Carolina Lombardi

Recommendations for the management of patients with obstructive sleep apnoea and hypertension

This article is aimed at addressing the current state-of-the-art in epidemiology, pathophysiology, diagnostic procedures and treatment options for appropriate management of obstructive sleep apnoea (OSA) in cardiovascular (in particular hypertensive) patients, as well as for the management of cardiovascular diseases (in particular arterial hypertension) in OSA patients. The present document is the result of work performed by a panel of experts participating in the European Union COST (Cooperation in Scientific and Technological research) Action B26 on OSA, with the endorsement of the European Respiratory Society and the European Society of Hypertension. In particular, these recommendations are aimed at reminding cardiovascular experts to consider the occurrence of sleep-related breathing disorders in patients with high blood pressure. They are also aimed at reminding respiration experts to consider the occurrence of hypertension in patients with respiratory problems at night.

Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project

Iron is tightly connected to oxygen homeostasis and erythropoiesis. Our aim was to better understand how hypoxia regulates iron acquisition for erythropoiesis in humans, a topic relevant to common hypoxia-related disorders. Forty-seven healthy volunteers participated in the HIGHCARE project. Blood samples were collected at sea level and after acute and chronic exposure to high altitude (3400-5400 m above sea level). We investigated the modifications in hematocrit, serum iron indices, erythropoietin, markers of erythropoietic activity, interleukin-6, and serum hepcidin. Hepcidin decreased within 40 hours after acute hypoxia exposure (P < .05) at 3400 m, reaching the lowest level at 5400 m (80% reduction). Erythropoietin significantly increased (P < .001) within 16 hours after hypoxia exposure followed by a marked erythropoietic response supported by the increased iron supply. Growth differentiation factor-15 progressively increased during the study period. Serum ferritin showed a very rapid decrease, suggesting the existence of hypoxia-dependent mechanism(s) regulating storage iron mobilization. The strong correlation between serum ferritin and hepcidin at each point during the study indicates that iron itself or the kinetics of iron use in response to hypoxia may signal hepcidin down-regulation. The combined and significant changes in other variables probably contribute to the suppression of hepcidin in this setting.

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.

Daytime sleepiness and neural cardiac modulation in sleep-related breathing disorders.

Sleep‐related breathing disorders are common causes of excessive daytime sleepiness, a socially and clinically relevant problem. Mechanisms responsible for daytime sleepiness are still largely unknown. We investigated whether specific alterations in autonomic cardiac modulation during sleep, commonly associated with sleep‐related breathing disorders, are related to excessive daytime sleepiness. Fifty‐three patients with sleep‐related breathing disorders underwent nocturnal polysomnography. Excessive daytime sleepiness was diagnosed as a Multiple Sleep Latency Test response less than or equal to 600 s. We explored the relation of excessive daytime sleepiness, objectively determined, with indices of autonomic cardiac regulation, such as baroreflex sensitivity and heart rate variability, with polysomnographic indices of the severity of sleep‐related breathing disorders and with quality of sleep. Patients with excessive daytime sleepiness, when compared with patients without, had significantly lower baroreflex sensitivity and significantly higher low‐to‐high frequency power ratio of heart rate variability during the different stages of nocturnal sleep. By contrast, no differences were found in indices quantifying the severity of sleep‐related breathing disorders or sleep quality. We demonstrated that excessive daytime sleepiness is accompanied by a deranged cardiac autonomic control at night, the latter probably reflecting autonomic arousals not detectable in the EEG. As abnormal autonomic regulation is also known to be associated with increased cardiovascular risk, a possible relation between excessive daytime sleepiness and cardiovascular events in patients with sleep‐related breathing disorders deserves to be investigated in future studies.

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.

Prognostic Value of Blood Pressure Variability and Average Blood Pressure Levels in Patients With Hypertension and Diabetes

