Shamsuzzaman, Abu

Abstract Rationale We previously demonstrated that children with obstructive sleep apnea have increased blood pressure associated with changes in left ventricular mass index. Others have shown in adults that blood pressure variability is an important predictor of changes in left ventricular mass. The baroreflex system buffers blood pressure changes by varying heart rate. We have thus hypothesized that (1) baroreflex system gain is increased during sleep, improving blood pressure buffering; (2) children with obstructive sleep apnea lack this baroreflex gain increase; and (3) reduced blood pressure buffering results in exaggerated blood pressure variability that is associated with end-organ damage. Objectives Compare measures of left ventricular mass index and nighttime baroreflex gain of healthy children to those of children with obstructive sleep apnea. Methods A total of 169 children (50 control subjects, 63 with mild obstructive sleep apnea, and 56 with severe obstructive sleep apnea) with a mean age of 9.9 years (±2.2) underwent echocardiography followed by polysomnography with continuous blood pressure measurement. Baroreflex gain was calculated in time and frequency domains. Measurements and Main Results Healthy children demonstrated a nighttime pattern of increasing baroreflex gain. Children with obstructive sleep apnea had decreased nighttime baroreflex gain compared with control subjects. Nighttime blood pressure and blood pressure variability were significantly correlated with left ventricular mass index. Conclusions Obstructive sleep apnea is associated with a decrease in nighttime baroreflex gain and an increase in blood pressure variability. This increase is correlated with changes in left ventricular mass index.

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.

Objective— There is increasing evidence of an association between leptin and increased cardiovascular risk. Higher leptin levels are associated with increased levels of C-reactive protein (CRP), which itself elicits proatherogenic effects in the vascular endothelium. We tested the hypothesis that leptin induces CRP expression in human coronary artery endothelial cells (HCAECs). Methods and Results— We confirmed the presence of both long and short isoforms of the leptin receptor in cultured HCAECs. Leptin but not IFNαA/D nor tumor necrosis factor (TNF) α, induced expression of CRP. A dose dependent increase of CRP mRNA and protein was observed with increasing concentration of leptin (0 to 400 ng/mL). This increased CRP expression was attenuated in the presence of anti-leptin receptor antibodies and also by inhibition of ERK1/2 by PD98059 (20 to 40 μmol/L). Time (0 to 60 minutes) and leptin concentration (0 to 200 ng/mL)-dependence of ERK1/2 phosphorylation were evident in response to leptin treatment. Leptin also elicited ROS generation. Inhibition of ROS by catalase (200 μg/mL) prevented ERK1/2 phosphorylation and CRP mRNA transcription. Conclusion— Leptin induces CRP expression in HCAECs via activation of the leptin receptor, increased ROS production, and phosphorylation of ERK1/2. These studies suggest a mechanism for the proatherogenic effects of leptin.

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.

Obesity has a high and rising prevalence and represents a major public health problem. Obstructive sleep apnea (OSA) is also common, affecting an estimated 15 million Americans, with a prevalence that is probably also rising as a consequence of increasing obesity. Epidemiologic data support a link between obesity and hypertension as well as between OSA and hypertension. For example, untreated OSA predisposes to an increased risk of new hypertension, and treatment of OSA lowers blood pressure, even during the daytime. Possible mechanisms whereby OSA may contribute to hypertension in obese individuals include sympathetic activation, hyperleptinemia, insulin resistance, elevated angiotensin II and aldosterone levels, oxidative and inflammatory stress, endothelial dysfunction, impaired baroreflex function, and perhaps by effects on renal function. The coexistence of OSA and obesity may have more widespread implications for cardiovascular control and dysfunction in obese individuals and may contribute to some of the clustering of abnormalities broadly defined as the metabolic syndrome. From the clinical and therapeutic perspectives, the presence of resistant hypertension and the absence of a nocturnal decrease in blood pressure in obese individuals should prompt the clinician to consider the diagnosis of OSA, especially if clinical symptoms suggestive of OSA (such as poor sleep quality, witnessed apnea, excessive daytime somnolence, and so forth) are also present.