INTRODUCTION

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THE ACCUMULATION of excess body fat is a major public health problem (6, 14, 39). The prevalence of overweight and obesity has increased dramatically in the last decade (17). Approximately 32% of adults in the United States are overweight, and an additional 22.5% are obese (17). Importantly, obesity is an important independent risk factor for cardiovascular morbidity and mortality (14, 39).

There is considerable heterogeneity in cardiovascular disease risks associated with obesity, some of which can be attributed to interindividual differences in regional body fat distribution. Abdominal obesity is associated with a clustering of several cardiovascular disease risk factors (11, 21, 33), and itself is an independent risk factor for cardiovascular mortality (24). This risk factor clustering, often referred to as the "metabolic syndrome," is more closely associated with abdominal visceral fat than obesity per se.

The results of previous studies (18, 19, 22) suggest that cardiovagal baroreflex gain may be reduced in severely obese humans. The cardiovagal baroreflex plays a key role in the beat-to-beat regulation of arterial blood pressure (13). Reductions in the gain of this reflex have been associated with electrical instability of the myocardium (5) and an increased risk for cardiovascular disease-related mortality (23). Therefore, the lower cardiovagal baroreflex gain in obesity, if observed, may have important implications for improving our understanding of the changes in cardiovascular physiology and cardiovascular disease risks that accompany obesity. However, previous studies on this issue have relied on a crude marker of total body adiposity, i.e., the body mass index. Therefore, the influence of excess adiposity on cardiovagal baroreflex gain remains unclear. Furthermore, there is currently no information available on the influence of elevated abdominal visceral fat on cardiovagal baroreflex gain. This represents a critical void in our existing knowledge because much of the cardiovascular disease risk associated with obesity has been attributed to elevated abdominal visceral fat (11, 21, 33).

Accordingly, we tested the hypotheses that cardiovagal baroreflex gain would be reduced in men with 1) elevated total body and abdominal fat compared with their age-matched peers with lower levels and 2) elevated abdominal visceral fat compared with their peers with lower levels of abdominal visceral fat but similar levels of total body and abdominal subcutaneous fat. To address these issues, we measured cardiovagal baroreflex gain (modified Oxford technique), body composition (dual energy X-ray absorptiometry), and abdominal visceral and subcutaneous fat (computed tomography) in sedentary men across a wide range of adiposity.

	METHODS

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Subjects. Twenty-one men (body mass index, <34.9 kg/m²) volunteered to participate in the present study. Women were excluded from the present study to avoid the potential confounds associated with their lower cardiovagal baroreflex gain (1, 4) and different body fat distribution pattern (25) compared with men. All subjects were normotensive (arterial blood pressure, <140/90 mmHg) as determined by casual blood pressure measurements and free from other overt cardiovascular diseases as determined from individual health histories. Subjects were further evaluated for the presence of overt cardiopulmonary disease by resting and maximal exercise electrocardiograms. Subjects were nonsmokers and nondiabetic (2-h postglucose load <200 mg/dl). Subjects were not taking any medications that could influence autonomic-circulatory function. All subjects were sedentary and were not participating in any regular physical activity (defined as >20 min on >2 days/wk). The nature, purpose, risks, and benefits were explained to each subject before obtaining informed consent. The Colorado State University Human Research Committee approved all experimental protocols.

Experimental procedures. Body mass was measured on a physician's balance to the nearest 0.1 kg. Height was measured using a stadiometer. Waist and hip circumference were measured using procedures recommended by the Arlie Conference (26); the waist-to-hip ratio was calculated. Body composition was measured using dual energy X-ray absorptiometry (DPX-IQ, Lunar Radiation) using software (version 4.5c). Computed tomography scans (HiSpeed CTi, GE Medical) were performed to quantify abdominal visceral and subcutaneous fat levels as previously described (16). A cross-sectional scan 10 mm thick, centered at the L4-L5 intervertebral space, was obtained using 170 mA with a scanning time of 2 s and a 512 × 512 matrix.

Experimental protocol. All subjects were studied in the morning between 7:00 and 11:00 AM after a 12-h overnight fast. Subjects were instructed to refrain from caffeine and alcohol consumption 24 h before all testing sessions. Subjects were also instructed to avoid participation in any vigorous activity 24 h before testing.

Data analysis. Abdominal visceral and subcutaneous fat regions were determined using commercially available medical imaging software (SliceOmatic, version 4.2, Tomovision). The total abdominal fat (i.e., adipose tissue) area was identified by selecting those pixels having an attenuation range of 30 to 190 Hounsfeld units (HU) (16). Abdominal visceral fat was calculated as the area of pixels in the appropriate HU range within the abdominal wall. Abdominal subcutaneous fat was calculated as the pixel area in the appropriate HU range outside the abdominal wall. Blinded repeat measurements of abdominal visceral and subcutaneous fat in a random sample (n = 10) were highly correlated [correlation coefficient (r) = 0. 99, P < 0.05].

Statistical analysis. Differences in subject characteristics and dependent variables between groups were assessed with independent Student's t-tests. Relations among variables were assessed using bivariate correlation analysis. The significance level was set a priori at P < 0.05.

