Bradley G. Phillips

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

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±4 years) and 9 obese control subjects (age 48±3 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.

Nocturnal Continuous Positive Airway Pressure Decreases Daytime Sympathetic Traffic in Obstructive Sleep Apnea

BACKGROUND Patients with obstructive sleep apnea (OSA) have high levels of muscle sympathetic nerve activity (MSNA). We tested the hypothesis that long-term continuous positive airway pressure (CPAP) treatment will decrease MSNA in OSA patients. METHODS AND RESULTS We measured blood pressure, heart rate, and MSNA in 11 normotensive, otherwise healthy patients with OSA who were treated with CPAP. The measurements were obtained at baseline and after 1 month, 6 months, and 1 year of CPAP treatment. These measurements were compared with those recorded in 9 otherwise healthy OSA patients who were not treated with CPAP for 1 year. In both untreated and treated patients, blood pressure and heart rate did not change over time. MSNA was similar during repeated measurements in the untreated group. By contrast, MSNA decreased significantly over time in patients treated with CPAP. This decrease was evident after both 6 months and 1 year of CPAP treatment (P=0.02 for both). CONCLUSIONS CPAP treatment decreases muscle sympathetic traffic in patients with OSA. This effect of CPAP is evident only after an extended duration of therapy.

Effects of obstructive sleep apnea on endothelin-1 and blood pressure

OBJECTIVE To evaluate blood pressure and humoral vasoconstrictor responses to recurrent episodes of obstructive sleep apnea and the effects of therapy by means of continuous positive airway pressure. PATIENTS AND METHODS We prospectively evaluated overnight changes in hemodynamics, oxygen saturation, the apnea-hypopnea index, circulating endothelin-1, norepinephrine and plasma renin activity in 22 patients with severe obstructive sleep apnea before and after successful therapy using continuous positive airway pressure therapy (three measurements). Measurements of endothelin-1 and blood pressure were also obtained on three occasions, at similar times, in 12 healthy control subjects without sleep disturbances. RESULTS Mean arterial pressure and endothelin-1 concentrations increased significantly after 4 h of untreated obstructive sleep apnea, and decreased after 5 h of continuous positive airway pressure. Changes in endothelin-1 levels were correlated with changes in mean arterial pressure (r = 0.44, P < 0.02) and with changes in oxygen saturation (r = 0.37, P < 0.05). Norepinephrine levels and plasma renin activity did not change significantly in patients with obstructive sleep apnea, and were not correlated with changes in blood pressure or oxygen saturation. In controls, blood pressure measurements at similar times during the night showed changes directionally opposite to that seen in obstructive sleep apnea, while endothelin-1 levels remained unchanged. CONCLUSIONS Sleep apnea elicits increases in blood pressure and endothelin-1, with reductions in both after treatment. Vasoconstrictor and mitogenic effects of endothelin-1 may be implicated in increased cardiovascular risk in patients with obstructive sleep apnea.

Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea

BACKGROUND Muscle sympathetic nerve activity (MSNA) is increased in patients with obstructive sleep apnea (OSA). We tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in OSA. METHODS AND RESULTS Using a double-blind, randomized, vehicle-controlled design, we examined the effects of chemoreflex deactivation (by comparing effects of breathing 100% oxygen for 15 minutes with effects of breathing room air for 15 minutes) on MSNA, heart rate, blood pressure, and minute ventilation in 14 untreated patients with OSA and in 12 normal subjects matched for age and body mass index. All control subjects underwent overnight polysomnography to exclude the existence of occult OSA. Baseline MSNA was markedly elevated in the patients with OSA compared with the control subjects (44+/-4 versus 30+/-3 bursts per minute; P=.01). In both control subjects and patients with OSA, heart rate decreased during administration of 100% oxygen but did not change during administration of room air. By contrast, both MSNA (P=.008) and mean arterial pressure (P=.02) were significantly reduced during chemoreflex deactivation by 100% oxygen only in patients with OSA but not in control subjects. CONCLUSIONS Tonic activation of excitatory chemoreflex afferents may contribute to increased efferent sympathetic activity to muscle circulation in patients with OSA.

