Richard Leung

High prevalence of unrecognized sleep apnoea in drug-resistant hypertension

Objectives To determine the prevalence of obstructive sleep apnoea (OSA) in adult patients with drug-resistant hypertension, a common problem in a tertiary care facility. Design Cross-sectional study. Setting University hypertension clinic. Patients and methods Adults with drug-resistant hypertension, defined as a clinic blood pressure of ⩾ 140/90 mmHg, while taking a sensible combination of three or more antihypertensive drugs, titrated to maximally recommended doses. Each of the 41 participants completed an overnight polysomnographic study and all but two had a 24 h ambulatory blood pressure measurement. Results Prevalence of OSA, defined as an apnoea-hypopnoea index of ⩾ 10 obstructive events per hour of sleep, was 83% in the 24 men and 17 women studied. Patients were generally late middle-aged (57.2 ± 1.6 years, mean ± SE), predominantly white (85%), obese (body mass index, 34.0 ± 0.9 kg/m2) and taking a mean of 3.6 ± 0.1 different antihypertensive medications daily. OSA was more prevalent in men than in women (96 versus 65%, P = 0.014) and more severe (mean apnoea–hypopnoea index of 32.2 ± 4.5 versus 14.0 ± 3.1 events/h, P = 0.004). There was no gender difference in body mass index or age. Women with OSA were significantly older and had a higher systolic blood pressure, lower diastolic blood pressure, wider pulse pressure and slower heart rate than women without OSA. Conclusions The extraordinarily high prevalence of OSA in these patients supports its potential role in the pathogenesis of drug-resistant hypertension, and justifies the undertaking of a randomized controlled trial to corroborate this hypothesis.

Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex

This study was undertaken to determine whether abolition of obstructive sleep apnoea (OSA) by continuous positive airway pressure (CPAP) could reduce blood pressure (BP) in patients with refractory hypertension. In 11 refractory hypertensive patients with OSA, the acute effects of CPAP on nocturnal BP were studied during sleep and its longer term effects on 24-h ambulatory BP after 2 months. During a single nights application, CPAP abolished OSA and reduced systolic BP in stage 2 sleep from 138.3±6.8 to 126.0±6.3 mmHg. There was also a trend towards a reduction in average diastolic BP (from 77.7±4.5 to 72.9±4.5). CPAP usage for 2 months was accompanied by an 11.0±4.4 mmHg reduction in 24-h systolic BP. In addition, both the nocturnal and daytime components of systolic BP fell significantly by 14.4±4.4 and 9.3±3.9 mmHg, respectively. Diastolic BP was reduced significantly at night by 7.8±3.0 mmHg. In patients with refractory hypertension, acute abolition of obstructive sleep apnoea by continuous positive airway pressure reduces nocturnal blood pressure. These data also suggest that continuous positive airway pressure may reduce nocturnal and daytime systolic blood pressure chronically. Randomised trials are needed to confirm the latter results.

Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell–precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

Obstructive Sleep Apnea and Incident Diabetes. A Historical Cohort Study

RATIONALE Despite emerging evidence that obstructive sleep apnea (OSA) may cause metabolic disturbances independently of other known risk factors, it remains unclear whether OSA is associated with incident diabetes. OBJECTIVES To evaluate whether risk of incident diabetes was related to the severity and physiologic consequences of OSA. METHODS A historical cohort study was conducted using clinical and provincial health administrative data. All adults without previous diabetes referred with suspected OSA who underwent a diagnostic sleep study at St. Michaels Hospital (Toronto, Canada) between 1994 and 2010 were followed through health administrative data until May 2011 to examine the occurrence of diabetes. All OSA-related variables collected from the sleep study were examined as predictors in Cox regression models, controlling for sex, age, body mass index, smoking status, comorbidities, and income. MEASUREMENTS AND MAIN RESULTS Over a median follow-up of 67 months, 1,017 (11.7%) of 8,678 patients developed diabetes, giving a cumulative incidence at 5 years of 9.1% (95% confidence interval, 8.4-9.8%). In fully adjusted models, patients with apnea-hypopnea index (AHI) greater than 30 had a 30% higher hazard of developing diabetes than those with AHI less than 5. Among other OSA-related variables, AHI in rapid eye movement sleep and time spent with oxygen saturation less than 90% were associated with incident diabetes, as were heart rate, neck circumference, and sleep time. CONCLUSIONS Among people with OSA, and controlling for multiple confounders, initial OSA severity and its physiologic consequences predicted subsequent risk for incident diabetes.

