Differential effects of leptin on adiponectin expression with weight gain versus obesity.

BACKGROUND/OBJECTIVE: Adiponectin exerts beneficial effects by reducing inflammation and improving lipid metabolism and insulin sensitivity. Although the adiponectin level is lower in obese individuals, whether weight gain reduces adiponectin expression in humans is controversial. We sought to investigate the role of weight gain, and consequent changes in leptin, on altering adiponectin expression in humans. METHODS/RESULTS: Forty-four normal-weight healthy subjects were recruited (mean age 29 years; 14 women) and randomized to either gain 5% of body weight by 8 weeks of overfeeding (n=34) or maintain weight (n=10). Modest weight gain of 3.8±1.2 kg resulted in increased adiponectin level (P=0.03), whereas weight maintenance resulted in no changes in adiponectin. Further, changes in adiponectin correlated positively with changes in leptin (P=0.0085). In-vitro experiments using differentiated human white preadipocytes showed that leptin increased adiponectin mRNA and protein expression, whereas a leptin antagonist had opposite effects. To understand the role of leptin in established obesity, we compared adipose tissue samples obtained from normal-weight versus obese subjects. We noted, first, that leptin activated cellular signaling pathways and increased adiponectin mRNA in the adipose tissue from normal-weight participants, but did not do so in the adipose tissue from obese participants. Second, we noted that obese subjects had increased caveolin-1 expression, which attenuates leptin-dependent increases in adiponectin. CONCLUSIONS: Modest weight gain in healthy individuals is associated with increases in adiponectin levels, which correlate positively with changes in leptin. In vitro, leptin induces adiponectin expression, which is attenuated by increased caveolin-1 expression. In addition, the adipose tissue from obese subjects shows increased caveolin-1 expression and impaired leptin signaling. This leptin signal impairment may prevent concordant increases in adiponectin levels in obese subjects despite their high levels of leptin. Therefore, impaired leptin signaling may contribute to low adiponectin expression in obesity and may provide a target for increasing adiponectin expression, hence improving insulin sensitivity and cardio-metabolic profile in obesity.

Diagnostic accuracy of body mass index to identify obesity in older adults: NHANES 1999-2004.

BACKGROUND: Body composition changes with aging lead to increased adiposity and decreased muscle mass, making the diagnosis of obesity challenging. Conventional anthropometry, including body mass index (BMI), while easy to use clinically may misrepresent adiposity. We determined the diagnostic accuracy of BMI using dual-energy X-ray absorptiometry (DEXA) in assessing the degree of obesity in older adults. METHODS: The National Health and Nutrition Examination Surveys 1999-2004 were used to identify adults aged ⩾60 years with DEXA measures. They were categorized (yes/no) as having elevated body fat by gender (men: ⩾25%; women ⩾35%) and by BMI ⩾25 and ⩾30 kg m(-)(2). The diagnostic performance of BMI was assessed. Metabolic characteristics were compared in discordant cases of BMI/body fat. Weighting and analyses were performed per NHANES (National Health and Nutrition Examination Survey) guidelines. RESULTS: We identified 4984 subjects (men: 2453; women: 2531). Mean BMI and % body fat was 28.0 kg m(-2) and 30.8% in men, and 28.5 kg m(-)(2) and 42.1% in women. A BMI ⩾30 kg m(-)(2) had a low sensitivity and moderately high specificity (men: 32.9 and 80.8%, concordance index 0.66; women: 38.5 and 78.5%, concordance 0.69) correctly classifying 41.0 and 45.1% of obese subjects. A BMI ⩾25 kg m(-2) had a moderately high sensitivity and specificity (men: 80.7 and 99.6%, concordance 0.81; women: 76.9 and 98.8%, concordance 0.84) correctly classifying 80.8 and 78.5% of obese subjects. In subjects with BMI <30 kg m(-)(2), body fat was considered elevated in 67.1% and 61.5% of men and women, respectively. For a BMI ⩾30 kg m(-)(2), sensitivity drops from 40.3% to 14.5% and 44.5% to 23.4%, whereas specificity remains elevated (>98%), in men and women, respectively, in those 60-69.9 years to subjects aged ⩾80 years. Correct classification of obesity using a cutoff of 30 kg m(-)(2) drops from 48.1 to 23.9% and 49.0 to 19.6%, in men and women in these two age groups. CONCLUSIONS: Traditional measures poorly identify obesity in the elderly. In older adults, BMI may be a suboptimal marker for adiposity.