Effects of Sleep Deprivation on Neural Circulatory Control

Effects of sleep deprivation on neural cardiovascular control may have important clinical implications. We tested the hypothesis that sleep deprivation increases heart rate, blood pressure, and sympathetic activity and potentiates their responses to stressful stimuli. We studied 8 healthy subjects (aged 40+/-5 years, 6 men and 2 women). Blood pressure, heart rate, forearm vascular resistance, and muscle sympathetic nerve activity were measured at rest and during 4 stressors (sustained handgrip, maximal forearm ischemia, mental stress, and cold pressor test). Measurements were obtained twice, once after normal sleep and once after a night of sleep deprivation. All measurements were obtained in a blinded, randomized manner. In comparison with normal sleep, sleep deprivation resulted in an increase in blood pressure (normal sleep versus sleep deprivation=82+/-8 versus 86+/-7 mm Hg, mean+/-SEM, P=0.012) and a decrease in muscle sympathetic nerve activity (normal sleep versus sleep deprivation=28+/-6 versus 22+/-6 bursts/min, P=0.017). Heart rate, forearm vascular resistance, and plasma catecholamines were not significantly changed by sleep deprivation, nor did sleep deprivation affect autonomic and hemodynamic responses to stressful stimuli. Sleep deprivation results in increased resting blood pressure, decreased muscle sympathetic nerve activity, and no change in heart rate. Thus, the pressor response to sleep deprivation is not mediated by muscle sympathetic vasoconstriction or tachycardia.

Gender-Selective Interaction Between Aging, Blood Pressure, and Sympathetic Nerve Activity

The mechanisms mediating the more striking age related increase in cardiovascular disease in women than in men are poorly understood. We tested the hypothesis that aging has a greater impact on sympathetic traffic in women than in men. Muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate were measured in 120 healthy males and 96 healthy females aged 20 to 72 years. MSNA increased with age in both sexes, but age explained 53% of MSNA variance in female subjects and only 8% of MSNA variance in male subjects. Both the slope and intercept of the regression lines were significantly different between male and female groups (P<0.01 and P<0.001, respectively). For each decade of life, women showed an increase of 6.5 bursts/min in comparison to an increase of 2.6 bursts/min in males. Menopause did not explain the age-related increase in sympathetic traffic. For every 10-burst/min increment in MSNA in subjects older than 40, mean blood pressure increased by 2.7 mm Hg in men and by 6.1 mm Hg in women. Aging is accompanied by a greater increase in sympathetic traffic in women than in men, independent of menopausal status. Sympathetic neural mechanisms may contribute importantly to the more marked influence of age on blood pressure and cardiovascular disease in women.

Independent Association Between Plasma Leptin and C-Reactive Protein in Healthy Humans

Background—C-reactive protein (CRP) is synthesized from the liver and is regulated by cytokines, especially interleukin-6. Leptin, the adipocyte-derived protein product of the ob gene, is related to amount of body fat. The long form of the leptin receptor resembles cytokine receptors, which include the interleukin-6 receptor. Both leptin and CRP may be increased in women, in obesity, and in inflammation, and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. We tested the hypothesis that leptin is associated with CRP levels independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables. Methods and Results—We studied 100 healthy volunteers (48 men, and 52 women). For all subjects, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P =0.0007). There was a strong and significant positive relationship between leptin and CRP in both women (R =0.61, P <0.0001) and men (R =0.55, P <0.0001) considered separately. The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P =0.01) and men (F=5.69, P =0.02). When only subjects with BMI <25 kg/m2 were considered (n=47), CRP was not linked to BMI (R =0.02, P =0.96), but a significant association between leptin and CRP was still evident (R =0.55, P <0.0001). Conclusions—Leptin and CRP levels are independently associated in normal humans, providing further evidence linking metabolic and inflammatory cardiovascular disease mechanisms.