Sleep-Disordered Breathing: Autonomic Mechanisms and Arrhythmias

Obstructive sleep apnea (OSA) is present in at least 2% to 4% of the general population. Central sleep apnea (CSA), though less common, is highly prevalent in patients with heart failure. Both forms of sleep apnea exert strong modulatory effects on the autonomic nervous system at night through a number of mechanisms including central respiratory-cardiac coupling in the brainstem, chemoreflex stimulation, baroreflexes, and reflexes relating to lung inflation. Arousals also contribute to the autonomic disturbance. Although sleep is normally a time when parasympathetic modulation of the heart predominates and myocardial electrical stability is enhanced, OSA and CSA disturb this quiescence, creating an autonomic profile in which both profound vagal activity leading to bradyarrhythmias, and sympatho-excitation favoring ventricular ectopy are observed. The resulting tendency toward cardiac arrhythmia may directly contribute to sudden cardiac death and premature mortality in patients with sleep apnea. Therapy consists largely of treatment with continuous positive airway pressure, which has been shown to improve autonomic profile and reduce nocturnal arrhythmias.

Continuous positive airway pressure increases heart rate variability in heart failure patients with obstructive sleep apnoea.

Patients with heart failure or OSA (obstructive sleep apnoea) have reduced HF-HRV (high-frequency heart rate variability), indicating reduced cardiac vagal modulation, a marker of poor prognosis. CPAP (continuous positive airway pressure) abolishes OSA in patients with heart failure, but effects on daytime HF-HRV have not been determined. We hypothesized that, in patients with heart failure, treatment of coexisting OSA by CPAP would increase morning HF-HRV. In 19 patients with heart failure (left ventricular ejection fraction <45%) and OSA (>/=20 apnoeas and hypopnoeas/h of sleep), HF-HRV was quantified before and 1 month after randomization to a control or CPAP-treated group. In the control group (n=7), there were no changes in HF-HRV over the 1 month study during wakefulness in the morning. In the CPAP-treated group (n=12) HF-HRV increased significantly during wakefulness in the morning [from 2.43+/-0.55 to 2.82+/-0.50 log(ms(2)/Hz); P=0.002] due to an increase in transfer function between changes in lung volume and changes in HF-HRV (92.37+/-96.03 to 219.07+/-177.14 ms/l; P=0.01). In conclusion, treatment of coexisting OSA by nocturnal CPAP in patients with heart failure increases HF-HRV during morning wakefulness, indicating improved vagal modulation of heart rate. This may contribute to improved prognosis.

Immunohistochemical and ultrastructural correlates of muscle-actin expression in pleomorphic adenomas and myoepitheliomas based on comparison of formalin and methanol fixation

The degree and range of differentiation of the cells referred to as myoepithelial-like in pleomorphic adenomas and the tumour cells of myoepitheliomas are not definitely established. This type of information is critical for establishing reliable diagnostic criteria, such as expression of muscle-specific actin and ultrastructural identification of myofilaments, in these and other salivary gland tumours. Pleomorphic adenomas (18) and myoepitheliomas (5), of which 10 cases were fixed only in formalin and 13 cases where tissues were fixed in both formalin and methanol/acetic acid, were studied. Each tumour and normal accompanying parotid was immunostained with two monoclonal antibodies for smooth muscle actin, HHF35 and MSA. Staining of myoepithelial cells was absent in certain samples of normal gland with both HHF35 (15%) and MSA (69%) when formalin-fixed tissue was used. Using formalin-fixed tissue from 15 pleomorphic adenomas/myoepitheliomas, 2 (14%) had focal positivity with HHF35, while 8 cases (57%) were positive with MSA. However, a certain degree of false positivity was suspected since in samples of normal parotid, both acinar and duct cells were frequently stained, particularly with MSA. With methanol/ acetic acid-fixed tissue only 4 of 13 cases (31%) were positive with either MSA or HHF35 and 2 of these only had a minor proportion of the tumour cells expressing muscle-specific actin. Using alcohol-fixed tissue, myoepithelial cells were strongly stained in all examples of normal parotid gland with both anti-actin antibodies. In 5 cases examined by electron microscopy, there was no apparent correlation between immunohistochemical results and the presence or absence of cytoplasmic filament accumulation. The results indicate considerable tumour cell heterogeneity in muscle-specific actin expression and suggest that non-luminal cells in pleomorphic adenomas and the tumour cells in myoepitheliomas may differentiate as classical myoepithelial cells, as partially differentiated (i.e. modified myoepithelial cells) or as the counterpart of basal cells present in the intra- and interlobular ducts of normal salivary gland.

