ContextObstructive sleep apnea (OSA) has been increasingly implicated in the
initiation and progression of cardiovascular diseases.ObjectiveTo systematically review the interactions of OSA with cardiovascular
pathophysiology and diseases.Data Sources and Study SelectionThe MEDLINE database from January 1966 to March 2003 was searched using
the Medical Subject Headings sleep, sleep apnea, obesity, hypertension, heart failure, cardiac
arrhythmia, coronary artery disease, stroke, sympathetic activity, endothelium, inflammation, and continuous positive airway pressure (CPAP) to identify peer-reviewed studies of OSA. Priority was given
to large prospective cohort studies and to randomized controlled trials.Data ExtractionWe identified 154 original investigations and reviews of sleep-related
breathing disorders. Data from these studies were examined for relevance and
extracted by one of the authors.Data SynthesisApproximately 1 in 5 adults has at least mild OSA (apnea-hypopnea index
[ie, the number of apneic and hypopneic events per hour], 5-15), and 1 in
15 adults has at least moderate OSA (apnea-hypopnea index, 15-30). Repetitive
apneic events disrupt the normal physiologic interactions between sleep and
the cardiovascular system. Such sleep fragmentation, as well as abnormalities
evident in patients with OSA (eg, increased sympathetic activation, vascular
endothelial dysfunction, increased oxidative stress, inflammation, increased
platelet aggregability, metabolic dysregulation), may be implicated in the
initiation and progression of cardiac and vascular disease. Persuasive data
implicate OSA in the development of hypertension, and OSA also may contribute
to cardiac ischemia, congestive heart failure, cardiac arrhythmias, and perhaps
also to cerebrovascular disease and stroke.ConclusionsObstructive sleep apnea is common, readily diagnosed, and usually treatable.
It frequently coexists undiagnosed in patients with cardiovascular disease,
activates disease mechanisms known to elicit cardiac and vascular damage,
and may be implicated in progression of cardiovascular disease and resistance
to conventional therapeutic strategies. In the absence of definitive evidence
from large-scale trials and a better understanding of potential cost-effectiveness,
the likely benefits of diagnosis and treatment of OSA are presently best appraised
on an individualized patient basis.

https://jamanetwork.com/journals/jama/articlepdf/197410/jcc30007.pdf

Obstructive sleep apnea: implications for cardiac and vascular disease.

Epidemiological studies have implicated obstructive sleep apnea (OSA) as an independent comorbid factor in cardiovascular and cerebrovascular diseases. It is postulated that recurrent episodes of occlusion of upper airways during sleep result in pathophysiological changes that may predispose to vascular diseases. Insulin resistance is a known risk factor for atherosclerosis, and we postulate that OSA represents a stress that promotes insulin resistance, hence atherogenesis. This study investigated the relationship between sleep-disordered breathing and insulin resistance, indicated by fasting serum insulin level and insulin resistance index based on the homeostasis model assessment method (HOMA-IR). A total of 270 consecutive subjects (197 male) who were referred for polysomnography and who did not have known diabetes mellitus were included, and 185 were documented to have OSA defined as an apnea–hypopnea index (AHI) ⩾ 5. OSA subjects were more insulin resistant, as indicated by higher levels of fasting s...

Obstructive sleep apnea is independently associated with insulin resistance.

Background—Patients with obstructive sleep apnea (OSA) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges, each of which may impair endothelial function. We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation, even in the absence of overt cardiovascular disease. Methods and Results—We studied 8 patients with OSA (age 44 64 years) and 9 obese control subjects (age 4863 years). Patients with OSA were newly diagnosed, never treated for OSA, on no medications, and free of any other known diseases. All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA. Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine (a vasodilator that stimulates endothelial release of nitric oxide), sodium nitroprusside (an exogenous nitric oxide donor), and verapamil (a calcium channel blocker). Conduit-vessel function was also evaluated by ultrasonography. Brachial artery diameter was measured under baseline conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). Patients with OSA had a blunted vasodilation in response to acetylcholine ( P,0.007), but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects. No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects. Conclusions—Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation. This may be implicated in the pathogenesis of hypertension and heart failure in this condition. (Circulation. 2000;102:26072610.)

Impairment of Endothelium-Dependent Vasodilation of Resistance Vessels in Patients With Obstructive Sleep Apnea

Sleep Apnea and Cardiovascular Disease

Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free oxygen radicals have been implicated in the pathogenesis of cardiovascular disorders. Therefore, we aimed to test the hypothesis that increased oxidative stress constitutes one underlying mechanism for the connection between OSA and cardiovascular disease. In 18 patients with OSA the release of superoxide from polymorphonuclear neutrophils was determined after stimulation with the bacterial tripeptide formylmethionylleucylphenylalanine (fMLP) and the calcium ionophore A23. Superoxide production was measured as superoxide dismutase-inhibitable reduction of cytochrome c. Blood samples were obtained before and after two nights of CPAP therapy and after 4.8 +/- 0.6 mo of follow-up. Ten healthy young volunteers and 10 lung cancer patients without OSA but a similar spectrum of comorbidity served as controls. Before CPAP, neutrophil superoxide generation was markedly enhanced in OSA when compared with both control groups. Effective CPAP therapy led to a rapid and long-lasting decrease of superoxide release in OSA. In conclusion, OSA is linked with a "priming" of neutrophils for enhanced respiratory burst. The increased superoxide generation, which might have major impact on the development of cardiovascular disorders, is virtually fully reversed by effective CPAP therapy.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.162.2.9908091

Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy.

