It has been well established that an individual's cardiorespiratory fitness is inversely associated with risk of cardiovascular disease and with all-cause mortality in both healthy individuals and cardiovascular disease patients (3,19,29).
Fatness and excess body weight do not necessarily imply a reduced ability to maximally consume oxygen, but excess fatness does have a detrimental effect on submaximal aerobic capacity (8). Abdominal fat, which is an emerging cardiovascular risk factor, may contribute to an individual's cardiorespiratory fitness level. Recently, estimated waist circumference, which is a marker of abdominal fat, showed a significantly negative association with cardiorespiratory fitness (V˙O2peak) for a given body mass index (BMI), independent of leisure-time physical activity level (5). Lee et al. (20) and Ross and Katzmarzyk (28) reported that cardiorespiratory fitness is associated with lower levels of total and abdominal fat measured by magnetic resonance imaging for a given BMI, independent of gender, indicating the substantial relationship between cardiorespiratory fitness and abdominal fat (visceral fat plus subcutaneous fat). It has been well established that epicardial fat (EF) tissue, an index of cardiac and visceral adiposity, could be a new cardiometabolic risk marker (11,12) as well as a potentially active player in the development of an unfavorable metabolic risk profile (9,10). As a cardiometabolic risk marker, this tissue may affect cardiorespiratory health as well as the autonomic nervous system. However, it is unknown whether EF thickness affects heart rate recovery (HRR)-a recognized indicator of the responsiveness of the autonomic nervous system-or anaerobic threshold (AT) and V˙O2peak.
In light of EF tissue's anatomic location, we hypothesized that this tissue would affect cardiorespiratory fitness and autonomic nervous system because EF tissue is a metabolically active visceral fat tissue and is a source of several bioactive molecules that can substantially modulate cardiovascular morphology and function. The purpose of this study was to explore the influence of the EF tissue on aspects of HRR and cardiorespiratory fitness in middle-aged men.
The subjects were recruited through advertisements in local newspapers. A total of 101 carefully screened healthy men were studied. The subjects were healthy, were not consuming any medication known to alter glucose and lipid metabolism, and were reportedly free of any diagnosed cardiovascular disease, any contraindication to exercise, or any known metabolic disorder. Men were categorized into low-EF (n = 34), moderate-EF (n = 34), and high-EF (n = 33) groups on the basis of EF thickness measurement. The nature, the purpose, and the potential risks of the study were explained to all the subjects, and voluntary informed written consent was obtained from all subjects before participation in the study. This study was conducted in accordance with the guidelines proposed in the Declaration of Helsinki, and the study protocol was reviewed and approved by the ethics committee of the University of Tsukuba, Japan.
Body height was measured to the nearest 0.1 cm using a wall-mounted stadiometer (TBF-215; Tanita, Tokyo, Japan), and body weight was measured to the nearest 0.01 kg using calibrated electronic digital scales (TBF-215; Tanita) in barefoot subjects. BMI was calculated by dividing the weight (kg) by the square of the height (m2). Waist circumference was measured at the level of the umbilicus in lightly clothed participants in the standing position. The mean of two consecutive records was used as the measured value. Dual-energy x-ray absorptiometry was performed using Lunar (software version 1.3Z, DPX-L; Lunar, Madison, WI) to measure body composition, which was assumed to consist of fat mass and fat- and bone-free mass, as previously described (16,25). The pixels of soft tissue were used to calculate the ratio of mass attenuation coefficients at 40-50 keV (low energy) and 80-100 keV (high energy). The subjects were made to lie supine with arms and legs at their sides during the 15-min scan; radiation exposure was <7 μSv. All the scans were performed by the same operator, and daily quality assurance tests were performed according to the manufacturer's directions.
Clinical assessment of epicardial adipose tissue.
