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Plasma Leptin Concentrations and Cardiac Autonomic Nervous System in Healthy Subjects with Different Body Weights

Department of Geriatric Medicine and Metabolic Diseases II, University of Naples, I-80138 Naples; and Centro Ricerche Cardiovascolari, Medicina Interna II, Ospedale L. Sacco, University of Milan (N.M.), 20100 Milan, Italy

Address all correspondence and requests for reprints to: Giuseppe Paolisso, M.D., Department of Geriatric Medicine and Metabolic Diseases, Servizio di Astanteria Medica, Piazza Miraglia 2, I-80138 Naples, Italy. E-mail: gpaoliss{at}tin.it

	Abstract

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Previous studies have shown that leptin stimulates sympathetic nervous system; heart rate variability (HRV) is a widely used technique for assessing the sympathovagal balance at the cardiac level. The aim of our study was to investigate a possible relationship between plasma leptin levels and the autonomic regulation using spectral analysis of HRV. In 120 healthy nonobese subjects the plasma leptin concentration was determined, and HRV was recorded at baseline and during tilt. All subjects were categorized in quartiles of plasma leptin concentration. Analysis of data showed a significant increase in body mass index, body fat, fasting plasma insulin, triglyceride concentration, and homeostatic model assessment values throughout the different quartiles of plasma leptin concentration. Concerning cardiovascular parameters, heart rate, arterial blood pressures, and RR intervals were not significantly different among the quartiles. Total power and high frequency (HF) in normalized units were significantly decreased, whereas low frequency (LF) normalized units was progressively increased from the first to the fourth quartile. Thus, the LF/HF ratio rose gradually and significantly from the lowest to the highest quartile. Such results were independent of the body fat estimate (P < 0.03 for the trend). The change in the LF/HF ratio was significantly enhanced during tilt (P < 0.001 vs. rest values for all quartiles); the effect was stronger in subjects in the fourth quartile of plasma leptin concentration (P < 0.005 for the trend). The latter parameter was also independent of body fat content and distribution (P < 0.01). Our study shows that increasing fasting plasma leptin concentrations are associated with a shift of the sympathovagal balance toward a progressive increase in sympathetic activation and an increased response to orthostatic stimulus in nonobese subjects with different body fat contents.

	Introduction

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LEPTIN IS THE peptide hormone product of the obese (ob) gene expressed in adipose tissue; it acts centrally, decreasing appetite and increasing energy expenditure (1). More recently, a possible impact of leptin on the autonomic nervous system (ANS) has been hypothesized. In fact, leptin has been shown to stimulate sympathetic nervous system (SNS) activity in thermogenic (2) and nonthermogenic organs (3) in animal models. In the same experimental model, chronic leptin infusion concentration has been also demonstrated to stimulate heart rate and increase arterial blood pressure (4). Whether such an effect of leptin is a physiological or pharmacological one still needs to be demonstrated. The latter question has important clinical implication, as SNS activation might promote atherosclerosis (5, 6) and trigger acute cardiovascular events (7, 8). Despite some criticism (9), spectral analysis of heart rate variability (HRV) is an well accepted noninvasive tool for assessing the state of the cardiac sympathovagal balance (10, 11). In fact, several studies have indicated that the powers of the low frequency (LF) and the high frequency (HF) component, occurring in synchrony with vasomotor waves and respiratory acts, respectively, appear to reflect in their reciprocal relationship the state of sympathovagal balance in numerous physiological and pathophysiological conditions (12, 13, 14, 15). Interestingly, correlation between body fat content and LF/HF ratio after glucose ingestion has been correlated in nonobese subjects with different degrees of body fat content (16). To the best of our knowledge, the possible relationship between different plasma leptin concentrations and HRV parameters has not yet been evaluated. Accordingly, we planned to investigate the possible association of physiologically occurring fasting leptin concentrations and cardiac sympathovagal balance in healthy nonobese subjects in baseline conditions and during the tilt test.

	Materials and Methods

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Subjects

One hundred and twenty healthy young males volunteered for the study. All subjects were nonsmokers, normotensive, and receiving no medication and had no evidence of metabolic or cardiovascular diseases. Subjects with a change in body weight of more than 2 kg during the preceding year were excluded from the study. All volunteers had normal glucose tolerance to a 75-g oral glucose load (17). Insulin resistance was derived by homeostatic model assessment (HOMA) according to Matthews et al. (18). All tests were performed in the morning and after an overnight fast (at least 12 h). After clear explanation of potential risks of the study, each volunteer gave informed consent to participate in the study, which was approved by the ethical committee of our institution.

