Malcolm Kohler

Mechanisms of vascular damage in obstructive sleep apnea

Obstructive sleep apnea (OSA) is characterized by repetitive apnea–hypopnea cycles during sleep, which are associated with oxygen desaturation and sleep disruption. Up to 30% of the adult population in Western countries are thought to be affected by asymptomatic OSA and approximately 2–4% by symptomatic OSA (also known as obstructive sleep apnea syndrome, or OSAS). Controlled trials have demonstrated that OSAS causes hypertension and prospective epidemiological studies have indicated that OSAS might be an independent risk factor for stroke and myocardial ischemia. Three biological mechanisms are thought to underpin the association of OSA with endothelial dysfunction and arterial disease: intermittent hypoxia leading to increased oxidative stress, systemic inflammation, and sympathetic activity; intrathoracic pressure changes leading to excessive mechanical stress on the heart and large artery walls; and arousal-induced reflex sympathetic activation with resultant repetitive blood-pressure rises. More clinical interventional trials are needed to determine the magnitude of the effect OSA has on cardiovascular damage and to enable a comparison with conventional vascular risk factors.

Effects of Continuous Positive Airway Pressure Therapy Withdrawal in Patients with Obstructive Sleep Apnea

RATIONALE To establish a new approach to investigate the physiological effects of obstructive sleep apnea (OSA), and to evaluate novel treatments, during a period of continuous positive airway pressure (CPAP) withdrawal. OBJECTIVES To determine the effects of CPAP withdrawal. METHODS Forty-one patients with OSA and receiving CPAP were randomized to either CPAP withdrawal (subtherapeutic CPAP), or continued CPAP, for 2 weeks. Polysomnography, sleepiness, psychomotor performance, endothelial function, blood pressure (BP), heart rate (HR), urinary catecholamines, blood markers of systemic inflammation, and metabolism were assessed. MEASUREMENTS AND MAIN RESULTS CPAP withdrawal led to a recurrence of OSA within a few days and a return of subjective sleepiness, but was not associated with significant deterioration of psychomotor performance within 2 weeks. Endothelial function, assessed by flow-mediated dilatation, decreased significantly in the CPAP withdrawal group compared with therapeutic CPAP (mean difference in change, -3.2%; 95% confidence interval [CI], -4.5, -1.9%; P < 0.001). Compared with continuing CPAP, 2 weeks of CPAP withdrawal was associated with a significant increase in morning systolic BP (mean difference in change, +8.5 mm Hg; 95% CI, +1.7, +15.3 mm Hg; P = 0.016), morning diastolic BP (mean difference in change, +6.9 mm Hg; 95% CI, +1.9, +11.9 mm Hg; P = 0.008), and morning HR (mean difference in change, +6.3 bpm, 95% CI, +0.4, +12.2 bpm; P = 0.035). CPAP withdrawal was associated with an increase in urinary catecholamines but did not lead to an increase in markers of systemic inflammation, insulin resistance, or blood lipids. CONCLUSIONS CPAP withdrawal usually leads to a rapid recurrence of OSA, a return of subjective sleepiness, and is associated with impaired endothelial function, increased urinary catecholamines, blood pressure, and heart rate. Thus the proposed study model appears to be suitable to evaluate physiological and therapeutic effects in OSA. Clinical trial registered with www.controlled-trials.com (ISRCTN93153804).

Endothelial Function and Arterial Stiffness in Minimally Symptomatic Obstructive Sleep Apnea

RATIONALE Moderate-severe obstructive sleep apnea (OSA) is associated with endothelial dysfunction, increased arterial stiffness, and hypertension. It is not known whether minimally symptomatic OSA is also associated with impaired vascular function. OBJECTIVES To determine whether minimally symptomatic OSA is associated with impaired vascular function. METHODS In 64 patients (7 females) with minimally symptomatic OSA (oxygen desaturation index, 23.1 [SD, 15.6]; Epworth Sleepiness Scale score, 8 [SD, 3.8]), and 15 matched control subjects without OSA, endothelial function was assessed by ultrasonographic measurement of flow-mediated dilatation, and by applanation tonometry-derived pulse wave analysis (forearm ischemia and salbutamol-induced changes in augmentation index, AI(x)). Arterial stiffness was assessed by AI(x) and ambulatory blood pressure (ABP) was measured over 1 week. MEASUREMENTS AND MAIN RESULTS In patients with OSA, flow-mediated dilatation was significantly lower than in control subjects (5.0% [SD, 2.7%] and 7.5% [SD, 3.3%], respectively; P = 0.003). AI(x) was significantly higher in the OSA group compared with the control group (26.0% [interquartile range (IQR), 19.0-29.5%] and 21.0% [IQR, 8.0-27.0%], respectively; P = 0.04). Change in AI(x) after both forearm ischemia and salbutamol was significantly smaller in patients with OSA (-2.0% [IQR, -5.0 to +4.0%] and -3.0% [IQR, -7.0 to 0.0%], respectively), than in control subjects (-6.0% [IQR, -8.0 to -5.0%] and -7.0% [IQR, -10.0 to -3.0%]; P = 0.005 and P = 0.04, respectively). ABP was similar (97.6 mm Hg [SD, 7.9 mm Hg] and 94.8 mm Hg [SD, 7.4 mm Hg], OSA and control groups, respectively; P = 0.21). CONCLUSIONS In patients with minimally symptomatic OSA, diverse properties of endothelial function are impaired and arterial stiffness is increased. Although this was not associated with a significantly increased ABP, the findings suggest that patients with minimally symptomatic OSA are at increased cardiovascular risk.