Obstructive sleep apnea and the prevalence and incidence of cancer

Background: A link between obstructive sleep apnea and cancer development or progression has been suggested, possibly through chronic hypoxemia, but supporting evidence is limited. We examined the association between the severity of obstructive sleep apnea and prevalent and incident cancer, controlling for known risk factors for cancer development. Methods: We included all adults referred with possible obstructive sleep apnea who underwent a first diagnostic sleep study at a single large academic hospital between 1994 and 2010. We linked patient data with data from Ontario health administrative databases from 1991 to 2013. Cancer diagnosis was derived from the Ontario Cancer Registry. We assessed the cross-sectional association between obstructive sleep apnea and prevalent cancer at the time of the sleep study (baseline) using logistic regression analysis. Cox regression models were used to investigate the association between obstructive sleep apnea and incident cancer among patients free of cancer at baseline. Results: Of 10 149 patients who underwent a sleep study, 520 (5.1%) had a cancer diagnosis at baseline. Over a median follow-up of 7.8 years, 627 (6.5%) of the 9629 patients who were free of cancer at baseline had incident cancer. In multivariable regression models, the severity of sleep apnea was not significantly associated with either prevalent or incident cancer after adjustment for age, sex, body mass index and smoking status at baseline (apnea–hypopnea index > 30 v. < 5: adjusted odds ratio [OR] 0.96, 95% confidence interval [CI] 0.71–1.30, for prevalent cancer, and adjusted hazard ratio [HR] 1.02, 95% CI 0.80–1.31, for incident cancer; sleep time spent with oxygen saturation < 90%, per 10-minute increase: adjusted OR 1.01, 95% CI 1.00–1.03, for prevalent cancer, and adjusted HR 1.00, 95% CI 0.99–1.02, for incident cancer). Interpretation: In a large cohort, the severity of obstructive sleep apnea was not independently associated with either prevalent or incident cancer. Additional studies are needed to elucidate whether there is an independent association with specific types of cancer.

FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets

Bin-Amphiphysin-Rvs (BAR) and Fes-CIP4 homology BAR (F-BAR) proteins generate tubular membrane invaginations reminiscent of the megakaryocyte (MK) demarcation membrane system (DMS), which provides membranes necessary for future platelets. The F-BAR protein PACSIN2 is one of the most abundant BAR/F-BAR proteins in platelets and the only one reported to interact with the cytoskeletal and scaffold protein filamin A (FlnA), an essential regulator of platelet formation and function. The FlnA-PACSIN2 interaction was therefore investigated in MKs and platelets. PACSIN2 associated with FlnA in human platelets. The interaction required FlnA immunoglobulin-like repeat 20 and the tip of PACSIN2 F-BAR domain and enhanced PACSIN2 F-BAR domain membrane tubulation in vitro. Most human and wild-type mouse platelets had 1 to 2 distinct PACSIN2 foci associated with cell membrane GPIbα, whereas Flna-null platelets had 0 to 4 or more foci. Endogenous PACSIN2 and transfected enhanced green fluorescent protein-PACSIN2 were concentrated in midstage wild-type mouse MKs in a well-defined invagination of the plasma membrane reminiscent of the initiating DMS and dispersed in the absence of FlnA binding. The DMS appeared less well defined, and platelet territories were not readily visualized in Flna-null MKs. We conclude that the FlnA-PACSIN2 interaction regulates membrane tubulation in MKs and platelets and likely contributes to DMS formation.

Timing of Nocturnal Ventricular Ectopy in Heart Failure Patients With Sleep Apnea

BACKGROUND Ventricular ectopy is frequent in heart failure (HF) patients with sleep apnea. A previous report indicated that in HF patients, ventricular premature beats (VPB) occurred more frequently during episodes of recurrent central sleep apnea (CSA) than during normal breathing, and their frequency was greater during hyperpnea than during apnea. We hypothesized that, because respiratory stimuli that might provoke ventricular ectopy are stronger during obstructive apneas than during central apneas, in contrast to CSA, VPBs would be more frequent during apnea than hyperpnea in HF patients with obstructive sleep apnea (OSA). METHODS HF patients in sinus rhythm who have OSA or CSA (apnea-hypopnea index, > or = 15 events per hour) and with > 30 VPBs per hour were matched for severity of cardiac dysfunction and sleep apnea. The frequency of VPBs was then assessed during stage 2 sleep during the apneic and the hyperpneic phases of recurrent obstructive or central apneas. RESULTS VPBs occurred more frequently during the apneic phase than during the hyperpneic phase in patients with OSA. In contrast, VPBs occurred more frequently during the hyperpneic phase than the apneic phase in patients with CSA. There was no difference in the degree of apnea-related oxygen desaturation between central and obstructive apneas. CONCLUSIONS In patients with HF, nocturnal ventricular ectopy oscillates in time with oscillations in ventilation, with VPBs occurring predominantly during apneas in patients with OSA, but during hyperpneas in patients with CSA. This difference in VPB timing between OSA and CSA may be attributable to the differences in timing of arrhythmic stresses in these patients.