	RESULTS

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Subject characteristics for LF and HF. Subject characteristics for LF and HF are shown in Table 1. No differences in age, height, V/S ratio, systolic blood pressure, diastolic blood pressure, or R-R interval were observed in the LF and HF groups (P > 0.05). Body mass, body mass index, waist and hip circumferences, waist-to-hip ratio, body fat percentage, fat mass, and total abdominal and abdominal visceral and subcutaneous fat areas were higher (all P < 0.05) in HF compared with LF. Maximal oxygen consumption expressed relative to body mass was significantly lower in HF compared with LF but not when expressed relative to fat-free mass (P > 0.05).

Cardiovagal baroreflex gain. Cardiovagal baroreflex gain was ~35% lower (P < 0.05) in HF compared with LF (14.3 ± 2.8 vs. 21.4 ± 2.8 ms/mmHg; Fig. 1).

View larger version (13K): [in this window] [in a new window]   Fig. 1.   Cardiovagal baroreflex gain in men with lower [lower fat (LF), n = 10] and higher [higher fat (HF), n = 11] levels of total body and abdominal fat. Values are means ± SE. *P < 0.05 vs. LF.

Subject characteristics for LAVF and HAVF. Subject characteristics are shown in Table 2. Age, height, body mass, body mass index, waist and hip circumference, waist-to-hip ratio, body fat percentage, body fat mass, systolic and diastolic blood pressure, R-R interval, and maximal oxygen consumption (either expression) were not significantly different between the two groups. Neither total abdominal nor abdominal subcutaneous fat area was significantly different in LAVF compared with HAVF. As expected, the V/S ratio and abdominal visceral fat were significantly higher in HAVF compared with LAVF.

Cardiovagal baroreflex gain in LAVF and HAVF men. Cardiovagal baroreflex gain was ~40% lower (P < 0.05) in HAVF compared with LAVF (13.0 ± 2.0 vs. 21.4 ± 3.6 ms/mmHg; Fig. 2).

View larger version (12K): [in this window] [in a new window]   Fig. 2.   Cardiovagal baroreflex gain in men with lower (LAVF, n = 7) and higher levels of abdominal visceral fat (HAVF, n = 10). Values are means ± SE. *P < 0.05 vs. LAVF.

Correlational analysis. Cardiovagal baroreflex gain was correlated with height (r = 0.58, P < 0.05), body mass index (r = 0.57, P < 0.05), waist-to-hip ratio (r = 0.40, P < 0.05), and total abdominal fat (r = 0.40, P < 0.05). However, correlations with waist circumference (r = 0.35, P = 0.058), body fat percentage (r = 0.35, P = 0.061), fat mass (r = 0.35, P = 0.058), abdominal visceral fat (r = 0.35, P = 0.058), abdominal subcutaneous fat (r = 0.36, P = 0.056), diastolic blood pressure (r = 0.310, P = 0.09), and maximal oxygen consumption expressed relative to body weight (r = 0.316, P = 0.08) did not reach statistical significance.

	DISCUSSION

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There were two important findings of the present study. First, cardiovagal baroreflex gain was reduced in men with higher levels of total body and abdominal fat compared with their age-matched peers with lower levels. Second, cardiovagal baroreflex gain was reduced in men with elevated abdominal visceral fat compared with their age-, total body weight-, and abdominal subcutaneous fat-matched peers with lower levels. Taken together, these observations suggest that the lower cardiovagal baroreflex gain observed in overweight and obese men is linked to their higher level of abdominal visceral fat.

The results of our study significantly extend previous findings in at least three important aspects. First, we characterized the entire sigmoid relation between systolic blood pressure and R-R interval and calculated the gain based on only the linear portion of the relation, at least in the majority of subjects in the present study. The reflex adjustments in R-R interval to pharmacologically provoked changes in systolic blood pressure are mediated by the efferent vagal activity because administration of atropine sulfate abolishes these responses (30, 32). The experimental approach used by Laederach-Hofmann et al. (22) to quantify cardiovagal baroreflex gain has been seriously challenged (37). Furthermore, Grassi et al. (18) used the steady-state drug infusion technique, during which central resetting may be more significant than that which occurs with the modified Oxford technique. In addition, it is unclear whether their gain estimates were calculated after excluding the threshold and saturation regions of the cardiovagal baroreflex.

Second, our observations indicate that the reduced cardiovagal baroreflex gain previously reported in severely obese adults (18, 22) is observed in overweight individuals and those with more mild-to-moderate levels of obesity. Therefore, our observations would appear generalizable to the largest segment of overweight/obese male adults (17). Furthermore, we rigorously screened the subjects in the present study for overt cardiovascular and metabolic disease. Previous studies were limited to severely obese individuals, in whom the prevalence of comorbidities increases dramatically (39). Taken together, our findings suggest that cardiovagal baroreflex gain may be reduced during the early period of weight gain and obesity development. The observation that weight gain is associated with reductions in cardiac vagal tone in nonobese individuals (2) is consistent with this postulate.

