body weight: 280.2+/-5.6 g, p<0.001; subcutaneous inguinal fat: 2.4+/-0.2 g, p<0.001; mesenteric fat: 1.8+/-0.1 g, p<0.001; retroperitoneal fat: 3.5+/-0.4 g, p<0.001; AUC: 1764+/-32 mMxmin, p<0.05). In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.

Growth and functional maturation of beta-cells in implants of endocrine cells purified from prenatal porcine pancreas.

The development of islet cell transplantation as a cure for diabetes is limited by the shortage of human donor organs. Moreover, currently used grafts exhibit a marginal beta-cell mass with an apparently low capacity for beta-cell renewal and growth. Although duct-associated nonendocrine cells have often been suggested as a potential source for beta-cell production, recent work in mice has demonstrated the role of beta-cells in postnatal growth of the pancreatic beta-cell mass. The present study investigated whether the beta-cell mass can grow in implants that are virtually devoid of nonendocrine cells. Endocrine islet cells were purified from prenatal porcine pancreases (gestation >110 days) and implanted under the kidney capsule of nude mice. beta-Cells initially presented with signs of immaturity: small size, low insulin content, undetectable C-peptide release, and an inability to correct hyperglycemia. They exhibited a proliferative activity that was highest during posttransplant week 1 (2.6 and 5% bromodeoxyuridine [BrdU]-positive beta-cells 4 and 72 h posttransplant) and then decreased over 20 weeks to rates measured in the pancreas (0.2% BrdU-positive cells). beta-Cell proliferation in implants first compensated for beta-cell loss during posttransplant week 1 and then increased the beta-cell number fourfold between posttransplant weeks 1 and 20. Rates of alpha-cell proliferation were only shortly and moderately increased, which explained the shift in cellular composition of the implant (beta-cell 40 vs. 90% and alpha-cell 40 vs. 7% at the start and posttransplant week 20, respectively). beta-Cells progressively matured during the 20 weeks after transplantation, with a twofold increase in cell volume, a sixfold increase in cellular insulin content, plasma C-peptide levels of 1-2 ng/ml, and an ability to correct diabetes. They became structurally organized as homogenous clusters with their secretory vesicles polarized toward fenestrated capillaries. We concluded that the immature beta-cell phenotype provides grafts with a marked potential for beta-cell growth and differentiation and hence may have a potential role in curing diabetes. Cells with this phenotype can be isolated from prenatal organs; their presence in postnatal organs needs to be investigated.

Genetic background determines the size and structure of the endocrine pancreas.

Key parameters of the endocrine pancreas, such as islet number, islet mass, beta-cell mass, and alpha-cell mass, were studied in different strains of inbred mice to investigate the impact of genetic background on the size and structure of the endocrine pancreas. Six mice from each of seven different strains of inbred mice were included in the study. For all parameters investigated, there was a pronounced interstrain variation. ANCOVA showed that only mouse strain was statistically significant as an explanatory parameter for the number of islets. Mouse strain, body weight, and pancreas mass reached statistical significance as explanatory parameters for the islet mass, with mouse strain as the most significant predictor. These data show that genetic background is the most important predictor of both the number of islets and total islet volume. We also conclude that inbred mice could be a valuable resource to identify the genes responsible for the size and structure of the endocrine pancreas.

The source(s) for new pancreatic beta cells in adult life.

The natural source for new pancreatic beta cells is an important issue both for understanding the pathogenesis of diabetes, and for possibly curing diabetes by increasing the number of beta cells. Dor et al. investigated beta-cell renewal and regeneration by genetic lineage analysis in mice during physiological growth and after partial pancreatectomy. The data conclusively showed that beta-cell replication was the only source for new beta cells without contributions from stem cells or other non-beta cells. This underlines the capacity for beta-cell self-renewal and casts doubt that other cell types are able to generate new beta cells in the intact pancreas.

The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211.

Glucagon-like peptide 1 (GLP-1) and GLP-1 receptor agonists increase the beta-cell mass in rodent models of type 2 diabetes and enhance the proliferation rate of beta cells in vitro, while the long-term effect in vivo in non-diabetic animals is unknown. We studied the endocrine pancreas in non-diabetic Sprague-Dawley rats after short- and long-term treatment with NN2211, an acetylated long-acting derivative of GLP-1. Four groups of rats (n=6 for each group) received two daily injections with either NN2211 or vehicle for 1 or 6 weeks. NN2211-treated rats displayed a 10% lower body weight after both 1 week (p<0.001) and 6 weeks (p<0.005) of treatment. The mean beta-cell mass in NN2211-treated rats was increased by 19% after 1 week of treatment (p<0.05), but normalized after 6 weeks of treatment. No difference in alpha-cell mass, volume-weighted mean islet volume, or pancreas mass was found after 1 or 6 weeks of treatment. We conclude that NN2211 treatment of non-diabetic rats induces a sustained lower body weight, and an only temporary increase in the beta-cell mass, while the alpha-cell mass and the volume-weighted mean islet volume are unaffected by the treatment.

Increased islet volume but unchanged islet number in ob/ob mice.

It is important for our understanding of the pancreatic islets to study whether new islets are able to form in the intact pancreas. We developed a new method to determine the total number and the mean volume of the pancreatic islets, and we used this method to study the expansion of the islet mass in ob/ob mice (n = 8), using ob/+ mice (n = 8) as controls. The total islet volume was increased by a factor of 3.6 in ob/ob mice compared with ob/+ mice, whereas, importantly, the total number of islets did not differ among ob/ob mice and ob/+ mice (3,193 +/- 160 islets in ob/ob mice vs. 3,184 +/- 142 islets in ob/+ mice, P = 0.97). The coefficient of variation in the volume distribution of islets was equal in the two groups, showing that in ob/ob mice, the existing islets expand their volume by the same proportion, without a net formation of new islets. We suggest that the pancreatic islets should be considered as anatomically such complex structures that islet neogenesis does not spontaneously occur in an intact pancreas. Cells within the existing islets are presumably the most important sources for islet cell hyperplasia during expansion of the total islet mass.

Postnatal development of beta-cells in rats. Proposed explanatory model.

The previously shown wave of beta-cell apoptosis and the apparent plateau in the beta-cell mass in the third week of life in rats are still unexplained events. Using a novel design-based stereological method we investigated the postnatal development of the beta-cell population in Sprague-Dawley rats. The total beta-cell mass increased from postnatal day 4 until day 16, to be followed by a plateau until day 24, after which it increased further. This plateau was caused by beta-cell hypotrophia as well as decreased net beta-cell formation. The beta-cell mass per unit body weight (the relative beta-cell mass) was five times higher at birth compared with the adult constant level that was reached at approximately 24 days of age. We propose an explanatory model for the postnatal development of the beta-cell population in rats. According to this model, beta-cells in the early postnatal period are immature, i.e. are not susceptible to the mechanism that in later life maintains a constant relative beta-cell mass. Within the following weeks the number of mature beta-cells increases, and from approximately day 24 and onwards the beta-cell population is dominated by mature beta-cells that adjust to match the body weight, keeping a constant relative beta-cell mass. Findings of an apoptotic wave, a plateau phase in the total beta-cell mass development, a period with beta-cell hypotrophia, and the disappearance of insulin-like growth factor II positive beta-cells at postnatal day 21 all fit well in the model.