Measurement of circulating cell-derived microparticles by flow cytometry: sources of variability within the assay.

INTRODUCTION Circulating cell-derived microparticles (MPs) have been implicated in several disease processes and elevated levels are found in many pathological conditions. The detection and accurate measurement of MPs, although attracting widespread interest, is hampered by a lack of standardisation. The aim of this study was to establish a reliable flow cytometric assay to measure distinct subtypes of MPs in disease and to identify any significant causes of variability in MP quantification. MATERIALS AND METHODS Circulating MPs within plasma were identified by their phenotype (platelet, endothelial, leukocyte and annexin-V positivity (AnnV+). The influence of key variables (i.e. time between venepuncture and centrifugation, washing steps, the number of centrifugation steps, freezing/long-term storage and temperature of thawing) on MP measurement were investigated. RESULTS Increasing time between venepuncture and centrifugation leads to increased MP levels. Washing samples results in decreased AnnV+MPs (P=0.002) and platelet-derived MPs (PMPs) (P=0.002). Double centrifugation of MPs prior to freezing decreases numbers of AnnV+MPs (P=0.0004) and PMPs (P=0.0004). A single freeze thaw cycle of samples led to an increase in AnnV+MPs (P=0.0020) and PMPs (P=0.0039). Long-term storage of MP samples at -80° resulted in decreased MP levels. CONCLUSIONS This study found that minor protocol changes significantly affected MP levels. This is one of the first studies attempting to standardise a method for obtaining and measuring circulating MPs. Standardisation will be essential for successful development of MP technologies, allowing direct comparison of results between studies and leading to a greater understanding of MPs in disease.

Effects of continuous positive airway pressure on systemic inflammation in patients with moderate to severe obstructive sleep apnoea: a randomised controlled trial

Background: Obstructive sleep apnoea syndrome (OSAS) has been associated with cardiovascular disease in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on systemic inflammation involved in the atherosclerotic process remains unclear. Methods: 100 men with moderate–severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 49) CPAP treatment for 4 weeks to investigate the effects of active treatment on inflammatory markers such as highly sensitive C reactive protein (hsCRP), interleukin (IL)6, interferon γ (IFNγ) and anti-inflammatory adiponectin. Results: 4 weeks of therapeutic CPAP did not significantly change blood levels of hsCRP compared with the subtherapeutic control group (difference between median changes −0.24 mg/l (95% CI −0.88 to +0.24); p = 0.30). Plasma levels of IL6 and IFNγ did not change significantly following therapeutic compared with subtherapeutic CPAP (difference between median changes +0.52 and −0.07 pg/ml (95% CI −0.72 to +1.94 and −0.81 to +0.44); p = 0.45 and p = 0.82, respectively). Furthermore, 4 weeks of therapeutic CPAP did not significantly change levels of adiponectin in plasma compared with the subtherapeutic control group (difference between median changes +0.05 pg/ml (95% CI −0.36 to +0.47); p = 0.84). If patients with hsCRP values above 8 mg/l at baseline were excluded, differences between the changes in hsCRP, IL6, IFNγ and adiponectin after 4 weeks of CPAP were smaller, and again not statistically different between groups. Conclusions: 4 weeks of CPAP treatment has no beneficial effect on blood markers of inflammation and adiponectin in patients with moderate–severe obstructive sleep apnoea.

Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial

Background Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. Methods This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. Results Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS −2.0 (95% CI −2.6 to −1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components. Conclusions In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.

Disability and survival in Duchenne muscular dystrophy

Background: Duchenne muscular dystrophy (DMD) leads to progressive impairment of muscle function, respiratory failure and premature death. Longitudinal data on the course of physical disability and respiratory function are sparse. Objectives: To assess prospectively physical impairment and disability, respiratory function and survival in patients with DMD over several years to describe the course of the disease with current care. Methods: In 43 patients with DMD, aged 5–35 years, yearly assessments of physical disability by the Duchenne muscular dystrophy physical Impairment and Dependence on care (DID) score, ranging from 9 (no disability) to 80 (complete dependence), and forced vital capacity (FVC), were obtained over a mean time interval of 5.4 (SD 2.1) years. Results: DID scores were correlated with age according to a hyperbolic function (f = 85.3×age/(10.05+age), R = 0.62, p<0.0001). FVC declined exponentially with age (f = 139.1×exp(−0.08×age), R = 0.52, p<0.0001). Mean age at which patients lost their ambulation was 9.4 (SD 2.4) years and they became dependent on an electric wheelchair at 14.6 (4.0) years. Age at the beginning of assisted ventilation was 19.8 (3.9) years, Three patients died during the observation period. The estimated probability of survival to age 30 years was 85% (median survival was 35 years). Conclusions: Our detailed observations of the progression of physical disability, dependence on care and respiratory impairment in patients with DMD from childhood to adult life is valuable for predicting the clinical course with current medical care. Compared with historical data, survival has improved considerably.

