Catherine A. Pesek

Selective Potentiation of Peripheral Chemoreflex Sensitivity in Obstructive Sleep Apnea

BACKGROUND The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Abnormalities in chemoreflex mechanisms may be implicated in increased cardiovascular stress in patients with obstructive sleep apnea (OSA). We tested the hypothesis that chemoreflex function is altered in patients with OSA. METHODS AND RESULTS We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor test in 16 untreated normotensive patients with OSA and 12 normal control subjects matched for age and body mass index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the patients with OSA than in the control subjects (43+/-4 versus 21+/-3 bursts per minute; P<0. 001). During hypoxia, patients with OSA had greater increases in minute ventilation (5.8+/-0.8 versus 3.2+/-0.7 L/min; P=0.02), heart rate (10+/-1 versus 7+/-1 bpm; P=0.03), and mean arterial pressure (7+/-2 versus 0+/-2 mm Hg; P=0.001) than control subjects. Despite higher ventilation and blood pressure (both of which inhibit sympathetic activity) in OSA patients, the MSNA increase during hypoxia was similar in OSA patients and control subjects. When the sympathetic-inhibitory influence of breathing was eliminated by apnea during hypoxia, the increase in MSNA in OSA patients (106+/-20%) was greater than in control subjects (52+/-23%; P=0.04). Prolongation of R-R interval with apnea during hypoxia was also greater in OSA patients (24+/-6%) than in control subjects (7+/-5%) (P=0.04). Autonomic, ventilatory, and blood pressure responses to hypercapnia and the cold pressor test in OSA patients were not different from those observed in control subjects. CONCLUSIONS OSA is associated with a selective potentiation of autonomic, hemodynamic, and ventilatory responses to peripheral chemoreceptor activation by hypoxia.

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.

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.

Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure.

BACKGROUND Sympathetic activation and respiratory abnormalities may each be implicated in the pathophysiology of congestive heart failure (CHF). Chemoreflexes are an important mechanism regulating both sympathetic drive and breathing. We therefore tested the hypothesis that chemoreflex function is altered in CHF. METHODS AND RESULTS We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor test in 9 patients with CHF and 9 control subjects matched for age and body mass index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the patients with CHF compared with control subjects (47+/-8 versus 23+/-3 bursts per minute, P<0.01). During hypercapnia, patients with CHF had greater increases in minute ventilation (6.7+/-1.4 versus 2.7+/-0.9 L/min, P=0.03) and heart rate (7.0+/-2.1 versus 0.6+/-1.2 bpm, P=0.02). Despite higher ventilation, which inhibits sympathetic activity, the MSNA increase in patients with CHF was also greater than that in control subjects (58+/-12% versus 21+/-9%, P=0.03). Ventilatory, autonomic, and blood pressure responses to hypoxia and the cold pressor test in CHF patients were not different from those in control subjects. CONCLUSIONS Chronic heart failure is characterized by a selective potentiation of ventilatory and sympathetic responses to central chemoreceptor activation by hypercapnia.

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.

Leptin interacts with heart rate but not sympathetic nerve traffic in healthy male subjects

Objective Administration of leptin to animals increases sympathetic nerve activity and heart rate. We therefore tested the hypothesis that plasma leptin is linked independently to muscle sympathetic nerve activity (MSNA) and heart rate in healthy humans. Methods We measured plasma leptin, plasma insulin, body mass index (BMI), percent body fat, waist : hip ratio, MSNA, heart rate and blood pressure in 88 healthy individuals (50 men and 38 women). Results In men, plasma leptin concentration correlated significantly with BMI (r = 0.75, P < 0.001), percent body fat (r = 0.70, P < 0.001), waist : hip ratio (r = 0.69, P < 0.001), insulin (r = 0.37, P = 0.009), and age (r = 0.38, P = 0.006). Only BMI and waist : hip ratio were linked independently to plasma leptin concentration (r = 0.78, P < 0.001). Plasma leptin concentrations also correlated with heart rate (r = 0.39, P = 0.006) and mean arterial pressure (MAP;r = 0.38, P = 0.007), but not with MSNA (r = 0.17, P = 0.24). After adjustment for BMI and waist : hip ratio, plasma leptin concentration correlated significantly only with heart rate (r = 0.29, P = 0.04), and not with MAP (r = 0.21, P = 0.14). Individuals were divided into high-leptin and low-leptin subgroups on the basis of plasma leptin concentrations adjusted for BMI and waist : hip ratio. Those with high leptin concentrations had significantly faster heart rates than those with low leptin. MAP and MSNA were similar in both subgroups. No relationship between leptin and either heart rate or MSNA was evident in women. Conclusions In normal men, heart rate, but not MSNA, is linked to plasma leptin concentration. This sex-specific relationship between heart rate and plasma leptin is independent of plasma insulin, BMI, waist : hip ratio and percentage body fat.

Human Obesity Is Characterized by a Selective Potentiation of Central Chemoreflex Sensitivity

The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Obesity is associated with an increased risk of alveolar hypoventilation and carbon dioxide retention, suggesting that abnormalities in chemoreflex control mechanisms may be implicated. We tested the hypothesis that chemoreflex function is altered in obesity. We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypercapnia, hypoxia, and the cold pressor test in 14 obese subjects and 14 normal-weight subjects matched for age and gender. During hypercapnia, the increase in minute ventilation was significantly greater in obese subjects (7.0+/-0.3 L/min) than in normal-weight subjects (3.3+/-1.1 L/min; P=0.03). Despite higher minute ventilation during hypercapnia in obese subjects, the increase in muscle sympathetic nerve activity was similar in obese and normal-weight subjects. When the inhibitory influence of breathing during hypercapnia was eliminated by apnea, the increase in sympathetic nerve activity in obese subjects (99+/-16%) was greater than in normal-weight subjects (44+/-16%; P=0.02). The magnitude of the ventilatory and autonomic responses to hypoxia and the cold pressor test was similar in obese and normal-weight subjects. We conclude that chemoreflex responses to hypercapnia are potentiated in eucapnic obese subjects. In contrast, responses to hypoxia and to the excitatory cold pressor stimulus in obese subjects are similar to those in normal-weight subjects. Thus, obesity is characterized by selective potentiation of central chemoreflex sensitivity.