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Emerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA.

Despite extensive research, there is currently no approved drug for obstructive sleep apnea (OSA) treatment. OSA is a heterogeneous condition that involves multiple dominating pathophysiological traits. Drug development in this field needs to address both pathophysiological mechanisms and associated comorbid conditions in order to meet requirements for long-term therapy in OSA. Several drug candidates have been proposed and ongoing phase II trials that target various forms of sleep-disordered breathing have been initiated. The field is moving toward tailored therapeutic approaches in patients with OSA.

Excessive sleepiness (ES) is a common symptom of OSA, which often persists despite primary OSA therapy. This phase III randomized withdrawal trial evaluated solriamfetol (JZP-110) for the treatment of ES in adults with OSA.

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The impact of treating OSA on renal function decline is controversial. Previous studies usually included small samples and did not consider specific effects of different CPAP modalities. The aim of this study was to evaluate the respective influence of fixed and autoadjusting CPAP modes on estimated glomerular filtration rate (eGFR) in a large sample of patients derived from the prospective European Sleep Apnea Database cohort.

There are several reasons to develop a pharmacologic remedy in obstructive sleep apnea (OSA); but so far, there is no generally effective drug available. Previous attempts to find a drug in OSA therapy were serendipity driven in small pilot trials. There is growing literature on phenotyping pathophysiologic mechanisms of OSA that may be exploited in strategic drug development programs. The current review addresses potential pitfalls encountered in previous studies and highlights several drug candidates under development in the field.

In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (HAROSA 1) and the other in patients refusing or not tolerating CPAP (HAROSA 2).

The carbonic anhydrase inhibitor sulthiame (STM) reduces obstructive sleep apnea (OSA) severity, increases overnight oxygenation and improves sleep quality. Insights into how STM modulates OSA pathophysiology (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation.

The catalytic function of the enzyme carbonic anhydrase (CA) plays a fundamental role in carbon dioxide (CO2), proton (H(+)), and bicarbonate (HCO3(-)) homeostasis. Hypoxia and tissue acidosis have been proposed to increase physiological CA activity in various compartments of the body. We hypothesized that CA activity in blood is upregulated in patients with obstructive sleep apnea (OSA).

Obstructive sleep apnea (OSA) is associated with an increased risk of motor vehicle accidents (MVAs). The rate of MVAs in patients suspected of having OSA was determined and the effect of continuous positive airway pressure (CPAP) was investigated.

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.

Conventional methods for cardiovascular disease risk stratification are based on quantification of recognized risk factors or assessment of biomarkers during the wake period. We evaluated an algorithm on the basis of a photoplethysmographic pulse wave recording during sleep for cardiovascular risk assessment.

Apnea hypopnea index (AHI) is used to study the association between obstructive sleep apnea (OSA) and hypertension, but the independent contributions of total sleep time (TST) and apneahypopnea event count to hypertension have not been previously investigated. We studied the relationship between polysomnographically assessed TST and hypertension in a sex-balanced community-dwelling cohort of hypertensive patients and normotensive controls (Skara Sleep Cohort).

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 apnea (OSA) in cardiovascular (particularly hypertensive) patients, as well as for the management of cardiovascular diseases (particularly arterial hypertension) in OSA patients. The present document is the result of the work done 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 (ERS) and the European Society of Hypertension (ESH). These recommendations are particularly aimed at reminding cardiovascular experts to consider the occurrence of sleep-related breathing disorders in patients with high blood pressure. They are at the same time aimed at reminding respiration experts to consider the occurrence of hypertension in patients with respiratory problems at night.

Cardiovascular (CV) risk assessment is important in clinical practice. An autonomic state indicator (ASI) algorithm based on pulse oximetry was developed and validated for CV risk assessment.

To evaluate the effect of bariatric surgery on sleep apnea symptoms and obesity-associated morbidity in patients with severe obesity.

Obstructive sleep apnoea (OSA) confers a risk of hypertension and cardiovascular complications. Both the renin–angiotensin–aldosterone system and OSA are important determinants of blood pressure, but it is not fully known how they interact. The aim of this study was to explore the interaction between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and OSA in the association with hypertension.

To assess the accuracy of a portable monitoring device based on peripheral arterial tonometry to diagnose obstructive sleep apnea (OSA). To propose a new standard for limited-channel device validation using synchronized polysomnography (PSG) home recordings and a population-based cohort.