Anthropometric determinations

Weight and height were measured using a standard technique. Body mass index (BMI) was calculated as body weight (kilograms)/height (meters)². Body fat (BF) was measured using a four terminal bioimpedance analyzer (IA 101/SC, RJL Spectrum Bioelectrical Impedance, Akern, Italy; RJL System, Florence, Italy).

Study protocol

All subjects were studied at 0800 h in a quiet comfortable room at a temperature ranging between 22–24 C. A venous blood sample for plasma metabolite determinations was immediately drawn. Then each subject rested in the supine position for at least 30 min before starting baseline Holter (Remco Italy Cardioline, Milan, Italy) recording, which lasted 60 min. Later the table was rotated to an upright position (head-up tilt test), which was maintained for 10 min. Transit from 0° at 90° took about 15 s. If hypotension developed during postural tilt, testing was stopped, and the subject was excluded from study (n = 4). Blood pressure and heart rate at baseline and during the studies were determined by Finapres (Omheda, Englewood, CO). Respiratory frequency was also calculated over a period of 2 min before the test. Subjects with a respiratory rate less than 10 breaths/min (i.e. <0.15 Hz) were excluded from the study. Ambulatory electrocardiograph monitoring was performed with 2-channel frequency modulatory tape recorders (AD 35, recorder model LP103, Remco Italy Cardioline, Milan, Italy). After accurate skin preparation, the electrodes were placed on the chest to obtain the bipolar chest leads CM1 (modified V1) on the first channel and CM4 (modified V4) on the second channel. Two independent and blind experienced investigators analyzed the ambulatory electrocardiograph recording tapes by Holter AD35 TOP (Remco Italy Cardioline). Ectopic beats were corrected for linear interpolation with the adjacent complexes. Electrocardiograph tracings with more than 1% premature beats were eliminated from the analysis. Power spectral analysis was calculated from a consecutive series of 512 intervals. An autoregressive algorithm computed the power spectral densities. Autoregressive spectral analysis was undertaken after estimation of model coefficients by the Levinson-Durbin algorithm (19). The model order selection was performed according to the Akaike (19) information criterion. Spectral components were identified and estimated using the spectral decomposition algorithm proposed by Johnsen and Andersen (20) and were then assigned, on the basic of their central frequency, to 1 of the 3 bands: very low frequency (VLF) band (from 0–0.03 Hz), LF band (from 0.04–0.15 Hz), and HF band (from 0.16–0.45 Hz). As the physiological explanation of the VLF component is much less defined and the existence of a specific physiological process attributable to that heart period change has been strongly questioned (11), only LF and HF components were considered. LF and HF components are reported in absolute as well as normalized units (nu), which represent the relative value of each power component in proportion to the total power minus the VLF component (11). Normalized units tend to minimize the effect of the changes in total power on the values of LF and HF components (11).

Analytical techniques

Plasma glucose was determined by the glucose oxidase method [Autoanalyzer, Beckman Coulter, Inc., Fullerton, CA; coefficient of variation (CV), 2.1 ± 0.2%]. Plasma total cholesterol (CV, 3.3 ± 0.3%), high density lipoprotein cholesterol (CV, 3.5 ± 0.4%), and triglyceride (CV, 3.7 ± 0.6%) concentrations were determined by routine methods (Ortho-Clinical Diagnostic, Milan, Italy). Blood samples for plasma hormone measurements were collected in heparinized tubes. After centrifugation, plasma insulin (Sorin Biomedical, Milan, Italy; CV, 3.2 ± 0.2%) and leptin (Linco Research, Inc., St. Louis, MO; CV, 4.1 ± 0.7%) concentrations were determined by RIA. To rule out the possible interference of day by day plasma leptin variation, we measured plasma leptin concentration at 24-h interval in 45 subjects. Plasma leptin concentrations had a very small interday variation (mean variation, 4.5 ± 0.8%). Furthermore, to avoid circadian variation in plasma leptin, blood was always sampled between 0800–0900 h. Plasma catecholamine concentrations were determined by high performance liquid chromatography (epinephrine CV, 4.8 ± 1.1%; norepinephrine CV, 5.1 ± 1.2%).

Statistical analysis

All results are the mean ± SD. Because the distribution of fasting plasma triglycerides, insulin, and leptin concentrations and of the frequency domain measures of HRV are extremely skewed, each value was also log-transformed to improve normality for statistical testing and back-transformed for presentation in tables and figures. The LF/HF ratio was calculated as difference between baseline values and those reported at the end of tilt. The nQuery test was used to predict the adequacy of sample size in each quartile. This test demonstrated that 22 subjects in each quartile were sufficient to obtain a significant difference in HRV parameters. ANOVA was used to assess differences among the leptin groups organized in quartiles. When P < 0.05 was found, Scheffe’s test was also performed. ANOVA for repeated measures was used for calculating the P value for the trend for each variable among the different groups. Pearson’s simple correlation allowed studying the association between two variables. Analysis of covariance allowed the study of differences in baseline LF/HF ratio among the different quartiles independently of body fat. Partial correlation allowed studying the relationship between two variables independently of covariates. Multivariate linear regression analysis allowed investigating the independent association among age, body fat, HOMA_IR, fasting plasma triglyceride and leptin concentrations, and baseline LF/HF ratio. All data were analyzed on an IBM PC computer by SOLO (BMDP, Cork, Ireland) software.