Diagnostic performance of body mass index to identify obesity as defined by body adiposity in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: The ideal means of identifying obesity in children and adolescents has not been determined although body mass index (BMI) is the most widely used screening tool. OBJECTIVE: We performed a systematic review and meta-analysis of studies assessing the diagnostic performance of BMI to detect adiposity in children up to 18 years. METHODS: Data sources were EMBASE, MEDLINE, Cochrane, Database of Systematic Reviews Cochrane CENTRAL, Web of Science and SCOPUS up to March 2013. Studies providing measures of diagnostic performance of BMI and using body composition technique for body fat percentage measurement were included. RESULTS: Thirty-seven eligible studies that evaluated 53 521 patients, with mean age ranging from 4 to 18 years were included in the meta-analysis. Commonly used BMI cut-offs for obesity showed pooled sensitivity to detect high adiposity of 0.73 (confidence interval [CI] 0.67-0.79), specificity of 0.93 (CI 0.88-0.96) and diagnostic odds ratio of 36.93 (CI 20.75-65.71). Males had lower sensitivity. Moderate heterogeneity was observed (I(2) = 48%) explained in meta-regression by differences across studies in race, BMI cut-off, BMI reference criteria (Center for Disease Control vs. International Obesity Task Force) and reference standard method assessing adiposity. CONCLUSION: BMI has high specificity but low sensitivity to detect excess adiposity and fails to identify over a quarter of children with excess body fat percentage.

Clinical characteristics of patients with resistant hypertension: the RESIST-POL study.

Recent studies indicate that resistant hypertension (RHTN) is present in about 12% of the treated hypertensive population. However, patients with true RHTN (confirmed out of the office) have not been widely studied. We prospectively studied 204 patients (123 male, 81 female, mean age 48.4 years, range 19-65 years) with truly RHTN (ambulatory daytime mean blood pressure >135/85 mm Hg). We evaluated the frequency of obstructive sleep apnea (OSA), renal artery stenosis (RAS), primary aldosteronism (PA) and other secondary forms of hypertension (HTN) and conditions. Mild, moderate and severe OSA were present in 55 (27.0%), 38 (18.6%) and 54 (26.5%) patients, respectively. Secondary forms of HTN were diagnosed in 49 patients (24.0%), the most frequent being PA (15.7%) and RAS (5.4%). Metabolic syndrome (MS) was present in 65.7% of patients. Excessive sodium excretion was evident in 33.3% of patients and depression in 36.8% patients. In patients with RHTN, OSA and MS were the most frequent conditions, frequently overlapping with each other and also with PA. Our data indicate that in the vast majority of patients with truly RHTN, at least one of three co-morbidities-OSA, MS and PA-is present. Other conditions, even though less frequent, should also be taken into the consideration.

Diagnostic performance of body mass index to identify obesity as defined by body adiposity: a systematic review and meta-analysis.