Nocturnal and early morning elevation of blood pressure are common acute manifestations of obstructive sleep apnea (OSA) that do not always carry over into a sustained daytime hypertension. Using pulse wave analysis, we examined the effect of OSA on arterial stiffness and central aortic blood pressure to assess whether each would be elevated independent of diurnal changes in peripheral blood pressure.

Current actigraphic algorithms are relatively less accurate in detecting sleep and wake in sleep apnea patients than in people without sleep apnea. In the current study, we attempted to validate a novel automatic algorithm, which was developed for actigraphic studies in normal subjects and patients with obstructive sleep apnea by comparing it on an epoch-by-epoch basis to standard polysomnography.

To characterize the role of alpha-receptors in autonomic control of digital skin blood flow change in response to obstructive apnea-hypopnea events.

Objective —To study various aspects of sleep quality and sleep patterns prior to and after coronary artery bypass surgery and their implications for 5-year survival.Methods —All patients from western Sweden who underwent coronary artery bypass grafting (CABG) between 1988 and 1991 (n = 2121) received a questionnaire addressing sleep habits prior to and 1 year after surgery.Various symptoms and habits related to sleep at the two evaluations were compared. Symptoms and habits related to sleep prior to CABG were then related to 5-year survival.Results —In all, 1224 patients took part in the evaluation. A highly significant improvement was observed with regard to the following symptoms and habits related to sleep: feeling refreshed upon awakening, feeling tired during daytime, waking up with headache, nightmares, sweating during night time, medication for pain relief at bedtime, involuntarily falling asleep during daytime, apnoea during sleep and mouth dryness during the night.Various symptoms and habits associated with sleep prior to CABG were generally not strongly related to prognosis. Exceptions were feeling refreshed upon awakening and infrequent consumption of pain relief medication at bedtime which both were associated with an improved long-term survival.Conclusions —A variety of symptoms associated with sleep improve highly significantly after CABG.The occurrence of these symptoms prior to CABG do not generally seem to influence the long-term prognosis.

We investigated whether the severity of obstructive sleep apnea (OSA) predicts blood pressure or cardiac left ventricular thickness in a clinical population of OSA patients, if adjustments are made for age, gender, use of antihypertensive agents, smoking, body mass index, history of coronary artery disease, hypercholesterolemia and circulating C-peptide concentrations.

To investigate whether a dose-effect relationship exists between the severity of obstructive sleep apnea (OSA) and subclinical indicators of myocardial or vascular dysfunction.

To test the hypothesis that sleep-related breathing disorder (SRBD) is associated with increasing severity of cardiovascular risk markers.

We studied vasoconstrictor sensitivity and cholinergic responsiveness of the forearm vasculature in 10 male patients with obstructive sleep apnea (OSA) and 10 healthy controls. Subjects with regular medication, known arterial hypertension, diabetes mellitus, or dyslipidemia were not included in this study. Age, body mass index, blood pressure, blood glucose, serum lipids, and baseline forearm vascular conductance (derived from venous occlusion plethysmography and intra-arterial blood pressure measurement) did not differ significantly between these two groups. With use of three dosage steps each, angiotensin II and acetylcholine were successively infused into the brachial artery. During infusion of angiotensin II, mean conductance was 39.6% lower (P= 0.002) in the OSA patients compared with that in the control subjects. Vascular responsiveness to increasing dosages of acetylcholine was not significantly altered in the OSA group. These findings suggest an enhanced vasoconstrictor sensitivity in the forearm vasculature in OSA. The hypothesis that endothelial function in OSA is impaired independently of other cardiovascular risk factors is not supported by the present results.

To test the hypothesis that sleep-related breathing disorder (SRBD) is associated with poor blood pressure control in hypertensive patients independent from confounding factors such as age, body mass index, alcohol, smoking and daytime blood gases.

We investigated whether the effect of long-term intermittent hypoxia (LTIH) on cardiovascular function may be modified by preexisting genetic traits. To induce LTIH experimentally, cycles of 90-s hypoxia (nadir 6%) followed by 90-s normoxia were applied to six Wistar-Kyoto and six spontaneously hypertensive rats during 8 h daily. Comparison with the same number of control animals after 70 days revealed no alteration of intra-arterial blood pressure or heart rate. Blood pressure responsiveness to a brief hypoxic stimulus was enhanced in the LTIH animals, regardless of strain, whereas the hypoxia-induced increase in heart rate was abolished. In the spontaneously hypertensive but not the Wistar-Kyoto rats, LTIH increased left ventricular weight-to-body weight ratio and content of atrial natriuretic peptide mRNA. Expression of B-type natriuretic peptide was unchanged (Northern blot). Slightly increased right ventricular weight-to-body weight ratios in the LTIH animals were associated with higher right ventricular atrial natriuretic peptide and B-type natriuretic peptide mRNA amounts. Consequently, the effects of LTIH on different components of cardiovascular function appear incompletely related to each other and differentially influenced by constitutional traits.