For direct assessment of the epicardial adipose tissue, each participant underwent echocardiography as proposed by Iacobellis et al. (9,10,12). With the subjects in the left lateral decubitus position, two-dimensionally guided M-mode echocardiography was performed using an Envisor C, Philips, with a 2.5-MHz transducer. The largest dimension of this space was in the end-diastolic period and was measured from the trailing edge to the leading edge on the free wall of the right ventricle; this measurement was considered as the maximum EF thickness in two standard echocardiographic views, namely, the parasternal long-axis and short-axis views, and an average of the measurements on both views was obtained for off-line analysis of the recorded videotape. To decrease the variability, three cardiac cycles were read and measured in the end-diastolic period of the right ventricle. According to previously described studies, the subjects were analyzed weight stable (<2 kg·3 months−1 of weight change) in this study; this was necessary because EF thickness was carefully considered in relation to the degree of weight loss (13,16,17). To assess the reproducibility of the echocardiographic measurement of EF thickness, subjects were randomly selected for off-line analysis by two observers who were unaware of metabolic and clinical data. The intraclass correlation coefficient was 0.91, and the interclass correlation coefficient was 0.93, suggesting an excellent reproducibility of this fat thickness.
AT and maximal aerobic capacity.
The subjects underwent a maximal graded exercise test on a cycling ergometer (818E; Monark, Stockholm, Sweden) for evaluation of cardiovascular function and simultaneous determination of the individual's peak oxygen uptake (V˙O2) and AT. After a 2-min warm-up at 0 W, the exercise was started at a workload of 15 W that was increased every 1 min by another 15 W until volitional exhaustion. During the test, ventilation and expired gases were measured using an automated gas exchange measuring system (Oxycon α system; Mijnhardt, Breda, The Netherlands), and the HR was constantly observed at rest and during the exercise and recovery periods using an ECG monitor (Dyna Scope; Fukudadenshi, Tokyo, Japan). AT, a discriminatory marker between cardiovascular and pulmonary limitations to exercise (32), was determined from V-slope AT, which was plotted using the V-slope technique as described in an earlier study (2). The V˙CO2 versus the V˙O2 curve was divided into two regions, each of which was fitted by linear regression, and the intersection between the two regression lines was regarded as the V-slope AT. The software of the Oxycon equipment automatically established the regression lines and their crossing points. The highest oxygen uptake achieved more than 30 s was determined as V˙O2peak. V˙O2peak was referred to the criteria described by Tanaka et al. (30). The overall efficiency of the cardiovascular system during maximal exercise was evaluated using the oxygen pulse (V˙O2/HR). The oxygen pulse is a noninvasive index of the efficiency of the ability of the body to transport oxygen to the working tissue, with more fit subjects having a higher oxygen pulse as compared with less fit subjects as previously described as an index of the oxygen used per HR (6). Moreover, the pulmonary efficiency at maximal exercise was evaluated using the volume of expired gas and the ventilatory equivalent for oxygen (V˙E/V˙O2).
Exercise testing was discontinued in case of the following reasons: perceived exertion rating >18, achievement of >90% of the age-predicted maximal HR or extreme fatigue such that pedaling on the bicycle was not possible, typical chest discomfort; severe arrhythmias, or >1 mm of horizontal or downward-sloping ST segment depression. Exercise capacity was measured in watts, which was converted to maximum oxygen consumption calculated as METs using the following formula according to a previous study (24).
Heart rate recovery.
At the cessation of exercise, arrival at the peak aerobic capacity, participants were placed sitting as soon as possible. HRR, which reflects vagal reactivation after exercise, was measured as beats per minute from five samples drawn recorded at 30-s intervals of between-maximal HR to HR through 2 min into recovery after the completion of the maximal exercise test according to previous studies (15,24).
Homeostasis model assessment of insulin resistance (HOMA), a surrogate measure of insulin resistance, is a simple index that is based on the glucose and insulin levels in a fasting blood sample (22,23) and is calculated as follows:
Blood pressure and biochemical analysis.