Finally, we measured body composition and abdominal visceral and subcutaneous fat in the present study. Thus the influence of adiposity per se could be addressed directly. Previous studies were limited in that they relied on body mass index, a relatively insensitive marker of total body adiposity. Importantly, our study is the first to demonstrate an important influence of elevated abdominal visceral fat on cardiovagal baroreflex gain in men.

We can only speculate on the mechanisms responsible for the lower cardiovagal baroreflex gain in the men with elevated total body and abdominal visceral fat in the present investigation. First, increasing levels of total body and abdominal visceral fat have been associated with reduced arterial distensibility (34). Carotid artery distensibility is an important physiological determinant of cardiovagal baroreflex gain (9). Therefore, it is possible that lower levels of carotid artery distensibility in the men with elevated abdominal visceral fat in the present study would reduce mechanical transduction of arterial blood pressure into barosensory stretch. This, in turn, would result in an attenuated baroreflex mediated increase in efferent cardiac vagal outflow (i.e., lengthening of the R-R interval).

Second, it is possible that central integration of afferent vagal nerve traffic is altered in men with elevated total body and abdominal visceral fat, and this, in turn, would result in a proportionally smaller increase in efferent vagal nerve traffic compared with men with lower levels of total body and abdominal visceral fat. In this regard, circulating neurohumoural factors could act centrally to modify the cardiovagal baroreflex in men with elevated total body and abdominal visceral fat. For example, obesity is associated with elevated activity of the renin-angiotensin-aldosterone system (15), and angiotensinogen is expressed more abundantly in abdominal visceral compared with subcutaneous fat (38). In addition, angiotensin II infusion reduces (27) and pharmacological reduction in angiotensin II concentrations improves cardiovagal baroreflex gain (28). Thus it is possible that elevated angiotensin II concentrations could contribute to the reduced cardiovagal baroreflex gain in individuals with elevated total body and abdominal visceral fat. Future studies are necessary to address this hypothesis.

Finally, impaired muscarinic receptor function has been demonstrated in an animal model of diet-induced obesity (31). Thus it is possible that the reduction in cardiovagal baroreflex gain observed in the men with elevated total body and abdominal visceral fat in the present study was due, in part, to reduced cardiac muscarinic receptor number and/or sensitivity. Importantly, both mechanical and neural factors determine cardiovagal baroreflex function (13, 20), and one or more of the above potential mechanisms could contribute to the lower gain observed in men with elevated total body and abdominal visceral fat.

There are some important clinical implications of the present study. First, excess adiposity, particularly in the abdominal visceral region, is an important risk factor for cardiovascular disease (14, 39). Reduced cardiovagal baroreflex gain is also associated with increased cardiovascular mortality (23). Therefore, reduced cardiovagal baroreflex gain may contribute to the greater risk observed in the men with characteristics of the metabolic syndrome. In turn, reductions in total body and abdominal visceral fat result in improvements in cardiovascular disease risk factors (10, 11). Thus it is possible that weight loss may improve cardiovagal baroreflex gain in men with excess total body and abdominal visceral fat and, in turn, lower their risk of cardiovascular disease.

Second, visceral obesity and the metabolic syndrome have been described as a neuroendocrine disorder characterized by dysregulation of the hypothalamic-pituitary-adrenal axis and parallel sympathetic nervous system activation (7, 8). The results of our investigation indicate that elevated abdominal visceral fat is also associated with reduced cardiovagal baroreflex gain. This finding is consistent with a previous report (3) indicating that cardiac vagal tone is reduced in obesity. Therefore, altered regulation of both the parasympathetic and sympathetic nervous systems may be a common feature of the neuroendocrine disorder that is characteristic of visceral obesity and the metabolic syndrome.

There are some potential limitations of the present study that should be addressed. First, we studied only sedentary, nonobese men 18-40 yr of age who were healthy and free of overt cardiovascular and metabolic disease. As such, the influence of adiposity in other groups (e.g., older or female adults) may differ from those reported here.

Second, the number of subjects studied in the present investigation was small. Thus it is possible that the inclusion of a larger number of subjects may yield a different outcome. Future studies will be necessary to confirm or refute our findings.

Third, we cannot exclude the possibility that abdominal subcutaneous fat contributes importantly to the lower cardiovagal baroreflex gain observed in overweight and obese men. Indeed, the results of our correlational analysis suggest that elevated abdominal subcutaneous fat may be associated with the lower cardiovagal baroreflex gain observed. However, the high correlation between total body fat and abdominal subcutaneous fat in the present study (r = >0.90) precluded us from further addressing this possibility.

Finally, it is possible that another factor not measured in the present study affects both abdominal visceral fat and cardiovagal baroreflex function and that the latter two are not mechanistically linked. Future studies may provide insight into this possibility.

In summary, the results of the present study indicate that cardiovagal baroreflex gain is reduced in men with elevated total body and abdominal fat. Our findings further suggest that the reduced cardiovagal baroreflex in overweight and obese men is linked to their elevated abdominal visceral fat level. The mechanisms responsible for this observation remain unclear. Importantly, these findings may have implications for understanding the increased risk of cardiovascular disease in men with elevated abdominal visceral fat and the metabolic syndrome.