Baroreflex Control of Sympathetic Nerve Activity and Heart Rate in Obstructive Sleep Apnea

-Patients with obstructive sleep apnea are at increased risk for hypertension. The mechanisms underlying this increased risk are not known. We tested the hypothesis that obstructive sleep apnea, independent of factors such as hypertension, obesity, and age, is characterized by impairment of baroreflex sensitivity. We measured muscle sympathetic nerve activity (MSNA) and heart rate responses to activation and deactivation of baroreceptors in newly diagnosed, never treated, normotensive patients with obstructive sleep apnea. These responses were compared with those obtained in healthy control subjects closely matched for age, body mass index, and blood pressure. Heart rate and MSNA changes during infusion of phenylephrine (baroreceptor activation) were similar in the control subjects and patients with sleep apnea. Infusion of nitroprusside (baroreceptor deactivation) elicited similar decreases in mean arterial pressure (MAP) but lesser MSNA increases in patients with sleep apnea than in control subjects. Calculation of DeltaMSNA/DeltaMAP ratio revealed that baroreflex regulation of sympathetic activity for similar blood pressure changes was diminished in patients with sleep apnea in comparison to normal control subjects (P=0.01). However, increases in heart rate during nitroprusside infusion were comparable in both groups. Sympathetic, blood pressure and heart rate responses to the cold pressor test were also similar in the 2 groups. Our results indicate that normotensive patients with sleep apnea have a selective impairment of the sympathetic response to baroreceptor deactivation but not to baroreceptor activation or to the cold pressor test. The impairment of baroreflex sympathetic modulation in patients with sleep apnea is not accompanied by any impairment of baroreflex control of heart rate.

Recent weight gain in patients with newly diagnosed obstructive sleep apnea

OBJECTIVE Patients with obstructive sleep apnea are often obese. Obesity may contribute to both sleep apnea itself and to the cardiovascular risk associated with sleep apnea. Weight loss in obese patients with sleep apnea may alleviate symptoms and decrease the severity of sleep apnea. Whether patients with obstructive sleep apnea are indeed predisposed to recent weight gain, as compared with similarly obese subjects without sleep apnea, is not known. PATIENTS AND METHODS We compared 1-year weight histories in 53 male and female patients newly diagnosed with obstructive sleep apnea, compared with 24 controls matched for gender, age, body mass index, and percent body fat. Sleep apnea patients had never been treated. Control subjects were proven to be free of sleep-disordered breathing by overnight polysomnography. RESULTS Patients with obstructive sleep apnea (n = 53) had a significant recent weight gain of 7.4 +/- 1.5 kg compared with a weight loss of 0.5 +/- 1.7 kg (P = 0.001) in similarly obese controls (n = 24). Male patients with obstructive sleep apnea (n = 28) had a history of significant weight gain (6.8 +/- 2.3 kg) over the year preceding the study compared with male control subjects (n = 13), in whom average weight fell by 0.58 +/- 2.4 kg (P = 0.03). Female patients (n = 25) with obstructive sleep apnea had an 8.0 +/- 1.9 kg weight gain compared with female controls (n = 11) who had a history of weight loss of 0.46 +/- 2.6 kg (P = 0.02). CONCLUSION These findings support the concept that patients with obstructive sleep apnea may be susceptible to increasing obesity in the period preceding the diagnosis of obstructive sleep apnea.

Sympathetic Activation by Sildenafil

Background—Sildenafil citrate is an effective and widely prescribed therapy for erectile dysfunction. Little is known about the effects of sildenafil on neural control of the circulation or about the effects of sildenafil on neurocirculatory stress responses. Methods and Results—We studied 14 normal volunteers (age 32±7 years) who were randomized in a double-blind crossover fashion to receive a single oral dose of sildenafil 100 mg or placebo on 2 separate study days. Blood pressure, heart rate, forearm vascular resistance, muscle sympathetic nerve activity, and plasma catecholamines were measured at baseline and at 30 and 60 minutes after sildenafil and after placebo administration. The effects of sildenafil and placebo on neural and circulatory responses to stressful stimuli (sustained handgrip, maximal forearm ischemia, mental stress, and the cold pressor test) were also evaluated. Blood pressure, heart rate, and forearm vascular resistance after sildenafil and placebo were similar. However, muscle sympathetic nerve activity increased strikingly after sildenafil (by 141±26%, mean±SEM) compared with placebo (3±8%) (P =0.006); plasma norepinephrine levels also increased by 31±5% after sildenafil administration (P =0.004). Sympathetic nerve traffic during mental, physical, and cold stresses was 2- to 8-fold higher after sildenafil than with placebo (P <0.05). Conclusions—Sildenafil causes a marked increase in sympathetic activation, evident both at rest and during stressful stimuli. Sympathetic activation by sildenafil may have implications for understanding cardiovascular events associated with sildenafil use.