OBJECTIVE: We performed a systematic review and meta-analysis of studies that assessed the performance of body mass index (BMI) to detect body adiposity. DESIGN: Data sources were MEDLINE, EMBASE, Cochrane, Database of Systematic Reviews, Cochrane CENTRAL, Web of Science, and SCOPUS. To be included, studies must have assessed the performance of BMI to measure body adiposity, provided standard values of diagnostic performance, and used a body composition technique as the reference standard for body fat percent (BF%) measurement. We obtained pooled summary statistics for sensitivity, specificity, positive and negative likelihood ratios (LRs), and diagnostic odds ratio (DOR). The inconsistency statistic (I2) assessed potential heterogeneity. RESULTS: The search strategy yielded 3341 potentially relevant abstracts, and 25 articles met our predefined inclusion criteria. These studies evaluated 32 different samples totaling 31 968 patients. Commonly used BMI cutoffs to diagnose obesity showed a pooled sensitivity to detect high adiposity of 0.50 (95% confidence interval (CI): 0.43-0.57) and a pooled specificity of 0.90 (CI: 0.86-0.94). Positive LR was 5.88 (CI: 4.24-8.15), I (2)=97.8%; the negative LR was 0.43 (CI: 0.37-0.50), I (2)=98.5%; and the DOR was 17.91 (CI: 12.56-25.53), I (2)=91.7%. Analysis of studies that used BMI cutoffs >or=30 had a pooled sensitivity of 0.42 (CI: 0.31-0.43) and a pooled specificity of 0.97 (CI: 0.96-0.97). Cutoff values and regional origin of the studies can only partially explain the heterogeneity seen in pooled DOR estimates. CONCLUSION: Commonly used BMI cutoff values to diagnose obesity have high specificity, but low sensitivity to identify adiposity, as they fail to identify half of the people with excess BF%.

Accuracy of body mass index in diagnosing obesity in the adult general population.

BACKGROUND: Body mass index (BMI) is the most widely used measure to diagnose obesity. However, the accuracy of BMI in detecting excess body adiposity in the adult general population is largely unknown. METHODS: A cross-sectional design of 13 601 subjects (age 20-79.9 years; 49% men) from the Third National Health and Nutrition Examination Survey. Bioelectrical impedance analysis was used to estimate body fat percent (BF%). We assessed the diagnostic performance of BMI using the World Health Organization reference standard for obesity of BF%>25% in men and>35% in women. We tested the correlation between BMI and both BF% and lean mass by sex and age groups adjusted for race. RESULTS: BMI-defined obesity (> or =30 kg m(-2)) was present in 19.1% of men and 24.7% of women, while BF%-defined obesity was present in 43.9% of men and 52.3% of women. A BMI> or =30 had a high specificity (men=95%, 95% confidence interval (CI), 94-96 and women=99%, 95% CI, 98-100), but a poor sensitivity (men=36%, 95% CI, 35-37 and women=49%, 95% CI, 48-50) to detect BF%-defined obesity. The diagnostic performance of BMI diminished as age increased. In men, BMI had a better correlation with lean mass than with BF%, while in women BMI correlated better with BF% than with lean mass. However, in the intermediate range of BMI (25-29.9 kg m(-2)), BMI failed to discriminate between BF% and lean mass in both sexes. CONCLUSIONS: The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly. A BMI cutoff of> or =30 kg m(-2) has good specificity but misses more than half of people with excess fat. These results may help to explain the unexpected better survival in overweight/mild obese patients.

Dynamic QT/RR coupling in patients with pacemakers.

The dynamic coupling between heart rate intervals (RR) and ventricular repolarization (QT) is analyzed. The analysis is based on measurements of 11 patients with pacemaker. In each measurement, there are at least 4 abrupt changes of RR preset by the pacemaker. With such a protocol, RR changes are important and well defined while disturbing factors and noise sources (such as those related with motion of patient) are minimized. The QT/RR coupling was described by 3 parameters (a1, b2, b3) transfer function (TRF) selected on the basis of a statistical analysis of performances of different TRF models. We found that our model is by far the best in its class: with more parameters (higher order models) the residuals remain almost the same while the extra parameters display variability much larger than that of our parameters. For all measurements, our TRF model describes more than 70% of QT variability. Within the patient set, we found interesting differences concerning dynamic non-linearity (response times longer with decreasing RR intervals than with increasing RR).