Obstructive sleep apnoea syndrome

Obstructive sleep apnoea syndrome (OSAS) is a common clinical condition in which the throat narrows or collapses repeatedly during sleep, causing obstructive sleep apnoea events. The syndrome is particularly prevalent in middle-aged and older adults. The mechanism by which the upper airway collapses is not fully understood but is multifactorial and includes obesity, craniofacial changes, alteration in upper airway muscle function, pharyngeal neuropathy and fluid shift towards the neck. The direct consequences of the collapse are intermittent hypoxia and hypercapnia, recurrent arousals and increase in respiratory efforts, leading to secondary sympathetic activation, oxidative stress and systemic inflammation. Excessive daytime sleepiness is a burden for the majority of patients. OSAS is also associated with cardiovascular co-morbidities, including hypertension, arrhythmias, stroke, coronary heart disease, atherosclerosis and overall increased cardiovascular mortality, as well as metabolic dysfunction. Whether treating sleep apnoea can fully reverse its chronic consequences remains to be established in adequately designed studies. Continuous positive airway pressure (CPAP) is the primary treatment modality in patients with severe OSAS, whereas oral appliances are also widely used in mild to moderate forms. Finally, combining different treatment modalities such as CPAP and weight control is beneficial, but need to be evaluated in randomized controlled trials. For an illustrated summary of this Primer, visit: http://go.nature.com/Lwc6te

Predictors of long-term compliance with continuous positive airway pressure

Background There are very few data on objectively assessed long-term compliance with continuous positive airway pressure (CPAP). No single factor has been consistently identified as predictive of continued CPAP use. Methods Adherence to and associations with objective CPAP use were examined in 639 of 3900 patients in whom CPAP treatment was started between 1994 and 2005. Kaplan–Meier survival analyses were used to estimate the proportion of patients still on CPAP. Cox regression models were used to explore the effects of covariates on continued use of CPAP. Results The median (IQR) follow-up time after initiating CPAP therapy was 3.9 (1.5–6.9) years and the average use of CPAP was 6.2 (4.5–7.3) h/night. The percentage of patients adherent to CPAP after 5 and 10 years was 81% and 70%, respectively. Multivariate analysis, including gender, age, neck circumference, Epworth Sleepiness Score, oxygen desaturation index (ODI) and research study participation, indicated that ODI was the only clinical variable independently associated with long-term adherence to CPAP (HR per 1 event=0.97, p<0.001, 95% CI 0.96 to 0.98). ODI categories were significantly associated with the risk for stopping CPAP in multivariate analysis (using ODI group 0–15/h as reference, HR for ODI group >15–30/h=0.68, p=0.100, 95% CI 0.43 to 1.08; for ODI group >30–60/h=0.37, p<0.001, 95% CI 0.22 to 0.60; and for ODI group >60/h=0.17, p=0.001, 95% CI 0.06 to 0.48). Conclusions The majority of patients with sleep-disordered breathing are using CPAP in the long term and the severity of sleep-disordered breathing rather than sleepiness determines long-term adherence to CPAP therapy.

An official american thoracic society statement: Continuous positive airway pressure adherence tracking systems the optimal monitoring strategies and outcome measures in adults

BACKGROUND Continuous positive airway pressure (CPAP) is considered the treatment of choice for obstructive sleep apnea (OSA), and studies have shown that there is a correlation between patient adherence and treatment outcomes. Newer CPAP machines can track adherence, hours of use, mask leak, and residual apnea-hypopnea index (AHI). Such data provide a strong platform to examine OSA outcomes in a chronic disease management model. However, there are no standards for capturing CPAP adherence data, scoring flow signals, or measuring mask leak, or for how clinicians should use these data. METHODS American Thoracic Society (ATS) committee members were invited, based on their expertise in OSA and CPAP monitoring. Their conclusions were based on both empirical evidence identified by a comprehensive literature review and clinical experience. RESULTS CPAP usage can be reliably determined from CPAP tracking systems, but the residual events (apnea/hypopnea) and leak data are not as easy to interpret as CPAP usage and the definitions of these parameters differ among CPAP manufacturers. Nonetheless, ends of the spectrum (very high or low values for residual events or mask leak) appear to be clinically meaningful. CONCLUSIONS Providers need to understand how to interpret CPAP adherence tracking data. CPAP tracking systems are able to reliably track CPAP adherence. Nomenclature on the CPAP adherence tracking reports needs to be standardized between manufacturers and AHIFlow should be used to describe residual events. Studies should be performed examining the usefulness of the CPAP tracking systems and how these systems affect OSA outcomes.