Possible atherogenic effects of hypoxia during obstructive sleep apnea. Discussion

Sleep apnoea is common in patients with heart failure. While most patients have central sleep apnoea (CSA), a minority have obstructive sleep apnoea (OSA). The pathophysiology of CSA is not well understood. We hypothesized that central chemosensitivity would be an important pathophysiological factor in patients with CSA, and not in OSA. The aim of this study was to compare ventilatory responses between patients with CSA and those with OSA. Acute ventilatory responses to eucapnic hypoxia and hyperoxic hypercapnia were measured during wakefulness in 34 patients (33 males and one female, aged 59+/-8 yrs (mean+/-SD)), with stable medically-treated left ventricular dysfunction (LVD) and sleep apnoea (18 OSA and 16 CSA). Patients with CSA had a decreased awake end-tidal carbon dioxide tension (4.1+/-0.5 kPa), increased ventilatory response to carbon dioxide (0.65+/-0.43 L.min.(-1).kPa PCO2(-1)), and eucapnic hypoxic responses in the normal range (0.6+/-0.4 L.min(-1)/% fall in arterial oxygen saturation (Sa,O2)). In contrast, patients with OSA had normal end-tidal carbon dioxide tension (4.9+/-0.5 kPa), and normal ventilatory responses to hypercapnia (0.29+/-0.16 L.min(-1).kPa PCO2(-1)) and hypoxia (0.5+/-0.5 L-min(-1)/% fall in Sa,O2). These findings suggest that augmented chemosensitivity to hypercapnia may be an important factor in the pathophysiology of central sleep apnoea in patients with heart failure.

https://erj.ersjournals.com/content/erj/11/1/7.full.pdf

Ventilatory control in patients with sleep apnoea and left ventricular dysfunction: comparison of obstructive and central sleep apnoea

Breathing O2 for up to 1 h has been shown to either not influence or slightly increase (6–13%) minute ventilation. However, end-tidal PCO2 was not kept constant in these experiments. In nine health...

Ventilatory response to isocapnic hyperoxia

Study Objectives: Pre-eclampsia is currently the predominant cause of maternal and fetal morbidity and mortality. Diurnal blood pressure variation is flattened or reversed in pre-eclampsia; however, sleep has not been extensively investigated in this disease. Our objective was therefore to study sleep architecture in this group of patients. Study Design: Full polysomnography using the Compumedics Sleepwatch System® or Compumedics p-series. Setting: NA Patients: 25 pre-eclamptic patients and 17 primigravidas with normal pregnancies and no history of cardiovascular disease or sleep disorder. With the exception of one subject, all pre-eclamptics were taking clonidine (a known suppressant of rapid eye movement-REM-sleep) for control of their hypertension. Interventions: NA Results: Pre-eclamptic subjects had markedly altered sleep architecture, with a markedly increased percentage of time spent in slow-wave sleep (SWS) (21 * 2% versus 43 * 3%, p < 0.001). There was a longer latency to rapid eye movement (REM) sleep (92 * 11 mins vs. 205 * 23 mins in control and pre-eclamptic subjects, respectively, p<0.001) and reduced time spent in REM (18 * 1% and 10 * 2% in control and pre-eclamptic subjects, respectively, p<0.001). Conclusions: While the increased REM latency and decreased REM time are most likely due to clonidine, this is unlikely to also account for the increased SWS. Two possible explanations for this include cerebral edema and release of cytokines, which are known to alter sleep structure.

Pre-eclampsia is associated with marked alterations in sleep architecture.

Overnight sleep studies were performed in 20 subjects with achondroplasia to document further the respiratory abnormalities present in this group. Somatosensory evoked potentials (SEPs) were recorded in 19 of the subjects to screen for the presence of brainstem abnormalities, which are one of the potential aetiological mechanisms. Fifteen children aged 1 to 14 years, and five young adults, aged 20 to 31 years were included. All had upper airway obstruction and 15 (75%) had a pathological apnoea index (greater than five per hour). Other sleep associated respiratory abnormalities, including partial obstruction, central apnoea, and abnormal electromyographic activity of accessory muscles of respiration, also showed a high prevalence. SEPs were abnormal in eight (42%), but there was no correlation between abnormal SEPs and apnoea during sleep, either qualitatively or quantitatively. A high prevalence of both sleep related respiratory abnormalities and abnormal SEPs in young subjects with achondroplasia was demonstrated. However, the sleep related respiratory abnormalities do not always result in significant blood gas disturbances or correlate with abnormal SEPs in this group.

https://adc.bmj.com/content/archdischild/69/2/191.full.pdf

C. E. Sullivan

Papers

Possible atherogenic effects of hypoxia during obstructive sleep apnea. Discussion

Ventilatory control in patients with sleep apnoea and left ventricular dysfunction: comparison of obstructive and central sleep apnoea

Ventilatory response to isocapnic hyperoxia

Pre-eclampsia is associated with marked alterations in sleep architecture.

Breathing abnormalities in sleep in achondroplasia.