Both systolic blood pressure and diastolic blood pressure were recorded after at least a 20-min rest period using a mercury manometer with the average of two measurements separated by at least a 3-min interval. Blood sampling was performed in overnight-fasted participants sitting upright after blood pressure measurement and a rest period of at least 20-30 min. The fasting blood samples were collected from the antecubital vein into tubes containing either sodium fluoride/ethylenediaminetetraacetic acid for glucose or into tubes containing no additive for lipids and insulin. In brief, blood samples were put into 8-mL tubes containing thrombin- and heparin-neutralizing agents (Venoject II; TERUMO, Tokyo, Japan). The tubes were immediately centrifuged at 3000 rpm for 10 min at 4°C. The blood in the 8-mL tubes was used for analyses of plasma concentrations of free fatty acids (FFA), insulin, and lipids. Plasma triglyceride and NEFA concentrations were determined by the enzymatic method by using kits. LDL cholesterol was calculated according to the formula of Friedewald et al. (7).
All values are presented as the mean ± SE. Sample size was estimated to be 101 subjects to detect changes varying between 10% and 30% for the EF thickness as a principle outcome measure during weight-loss program tested in the hypothesis; alpha error rate was 0.05, and statistical power varied between 80% and 90% with two-sided alternative hypotheses. Assumptions of normality were investigated graphically with the Kolmogorov-Smirnov test, and when significant, the distribution of log-transformed variables was also checked in the same way. The data were analyzed by one-way ANOVA followed by Dunnett's multiple comparison test. A two-way ANOVA with repeated measures was used to analyze the data. If a significant difference was detected after adjusting for the change of body weight, these were further evaluated by post hoc Tukey's test and a Bonferroni-corrected 95% confidence interval. Pearson's partial correlation coefficient was used to study the associations between peak oxygen uptake and EF thickness after adjusting for age and body weight. To determine the variables independently associated with V˙O2peak variance, the hierarchical multiple linear regression analysis was performed. The data were analyzed using the SPSS 13.0 version for Windows package (SPSS Inc., Chicago, IL). A statistically significant level of P < 0.05 was chosen. Two-tailed P values have been used in the text.
As shown in Table 1, the three EF thickness groups had similar age and blood pressure ranges. However, BMI, body weight, and waist circumstance as adiposity markers were significantly different among the groups. As shown in Table 2, for a given level of EF thickness, men with low-EF thickness had lower serum insulin concentrations and insulin sensitivity (HOMA) than men with moderate- or high-EF thickness. Levels of cholesterol, hepatic enzymes, lipoproteins, and plasma glucose were not significantly different among groups (P > 0.05).
Compared with men in the lowest EF tertile, men in the highest tertile had significantly lower HRR value (P < 0.05) in beats per min at 60, 90, and 120 s, indicating autonomic dysfunction. Low-, moderate-, and high-EF groups averaged -33.8, -30.2, and -25.9 beats·min−1 at 60 s; -46.2, -37.6, and -34.0 beats·min−1 at 90 s; and -52.7, -44.4, and -40.7 beats·min−1 at 120 s, respectively, as shown in Figure 1.
As depicted in Figure 2, EF thickness was directly associated with V˙O2peak after adjustment for age and body weight. Moreover, AT levels, which have been used as an effective gauge of physical fitness in the general population, were significantly different among groups (P = 0.03). AT level was negatively associated with EF thickness (r = -0.228, P = 0.022) on the basis of a significant decrease of METs as exercise capacity with a volume-response relationship to EF thickness, as shown in Table 3. However, pulmonary efficiency at maximal exercise (V˙E/V˙O2), also shown in Table 3, was not significantly different among tertiles. Moreover, the EF thickness was negatively associated with HRR at 1 min (r = -0.15, P < 0.05) and HRR at 2 min (r = -0.16, P < 0.05), respectively.