Obesity-related cardiovascular disease: implications of obstructive sleep apnea.

Obesity and obstructive sleep apnea (OSA) often coexist. OSA has been linked to cardiovascular disease. Thus, OSA may contribute to the cardiovascular consequences of obesity. In this review, we explore clinical and pathophysiological interactions between obesity, cardiovascular disease and OSA. We discuss the mechanisms whereby OSA may contribute to hypertension, atherosclerosis, insulin resistance and atrial fibrillation associated with obesity, and emphasize the potential implications for understanding why only a subgroup of obese patients develop cardiovascular disease. Identification of the OSA-dependent and OSA-independent pathways in the cardiovascular pathophysiology of obesity may hold clinical and therapeutic promise.

Noninvasive detection of vessel stiffness from continuous blood pressure recordings in hypertensive subjects.

This paper presents results of blood pressure dynamicity analysis aimed at vessel stiffness detection and subsequent cardiac risk stratification. We analyzed ECG and BP parameters from 12 normotensive young healthy volunteers, 10 old healthy volunteers, and two groups of hypertensive patients -- 12 young non-medicated hypertensive subjects with no other known complications and 16 hypertensive non-medicated subjects with confirmed obesity (according to waist circumference), hyperlipidemia or diabetes mellitus. The dynamic parameters obtained from a derivative continuous blood pressure signal provide additional information about vessel compliance. They can differentiate hypertensive subjects according to the level of cardiovascular risk.

Recognition, diagnosis and management of obesity after myocardial infarction.

OBJECTIVE: We investigated the documentation of obesity as a medical problem, and subsequent management recommendations, in patients after myocardial infarction (MI). DESIGN: We performed a cross-sectional analysis of a randomly selected sample of 627 patients discharged after an MI, from five US teaching hospitals between 1/1/01 and 12/31/02. Information was extracted from clinical notes using standardized definitions. RESULTS: Mean body mass index (BMI) was 31+/-13 kg/m2, which was documented in only 14% of patients and had to be calculated post hoc in the rest. Waist circumference and waist/hip ratio were not documented at all; 83% of patients were overweight, 55% obese, and 8% morbidly obese. In only 20% of patients with BMI> or =30 kg/m2 was the diagnosis of obesity documented either as a current medical problem, as part of past medical history or as a final diagnosis. A dietary counseling was carried out in 61% of patients with BMI> or =25 kg/m2 and in 61% of patients with BMI<25 kg/m2, P=0.96. Weight loss was described as part of the goals/plan at discharge in 7% of overweight and 9% of obese patients. There was no change in either the level of recognition of obesity (22 vs 19%, P=0.3) or in the proportion of obese patients for whom weight loss was described as part of the goals/plan at discharge (8 vs 10%, P=0.7) before (n=301) compared to after (n=326) the Call to Action in Obesity by the Surgeon General in December 2001. CONCLUSION: Obesity is underecognized, underdiagnosed and undertreated in persons with acute MI.

Sleep apnea and hypertension.

Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing and frequently coexists with obesity. Almost 15 million Americans are affected by this disorder. This prevalence is likely increasing, given the current epidemic of obesity. Recent data confirm an association between sleep apnea and several cardiovascular disease conditions, suggesting that OSA may be a new risk factor for coronary artery disease, heart failure, heart rhythm disturbances and hypertension, independent of body mass index. In this review, the authors focus on the nature of the association between OSA and hypertension, the evidence suggesting a causal interaction, and discuss the potential pathophysiologic mechanisms responsible. These mechanisms include activation of the sympathetic and renin-angiotensin-aldosterone systems (RAAS), oxidative stress, and systemic and vascular inflammation, all of which could link OSA to a sustained increase in blood pressure. The authors also review potential therapeutic strategies for the hypertensive patient with OSA.

Chemoreflexes--physiology and clinical implications.