	Results

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Baseline data

The clinical characteristics of the study groups are reported in Table 1. All subjects were adult, nonobese, and normotensive. The fasting plasma leptin concentration was significantly correlated with BMI, body fat, HOMA, triglycerides, and the main index of cardiac ANS (Table 2). Metabolic and cardiovascular data stratified in quartiles are reported in Table 3. Analysis of data showed a significant increase in BMI, body fat, fasting plasma insulin and triglyceride concentrations, and HOMA_IR values throughout the different quartiles. In contrast, fasting plasma glucose, catecholamine, and low and high density lipoprotein cholesterol levels were similar in all quartiles studied. As far as the cardiovascular parameters are concerned, heart rate, systolic and diastolic blood pressures, and RR intervals were not significantly different among the quartiles. Total power and HF (in nu) showed a significant declining trend, whereas LF was progressively increased from the first to the fourth quartile. Thus, the LF/HF ratio rose progressively and significantly from the lowest to the highest quartile. Interestingly, this finding was independent of body fat (P < 0.03 for the trend). In the whole group of subjects (n = 120), the fasting plasma leptin concentration and baseline LF/HF ratio were significantly correlated (r = 0.43; P < 0.001); this relation was independent of body fat and waist/hip ratio (r = 0.24; P < 0.009). The independent role of fasting plasma leptin concentration on the baseline LF/HF ratio was also investigated by multivariate linear regression analysis in the whole group of subjects (n = 120; Table 4). This analysis demonstrated that age, body fat, HOMA_IR values, and fasting plasma triglycerides and leptin concentrations were all significantly and independently associated with the baseline LF/HF ratio. Furthermore, stepwise multivariate analysis indicated that the whole model explained 63% of the variability in the baseline LF/HF ratio, and fasting plasma leptin explained 28% of the variability in the dependent variable.

Changes in HRV parameters in different quartiles of plasma leptin concentration are reported in Table 5. Briefly, changes in total power, RR intervals, and HF were significantly reduced during the tilt stimulus (P < 0.01 vs. rest values for all parameters and quartiles); the effect was stronger in subjects in the fourth quartile than those in the first quartile. Changes in LF and LF/HF ratio appeared significantly increased during tilt (P < 0.001 vs. rest values for all parameters and quartiles), with subjects in the fourth quartile having the strongest response. After adjusting for body fat content and distribution, all trends were still significant (Table 5). Plasma catecholamine concentrations showed a similar response in all groups (Table 5).

	Discussion

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Our study demonstrates that the plasma leptin concentration is associated with an increase in the LF/HF ratio, an index of cardiac sympathovagal balance, independently of anthropometric characteristics and of insulin resistance in healthy subjects. Furthermore, we demonstrate an association between the extent of the stimulation of the LF/HF ratio by tilt test parallels and the rise in plasma leptin concentration, a finding independent of body fat distribution and changes in plasma catecholamine concentrations.

Previous studies have shown that plasma leptin may affect ANS activity. In particular, leptin has been shown to enhance norepinephrine turnover in interscapular brown adipose tissue, suggesting increased sympathetic outflow to this thermogenic organ in animal models (2). This effect had a slow onset, suggesting an influence of leptin on the central nervous system (4). The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 µg/kg (plasma concentration, 5 ng/mL). Leptin-induced sympathetic activation was still apparent after transaction of the sympathetic nerve distal to the recording site, implying that the increase in activity was from efferent, not afferent, nerves. This was confirmed by the disappearance of sympathetic activity after ganglion blockade with iv chlorisondamine (30 mg/kg). In contrast, leptin did not cause SNS activation in obese Zucker rats, which are known to possess a mutation in the leptin receptor gene. Such a phenomenon implies that functional receptors (and possibly secondary signaling mechanisms) are necessary to elicit a nervous system response. Evidence has been also accumulated that leptin increased sympathetic nerve activity in nonthermogenic organs, such as kidney, hindlimb, and adrenal gland (21). In humans, the relationship between plasma leptin concentration and ANS has been shown in Pima Indians, in whom the plasma leptin concentration correlated with basal muscle sympathetic nerve activity (22).