To determine the significant predictors that could explain the V˙O2peak as the dependent variable, the hierarchical multiple linear regression analysis was performed. In the middle-aged men, 16.9% of the variance in V˙O2peak as the dependent factor was explained by age, BMI, trunk fat, total fat, and EF thickness. The EF thickness alone explained 12.2% of V˙O2peak variance, independent of age, BMI, fat-free mass, total fat mass, legs fat mass, and trunk fat mass. The EF thickness was the strongest variable associated with V˙O2peak as the dependent variable in this population (β = -1.182, P = 0.001), as shown in Table 4.
It has been well established that EF tissue, which is a recognized indicator of cardiac risk, is a potentially active player in the development of an unfavorable metabolic risk profile (9-12) and is significantly correlated with the severity of coronary artery disease (1,31); however, to the best of our knowledge, only a few studies have been conducted to determine the association between EF thickness and autonomic dysfunction and cardiovascular fitness.
In the present study, considering this fat tissue's anatomic location, we investigated the impact of EF thickness on cardiovascular autonomic dysfunction and fitness in men. The major findings are as follows. First, higher EF thickness as assessed by echocardiography is independently associated with lower HRR at 1 and 2 min, a measure of autonomic dysfunction. Second, this fat tissue is associated with cardiorespiratory fitness (AT and V˙O2peak). Third, in the stepwise multiple linear regression analysis, EF thickness alone explained 12.2% of V˙O2peak variance, independent of age, BMI, fat-free mass, total fat mass, legs fat mass, and trunk fat mass; this indicates the possible involvement of EF tissue in cardiorespiratory fitness regardless of fat levels in other areas of the body, at least among men. Moreover, despite the hierarchical multiple linear regression analysis with other variables, there was the difference of 4.7% only, suggesting that the EF thickness was the strongest variable associated with V˙O2peak variance, at least for middle-aged obese men.
Previous studies have documented increased adiposity as a well-known cardiovascular risk factor in both children and adults (26). Nevertheless, the mechanism by which excess body fat influences cardiorespiratory fitness is not completely known; the relationships between variables are controversial. Some lines of evidence suggest that high cardiorespiratory fitness is associated with lower levels of total and abdominal obesity, independent of BMI, as in the Canada Fitness Survey (28). In addition, Wong et al. (34) reported that cardiorespiratory fitness is associated with lower abdominal fat in men, independent of BMI. In other cases, studies have demonstrated that maximal aerobic capacity, expressed by relative maximal oxygen consumption, is not influenced by body fat in prepubertal children (8) and in obese women (26). Taken together, sex or race-based differences and differences in degree of obesity could account for the disparity among the previous studies. In the present study, the EF tissue, an index of cardiac and visceral adiposity, is negatively associated with cardiorespiratory fitness in men, independent of body weight. With respect to visceral fat, EF tissue may also influence cardiorespiratory fitness in men.
Our high-EF group exhibited a blunted HR response to exercise stress, as compared with the low-EF group. It has been reported that a delay in the decrease of the HR during the first minute after maximal exercise testing is strongly predictive of mortality at 6 yr (relative risk = 4.0) (4). Although the mechanisms by which EF tissue influences cardiorespiratory fitness are not completely known, the low-EF group's HRR level at l min after maximal exercise testing tended to be higher than that of the high-EF group in the present study. Moreover, the rate at which the HR declined (HRR during 120 s) was significantly higher in low-EF men than that in the high-EF group, indicating a faster recovery. Taken together, this suggests that a higher EF level would cause decreased vagal reactivation (i.e., a reduction in the parasympathetic nervous system). It is well known that AT as a response to exercise testing is an effective gauge of physical fitness in both patients with cardiorespiratory disease and healthy normal subjects, including athletes (18,21). In the present study, AT level was negatively associated with EF thickness (r = -0.228, P = 0.022), indicating that greater EF thickness reduces exercise tolerance as measured by cardiovascular and pulmonary responses to exercise.