The chemoreflexes are important modulators of sympathetic activation. The peripheral chemoreceptors located in the carotid bodies respond primarily to hypoxaemia. Central chemoreceptors located in the region of the brainstem respond to hypercapnia. Activation of either the hypoxic or hypercapnic chemoreflex elicits both hyperventilation and sympathetic activation. During apnoea, when the inhibitory influence of stretch of the pulmonary afferents is eliminated, there is a potentiation of the sympathetic response to both hypoxia and hypercapnia. This inhibitory influence of the pulmonary afferents is more marked on the sympathetic response to peripheral compared with central chemoreceptor activation. The arterial baroreflexes also have a powerful inhibitory influence on the chemoreflexes. This inhibition is again more marked with respect to the peripheral compared with central chemoreflexes. In patients with hypertension, there is a marked increase in the sympathetic and ventilatory response to hypoxaemia. During apnoea, with elimination of the inhibitory influence of breathing, the sympathetic response in untreated mild hypertensive patients is strikingly greater than that seen in matched normotensive controls. This potentiated peripheral chemoreflex sensitivity in hypertension may be explained in part by impaired baroreflex function in these patients. Enhanced peripheral chemoreflex sensitivity is also evident in patients with obstructive sleep apnoea. This peripheral chemoreflex enhancement is not explained by obesity, as obese individuals have a selective potentiation of the central chemoreceptors with peripheral chemoreflex responses similar to those seen in lean controls. Increased sensitivity to hypoxaemia has important implications in patients with obstructive sleep apnoea who experience repetitive and severe hypoxaemic stress. Tonic activation of the chemoreflex may also contribute to the high levels of sympathetic activity evident even during normoxic daytime wakefulness in sleep apnoea patients. Administration of 100% oxygen in patients with sleep apnoea results in reductions in heart rate, blood pressure and central sympathetic outflow. In patients with heart failure, the central chemoreflex response to hypercapnia is markedly and selectively enhanced. This increased central chemoreflex sensitivity may contribute to the development of central sleep apnoea in heart failure patients. Administration of 100% oxygen does not lower sympathetic activity in patients with heart failure, providing further evidence against any peripheral chemoreflex potentiation. The peripheral and central chemoreflexes have powerful effects on sympathetic activity in both health and disease and may contribute importantly to disease pathophysiology, particularly in conditions such as hypertension, obstructive sleep apnoea and heart failure.

Sympathetic nerve activity in obstructive sleep apnoea.

The mechanisms underlying the link between obstructive sleep apnoea (OSA) and cardiovascular disease are not completely established. However, there is increasing evidence that autonomic mechanisms are implicated. A number of studies have consistently shown that patients with OSA have high levels of sympathetic nerve traffic. During sleep, repetitive episodes of hypoxia, hypercapnia and obstructive apnoea act through chemoreceptor reflexes and other mechanisms to increase sympathetic drive. Remarkably, the high sympathetic drive is present even during daytime wakefulness when subjects are breathing normally and no evidence of hypoxia or chemoreflex activation is apparent. Several neural and humoral mechanisms may contribute to maintenance of higher sympathetic activity and blood pressure. These mechanisms include chemoreflex and baroreflex dysfunction, altered cardiovascular variability, vasoconstrictor effects of nocturnal endothelin release and endothelial dysfunction. Long-term continuous positive airway pressure treatment decreases muscle sympathetic nerve activity in OSA patients. The vast majority of OSA patients remain undiagnosed. Unrecognized OSA may contribute, in part, to the metabolic and cardiovascular derangements that are thought to be linked to obesity, and to the association between obesity and cardiovascular risk. Furthermore, acting through sympathetic neural mechanisms, OSA may contribute to or augment elevated levels of blood pressure in a large proportion of the hypertensive patient population.

Non-invasive model-based estimation of the sinus node dynamic properties from spontaneous cardiovascular variability series.

