Winnicki, Mikołaj

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.

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 — Most subjects with blood/injury phobia experience syncope or presyncope as part of the phobic response. We tested the hypothesis that these subjects have a constitutional autonomic dysregulation that predisposes them to vasovagal syncope during head-up tilt. Methods and Results — We studied 11 subjects (9 females, 2 males) who had a history of syncope or presyncope only in response to a blood or injury stimulus and 11 healthy matched controls (10 females, 1 male) without a history of syncope. Blood pressure (BP) and heart rate (HR) were measured during a 15-minute baseline period with subjects in the supine position and then during 45 minutes of head-up tilt to 70°. Measurements at rest did not differ between the blood phobic and control subjects. During tilt, 9 (82%) of the 11 blood phobic subjects experienced presyncope or syncope, leading to termination of the study after 22±17 minutes of tilt. Only 1 (9%) of the 11 control subjects experienced presyncope (χ 2 =11.7, P =0.001). Hemodynamic responses to tilt were consistent with a vasovagal mechanism in the blood phobic subjects, with simultaneous decreases in BP and HR during tilt. During tilt, systolic BP fell by 21±15 mm Hg ( P =0.001), and HR fell by 22±25 bpm ( P =0.01). By contrast, BP and HR were very stable in the control group. Conclusions — Subjects with syncope related to blood/injury phobia have an underlying autonomic dysregulation predisposing them to neurally mediated syncope, even in the absence of any blood or injury stimulus. Fainting related to these stimuli may in large part be due to dysfunction in neural circulatory control, which may secondarily lead to the phobia because of repeated syncopal events.

Background Leptin, the protein product of the ob gene, has been linked to a faster heart rate in animal and human studies. The interaction between leptin and heart rate in the denervated heart is not known. Therefore, we studied the relationship between plasma leptin levels and heart rate in heart transplant recipients. Methods and Results We studied 32 male patients (mean age, 56.5±9.3 years; range, 41 to 74 years) after orthotopic heart transplantation. All subjects underwent a physical examination, anthropometric measurements, blood chemistry analysis, and office blood pressure measurements. A blood sample was collected from each subject while fasting. In univariate analysis, heart rate was related to leptin levels ( r =0.47, P =0.007) but heart rate was not related to systolic or diastolic blood pressure, mean arterial pressure, body mass index, or catecholamines. Leptin levels were only strongly associated with heart rate and body mass index ( r =0.73, P <0.0001). In multivariate analysis, heart rate was independently and positively associated with leptin levels (F=2.61, P =0.017). We also observed a strong, independent association between leptin levels and body mass index (F=5.8, P <0.00001). Conclusions We show an independent association between leptin levels and heart rate in heart transplant recipients. We speculate that this may be due, in part, to a direct effect of leptin on heart rate, conceivably mediated through cardiac leptin receptors.

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/m 2 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.

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, <18 bursts/min), subjects in the third tertile (highest MSNA, >25 bursts/min) had significantly greater daytime blood pressure variability, whether expressed as absolute values (10.2±0.5 versus 8.1±0.4 mm Hg for systolic blood pressure and 9.4±0.4 versus 7.2±0.4 mm Hg for diastolic blood pressure; P <0.01 for both comparisons) or as variation coefficients (8.1±0.4% versus 6.6±0.3% for systolic blood pressure and 12.7±0.7% versus 10.1±0.6% for diastolic blood pressure; P <0.01 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 (17±2 versus 10±2 mm Hg, P =0.02, or 13±1% versus 8.2±1.4%, P =0.02). 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.

Background — Leptin has been implicated in cardiovascular disease. A diet rich in fish has been associated with decreased cardiac and vascular risk. Methods and Results — We examined the relationship between diet and leptin in 2 related homogeneous African tribal populations of Tanzania. One tribe consumes freshwater fish as their main diet component (n=279), and the other tribe consumes a primarily vegetarian diet (n=329). In multivariate analysis, plasma leptin levels were associated with type of diet (F=14.3, P <0.001), independent of age, body mass index, body fat, alcohol consumption, or insulin. Both male (2.5±2 [fish diet] versus 11.2±2.4 [vegetarian diet] ng/mL, P =0.017) and female (5.0±1.9 [fish diet] versus 11.8±1.4 [vegetarian diet] ng/mL, P =0.007) fish eaters had lower plasma leptin levels than did their vegetable diet counterparts, even though body mass index values were virtually identical. Conclusions — A diet rich in fish is associated with lower plasma leptin, independent of body fat. These findings may have implications for understanding the reduced cardiovascular risk in subjects on a high-fish diet.

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 [range] 0.33 [0.09 to 2.73] versus 0.09 [0.02 to 0.9] mg/dL, P <0.0003). In multivariate analysis, CRP levels were independently associated with OSA severity (F=6.8, P =0.032). Conclusions — OSA is associated with elevated levels of CRP, a marker of inflammation and of cardiovascular risk. The severity of OSA is proportional to the CRP level.