The results concerning the effect of plasma leptin on the ANS at the cardiovascular level are controversial. In rats, iv leptin infusion did not affect heart rate or arterial blood pressure (23, 24). Nevertheless, in this study the rats were anesthetized, and thus the effect of leptin on the cardiovascular ANS might be offset. On the other hand, others have shown that a chronic rise in circulating leptin cause sustained increases in arterial blood pressure and heart rate, consistent with a possible role of leptin in obesity hypertension (4). Why the acute rise in the plasma leptin concentration increased heart rate was not explained; nevertheless, a possible impact of plasma leptin on cardiac sympatovagal balance was hypothesized (25). A possible interference between plasma leptin and the cardiovascular apparatus is also strengthened by the evidence that hyperleptinemia might be a component of a metabolic syndrome and also a cardiovascular risk factor (26). In fact, fasting plasma leptin was significantly correlated with arterial blood pressure, BMI, fasting plasma triglycerides, and serum uric acid (26).

Our data for HRV are in agreement with the data demonstrating an excitatory effect of plasma leptin on cardiac ANS activity. Interestingly, our data demonstrated that the association between the variation in plasma leptin concentration and the cardiac ANS activity was independent of body fat. Despite the fact that the plasma leptin concentration is strictly correlated with body fat content, the relationship between plasma leptin concentration and cardiac ANS activity independently of body fat might be supported by the following experimental evidence: 1): direct activation of SNS activity (4, 27); 2) increase in norepinephrine turnover, as demonstrated in interscapular brown tissue (2, 23); and 3) decline of cholinergic activity at the cardiac level (25). All of those possibilities are also strengthened by evidence that leptin receptor messenger ribonucleic acid is expressed in the heart (28). Our data are in agreement with the prospective data showing a strong predictive role of obesity in sudden death (29). In fact, one can hypothesize that increased body fat content might be associated with a rise in plasma leptin concentration, which, in turn, could make the cardiac ANS more sensitive and thus contribute to sudden death. Of course, only longitudinal future studies specifically designed to address this point can provide prove our hypothesis. Nevertheless, one cannot rule out that an increased body fat content might affect cardiac ANS through overactivity of the SNS (30, 31). Indeed, our study did not assess either muscle sympathetic nerve activity or plasma catecholamine turnover, so the latter hypothesis cannot be completely excluded. Notwithstanding, we measured the plasma catecholamine concentration at baseline and after orthostatic stimulus, and no significant difference among the study groups was found on either occasion.

A potential limitation of our study was that only association among different variables were determined, and thus no cause-effect relationship would be drawn. Notwithstanding, human leptin is still not commercially available, and thus the effect of acute change in plasma leptin concentration, independently of other metabolic variables, cannot be investigated.

Our data were only related to Caucasian men. Indeed, the limitation in race was only due to geographic reasons, as Caucasians represent more than 98% of the populatin of Italy. As far as gender is concerned, we only focused on men because of the sexual dimorphism (32, 33, 34) in plasma leptin concentrations. Indeed, it has been hypothesized that changes in the quality and quantity of sex hormones may significantly affect the plasma leptin concentration (33, 34). Thus, a study in women should also take into account menstrual cycle variations and include pre- and postmenopausal women; these variables make it difficult to compare women and men, and thus women should be investigated in a more appropriate experimental design.

An unexpected finding of our study was that the association between the plasma leptin concentration and the cardiac ANS was independent of insulin resistance. The relationship between insulin resistance and cardiac sympathovagal balance is still debated. Briefly, it has been shown that hyperinsulinemia/insulin resistance might attenuate the variability of the sinoatrial node activity in response to both sympathetic and parasympathetic influences in obese subjects (35). Our results do not confirm this finding, as we found that subjects high HOMA_IR values and high plasma leptin concentrations had the strongest LF/HF response to tilt. The apparent discrepancy between our study and others may be due to the fact the subjects have different degrees of body fat, but they were not obese. Thus, one can hypothesize the occurrence of a threshold for plasma insulin concentration before the variability in sinoatrial node activity would be reduced. Nevertheless, only a dose-effect curve between plasma insulin concentration and variability in sinoatrial node activity would resolve such question.

In conclusion, our study demonstrates that increasing fasting plasma leptin concentrations are associated with a shift of the sympathovagal balance toward a progressive increase in sympathetic activation and an increased response to orthostatic stimulus in nonobese subjects with different body fat contents. Nevertheless, only future studies made by acute changes in the human plasma leptin concentration will be able to demonstrate a cause-effect relationship.

Received October 14, 1999.

Revised December 14, 1999.

Accepted December 15, 1999.

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