A non-invasive model-based approach to the estimation of sinus node dynamic properties is proposed. The model exploits the spontaneous beat-to-beat variability of heart period and systolic arterial pressure and the sampled respiration, thus surrogating the information from direct measures of neural activity. The residual heart period variability not related to baroreflex, to direct effects of respiration and to low frequency influences independent of baroreflex, is interpreted as the effect of the dynamic properties of the sinus node and modelled as a regression of the RR interval over its previous value. Therefore the sinus node transfer function is modelled by means of a filter with a real pole z = mu (and a zero in the origin). It was found that: first, in young healthy subjects the nodal tissue responded as a low-pass filter with mu = 0.76 +/- 0.12 (mean +/- SD); secondly, ageing did not significantly modify either its shape or gain at 0 Hz; thirdly, in heart transplant recipients, the dynamic transduction properties were lost (all-pass filter, p = 0.06 +/- 0.16, p < 0.001); fourthly, low-dose atropine left the sinus node dynamic properties unmodified; fifthly, high-dose atropine affected the dynamic transduction properties by increasing the gain at 0 Hz and rendering steeper its roll-off (the percent increase of mu with respect to baseline was 18.3 +/- 22.3, p < 0.05).

Obstructive sleep apnea and vascular disease.

There is emerging evidence linking obstructive sleep apnea (OSA) to vascular disease, including hypertension. This relationship may be independent of co-morbidity, such as obesity. Even apparently healthy OSA patients have evidence of subtle functional vascular abnormalities that are known to occur in patients with hypertension and atherosclerosis. Untreated OSA may possibly contribute to the initiation and/or progression of pathophysiologic mechanisms involved in hypertension, heart failure, cardiac ischemia and stroke. This brief commentary will examine the evidence and mechanisms linking OSA to vascular disease.

Sleep disordered breathing and hypertension.

Patients with sleep apnea may be at increased risk for cardiovascular disease. Recently, the link between hypertension and sleep apnea has been strengthened by findings of two large epidemiologic studies. Neurohumoral and hemodynamic responses to repetitive episodes of hypoxemia and apnea may offer a pathophysiologic basis for patients with sleep apnea having an increased risk for hypertension. Sympathetic, humoral, and cellular responses to sleep apnea over the long term may cause vascular dysfunction and consequent hypertension. These responses may be exacerbated by sleep deprivation, which occurs commonly in patients with sleep apnea because of poor sleep architecture. Patients with sleep apnea are often obese and may be predisposed to weight gain. Hence, obesity may further contribute to cardiovascular risk in this patient population. Alleviation of sleep disordered breathing may be accompanied by lower blood pressure in hypertensive patients with sleep apnea.

Differential characteristics of neural circulatory control: early versus late after cardiac transplantation.

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.

Predisposition to vasovagal syncope in subjects with blood/injury phobia.

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 degrees. 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 (chi(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.

Rhythms, rhymes, and reasons--spectral oscillations in neural cardiovascular control.

Cardiovascular neural regulation is an integrated response to a continuous interaction of inhibitory and excitatory stimuli. Neural control of the circulation appears to be coded simultaneously in different modalities as amplitude (strength of signal or tonic activity) and frequency (oscillatory or phasic activity). Changes in tonic activity appear to be accompanied by tightly linked modulations in oscillatory characteristics. This is true within a narrow range of physiologic conditions, and the relationship is eliminated in extreme cardiovascular pathophysiology. Nevertheless, the oscillatory patterns in cardiovascular neural control appear to be widespread so that low and high frequency oscillatory patterns are evident even in sympathetic traffic to skin (Cogliati et al., 2000). Thus, it is likely that there is a functional significance to these oscillations. Recent data from Nafz et al. (1999) suggest that the presence of LF oscillatory characteristics in renal perfusion may attenuate renin-angiotensin activation during renal hypotension. These findings may have direct relevance to poorer outcomes observed in heart failure patients in whom an absence of LF oscillatory power was observed in RR interval and sympathetic traffic (Van de Borne et al., 1997a).