• The effects of nasal valve dilation on snoring and obstructed breathing were studied in 11 patients with habitual snoring and/or obstructive sleep apnea. The anterior part of the nose, the valve region, was dilated by means of a plastic device. Ten patients underwent polysomnographic investigation including pulse oximetry and measurement of snoring noise with and without the nasal dilator in a randomized manner. Snoring, nocturnal arousals, and daytime hypersomnolence were rated by the patient and partner on a questionnaire before and after a 10-day treatment period with the dilator. The nasal airflow, as assessed by rhinomanometry when awake in the sitting position, increased by 18% (range, 5.5% to 45%) when the nasal dilator was used. The frequency and severity of obstructed breathing decreased significantly with the nasal dilator. The apnea index with and without the nasal dilator was 6.4 (range, 1.3 to 15) and 18 (range, 1.8 to 60), respectively. The mean decrease of the apnea index was 47%. The overnight minimum arterial oxygen saturation ( with and without the nasal dilator was 84% (range, 76% to 88%) and 78% (range, 68% to 89%), respectively. There was a substantial decrease in snoring noise (number of epochs with Leq values, equal energy level, above 55 or 60 dB) with the dilator in all patients who presented with snoring noise above these levels during the control night. No subjective effects on arousal frequency or daytime hypersomnolence were reported. Four of 11 patients were positive to continue using the nasal dilator.(Arch Otolaryngol Head Neck Surg. 1992;118:281-284)

The hemodynamic effects during rest and exercise of oral snuff were investigated in an open, placebocontrolled study of nine habitual users of oral snuff. Blood pressure, heart rate, and central hemodynam-ics were measured noninvasively. Plasma concentrations of nicotine, cotinine, norepinephrine, and epi-nephrine, as well as neuropeptide Y-like immunoreactivity were measured before and after snuff intake during rest and exercise. Snuff intake induced a significant increase in heart rate and blood pressure and a decrease in stroke volume during rest. Hemodynamic changes were unrelated to nicotine or cotinine concentrations. Resting levels of norepinephrine and neuropeptide Y-like immunoreactivity were similar with or without snuff, whereas epinephrine was slightly increased 30 minutes after snuff intake. The exercise-induced increase in norepinephrine and neuropeptide Y-like immunoreactivity did not differ between the days subjects received snuff and the days they received placebo. In contrast, maximum work load was associated with a slight increase in circulating epinephrine after snuff intake. The findings suggest that snuff intake is associated with significant hemodynamic effects during rest but not during exercise. These effects could not be readily explained by activation of the sympathetic nervous system.Clinical Pharmacology and Therapeutics (1992) 52, 394–401; doi:10.1038/clpt.1992.161

We wished to determine whether pharmacologic inhibition of the exaggerated sympathetic nerve activity in congestive heart failure (CHF) could restore the renal response to exogenous atrial natriuretic peptide (ANP) administration. Left ventricular (LV) myocardial infarction was induced in Sprague-Dawley rats (n 16) by coronary artery ligature. Four to 6 weeks postoperatively, an isotonic saline (controls) or clonidine 5 µg/h infusion was given. Four hours later, all animals received incremental doses of rat ANP (99-126) (0.25, 0.5 and 1.0µg/kg/min). The continuous clonidine infusion transiently increased urinary volume (UV) as compared with the saline controls. Mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) were significantly decreased by clonidine. The graded ANP infusions significantly increased UV (saline 39.13 ± 12.45 and clonidine 90.25 ± 13.69 (µl/min, p<0.05) and UNaV (saline 4.26 ± 1.10 and clonidine 8.81 ± 1.59 µmol/min, p<0.05) in clonidine-pretreated rats as compared with salinepretreated rats. We conclude that the diuretic and natriuretic responses to ANP are significantly increased in CHF after presynaptic inhibition of NE release by lowdose clonidine