In the present study, there is no clear consensus on how increased EF tissue contributes to physiological responses involved in gas exchange resulting from a cardiopulmonary exercise test. Fick's principle states that V˙O2peak will occur when the maximal arteriovenous oxygen difference and the cardiac output reach their maximums during an exercise test (14); thus, V˙O2peak is directly related to the maximal arteriovenous oxygen difference and cardiac output. It has been suggested that higher cardiac output in response to exercise testing in overweight people compared with normal-weight people may be explained by higher stroke volume, possibly resulting from increased blood volume. Moreover, it has been suggested that the large differences in V˙O2peak values in the general population are due primarily to large differences in maximal stroke volume (27). In the present study with stepwise multiple linear regression analysis, EF thickness explained V˙O2peak variance, indicating the possible involvement of EF tissue in cardiorespiratory fitness independent of other regional fat compartments, at least among men. The present study did not directly assess factors influencing V˙O2peak, and further study will be required to assess the effect of EF tissue on cardiac output and stroke volume in the physiological response to cardiorespiratory exercise testing.
The clinical significance of structural change in EF thickness is gradually emerging. For instance, it has been suggested that regular physical activity and weight control are important with respect to cardiovascular health. Indeed, recent studies have demonstrated that EF thickness can be modified by participation in regular, organized physical activity or by diet-induced weight loss in an obese population: we have previously demonstrated that 12-wk aerobic exercise training may be an effective nonpharmacological strategy for decreasing ventricular EF thickness and visceral fat in obese men (17). Moreover, recent studies by the authors and others have demonstrated that weight-loss intervention programs, such as bariatric surgery (33), very-low-calorie diets (13), and low-calorie diets (16), significantly decreased ventricle EF thickness in an obese population. Further work will be required to assess changes in the adipose tissue surrounding the heart after any pharmaceutical program and to describe the associations between change in EF thickness and cardiovascular fitness and autonomic function in a longitudinal study.
A limitation of our study is that it included only male and predominantly overweight and obese subjects. Consequently, our results may not apply to more diverse or healthier populations. For instance, in our multiple regression analysis, V˙O2peak appeared not greatly to be associated with the main variables of interest, such as age and BMI (Table 4). Therefore, further studies are required to analyze these effects in the opposite sex and across a wide spectrum of body compositions as well as various ages. Other limitations include the use of a participant sample and cross-sectional data that do not allow assessment of causal relationships. Although our analysis has not explained the pathophysiology of the link between EF thickness and cardiovascular fitness and autonomic dysfunction after maximal exercise testing, EF thickness level may well represent a marker of physical fitness in middle-aged overweight and obese men.
In summary, this study describes how ventricle EF thickness measured by echocardiography is associated with HRR after peak exercise and cardiovascular fitness in middle-aged, healthy men. Men with higher EF thickness were found to have a slower 1- and 2-min HRR after a maximum-effort, symptom-limited cycle ergometric exercise test and a lower level of whole-body physical fitness, measured as V˙O2peak. This might explain our findings regarding the involvement of AT as cardiovascular and pulmonary limitations to exercise and V˙O2peak as cardiorespiratory fitness of degree of EF thickness, at least for men. These data suggest that moderately obese men with high-EF tissue levels demonstrate reduced cardiorespiratory fitness and differing parasympathetic activity responses to exercise testing than men with lower EF levels.
The authors gratefully acknowledge the participants of this study and the medical personnel at Higashi Toride Hospital involved in the study. They are also very grateful to the laboratory inspectors and the members of Tanaka laboratory for their outstanding work with the recruitment of subjects and for assistance during data collection. Results of the present study do not constitute endorsement of the product by the American College of Sports Medicine.
This research was supported by a Grant-in-Aid for Scientific Research (#20650112) from the Japan Ministry of Education, Culture, Sports, Science and Technology.
The authors declared that they have no conflict of interest.
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