Somers, Virend K.

Abstract Rationale Adenotonsillectomy, the first line of treatment of sleep-disordered breathing (SDB), is the most commonly performed pediatric surgery. Predictors of the recurrence of SDB after adenotonsillectomy and its impact on cardiovascular risk factors have not been identified. Objectives Demonstrate that gain velocity in body mass index (BMI) defined as unit increase in BMI/year confers an independent risk for the recurrence of SDB 1 year after adenotonsillectomy. Methods Children with SDB and hypertrophy of the tonsils and a comparison group of healthy children were followed prospectively for 1 year. Measurements and Main Results Serial polysomnographies, BMI, and blood pressure were obtained before adenotonsillectomy and 6 weeks, 6 months, and 1 year postoperatively. Gain velocity in BMI, BMI and being African American (odds ratios, 4–6/unit change/yr; 1.4/unit and 15, respectively) provided equal amounts of predictive power to the risk of recurrence of SDB. In the group that experienced recurrence, systolic blood pressure at 1 year was higher than at baseline and higher than in children who did not experience recurrence. Conclusions Three clinical parameters confer independent increased risk for high recurrence of SDB after adenotonsillectomy: gain velocity in BMI, obesity, and being African American. A long-term follow-up of children with SDB and monitoring of gain velocity in BMI are essential to identifying children at risk for recurrence of SDB and in turn at risk for hypertension.

Questions remain as to whether pediatric sleep disordered breathing increases the risk for elevated blood pressure and blood pressure–dependent cardiac remodeling. We tested the hypothesis that activity-adjusted morning blood pressure surge, blood pressure load, and diurnal and nocturnal blood pressure are significantly higher in children with sleep disordered breathing than in healthy controls and that these blood pressure parameters relate to left ventricular remodeling. 24-hour ambulatory blood pressure parameters were compared between groups. The associations between blood pressure and left ventricular relative wall thickness and mass were measured. 140 children met the inclusion criteria. In children with apnea hypopnea index <5 per hour, a significant difference from controls was the morning blood surge. Significant increases in blood pressure surge, blood pressure load, and in 24-hour ambulatory blood pressure were evident in those whom the apnea hypopnea index exceeded 5 per hour. Sleep disordered breathing and body mass index had similar effect on blood pressure parameters except for nocturnal diastolic blood pressure, where sleep disordered breathing had a significantly greater effect than body mass index. Diurnal and nocturnal systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure predicted the changes in left ventricular relative wall thickness. Therefore, sleep disordered breathing in children who are otherwise healthy is independently associated with an increase in morning blood pressure surge, blood pressure load, and 24-hour ambulatory blood pressure. The association between left ventricular remodeling and 24-hour blood pressure highlights the role of sleep disordered breathing in increasing cardiovascular morbidity.

Background Reappearance of low-frequency (LF) (±0.10 Hz) oscillations in RR interval (RR) after cardiac transplantation is indicative of sympathetic efferent reinnervation. We hypothesized that restored LF oscillations in RR in heart transplant recipients (HTRs) are linked to oscillations in muscle sympathetic nerve traffic (MSNA). Methods and Results RR, RR variability, and MSNA were recorded 5±2 months (n=7, short-term HTRs) and 138±8 months (n=7, long-term HTRs) after heart transplantation and compared with matched hypertensive patients (n=7). A coherence function determined the coupling between LF oscillations in MSNA and RR. RR variance did not differ between short-term and long-term HTRs. However, LF variability was only 1±0.5 ms 2 in the short-term HTRs but was 15±8 ms 2 in the long-term HTRs ( P <0.05). Normalized LF variability was also higher in the long-term HTRs (40±14 normalized unites) versus the short-term HTRs (6±3 normalized united, P <0.05) but did not differ from the LF variability of the hypertensive patients. Long-term HTRs were taking less cyclosporine ( P <0.01) but had higher MSNA than the short-term HTRs (62±7 versus 31±7 burst/min, respectively, P <0.05). Coherence between LF oscillations in MSNA and RR was similar in the long-term HTRs (0.59±0.11) and the hypertensive patients (0.60±0.07) and was 3-fold greater than in the short-term HTRs (0.20±0.06, P <0.05). Conclusions Cardiac reinnervation after long-term heart transplantation is characterized by a restoration of the coherence between LF oscillations in RR and MSNA. Higher MSNA in long-term than in short-term HTRs suggests that time elapsed after cardiac transplantation may be a major determinant of sympathetic excitation in heart transplant recipients.

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.