Elevated blood pressure (BP) is a major risk factor for cardiovascular (CV) events and mortality (1) and a leading contributor to the global disease burden (2). Overwhelming evidence is now available showing that BP measured in the office shows a linear relationship with a number of CV and renal outcomes as well as with overall mortality and that lowering of office BP (OBP) with treatment is effective in reducing morbidity and mortality (3,4). However, application over the last 40 years of techniques for out-of-office BP monitoring including home BP monitoring (HBPM) and 24-h ambulatory BP monitoring (ABPM) has led to further important findings. In particular, 1 ) average BP measured in everyday life conditions may be an even better predictor of CV outcomes than isolated OBP readings and 2 ) the extent of fluctuations of BP over time may provide additional, independent prognostic information compared with both isolated office readings and average ambulatory BP (ABP) levels, respectively. These findings are of upmost relevance in the case of diabetic patients who are characterized by a significantly higher risk of CV events compared with nondiabetic individuals, with diabetes itself currently considered a CV disease equivalent (5,6). The aim of the present article is to review the available evidence on the prognostic importance of BP mean levels and of BP variability (BPV) estimates and to critically evaluate whether antihypertensive treatment strategies should be targeted at reducing not only average BP levels but also the degree of BPV in order to optimize CV protection in diabetic patients. ### Prognostic value of OBP values Consistent evidence from observational studies has indicated that the risk of CV morbidity and mortality has a strong and continuous relationship with OBP levels (3), without any evidence of a threshold down to at least 115/75 mmHg (4). Furthermore, large meta-analyses of major interventional trials …

A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder.

Sleep‐related eating disorder (SRED) is characterized by recurrent arousals from sleep associated with compulsive ingestion of food. No controlled therapeutic trials are available for SRED. We assessed the safety, tolerability and efficacy of pramipexole, a dopamine D3‐receptor agonist, in the treatment of SRED. Eleven consecutive patients with SRED in the absence of concurrent daytime eating disorders underwent actigraphic recording and subjective sleep diary evaluation for a week before and every week for 2 weeks of treatment with pramipexole 0.18–0.36 mg or placebo, administered in a double‐blind crossover randomized sequence. The primary outcomes of the trial were actigraphic measures of night sleep parameters (sleep efficiency, motor activity mean and median, number and duration of wake episodes), secondary outcomes were the number of good sleep nights/weekly, number and duration of nocturnal awakenings/night, and visual analogue preference score. Pramipexole was well tolerated without any patient withdrawing from the study. Pramipexole reduced night‐time activity median (P = 0.02) and increased the number of nights of good sleep/week (P = 0.02). All other measurements remained unaffected. Pramipexole at low doses was well tolerated, improving some measures of sleep quality and reducing median night activity in SRED. Further studies with higher dosages and for longer time‐periods are warranted.

Status dissociatus after surgery for tegmental ponto‐mesencephalic cavernoma: A state‐dependent disorder of motor control during sleep

After surgery for a tegmental ponto‐mesencephalic cavernoma, a patient developed sleep‐related excessive fragmentary myoclonus, diffuse myoclonic jerks, simple quasipurposeful movements of the limbs, and rapid eye movement (REM) sleep behaviour disorder as motor features of status dissociatus, a condition in which elements of one state of being (wake, NREM and REM sleep) pathologically intrude into another.

Familial nocturnal facio-mandibular myoclonus mimicking sleep bruxism

Abstract—A mother and son presented with a multi-decade history of nocturnal tongue biting and bleeding. In both patients, video polysomnographic recordings documented bursts of electromyographic activity originating in the masseter and spreading to orbicularis oris and oculi muscles, present only during sleep. Faciomandibular myoclonic activity during sleep mimics sleep bruxism and may be familial.

Blood pressure variability: assessment, predictive value, and potential as a therapeutic target

A large body of evidence has consistently supported the relationship between blood pressure (BP) levels and the risk of cardiovascular complications. In recent years, several independent studies have also indicated that this risk may not only depend on the magnitude of the blood pressure elevation per se but also on the presence of other associated conditions such as increased blood pressure variability. This concept has been supported by a series of reports, most of which post hoc analyses of clinical trials in hypertension, showing that increasing values of BP variability (BPV) (either in the short term, in the midterm, or in the long term) may predict development, progression, and severity of cardiac, vascular, and renal organ damage, as well as cardiovascular events and mortality. Remarkably, studies conducted in populations at high cardiovascular risk have shown increasing values of BPV in the individual subjects (so-called intra- or within-individual BPV) to be strong predictors of cardiovascular morbidity and mortality, even to a larger extent than average BP values. However, in subjects at low to moderate cardiovascular risk, the contribution of BPV to cardiovascular risk prediction over and beyond average BP values has been shown to be only moderate. The aim of this paper is to critically review the evidence addressing the prognostic relevance of different components of BPV addressing a yet open question, i.e., whether routine assessment of BPV in clinical practice should be regarded as an additional target of antihypertensive treatment to improve cardiovascular protection.