Background-Obstructive sleep apnea (OSA) has been increasingly linked to cardiovascular and cerebrovascular disease.Inflammatory processes associated with OSA may contribute to cardiovascular morbidity in these patients. We tested the hypothesis that OSA patients have increased plasma C-reactive protein (CRP). Methods and Results-We studied 22 patients (18 males and 4 females) with newly diagnosed OSA, who were free of other diseases, had never been treated for OSA, and were taking no medications. We compared CRP measurements in these patients to measurements obtained in 20 control subjects (15 males and 5 females) who were matched for age and body mass index, and in whom occult OSA was excluded. Plasma CRP levels were significantly higher in patients with OSA than in controls (median Epidemiological studies show that an elevated CRP level in the high-normal (0.2 to 1.5 mg/dL) range in apparently healthy men and women is a strong predictor of cardiovascular risk. 7,8 In patients with acute coronary artery disease, stable angina pectoris, and a history of myocardial infarction, higher CRP is also associated with future cardiovascular events. 9 10 OSA results in repetitive and severe nocturnal hypoxemia and sleep disturbances. 11 The hypoxemia of high altitude results in increases in interleukin-6 (IL-6) 12 and CRP 12,13 in normal humans. Sleep deprivation also induces an increase in cytokines. 4,14 We tested the hypothesis that OSA patients have increased plasma CRP. MethodsWe compared subjects with moderate to severe OSA (apnea hypopnea index [AHI] Ն20) to those without OSA (AHI Յ5). We studied 22 patients (18 males and 4 females) with newly diagnosed OSA, who were free of other diseases, had never been treated for OSA, and were taking no medications. We compared CRP measurements in these patients to measurements obtained from 20 control subjects (15 males and 5 females) who were matched for age and body mass index (BMI), and in whom occult OSA was excluded. The control group was free of any acute or chronic cardiovascular, inflammatory, or sleep disorders, and no control subjects were taking medications at the time of the sleep study. The presence and severity of sleep apnea were determined by standard overnight polysomnography, including electroencephalography, electrooculography, electromyography, oximetry, thermistor measurements of airflow, and measurements of rib cage and abdominal movements when breathing. The sleep studies followed a split-night protocol. The first half of the study intended to diagnose OSA, with a therapeutic trial of continuous positive airway pressure during the second half of the night. An apnea was defined as complete cessation of airflow for at least 10 seconds. Hypopnea was defined as a reduction of respiratory signals for at least 10 seconds associated with oxygen desaturation of Ն4%. The AHI was calculated as the total number of respiratory events per hour of sleep.Baseline demographic data, heart rate, blood pressure (SpaceLabs blood pressure monitor 90207), and venous blood ...

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.

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 (Fϭ12.39, Pϭ0.0007). There was a strong and significant positive relationship between leptin and CRP in both women (Rϭ0.61, PϽ0.0001) and men (Rϭ0.55, PϽ0.0001) 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 (Fϭ7.13, Pϭ0.01) and men (Fϭ5.69, Pϭ0.02). When only subjects with BMI Ͻ25 kg/m 2 were considered (nϭ47), CRP was not linked to BMI (Rϭ0.02, Pϭ0.96), but a significant association between leptin and CRP was still evident (Rϭ0.55, PϽ0.0001). Conclusions-Leptin

Abstract-The physiological mechanisms mediating the variability and diurnal rhythm of blood pressure are unclear. We tested the hypothesis that resting sympathetic activity is linked to the variability characteristics and 24-hour profile of ambulatory blood pressure measurements. We evaluated the relationship between muscle sympathetic nerve activity (MSNA) and the level, variability, and nocturnal fall of ambulatory blood pressure in 69 normal men. Subjects were subdivided according to the tertiles of MSNA distributions. Mean 24-hour blood pressure was not significantly different across the 3 groups. Compared with subjects in the first tertile (lowest MSNA, Ͻ18 bursts/min), subjects in the third tertile (highest MSNA, Ͼ25 bursts/min) had significantly greater daytime blood pressure variability, whether expressed as absolute values (10.2Ϯ0.5 versus 8.1Ϯ0.4 mm Hg for systolic blood pressure and 9.4Ϯ0.4 versus 7.2Ϯ0.4 mm Hg for diastolic blood pressure; PϽ0.01 for both comparisons) or as variation coefficients (8.1Ϯ0.4% versus 6.6Ϯ0.3% for systolic blood pressure and 12.7Ϯ0.7% versus 10.1Ϯ0.6% for diastolic blood pressure; PϽ0.01 for both comparisons). Subjects in the third tertile also had a more striking absolute and percentage fall in systolic blood pressure from daytime to nighttime than subjects in the first tertile (17Ϯ2 versus 10Ϯ2 mm Hg, Pϭ0.02, or 13Ϯ1% versus 8.2Ϯ1.4%, Pϭ0.02). In conclusion, higher resting measurements of sympathetic traffic are associated with greater daytime blood pressure variability and a more marked nocturnal decline in blood pressure in normal subjects. These findings suggest that sympathetic neural mechanisms may contribute importantly to the regulation of blood pressure over the 24-hour period. (Hypertension. 2002;39:168-172.)

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.

Factors related to the development of microalbuminuria in hypertension are not well known. We did a prospective study to investigate whether glomerular hyperfiltration precedes the development of microalbuminuria in hypertension. We assessed 502 never-treated subjects screened for stage 1 hypertension without microalbuminuria at baseline and followed up for 7.8 years. Creatinine clearance was measured at entry. Urinary albumin and ambulatory blood pressure were measured at entry and during the follow-up until subjects developed sustained hypertension needing antihypertensive treatment. Subjects with hyperfiltration (creatinine clearance >150 ml/min/1.73 m2, top quintile of the distribution) were younger and heavier than the rest of the group and had a greater follow-up increase in urinary albumin than subjects with normal filtration (P<0.001). In multivariable linear regression, creatinine clearance adjusted for confounders was a strong independent predictor of final urinary albumin (P<0.001). In multivariable Cox regression, patients with hyperfiltration had an adjusted hazard ratio for the development of microalbuminuria based on at least one positive measurement of 4.0 (95% confidence interval (CI), 2.1-7.4, P<0.001) and an adjusted hazard ratio for the development of microalbuminuria based on two consecutive positive measurements of 4.4 (95% CI, 2.1-9.2, P<0.001), as compared with patients with normal filtration. Age, female gender, and 24 h systolic blood pressure were other significant predictors of microalbuminuria. In conclusion, stage 1 hypertensive subjects with glomerular hyperfiltration are at increased risk of developing microalbuminuria. Early intervention with medical therapy may be beneficial in these subjects even if their blood pressure falls below normal limits during follow-up.

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WOLK, ROBERT, ANNA SVATIKOVA, CHRISTY A.